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[0001] This application is a continuation of U.S. patent application Ser. No. 10/863,973, filed on Jun. 9, 2004, which is a continuation-in-part of International Patent Application No. PCT/US03/04566, filed Feb. 14, 2003, and parent U.S. patent application Ser. No. 10/863,973 is also a continuation-in-part of International Patent Application No. PCT/US04/16390, filed May 24, 2004, which is a continuation-in-part of U.S. patent application Ser. No. 10/826,966, filed Apr. 16, 2004, which is continuation-in-part of U.S. patent application Ser. No. 10/757,803, filed Jan. 14, 2004, which is a continuation-in-part of U.S. patent application Ser. No. 10/720,448, filed Nov. 24, 2003, which is a continuation-in-part of U.S. patent application Ser. No. 10/693,059, filed Oct. 23, 2003, which is a continuation-in-part of U.S. patent application Ser. No. 10/444,853, filed May 23, 2003, which is a continuation-in-part of International Patent Application No. PCT/US03/05346, filed Feb. 20, 2003, and a continuation-in-part of International Patent Application No. PCT/US03/05028, filed Feb. 20, 2003, both of which claim the benefit of U.S. Provisional Application No. 60/358,580, filed Feb. 20, 2002, U.S. Provisional Application No. 60/363,124, filed Mar. 11, 2002, U.S. Provisional Application No. 60/386,782, filed Jun. 6, 2002, U.S. Provisional Application No. 60/406,784, filed Aug. 29, 2002, U.S. Provisional Application No. 60/408,378, filed Sep. 5, 2002, U.S. Provisional Application No. 60/409,293, filed Sep. 9, 2002, and U.S. Provisional Application No. 60/440,129, filed Jan. 15, 2003. The instant application claims the benefit of all the listed applications, which are hereby incorporated by reference herein in their entireties, including the drawings.
SEQUENCE LISTING
[0002] The sequence listing submitted via EFS, in compliance with 37 CFR §1.52(e)(5), is incorporated herein by reference. The sequence listing text file submitted via EFS contains the file “SequenceListing17USCNT”, created on Sep. 3, 2008, which is 483,552 bytes in size.
FIELD OF THE INVENTION
[0003] The present invention relates to compounds, compositions, and methods for the study, diagnosis, and treatment of traits, diseases and conditions that respond to the modulation of interleukin gene expression and/or activity, such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, and IL-27 genes and genes encoding interleukin receptors of IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, and IL-27 genes. The present invention is also directed to compounds, compositions, and methods relating to traits, diseases and conditions that respond to the modulation of expression and/or activity of genes involved in interleukin gene expression pathways or other cellular processes that mediate the maintenance or development of such traits, diseases and conditions. Specifically, the invention relates to small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules capable of mediating RNA interference (RNAi) against interleukin gene expression. Such small nucleic acid molecules are useful, for example, in providing compositions for treatment or prevention of traits, diseases and conditions that can respond to modulation of interleukin gene expression in a subject, such as inflammatory, respiratory, pulmonary, autoimmune, cardiovascular, neurodegenerative, and/or proliferative and cancerous diseases, traits, or conditions.
BACKGROUND OF THE INVENTION
[0004] The following is a discussion of relevant art pertaining to RNAi. The discussion is provided only for understanding of the invention that follows. The summary is not an admission that any of the work described below is prior art to the claimed invention.
[0005] RNA interference refers to the process of sequence-specific post-transcriptional gene silencing in animals mediated by short interfering RNAs (siRNAs) (Zamore et al., 2000 , Cell, 101, 25-33; Fire et al., 1998 , Nature, 391, 806; Hamilton et al., 1999 , Science, 286, 950-951; Lin et al., 1999 , Nature, 402, 128-129; Sharp, 1999 , Genes & Dev., 13:139-141 ; and Strauss, 1999 , Science, 286, 886). The corresponding process in plants (Heifetz et al., International PCT Publication No. WO 99/61631) is commonly referred to as post-transcriptional gene silencing or RNA silencing and is also referred to as quelling in fungi. The process of post-transcriptional gene silencing is thought to be an evolutionarily-conserved cellular defense mechanism used to prevent the expression of foreign genes and is commonly shared by diverse flora and phyla (Fire et al., 1999 , Trends Genet., 15, 358). Such protection from foreign gene expression may have evolved in response to the production of double-stranded RNAs (dsRNAs) derived from viral infection or from the random integration of transposon elements into a host genome via a cellular response that specifically destroys homologous single-stranded RNA or viral genomic RNA. The presence of dsRNA in cells triggers the RNAi response through a mechanism that has yet to be fully characterized. This mechanism appears to be different from other known mechanisms involving double-stranded RNA-specific ribonucleases, such as the interferon response that results from dsRNA-mediated activation of protein kinase PKR and 2′,5′-oligoadenylate synthetase resulting in non-specific cleavage of mRNA by ribonuclease L (see for example U.S. Pat. Nos. 6,107,094; 5,898,031; Clemens et al., 1997 , J. Interferon & Cytokine Res., 17, 503-524; Adah et al., 2001 , Curr. Med. Chem., 8, 1189).
[0006] The presence of long dsRNAs in cells stimulates the activity of a ribonuclease III enzyme referred to as dicer (Bass, 2000, Cell, 101, 235; Zamore et al., 2000, Cell, 101, 25-33; Hammond et al., 2000, Nature, 404, 293). Dicer is involved in the processing of the dsRNA into short pieces of dsRNA known as short interfering RNAs (siRNAs) (Zamore et al., 2000, Cell, 101, 25-33; Bass, 2000, Cell, 101, 235; Berstein et al., 2001 , Nature, 409, 363). Short interfering RNAs derived from dicer activity are typically about 21 to about 23 nucleotides in length and comprise about 19 base pair duplexes (Zamore et al., 2000, Cell, 101, 25-33; Elbashir et al., 2001 , Genes Dev., 15, 188). Dicer has also been implicated in the excision of 21- and 22-nucleotide small temporal RNAs (stRNAs) from precursor RNA of conserved structure that are implicated in translational control (Hutvagner et al., 2001 , Science, 293, 834). The RNAi response also features an endonuclease complex, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single-stranded RNA having sequence complementary to the antisense strand of the siRNA duplex. Cleavage of the target RNA takes place in the middle of the region complementary to the antisense strand of the siRNA duplex (Elbashir et al., 2001 , Genes Dev., 15, 188).
[0007] RNAi has been studied in a variety of systems. Fire et al., 1998 , Nature, 391, 806, were the first to observe RNAi in C. elegans . Bahramian and Zarbl, 1999 , Molecular and Cellular Biology, 19, 274-283 and Wianny and Goetz, 1999 , Nature Cell Biol., 2, 70, describe RNAi mediated by dsRNA in mammalian systems. Hammond et al., 2000 , Nature, 404, 293, describe RNAi in Drosophila cells transfected with dsRNA. Elbashir et al., 2001 , Nature, 411, 494 and Tuschl et al., International PCT Publication No. WO 01/75164, describe RNAi induced by introduction of duplexes of synthetic 21-nucleotide RNAs in cultured mammalian cells including human embryonic kidney and HeLa cells. Recent work in Drosophila embryonic lysates (Elbashir et al., 2001 , EMBO J., 20, 6877 and Tuschl et al., International PCT Publication No. WO 01/75164) has revealed certain requirements for siRNA length, structure, chemical composition, and sequence that are essential to mediate efficient RNAi activity. These studies have shown that 21-nucleotide siRNA duplexes are most active when containing 3′-terminal dinucleotide overhangs. Furthermore, complete substitution of one or both siRNA strands with 2′-deoxy (2′-H) or 2′-O-methyl nucleotides abolishes RNAi activity, whereas substitution of the 3′-terminal siRNA overhang nucleotides with 2′-deoxy nucleotides (2′-H) was shown to be tolerated. Single mismatch sequences in the center of the siRNA duplex were also shown to abolish RNAi activity. In addition, these studies also indicate that the position of the cleavage site in the target RNA is defined by the 5′-end of the siRNA guide sequence rather than the 3′-end of the guide sequence (Elbashir et al., 2001 , EMBO J., 20, 6877). Other studies have indicated that a 5′-phosphate on the target-complementary strand of an siRNA duplex is required for siRNA activity and that ATP is utilized to maintain the 5′-phosphate moiety on the siRNA (Nykanen et al., 2001 , Cell, 107, 309).
[0008] Studies have shown that replacing the 3′-terminal nucleotide overhanging segments of a 21-mer siRNA duplex having two-nucleotide 3′-overhangs with deoxyribonucleotides does not have an adverse effect on RNAi activity. Replacing up to four nucleotides on each end of the siRNA with deoxyribonucleotides has been reported to be well tolerated, whereas complete substitution with deoxyribonucleotides results in no RNAi activity (Elbashir et al., 2001 , EMBO J., 20, 6877 and Tuschl et al., International PCT Publication No. WO 01/75164). In addition, Elbashir et al., supra, also report that substitution of siRNA with 2′-O-methyl nucleotides completely abolishes RNAi activity. Li et al., International PCT Publication No. WO 00/44914, and Beach et al., International PCT Publication No. WO 01/68836 preliminarily suggest that siRNA may include modifications to either the phosphate-sugar backbone or the nucleoside to include at least one of a nitrogen or sulfur heteroatom, however, neither application postulates to what extent such modifications would be tolerated in siRNA molecules, nor provides any further guidance or examples of such modified siRNA. Kreutzer et al., Canadian Patent Application No. 2,359,180, also describe certain chemical modifications for use in dsRNA constructs in order to counteract activation of double-stranded RNA-dependent protein kinase PKR, specifically 2′-amino or 2′-O-methyl nucleotides, and nucleotides containing a 2′-O or 4′-C methylene bridge. However, Kreutzer et al. similarly fails to provide examples or guidance as to what extent these modifications would be tolerated in dsRNA molecules.
[0009] Parrish et al., 2000 , Molecular Cell, 6, 1077-1087, tested certain chemical modifications targeting the unc-22 gene in C. elegans using long (>25 nt) siRNA transcripts. The authors describe the introduction of thiophosphate residues into these siRNA transcripts by incorporating thiophosphate nucleotide analogs with T7 and T3 RNA polymerase and observed that RNAs with two phosphorothioate modified bases also had substantial decreases in effectiveness as RNAi. Further, Parrish et al. reported that phosphorothioate modification of more than two residues greatly destabilized the RNAs in vitro such that interference activities could not be assayed. Id. at 1081. The authors also tested certain modifications at the 2′-position of the nucleotide sugar in the long siRNA transcripts and found that substituting deoxynucleotides for ribonucleotides produced a substantial decrease in interference activity, especially in the case of Uridine to Thymidine and/or Cytidine to deoxy-Cytidine substitutions. Id. In addition, the authors tested certain base modifications, including substituting, in sense and antisense strands of the siRNA, 4-thiouracil, 5-bromouracil, 5-iodouracil, and 3-(aminoallyl)uracil for uracil, and inosine for guanosine. Whereas 4-thiouracil and 5-bromouracil substitution appeared to be tolerated, Parrish reported that inosine produced a substantial decrease in interference activity when incorporated in either strand. Parrish also reported that incorporation of 5-iodouracil and 3-(aminoallyl)uracil in the antisense strand resulted in a substantial decrease in RNAi activity as well.
[0010] The use of longer dsRNA has been described. For example, Beach et al., International PCT Publication No. WO 01/68836, describes specific methods for attenuating gene expression using endogenously-derived dsRNA. Tuschl et al., International PCT Publication No. WO 01/75164, describe a Drosophila in vitro RNAi system and the use of specific siRNA molecules for certain functional genomic and certain therapeutic applications; although Tuschl, 2001 , Chem. Biochem., 2, 239-245, doubts that RNAi can be used to cure genetic diseases or viral infection due to the danger of activating interferon response. Li et al., International PCT Publication No. WO 00/44914, describe the use of specific long (141 bp-488 bp) enzymatically synthesized or vector expressed dsRNAs for attenuating the expression of certain target genes. Zernicka-Goetz et al., International PCT Publication No. WO 01/36646, describe certain methods for inhibiting the expression of particular genes in mammalian cells using certain long (550 bp-714 bp), enzymatically synthesized or vector expressed dsRNA molecules. Fire et al., International PCT Publication No. WO 99/32619, describe particular methods for introducing certain long dsRNA molecules into cells for use in inhibiting gene expression in nematodes. Plaetinck et al., International PCT Publication No. WO 00/01846, describe certain methods for identifying specific genes responsible for conferring a particular phenotype in a cell using specific long dsRNA molecules. Mello et al., International PCT Publication No. WO 01/29058, describe the identification of specific genes involved in dsRNA-mediated RNAi. Pachuck et al., International PCT Publication No. WO 00/63364, describe certain long (at least 200 nucleotide) dsRNA constructs. Deschamps Depaillette et al., International PCT Publication No. WO 99/07409, describe specific compositions consisting of particular dsRNA molecules combined with certain anti-viral agents. Waterhouse et al., International PCT Publication No. 99/53050 and 1998 , PNAS, 95, 13959-13964, describe certain methods for decreasing the phenotypic expression of a nucleic acid in plant cells using certain dsRNAs. Driscoll et al., International PCT Publication No. WO 01/49844, describe specific DNA expression constructs for use in facilitating gene silencing in targeted organisms.
[0011] Others have reported on various RNAi and gene-silencing systems. For example, Parrish et al., 2000 , Molecular Cell, 6, 1077-1087, describe specific chemically-modified dsRNA constructs targeting the unc-22 gene of C. elegans . Grossniklaus, International PCT Publication No. WO 01/38551, describes certain methods for regulating polycomb gene expression in plants using certain dsRNAs. Churikov et al., International PCT Publication No. WO 01/42443, describe certain methods for modifying genetic characteristics of an organism using certain dsRNAs. Cogoni et al., International PCT Publication No. WO 01/53475, describe certain methods for isolating a Neurospora silencing gene and uses thereof. Reed et al., International PCT Publication No. WO 01/68836, describe certain methods for gene silencing in plants. Honer et al., International PCT Publication No. WO 01/70944, describe certain methods of drug screening using transgenic nematodes as Parkinson's Disease models using certain dsRNAs. Deak et al., International PCT Publication No. WO 01/72774, describe certain Drosophila -derived gene products that may be related to RNAi in Drosophila . Arndt et al., International PCT Publication No. WO 01/92513 describe certain methods for mediating gene suppression by using factors that enhance RNAi. Tuschl et al., International PCT Publication No. WO 02/44321, describe certain synthetic siRNA constructs. Pachuk et al., International PCT Publication No. WO 00/63364, and Satishchandran et al., International PCT Publication No. WO 01/04313, describe certain methods and compositions for inhibiting the function of certain polynucleotide sequences using certain long (over 250 bp), vector expressed dsRNAs. Echeverri et al., International PCT Publication No. WO 02/38805, describe certain C. elegans genes identified via RNAi. Kreutzer et al., International PCT Publications Nos. WO 02/055692, WO 02/055693, and EP 1144623 B1 describes certain methods for inhibiting gene expression using dsRNA. Graham et al., International PCT Publications Nos. WO 99/49029 and WO 01/70949, and AU 4037501 describe certain vector expressed siRNA molecules. Fire et al., U.S. Pat. No. 6,506,559, describe certain methods for inhibiting gene expression in vitro using certain long dsRNA (299 bp-1033 bp) constructs that mediate RNAi. Martinez et al., 2002 , Cell, 110, 563-574, describe certain single-stranded siRNA constructs, including certain 5′-phosphorylated single-stranded siRNAs that mediate RNA interference in HeLa cells. Harborth et al., 2003, Antisense & Nucleic Acid Drug Development, 13, 83-105, describe certain chemically and structurally modified siRNA molecules. Chiu and Rana, 2003, RNA, 9, 1034-1048, describe certain chemically and structurally modified siRNA molecules. Woolf et al., International PCT Publication Nos. WO 03/064626 and WO 03/064625 describe certain chemically modified dsRNA constructs.
SUMMARY OF THE INVENTION
[0012] This invention relates to compounds, compositions, and methods useful for modulating interleukin and/or interleukin receptor gene expression using short interfering nucleic acid (siNA) molecules. This invention also relates to compounds, compositions, and methods useful for modulating the expression and activity of other genes involved in pathways of interleukin and/or interleukin receptor gene expression and/or activity by RNA interference (RNAi) using small nucleic acid molecules. In particular, the instant invention features small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules and methods used to modulate the expression of interleukin and/or interleukin receptor genes.
[0013] An siNA of the invention can be unmodified or chemically-modified. An siNA of the instant invention can be chemically synthesized, expressed from a vector or enzymatically synthesized. The instant invention also features various chemically-modified synthetic short interfering nucleic acid (siNA) molecules capable of modulating interleukin and/or interleukin receptor gene expression or activity in cells by RNA interference (RNAi). The use of chemically-modified siNA improves various properties of native siNA molecules through increased resistance to nuclease degradation in vivo and/or through improved cellular uptake. Further, contrary to earlier published studies, siNA having multiple chemical modifications retains its RNAi activity. The siNA molecules of the instant invention provide useful reagents and methods for a variety of therapeutic, diagnostic, target validation, genomic discovery, genetic engineering, and pharmacogenomic applications.
[0014] In one embodiment, the invention features one or more siNA molecules and methods that independently or in combination modulate the expression of interleukin and/or interleukin receptor genes encoding proteins, such as proteins comprising interleukins (e.g., IL-1-IL-27) and interleukin receptors (e.g., IL-IR-1L-27R), such as genes encoding sequences comprising those sequences referred to by GenBank Accession Nos. shown in Table I, referred to herein generally as interleukin and/or interleukin receptor. The description below of the various aspects and embodiments of the invention is provided with reference to exemplary interleukin and interleukin receptor genes referred to herein as interleukin and/or interleukin receptor. However, the various aspects and embodiments are also directed to other interleukin and/or interleukin receptor genes, such as interleukin and/or interleukin receptor homolog genes, transcript variants, and polymorphisms (e.g., single nucleotide polymorphism, (SNPs)) associated with certain interleukin and/or interleukin receptor genes, for example genes associated with diseases, traits, or conditions described herein or otherwise known in the art. As such, the various aspects and embodiments are also directed to other genes that are involved in interleukin and/or interleukin receptor mediated pathways of signal transduction or gene expression. These additional genes can be analyzed for target sites using the methods described for interleukin and/or interleukin receptor genes herein. Thus, the modulation of other genes and the effects of such modulation of the other genes can be performed, determined, and measured as described herein.
[0015] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a interleukin and/or interleukin receptor gene, wherein said siNA molecule comprises about 19 to about 21 base pairs.
[0016] In one embodiment, the invention features an siNA molecule that down-regulates expression of a interleukin and/or interleukin receptor gene, for example, wherein the interleukin and/or interleukin receptor gene comprises interleukin and/or interleukin receptor encoding sequence. In one embodiment, the invention features an siNA molecule that down-regulates expression of a interleukin and/or interleukin receptor gene, for example, wherein the interleukin and/or interleukin receptor gene comprises interleukin and/or interleukin receptor non-coding sequence or regulatory elements involved in interleukin and/or interleukin receptor gene expression.
[0017] In one embodiment, an siNA of the invention is used to inhibit the expression of interleukin and/or interleukin receptor genes or a interleukin and/or interleukin receptor gene family, wherein the genes or gene family sequences share sequence homology. Such homologous sequences can be identified as is known in the art, for example using sequence alignments. siNA molecules can be designed to target such homologous sequences, for example using perfectly complementary sequences or by incorporating non-canonical base pairs, for example mismatches and/or wobble base pairs, that can provide additional target sequences. In instances where mismatches are identified, non-canonical base pairs, for example mismatches and/or wobble bases, can be used to generate siNA molecules that target both more than one gene sequences. In a non-limiting example, non-canonical base pairs such as UU and CC base pairs are used to generate siNA molecules that are capable of targeting sequences for differing interleukin and/or interleukin receptor targets that share sequence homology (e.g., differing interleukin genes or differing allelic variants thereof). As such, one advantage of using siNAs of the invention is that a single siNA can be designed to include nucleic acid sequence that is complementary to the nucleotide sequence that is conserved between the homologous genes. In this approach, a single siNA can be used to inhibit expression of more than one interleukin and/or interleukin receptor gene instead of using more than one siNA molecule to target the different genes.
[0018] In one embodiment, the invention features an siNA molecule having RNAi activity against interleukin and/or interleukin receptor RNA, wherein the siNA molecule comprises a sequence complementary to any RNA having interleukin and/or interleukin receptor encoding sequence, such as those sequences having GenBank Accession Nos. shown in Table I. In another embodiment, the invention features an siNA molecule having RNAi activity against interleukin and/or interleukin receptor RNA, wherein the siNA molecule comprises a sequence complementary to an RNA having variant interleukin and/or interleukin receptor encoding sequence, for example other mutant interleukin and/or interleukin receptor genes not shown in Table I but known in the art to be associated with diseases, traits, or conditions described herein or otherwise known in the art. Chemical modifications as shown in Tables III and IV or otherwise described herein can be applied to any siNA construct of the invention. In another embodiment, an siNA molecule of the invention includes a nucleotide sequence that can interact with nucleotide sequence of a interleukin and/or interleukin receptor gene and thereby mediate silencing of interleukin and/or interleukin receptor gene expression, for example, wherein the siNA mediates regulation of interleukin and/or interleukin receptor gene expression by cellular processes that modulate the chromatin structure or methylation patterns of the interleukin and/or interleukin receptor gene and prevent transcription of the interleukin and/or interleukin receptor gene.
[0019] In one embodiment, siNA molecules of the invention are used to down regulate or inhibit the expression of interleukin and/or interleukin receptor proteins arising from interleukin and/or interleukin receptor haplotype polymorphisms that are associated with a disease or condition, (e.g., proliferative, inflammatory, autoimmune, respiratory, pulmonary, cardiovascular, neurodegenerative diseases). Analysis of interleukin and/or interleukin receptor genes, or interleukin and/or interleukin receptor protein or RNA levels can be used to identify subjects with such polymorphisms or those subjects who are at risk of developing traits, conditions, or diseases described herein. These subjects are amenable to treatment, for example, treatment with siNA molecules of the invention and any other composition useful in treating diseases related to interleukin and/or interleukin receptor gene expression. As such, analysis of interleukin and/or interleukin receptor protein or RNA levels can be used to determine treatment type and the course of therapy in treating a subject. Monitoring of interleukin and/or interleukin receptor protein or RNA levels can be used to predict treatment outcome and to determine the efficacy of compounds and compositions that modulate the level and/or activity of certain interleukin and/or interleukin receptor proteins associated with a trait, condition, or disease.
[0020] In one embodiment of the invention an siNA molecule comprises an antisense strand comprising a nucleotide sequence that is complementary to a nucleotide sequence or a portion thereof encoding a interleukin and/or interleukin receptor protein. The siNA further comprises a sense strand, wherein said sense strand comprises a nucleotide sequence of a interleukin and/or interleukin receptor gene or a portion thereof.
[0021] In another embodiment, the invention features an siNA molecule comprising a nucleotide sequence in the antisense region of the siNA molecule that is complementary to a nucleotide sequence or portion of sequence of a interleukin and/or interleukin receptor gene. In another embodiment, the invention features an siNA molecule comprising a region, for example, the antisense region of the siNA construct, complementary to a sequence comprising a interleukin and/or interleukin receptor gene sequence or a portion thereof.
[0022] In one embodiment, the antisense region of interleukin and/or interleukin receptor siNA constructs comprises a sequence complementary to sequence having any of SEQ ID NOs. 1-81, 163-213, 265-464, 665-735, 807-1029, or 1253-1260. In one embodiment, the antisense region of interleukin and/or interleukin receptor constructs comprises sequence having any of SEQ ID NOs. 82-162, 214-264, 465-664, 736-806, 1030-1252, 1319-1326, 1335-1342, 1351-1358, 1367-1374, 1383-1406, 1415-1422, 1431-1438, 1447-1454, 1463-1470, 1479-1502, 1511-1518, 1527-1534, 1543-1550, 1559-1566, 1575-1598, 1607-1614, 1623-1630, 1649-1656, 1665-1682, 1691-1714, 1723-1730, 1739-1746, 1755-1762, 1771-1778, 1787-1810, 1812, 1814, 1816, 1819, 1821, 1823, 1825, or 1828. In another embodiment, the sense region of interleukin and/or interleukin receptor constructs comprises sequence having any of SEQ ID NOs. 1-81, 163-213, 265-464, 665-735, 807-1029, 1253-1260, 1311-1318, 1327-1334, 1343-1350, 1359-1366, 1375-1382, 1269-1276, 1407-1414, 1423-1430, 1439-1446, 1455-1462, 1471-1478, 1277-1284, 1503-1510, 1519-1526, 1535-1542, 1551-1558, 1567-1574, 1285-1292, 1599-1606, 1615-1622, 1631-1648, 1657-1664, 1683-1690, 1303-1310, 1715-1722, 1731-1738, 1747-1754, 1763-1770, 1779-1786, 1811, 1813, 1815, 1817, 1818, 1820, 1822, 1824, 1826, or 1827.
[0023] In one embodiment, an siNA molecule of the invention comprises any of SEQ ID NOs. 1-1828. The sequences shown in SEQ ID NOs: 1-1828 are not limiting. An siNA molecule of the invention can comprise any contiguous interleukin and/or interleukin receptor sequence (e.g., about 19 to about 25, or about 19, 20, 21, 22, 23, 24, or 25 contiguous interleukin and/or interleukin receptor nucleotides).
[0024] In yet another embodiment, the invention features an siNA molecule comprising a sequence, for example, the antisense sequence of the siNA construct, complementary to a sequence or portion of sequence comprising sequence represented by GenBank Accession Nos. shown in Table I. Chemical modifications in Tables III and IV and described herein can be applied to any siNA construct of the invention.
[0025] In one embodiment of the invention an siNA molecule comprises an antisense strand having about 19 to about 29 (e.g., about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29) nucleotides, wherein the antisense strand is complementary to a RNA sequence encoding a interleukin and/or interleukin receptor protein, and wherein said siNA further comprises a sense strand having about 19 to about 29 (e.g., about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29) nucleotides, and wherein said sense strand and said antisense strand are distinct nucleotide sequences with at least about 19 complementary nucleotides.
[0026] In another embodiment of the invention an siNA molecule of the invention comprises an antisense region having about 19 to about 29 (e.g., about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29) nucleotides, wherein the antisense region is complementary to a RNA sequence encoding a interleukin and/or interleukin receptor protein, and wherein said siNA further comprises a sense region having about 19 to about 29 (e.g., about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29) nucleotides, wherein said sense region and said antisense region comprise a linear molecule with at least about 19 complementary nucleotides.
[0027] In one embodiment, an siNA molecule of the invention has RNAi activity that modulates expression of RNA encoded by a interleukin and/or interleukin receptor gene. Because interleukin and/or interleukin receptor genes can share some degree of sequence homology with each other, siNA molecules can be designed to target a class of interleukin and/or interleukin receptor genes or alternately specific interleukin and/or interleukin receptor genes (e.g., polymorphic variants) by selecting sequences that are either shared amongst different interleukin and/or interleukin receptor targets or alternatively that are unique for a specific interleukin and/or interleukin receptor target. Therefore, in one embodiment, the siNA molecule can be designed to target conserved regions of interleukin and/or interleukin receptor RNA sequences having homology among several interleukin and/or interleukin receptor gene variants so as to target a class of interleukin and/or interleukin receptor genes with one siNA molecule. Accordingly, in one embodiment, the siNA molecule of the invention modulates the expression of one or both interleukin and/or interleukin receptor alleles in a subject. In another embodiment, the siNA molecule can be designed to target a sequence that is unique to a specific interleukin and/or interleukin receptor RNA sequence (e.g., a single interleukin and/or interleukin receptor allele or interleukin and/or interleukin receptor single nucleotide polymorphism (SNP)) due to the high degree of specificity that the siNA molecule requires to mediate RNAi activity.
[0028] In one embodiment, nucleic acid molecules of the invention that act as mediators of the RNA interference gene silencing response are double-stranded nucleic acid molecules. In another embodiment, the siNA molecules of the invention consist of duplex nucleic acid molecules containing about 19 base pairs between oligonucleotides comprising about 19 to about 25 (e.g., about 19, 20, 21, 22, 23, 24, or 25) nucleotides. In yet another embodiment, siNA molecules of the invention comprise duplex nucleic acid molecules with overhanging ends of about 1 to about 3 (e.g., about 1, 2, or 3) nucleotides, for example, about 21-nucleotide duplexes with about 19 base pairs and 3′-terminal mononucleotide, dinucleotide, or trinucleotide overhangs.
[0029] In one embodiment, the invention features one or more chemically-modified siNA constructs having specificity for interleukin and/or interleukin receptor expressing nucleic acid molecules, such as RNA encoding a interleukin and/or interleukin receptor protein. Non-limiting examples of such chemical modifications include without limitation phosphorothioate internucleotide linkages, 2′-deoxyribonucleotides, 2′-O-methyl ribonucleotides, 2′-deoxy-2′-fluoro ribonucleotides, “universal base” nucleotides, “acyclic” nucleotides, 5-C-methyl nucleotides, and terminal glyceryl and/or inverted deoxy abasic residue incorporation. These chemical modifications, when used in various siNA constructs, are shown to preserve RNAi activity in cells while at the same time, dramatically increasing the serum stability of these compounds. Furthermore, contrary to the data published by Parrish et al., supra, applicant demonstrates that multiple (greater than one) phosphorothioate substitutions are well-tolerated and confer substantial increases in serum stability for modified siNA constructs.
[0030] In one embodiment, an siNA molecule of the invention comprises modified nucleotides while maintaining the ability to mediate RNAi. The modified nucleotides can be used to improve in vitro or in vivo characteristics such as stability, activity, and/or bioavailability. For example, an siNA molecule of the invention can comprise modified nucleotides as a percentage of the total number of nucleotides present in the siNA molecule. As such, an siNA molecule of the invention can generally comprise about 5% to about 100% modified nucleotides (e.g., about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95% or 100% modified nucleotides). The actual percentage of modified nucleotides present in a given siNA molecule will depend on the total number of nucleotides present in the siNA. If the siNA molecule is single-stranded, the percent modification can be based upon the total number of nucleotides present in the single-stranded siNA molecules. Likewise, if the siNA molecule is double-stranded, the percent modification can be based upon the total number of nucleotides present in the sense strand, antisense strand, or both the sense and antisense strands.
[0031] One aspect of the invention features a double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a interleukin and/or interleukin receptor gene. In one embodiment, the double-stranded siNA molecule comprises one or more chemical modifications and each strand of the double-stranded siNA is about 21 nucleotides long. In one embodiment, the double-stranded siNA molecule does not contain any ribonucleotides. In another embodiment, the double-stranded siNA molecule comprises one or more ribonucleotides. In one embodiment, each strand of the double-stranded siNA molecule comprises about 19 to about 29 (e.g., about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29) nucleotides, wherein each strand comprises about 19 nucleotides that are complementary to the nucleotides of the other strand. In one embodiment, one of the strands of the double-stranded siNA molecule comprises a nucleotide sequence that is complementary to a nucleotide sequence or a portion thereof of the interleukin and/or interleukin receptor gene, and the second strand of the double-stranded siNA molecule comprises a nucleotide sequence substantially similar to the nucleotide sequence of the interleukin and/or interleukin receptor gene or a portion thereof.
[0032] In another embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a interleukin and/or interleukin receptor gene comprising an antisense region, wherein the antisense region comprises a nucleotide sequence that is complementary to a nucleotide sequence of the interleukin and/or interleukin receptor gene or a portion thereof, and a sense region, wherein the sense region comprises a nucleotide sequence substantially similar to the nucleotide sequence of the interleukin and/or interleukin receptor gene or a portion thereof. In one embodiment, the antisense region and the sense region each comprise about 19 to about 23 (e.g. about 19, 20, 21, 22, or 23) nucleotides, wherein the antisense region comprises about 19 nucleotides that are complementary to nucleotides of the sense region.
[0033] In another embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a interleukin and/or interleukin receptor gene comprising a sense region and an antisense region, wherein the antisense region comprises a nucleotide sequence that is complementary to a nucleotide sequence of RNA encoded by the interleukin and/or interleukin receptor gene or a portion thereof and the sense region comprises a nucleotide sequence that is complementary to the antisense region.
[0034] In one embodiment, an siNA molecule of the invention comprises blunt ends, i.e., ends that do not include any overhanging nucleotides. For example, an siNA molecule comprising modifications described herein (e.g., comprising nucleotides having Formulae I-VII or siNA constructs comprising “Stab 00”-“Stab 25” (Table IV) or any combination thereof (see Table IV)) and/or any length described herein can comprise blunt ends or ends with no overhanging nucleotides.
[0035] In one embodiment, any siNA molecule of the invention can comprise one or more blunt ends, i.e. where a blunt end does not have any overhanging nucleotides. In one embodiment, the blunt ended siNA molecule has a number of base pairs equal to the number of nucleotides present in each strand of the siNA molecule. In another embodiment, the siNA molecule comprises one blunt end, for example wherein the 5′-end of the antisense strand and the 3′-end of the sense strand do not have any overhanging nucleotides. In another example, the siNA molecule comprises one blunt end, for example wherein the 3′-end of the antisense strand and the 5′-end of the sense strand do not have any overhanging nucleotides. In another example, an siNA molecule comprises two blunt ends, for example wherein the 3′-end of the antisense strand and the 5′-end of the sense strand as well as the 5′-end of the antisense strand and 3′-end of the sense strand do not have any overhanging nucleotides. A blunt ended siNA molecule can comprise, for example, from about 18 to about 30 nucleotides (e.g., about 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, or 30 nucleotides). Other nucleotides present in a blunt ended siNA molecule can comprise mismatches, bulges, loops, or wobble base pairs, for example, to modulate the activity of the siNA molecule to mediate RNA interference.
[0036] By “blunt ends” is meant symmetric termini or termini of a double-stranded siNA molecule having no overhanging nucleotides. The two strands of a double-stranded siNA molecule align with each other without over-hanging nucleotides at the termini. For example, a blunt ended siNA construct comprises terminal nucleotides that are complementary between the sense and antisense regions of the siNA molecule.
[0037] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a interleukin and/or interleukin receptor gene, wherein the siNA molecule is assembled from two separate oligonucleotide fragments wherein one fragment comprises the sense region and the second fragment comprises the antisense region of the siNA molecule. The sense region can be connected to the antisense region via a linker molecule, such as a polynucleotide linker or a non-nucleotide linker.
[0038] In one embodiment, the invention features double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a interleukin and/or interleukin receptor gene, wherein the siNA molecule comprises about 19 to about 21 base pairs, and wherein each strand of the siNA molecule comprises one or more chemical modifications. In another embodiment, one of the strands of the double-stranded siNA molecule comprises a nucleotide sequence that is complementary to a nucleotide sequence of a interleukin and/or interleukin receptor gene or a portion thereof, and the second strand of the double-stranded siNA molecule comprises a nucleotide sequence substantially similar to the nucleotide sequence or a portion thereof of the interleukin and/or interleukin receptor gene. In another embodiment, one of the strands of the double-stranded siNA molecule comprises a nucleotide sequence that is complementary to a nucleotide sequence of a interleukin and/or interleukin receptor gene or portion thereof, and the second strand of the double-stranded siNA molecule comprises a nucleotide sequence substantially similar to the nucleotide sequence or portion thereof of the interleukin and/or interleukin receptor gene. In another embodiment, each strand of the siNA molecule comprises about 19 to about 23 nucleotides, and each strand comprises at least about 19 nucleotides that are complementary to the nucleotides of the other strand. The interleukin and/or interleukin receptor gene can comprise, for example, sequences referred to in Table I.
[0039] In one embodiment, an siNA molecule of the invention comprises no ribonucleotides. In another embodiment, an siNA molecule of the invention comprises ribonucleotides.
[0040] In one embodiment, an siNA molecule of the invention comprises an antisense region comprising a nucleotide sequence that is complementary to a nucleotide sequence of a interleukin and/or interleukin receptor gene or a portion thereof, and the siNA further comprises a sense region comprising a nucleotide sequence substantially similar to the nucleotide sequence of the interleukin and/or interleukin receptor gene or a portion thereof. In another embodiment, the antisense region and the sense region each comprise about 19 to about 23 nucleotides and the antisense region comprises at least about 19 nucleotides that are complementary to nucleotides of the sense region. The interleukin and/or interleukin receptor gene can comprise, for example, sequences referred to in Table I.
[0041] In one embodiment, an siNA molecule of the invention comprises a sense region and an antisense region, wherein the antisense region comprises a nucleotide sequence that is complementary to a nucleotide sequence of RNA encoded by a interleukin and/or interleukin receptor gene, or a portion thereof, and the sense region comprises a nucleotide sequence that is complementary to the antisense region. In one embodiment, the siNA molecule is assembled from two separate oligonucleotide fragments, wherein one fragment comprises the sense region and the second fragment comprises the antisense region of the siNA molecule. In another embodiment, the sense region is connected to the antisense region via a linker molecule. In another embodiment, the sense region is connected to the antisense region via a linker molecule, such as a nucleotide or non-nucleotide linker. The interleukin and/or interleukin receptor gene can comprise, for example, sequences referred in to Table I.
[0042] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a interleukin and/or interleukin receptor gene comprising a sense region and an antisense region, wherein the antisense region comprises a nucleotide sequence that is complementary to a nucleotide sequence of RNA encoded by the interleukin and/or interleukin receptor gene or a portion thereof and the sense region comprises a nucleotide sequence that is complementary to the antisense region, and wherein the siNA molecule has one or more modified pyrimidine and/or purine nucleotides. In one embodiment, the pyrimidine nucleotides in the sense region are 2′-O-methylpyrimidine nucleotides or 2′-deoxy-2′-fluoro pyrimidine nucleotides and the purine nucleotides present in the sense region are 2′-deoxy purine nucleotides. In another embodiment, the pyrimidine nucleotides in the sense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides and the purine nucleotides present in the sense region are 2′-O-methyl purine nucleotides. In another embodiment, the pyrimidine nucleotides in the sense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides and the purine nucleotides present in the sense region are 2′-deoxy purine nucleotides. In one embodiment, the pyrimidine nucleotides in the antisense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides and the purine nucleotides present in the antisense region are 2′-O-methyl or 2′-deoxy purine nucleotides. In another embodiment of any of the above-described siNA molecules, any nucleotides present in a non-complementary region of the sense strand (e.g. overhang region) are 2′-deoxy nucleotides.
[0043] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a interleukin and/or interleukin receptor gene, wherein the siNA molecule is assembled from two separate oligonucleotide fragments wherein one fragment comprises the sense region and the second fragment comprises the antisense region of the siNA molecule, and wherein the fragment comprising the sense region includes a terminal cap moiety at the 5′-end, the 3′-end, or both of the 5′ and 3′ ends of the fragment. In one embodiment, the terminal cap moiety is an inverted deoxy abasic moiety or glyceryl moiety. In one embodiment, each of the two fragments of the siNA molecule comprise about 21 nucleotides.
[0044] In one embodiment, the invention features an siNA molecule comprising at least one modified nucleotide, wherein the modified nucleotide is a 2′-deoxy-2′-fluoro nucleotide. The siNA can be, for example, of length between about 12 and about 36 nucleotides. In one embodiment, all pyrimidine nucleotides present in the siNA are 2′-deoxy-2′-fluoro pyrimidine nucleotides. In one embodiment, the modified nucleotides in the siNA include at least one 2′-deoxy-2′-fluoro cytidine or 2′-deoxy-2′-fluoro uridine nucleotide. In another embodiment, the modified nucleotides in the siNA include at least one 2′-deoxy-2′-fluoro cytidine and at least one 2′-deoxy-2′-fluoro uridine nucleotides. In one embodiment, all uridine nucleotides present in the siNA are 2′-deoxy-2′-fluoro uridine nucleotides. In one embodiment, all cytidine nucleotides present in the siNA are 2′-deoxy-2′-fluoro cytidine nucleotides. In one embodiment, all adenosine nucleotides present in the siNA are 2′-deoxy-2′-fluoro adenosine nucleotides. In one embodiment, all guanosine nucleotides present in the siNA are 2′-deoxy-2′-fluoro guanosine nucleotides. The siNA can further comprise at least one modified internucleotidic linkage, such as phosphorothioate linkage. In one embodiment, the 2′-deoxy-2′-fluoronucleotides are present at specifically selected locations in the siNA that are sensitive to cleavage by ribonucleases, such as locations having pyrimidine nucleotides.
[0045] In one embodiment, the invention features a method of increasing the stability of an siNA molecule against cleavage by ribonucleases comprising introducing at least one modified nucleotide into the siNA molecule, wherein the modified nucleotide is a 2′-deoxy-2′-fluoro nucleotide. In one embodiment, all pyrimidine nucleotides present in the siNA are 2′-deoxy-2′-fluoro pyrimidine nucleotides. In one embodiment, the modified nucleotides in the siNA include at least one 2′-deoxy-2′-fluoro cytidine or 2′-deoxy-2′-fluoro uridine nucleotide. In another embodiment, the modified nucleotides in the siNA include at least one 2′-deoxy-2′-fluoro cytidine and at least one 2′-deoxy-2′-fluoro uridine nucleotides. In one embodiment, all uridine nucleotides present in the siNA are 2′-deoxy-2′-fluoro uridine nucleotides. In one embodiment, all cytidine nucleotides present in the siNA are 2′-deoxy-2′-fluoro cytidine nucleotides. In one embodiment, all adenosine nucleotides present in the siNA are 2′-deoxy-2′-fluoro adenosine nucleotides. In one embodiment, all guanosine nucleotides present in the siNA are 2′-deoxy-2′-fluoro guanosine nucleotides. The siNA can further comprise at least one modified internucleotidic linkage, such as phosphorothioate linkage. In one embodiment, the 2′-deoxy-2′-fluoronucleotides are present at specifically selected locations in the siNA that are sensitive to cleavage by ribonucleases, such as locations having pyrimidine nucleotides.
[0046] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a interleukin and/or interleukin receptor gene comprising a sense region and an antisense region, wherein the antisense region comprises a nucleotide sequence that is complementary to a nucleotide sequence of RNA encoded by the interleukin and/or interleukin receptor gene or a portion thereof and the sense region comprises a nucleotide sequence that is complementary to the antisense region, and wherein the purine nucleotides present in the antisense region comprise 2′-deoxy-purine nucleotides. In an alternative embodiment, the purine nucleotides present in the antisense region comprise 2′-O-methyl purine nucleotides. In either of the above embodiments, the antisense region can comprise a phosphorothioate internucleotide linkage at the 3′ end of the antisense region. Alternatively, in either of the above embodiments, the antisense region can comprise a glyceryl modification at the 3′ end of the antisense region. In another embodiment of any of the above-described siNA molecules, any nucleotides present in a non-complementary region of the antisense strand (e.g. overhang region) are 2′-deoxy nucleotides.
[0047] In one embodiment, the antisense region of an siNA molecule of the invention comprises sequence complementary to a portion of a interleukin and/or interleukin receptor transcript having sequence unique to a particular interleukin and/or interleukin receptor disease related allele, such as sequence comprising a single nucleotide polymorphism (SNP) associated with the disease specific allele. As such, the antisense region of an siNA molecule of the invention can comprise sequence complementary to sequences that are unique to a particular allele to provide specificity in mediating selective RNAi against the disease, condition, or trait related allele.
[0048] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that down-regulates expression of a interleukin and/or interleukin receptor gene, wherein the siNA molecule is assembled from two separate oligonucleotide fragments wherein one fragment comprises the sense region and the second fragment comprises the antisense region of the siNA molecule. In another embodiment about 19 nucleotides of each fragment of the siNA molecule are base-paired to the complementary nucleotides of the other fragment of the siNA molecule and wherein at least two 3′ terminal nucleotides of each fragment of the siNA molecule are not base-paired to the nucleotides of the other fragment of the siNA molecule. In one embodiment, each of the two 3′ terminal nucleotides of each fragment of the siNA molecule is a 2′-deoxy-pyrimidine nucleotide, such as a 2′-deoxy-thymidine. In another embodiment, all 21 nucleotides of each fragment of the siNA molecule are base-paired to the complementary nucleotides of the other fragment of the siNA molecule. In another embodiment, about 19 nucleotides of the antisense region are base-paired to the nucleotide sequence or a portion thereof of the RNA encoded by the interleukin and/or interleukin receptor gene. In another embodiment, about 21 nucleotides of the antisense region are base-paired to the nucleotide sequence or a portion thereof of the RNA encoded by the interleukin and/or interleukin receptor gene. In any of the above embodiments, the 5′-end of the fragment comprising said antisense region can optionally include a phosphate group.
[0049] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that inhibits the expression of a interleukin and/or interleukin receptor RNA sequence (e.g., wherein said target RNA sequence is encoded by a interleukin and/or interleukin receptor gene involved in the interleukin and/or interleukin receptor pathway), wherein the siNA molecule does not contain any ribonucleotides and wherein each strand of the double-stranded siNA molecule is about 21 nucleotides long. Examples of non-ribonucleotide containing siNA constructs are combinations of stabilization chemistries shown in Table IV in any combination of Sense/Antisense chemistries, such as Stab 7/8, Stab 7/11, Stab 8/8, Stab 18/8, Stab 18/11, Stab 12/13, Stab 7/13, Stab 18/13, Stab 7/19, Stab 8/19, Stab 18/19, Stab 7/20, Stab 8/20, or Stab 18/20.
[0050] In one embodiment, the invention features a chemically synthesized double-stranded RNA molecule that directs cleavage of a interleukin and/or interleukin receptor RNA via RNA interference, wherein each strand of said RNA molecule is about 21 to about 23 nucleotides in length; one strand of the RNA molecule comprises nucleotide sequence having sufficient complementarity to the interleukin and/or interleukin receptor RNA for the RNA molecule to direct cleavage of the interleukin and/or interleukin receptor RNA via RNA interference; and wherein at least one strand of the RNA molecule comprises one or more chemically modified nucleotides described herein, such as deoxynucleotides, 2′-O-methyl nucleotides, 2′-deoxy-2′-fluoro nucleotides, 2′-O-methoxyethyl nucleotides etc.
[0051] In one embodiment, the invention features a medicament comprising an siNA molecule of the invention.
[0052] In one embodiment, the invention features an active ingredient comprising an siNA molecule of the invention.
[0053] In one embodiment, the invention features the use of a double-stranded short interfering nucleic acid (siNA) molecule to down-regulate expression of a interleukin and/or interleukin receptor gene, wherein the siNA molecule comprises one or more chemical modifications and each strand of the double-stranded siNA is about 18 to about 28 or more (e.g., about 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, or 28 or more) nucleotides long.
[0054] In one embodiment, the invention features the use of a double-stranded short interfering nucleic acid (siNA) molecule that inhibits expression of a interleukin and/or interleukin receptor gene, wherein one of the strands of the double-stranded siNA molecule is an antisense strand which comprises nucleotide sequence that is complementary to nucleotide sequence of interleukin and/or interleukin receptor RNA or a portion thereof, the other strand is a sense strand which comprises nucleotide sequence that is complementary to a nucleotide sequence of the antisense strand and wherein a majority of the pyrimidine nucleotides present in the double-stranded siNA molecule comprises a sugar modification.
[0055] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that inhibits expression of a interleukin and/or interleukin receptor gene, wherein one of the strands of the double-stranded siNA molecule is an antisense strand which comprises nucleotide sequence that is complementary to nucleotide sequence of interleukin and/or interleukin receptor RNA or a portion thereof, wherein the other strand is a sense strand which comprises nucleotide sequence that is complementary to a nucleotide sequence of the antisense strand and wherein a majority of the pyrimidine nucleotides present in the double-stranded siNA molecule comprises a sugar modification.
[0056] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that inhibits expression of a interleukin and/or interleukin receptor gene, wherein one of the strands of the double-stranded siNA molecule is an antisense strand which comprises nucleotide sequence that is complementary to nucleotide sequence of interleukin and/or interleukin receptor RNA that encodes a protein or portion thereof, the other strand is a sense strand which comprises nucleotide sequence that is complementary to a nucleotide sequence of the antisense strand and wherein a majority of the pyrimidine nucleotides present in the double-stranded siNA molecule comprises a sugar modification. In one embodiment, each strand of the siNA molecule comprises about 18 to about 29 or more (e.g., about 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29 or more) nucleotides, wherein each strand comprises at least about 18 nucleotides that are complementary to the nucleotides of the other strand. In one embodiment, the siNA molecule is assembled from two oligonucleotide fragments, wherein one fragment comprises the nucleotide sequence of the antisense strand of the siNA molecule and a second fragment comprises nucleotide sequence of the sense region of the siNA molecule. In one embodiment, the sense strand is connected to the antisense strand via a linker molecule, such as a polynucleotide linker or a non-nucleotide linker. In a further embodiment, the pyrimidine nucleotides present in the sense strand are 2′-deoxy-2′fluoro pyrimidine nucleotides and the purine nucleotides present in the sense region are 2′-deoxy purine nucleotides. In another embodiment, the pyrimidine nucleotides present in the sense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides and the purine nucleotides present in the sense region are 2′-O-methyl purine nucleotides. In still another embodiment, the pyrimidine nucleotides present in the antisense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides and any purine nucleotides present in the antisense strand are 2′-deoxy purine nucleotides. In another embodiment, the antisense strand comprises one or more 2′-deoxy-2′-fluoro pyrimidine nucleotides and one or more 2′-O-methyl purine nucleotides. In another embodiment, the pyrimidine nucleotides present in the antisense strand are 2′-deoxy-2′-fluoro pyrimidine nucleotides and any purine nucleotides present in the antisense strand are 2′-O-methyl purine nucleotides. In a further embodiment the sense strand comprises a 3′-end and a 5′-end, wherein a terminal cap moiety (e.g., an inverted deoxy abasic moiety or inverted deoxy nucleotide moiety such as inverted thymidine) is present at the 5′-end, the 3′-end, or both of the 5′ and 3′ ends of the sense strand. In another embodiment, the antisense strand comprises a phosphorothioate internucleotide linkage at the 3′ end of the antisense strand. In another embodiment, the antisense strand comprises a glyceryl modification at the 3′ end. In another embodiment, the 5′-end of the antisense strand optionally includes a phosphate group.
[0057] In any of the above-described embodiments of a double-stranded short interfering nucleic acid (siNA) molecule that inhibits expression of a interleukin and/or interleukin receptor gene, wherein a majority of the pyrimidine nucleotides present in the double-stranded siNA molecule comprises a sugar modification, each of the two strands of the siNA molecule can comprise about 21 nucleotides. In one embodiment, about 21 nucleotides of each strand of the siNA molecule are base-paired to the complementary nucleotides of the other strand of the siNA molecule. In another embodiment, about 19 nucleotides of each strand of the siNA molecule are base-paired to the complementary nucleotides of the other strand of the siNA molecule, wherein at least two 3′ terminal nucleotides of each strand of the siNA molecule are not base-paired to the nucleotides of the other strand of the siNA molecule. In another embodiment, each of the two 3′ terminal nucleotides of each fragment of the siNA molecule is a 2′-deoxy-pyrimidine, such as 2′-deoxy-thymidine. In one embodiment, each strand of the siNA molecule is base-paired to the complementary nucleotides of the other strand of the siNA molecule. In one embodiment, about 19 nucleotides of the antisense strand are base-paired to the nucleotide sequence of the interleukin and/or interleukin receptor RNA or a portion thereof. In one embodiment, about 21 nucleotides of the antisense strand are base-paired to the nucleotide sequence of the interleukin and/or interleukin receptor RNA or a portion thereof.
[0058] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that inhibits expression of a interleukin and/or interleukin receptor gene, wherein one of the strands of the double-stranded siNA molecule is an antisense strand which comprises nucleotide sequence that is complementary to nucleotide sequence of interleukin and/or interleukin receptor RNA or a portion thereof, the other strand is a sense strand which comprises nucleotide sequence that is complementary to a nucleotide sequence of the antisense strand and wherein a majority of the pyrimidine nucleotides present in the double-stranded siNA molecule comprises a sugar modification, and wherein the 5′-end of the antisense strand optionally includes a phosphate group.
[0059] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that inhibits expression of a interleukin and/or interleukin receptor gene, wherein one of the strands of the double-stranded siNA molecule is an antisense strand which comprises nucleotide sequence that is complementary to nucleotide sequence of interleukin and/or interleukin receptor RNA or a portion thereof, the other strand is a sense strand which comprises nucleotide sequence that is complementary to a nucleotide sequence of the antisense strand and wherein a majority of the pyrimidine nucleotides present in the double-stranded siNA molecule comprises a sugar modification, and wherein the nucleotide sequence or a portion thereof of the antisense strand is complementary to a nucleotide sequence of the untranslated region or a portion thereof of the interleukin and/or interleukin receptor RNA.
[0060] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that inhibits expression of a interleukin and/or interleukin receptor gene, wherein one of the strands of the double-stranded siNA molecule is an antisense strand which comprises nucleotide sequence that is complementary to nucleotide sequence of interleukin and/or interleukin receptor RNA or a portion thereof, wherein the other strand is a sense strand which comprises nucleotide sequence that is complementary to a nucleotide sequence of the antisense strand, wherein a majority of the pyrimidine nucleotides present in the double-stranded siNA molecule comprises a sugar modification, and wherein the nucleotide sequence of the antisense strand is complementary to a nucleotide sequence of the interleukin and/or interleukin receptor RNA or a portion thereof that is present in the interleukin and/or interleukin receptor RNA.
[0061] In one embodiment, the invention features a composition comprising an siNA molecule of the invention in a pharmaceutically acceptable carrier or diluent.
[0062] In a non-limiting example, the introduction of chemically-modified nucleotides into nucleic acid molecules provides a powerful tool in overcoming potential limitations of in vivo stability and bioavailability inherent to native RNA molecules that are delivered exogenously. For example, the use of chemically-modified nucleic acid molecules can enable a lower dose of a particular nucleic acid molecule for a given therapeutic effect since chemically-modified nucleic acid molecules tend to have a longer half-life in serum. Furthermore, certain chemical modifications can improve the bioavailability of nucleic acid molecules by targeting particular cells or tissues and/or improving cellular uptake of the nucleic acid molecule. Therefore, even if the activity of a chemically-modified nucleic acid molecule is reduced as compared to a native nucleic acid molecule, for example, when compared to an all-RNA nucleic acid molecule, the overall activity of the modified nucleic acid molecule can be greater than that of the native molecule due to improved stability and/or delivery of the molecule. Unlike native unmodified siNA, chemically-modified siNA can also minimize the possibility of activating interferon activity in humans.
[0063] In any of the embodiments of siNA molecules described herein, the antisense region of an siNA molecule of the invention can comprise a phosphorothioate internucleotide linkage at the 3′-end of said antisense region. In any of the embodiments of siNA molecules described herein, the antisense region can comprise about one to about five phosphorothioate internucleotide linkages at the 5′-end of said antisense region. In any of the embodiments of siNA molecules described herein, the 3′-terminal nucleotide overhangs of an siNA molecule of the invention can comprise ribonucleotides or deoxyribonucleotides that are chemically-modified at a nucleic acid sugar, base, or backbone. In any of the embodiments of siNA molecules described herein, the 3′-terminal nucleotide overhangs can comprise one or more universal base ribonucleotides. In any of the embodiments of siNA molecules described herein, the 3′-terminal nucleotide overhangs can comprise one or more acyclic nucleotides.
[0064] One embodiment of the invention provides an expression vector comprising a nucleic acid sequence encoding at least one siNA molecule of the invention in a manner that allows expression of the nucleic acid molecule. Another embodiment of the invention provides a mammalian cell comprising such an expression vector. The mammalian cell can be a human cell. The siNA molecule of the expression vector can comprise a sense region and an antisense region. The antisense region can comprise sequence complementary to a RNA or DNA sequence encoding interleukin and/or interleukin receptor and the sense region can comprise sequence complementary to the antisense region. The siNA molecule can comprise two distinct strands having complementary sense and antisense regions. The siNA molecule can comprise a single strand having complementary sense and antisense regions.
[0065] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi) against interleukin and/or interleukin receptor inside a cell or reconstituted in vitro system, wherein the chemical modification comprises one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) nucleotides comprising a backbone modified internucleotide linkage having Formula I:
[0000]
[0000] wherein each R1 and R2 is independently any nucleotide, non-nucleotide, or polynucleotide which can be naturally-occurring or chemically-modified, each X and Y is independently O, S, N, alkyl, or substituted alkyl, each Z and W is independently O, S, N, alkyl, substituted alkyl, O-alkyl, S-alkyl, alkaryl, aralkyl, or acetyl and wherein W, X, Y, and Z are optionally not all O. In another embodiment, a backbone modification of the invention comprises a phosphonoacetate and/or thiophosphonoacetate internucleotide linkage (see for example Sheehan et al., 2003 , Nucleic Acids Research, 31, 4109-4118).
[0066] The chemically-modified internucleotide linkages having Formula I, for example, wherein any Z, W, X, and/or Y independently comprises a sulphur atom, can be present in one or both oligonucleotide strands of the siNA duplex, for example, in the sense strand, the antisense strand, or both strands. The siNA molecules of the invention can comprise one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) chemically-modified internucleotide linkages having Formula I at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of the sense strand, the antisense strand, or both strands. For example, an exemplary siNA molecule of the invention can comprise about 1 to about 5 or more (e.g., about 1, 2, 3, 4, 5, or more) chemically-modified internucleotide linkages having Formula I at the 5′-end of the sense strand, the antisense strand, or both strands. In another non-limiting example, an exemplary siNA molecule of the invention can comprise one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) pyrimidine nucleotides with chemically-modified internucleotide linkages having Formula I in the sense strand, the antisense strand, or both strands. In yet another non-limiting example, an exemplary siNA molecule of the invention can comprise one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) purine nucleotides with chemically-modified internucleotide linkages having Formula I in the sense strand, the antisense strand, or both strands. In another embodiment, an siNA molecule of the invention having internucleotide linkage(s) of Formula I also comprises a chemically-modified nucleotide or non-nucleotide having any of Formulae I-VII.
[0067] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi) against interleukin and/or interleukin receptor inside a cell or reconstituted in vitro system, wherein the chemical modification comprises one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) nucleotides or non-nucleotides having Formula II:
[0000]
[0000] wherein each R3, R4, R5, R6, R7, R8, R10, R11 and R12 is independently H, OH, alkyl, substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SO-alkyl, alkyl-SH, alkyl-OH, O-alkyl-OH, O-alkyl-SH, S-alkyl-OH, S-alkyl-SH, alkyl-5-alkyl, alkyl-O-alkyl, ONO2, NO2, N3, NH2, aminoalkyl, aminoacid, aminoacyl, ONH2, O-aminoalkyl, O-aminoacid, O-aminoacyl, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, or group having Formula I or II; R9 is O, S, CH2, S═O, CHF, or CF2, and B is a nucleosidic base such as adenine, guanine, uracil, cytosine, thymine, 2-aminoadenosine, 5-methylcytosine, 2,6-diaminopurine, or any other non-naturally occurring base that can be complementary or non-complementary to target RNA or a non-nucleosidic base such as phenyl, naphthyl, 3-nitropyrrole, 5-nitroindole, nebularine, pyridone, pyridinone, or any other non-naturally occurring universal base that can be complementary or non-complementary to target RNA.
[0068] The chemically-modified nucleotide or non-nucleotide of Formula II can be present in one or both oligonucleotide strands of the siNA duplex, for example in the sense strand, the antisense strand, or both strands. The siNA molecules of the invention can comprise one or more chemically-modified nucleotide or non-nucleotide of Formula II at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of the sense strand, the antisense strand, or both strands. For example, an exemplary siNA molecule of the invention can comprise about 1 to about 5 or more (e.g., about 1, 2, 3, 4, 5, or more) chemically-modified nucleotides or non-nucleotides of Formula II at the 5′-end of the sense strand, the antisense strand, or both strands. In anther non-limiting example, an exemplary siNA molecule of the invention can comprise about 1 to about 5 or more (e.g., about 1, 2, 3, 4, 5, or more) chemically-modified nucleotides or non-nucleotides of Formula II at the 3′-end of the sense strand, the antisense strand, or both strands.
[0069] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi) against interleukin and/or interleukin receptor inside a cell or reconstituted in vitro system, wherein the chemical modification comprises one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) nucleotides or non-nucleotides having Formula III:
[0000]
[0000] wherein each R3, R4, R5, R6, R7, R8, R10, R11 and R12 is independently H, OH, alkyl, substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SO-alkyl, alkyl-SH, alkyl-OH, O-alkyl-OH, O-alkyl-SH, S-alkyl-OH, S-alkyl-SH, alkyl-5-alkyl, alkyl-O-alkyl, ONO2, NO2, N3, NH2, aminoalkyl, aminoacid, aminoacyl, ONH2, O-aminoalkyl, O-aminoacid, O-aminoacyl, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, or group having Formula I or II; R9 is O, S, CH2, S═O, CHF, or CF2, and B is a nucleosidic base such as adenine, guanine, uracil, cytosine, thymine, 2-aminoadenosine, 5-methylcytosine, 2,6-diaminopurine, or any other non-naturally occurring base that can be employed to be complementary or non-complementary to target RNA or a non-nucleosidic base such as phenyl, naphthyl, 3-nitropyrrole, 5-nitroindole, nebularine, pyridone, pyridinone, or any other non-naturally occurring universal base that can be complementary or non-complementary to target RNA.
[0070] The chemically-modified nucleotide or non-nucleotide of Formula III can be present in one or both oligonucleotide strands of the siNA duplex, for example, in the sense strand, the antisense strand, or both strands. The siNA molecules of the invention can comprise one or more chemically-modified nucleotide or non-nucleotide of Formula III at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of the sense strand, the antisense strand, or both strands. For example, an exemplary siNA molecule of the invention can comprise about 1 to about 5 or more (e.g., about 1, 2, 3, 4, 5, or more) chemically-modified nucleotide(s) or non-nucleotide(s) of Formula III at the 5′-end of the sense strand, the antisense strand, or both strands. In anther non-limiting example, an exemplary siNA molecule of the invention can comprise about 1 to about 5 or more (e.g., about 1, 2, 3, 4, 5, or more) chemically-modified nucleotide or non-nucleotide of Formula III at the 3′-end of the sense strand, the antisense strand, or both strands.
[0071] In another embodiment, an siNA molecule of the invention comprises a nucleotide having Formula II or III, wherein the nucleotide having Formula II or III is in an inverted configuration. For example, the nucleotide having Formula II or III is connected to the siNA construct in a 3′-3′,3′-2′,2′-3′, or 5′-5′ configuration, such as at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of one or both siNA strands.
[0072] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi) against interleukin and/or interleukin receptor inside a cell or reconstituted in vitro system, wherein the chemical modification comprises a 5′-terminal phosphate group having Formula IV:
[0000]
[0000] wherein each X and Y is independently O, S, N, alkyl, substituted alkyl, or alkylhalo; wherein each Z and W is independently O, S, N, alkyl, substituted alkyl, O-alkyl, S-alkyl, alkaryl, aralkyl, alkylhalo, or acetyl; and wherein W, X, Y and Z are not all O.
[0073] In one embodiment, the invention features an siNA molecule having a 5′-terminal phosphate group having Formula IV on the target-complementary strand, for example, a strand complementary to a target RNA, wherein the siNA molecule comprises an all RNA siNA molecule. In another embodiment, the invention features an siNA molecule having a 5′-terminal phosphate group having Formula IV on the target-complementary strand wherein the siNA molecule also comprises about 1 to about 3 (e.g., about 1, 2, or 3) nucleotide 3′-terminal nucleotide overhangs having about 1 to about 4 (e.g., about 1, 2, 3, or 4) deoxyribonucleotides on the 3′-end of one or both strands. In another embodiment, a 5′-terminal phosphate group having Formula IV is present on the target-complementary strand of an siNA molecule of the invention, for example an siNA molecule having chemical modifications having any of Formulae I-VII.
[0074] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi) against interleukin and/or interleukin receptor inside a cell or reconstituted in vitro system, wherein the chemical modification comprises one or more phosphorothioate internucleotide linkages. For example, in a non-limiting example, the invention features a chemically-modified short interfering nucleic acid (siNA) having about 1, 2, 3, 4, 5, 6, 7, 8 or more phosphorothioate internucleotide linkages in one siNA strand. In yet another embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) individually having about 1, 2, 3, 4, 5, 6, 7, 8 or more phosphorothioate internucleotide linkages in both siNA strands. The phosphorothioate internucleotide linkages can be present in one or both oligonucleotide strands of the siNA duplex, for example in the sense strand, the antisense strand, or both strands. The siNA molecules of the invention can comprise one or more phosphorothioate internucleotide linkages at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of the sense strand, the antisense strand, or both strands. For example, an exemplary siNA molecule of the invention can comprise about 1 to about 5 or more (e.g., about 1, 2, 3, 4, 5, or more) consecutive phosphorothioate internucleotide linkages at the 5′-end of the sense strand, the antisense strand, or both strands. In another non-limiting example, an exemplary siNA molecule of the invention can comprise one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) pyrimidine phosphorothioate internucleotide linkages in the sense strand, the antisense strand, or both strands. In yet another non-limiting example, an exemplary siNA molecule of the invention can comprise one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) purine phosphorothioate internucleotide linkages in the sense strand, the antisense strand, or both strands.
[0075] In one embodiment, the invention features an siNA molecule, wherein the sense strand comprises one or more, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2′-deoxy, 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or about one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of the sense strand; and wherein the antisense strand comprises about 1 to about 10 or more, specifically about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2′-deoxy, 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of the antisense strand. In another embodiment, one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, pyrimidine nucleotides of the sense and/or antisense siNA strand are chemically-modified with 2′-deoxy, 2′-O-methyl and/or 2′-deoxy-2′-fluoro nucleotides, with or without one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, phosphorothioate internucleotide linkages and/or a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends, being present in the same or different strand.
[0076] In another embodiment, the invention features an siNA molecule, wherein the sense strand comprises about 1 to about 5, specifically about 1, 2, 3, 4, or 5 phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1, 2, 3, 4, 5, or more) 2′-deoxy, 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or one or more (e.g., about 1, 2, 3, 4, 5, or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3-end, the 5′-end, or both of the 3′- and 5′-ends of the sense strand; and wherein the antisense strand comprises about 1 to about 5 or more, specifically about 1, 2, 3, 4, 5, or more phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2′-deoxy, 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of the antisense strand. In another embodiment, one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more, pyrimidine nucleotides of the sense and/or antisense siNA strand are chemically-modified with 2′-deoxy, 2′-O-methyl and/or 2′-deoxy-2′-fluoro nucleotides, with or without about 1 to about 5 or more, for example about 1, 2, 3, 4, 5, or more phosphorothioate internucleotide linkages and/or a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends, being present in the same or different strand.
[0077] In one embodiment, the invention features an siNA molecule, wherein the antisense strand comprises one or more, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more phosphorothioate internucleotide linkages, and/or about one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2′-deoxy, 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of the sense strand; and wherein the antisense strand comprises about 1 to about 10 or more, specifically about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2′-deoxy, 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of the antisense strand. In another embodiment, one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more pyrimidine nucleotides of the sense and/or antisense siNA strand are chemically-modified with 2′-deoxy, 2′-O-methyl and/or 2′-deoxy-2′-fluoro nucleotides, with or without one or more, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more phosphorothioate internucleotide linkages and/or a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends, being present in the same or different strand.
[0078] In another embodiment, the invention features an siNA molecule, wherein the antisense strand comprises about 1 to about 5 or more, specifically about 1, 2, 3, 4, 5 or more phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2′-deoxy, 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of the sense strand; and wherein the antisense strand comprises about 1 to about 5 or more, specifically about 1, 2, 3, 4, 5 or more phosphorothioate internucleotide linkages, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) 2′-deoxy, 2′-O-methyl, 2′-deoxy-2′-fluoro, and/or one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more) universal base modified nucleotides, and optionally a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of the antisense strand. In another embodiment, one or more, for example about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 or more pyrimidine nucleotides of the sense and/or antisense siNA strand are chemically-modified with 2′-deoxy, 2′-O-methyl and/or 2′-deoxy-2′-fluoro nucleotides, with or without about 1 to about 5, for example about 1, 2, 3, 4, 5 or more phosphorothioate internucleotide linkages and/or a terminal cap molecule at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends, being present in the same or different strand.
[0079] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule having about 1 to about 5, specifically about 1, 2, 3, 4, 5 or more phosphorothioate internucleotide linkages in each strand of the siNA molecule.
[0080] In another embodiment, the invention features an siNA molecule comprising 2′-5′ internucleotide linkages. The 2′-5′ internucleotide linkage(s) can be at the 3′-end, the 5′-end, or both of the 3′- and 5′-ends of one or both siNA sequence strands. In addition, the 2′-5′ internucleotide linkage(s) can be present at various other positions within one or both siNA sequence strands, for example, about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more including every internucleotide linkage of a pyrimidine nucleotide in one or both strands of the siNA molecule can comprise a 2′-5′ internucleotide linkage, or about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more including every internucleotide linkage of a purine nucleotide in one or both strands of the siNA molecule can comprise a 2′-5′ internucleotide linkage.
[0081] In another embodiment, a chemically-modified siNA molecule of the invention comprises a duplex having two strands, one or both of which can be chemically-modified, wherein each strand is about 18 to about 27 (e.g., about 18, 19, 20, 21, 22, 23, 24, 25, 26, or 27) nucleotides in length, wherein the duplex has about 18 to about 23 (e.g., about 18, 19, 20, 21, 22, or 23) base pairs, and wherein the chemical modification comprises a structure having any of Formulae I-VII. For example, an exemplary chemically-modified siNA molecule of the invention comprises a duplex having two strands, one or both of which can be chemically-modified with a chemical modification having any of Formulae I-VII or any combination thereof, wherein each strand consists of about 21 nucleotides, each having a 2-nucleotide 3′-terminal nucleotide overhang, and wherein the duplex has about 19 base pairs. In another embodiment, an siNA molecule of the invention comprises a single-stranded hairpin structure, wherein the siNA is about 36 to about 70 (e.g., about 36, 40, 45, 50, 55, 60, 65, or 70) nucleotides in length having about 18 to about 23 (e.g., about 18, 19, 20, 21, 22, or 23) base pairs, and wherein the siNA can include a chemical modification comprising a structure having any of Formulae I-VII or any combination thereof. For example, an exemplary chemically-modified siNA molecule of the invention comprises a linear oligonucleotide having about 42 to about 50 (e.g., about 42, 43, 44, 45, 46, 47, 48, 49, or 50) nucleotides that is chemically-modified with a chemical modification having any of Formulae I-VII or any combination thereof, wherein the linear oligonucleotide forms a hairpin structure having about 19 base pairs and a 2-nucleotide 3′-terminal nucleotide overhang. In another embodiment, a linear hairpin siNA molecule of the invention contains a stem loop motif, wherein the loop portion of the siNA molecule is biodegradable. For example, a linear hairpin siNA molecule of the invention is designed such that degradation of the loop portion of the siNA molecule in vivo can generate a double-stranded siNA molecule with 3′-terminal overhangs, such as 3′-terminal nucleotide overhangs comprising about 2 nucleotides.
[0082] In another embodiment, an siNA molecule of the invention comprises a hairpin structure, wherein the siNA is about 25 to about 50 (e.g., about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) nucleotides in length having about 3 to about 25 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) base pairs, and wherein the siNA can include one or more chemical modifications comprising a structure having any of Formulae I-VII or any combination thereof. For example, an exemplary chemically-modified siNA molecule of the invention comprises a linear oligonucleotide having about 25 to about 35 (e.g., about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) nucleotides that is chemically-modified with one or more chemical modifications having any of Formulae I-VII or any combination thereof, wherein the linear oligonucleotide forms a hairpin structure having about 3 to about 23 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, or 23) base pairs and a 5′-terminal phosphate group that can be chemically modified as described herein (for example a 5′-terminal phosphate group having Formula IV). In another embodiment, a linear hairpin siNA molecule of the invention contains a stem loop motif, wherein the loop portion of the siNA molecule is biodegradable. In one embodiment, a linear hairpin siNA molecule of the invention comprises a loop portion comprising a non-nucleotide linker.
[0083] In another embodiment, an siNA molecule of the invention comprises an asymmetric hairpin structure, wherein the siNA is about 25 to about 50 (e.g., about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50) nucleotides in length having about 3 to about 20 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20) base pairs, and wherein the siNA can include one or more chemical modifications comprising a structure having any of Formulae I-VII or any combination thereof. For example, an exemplary chemically-modified siNA molecule of the invention comprises a linear oligonucleotide having about 25 to about 35 (e.g., about 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, or 35) nucleotides that is chemically-modified with one or more chemical modifications having any of Formulae I-VII or any combination thereof, wherein the linear oligonucleotide forms an asymmetric hairpin structure having about 3 to about 18 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) base pairs and a 5′-terminal phosphate group that can be chemically modified as described herein (for example a 5′-terminal phosphate group having Formula IV). In one embodiment, an asymmetric hairpin siNA molecule of the invention contains a stem loop motif, wherein the loop portion of the siNA molecule is biodegradable. In another embodiment, an asymmetric hairpin siNA molecule of the invention comprises a loop portion comprising a non-nucleotide linker.
[0084] In another embodiment, an siNA molecule of the invention comprises an asymmetric double-stranded structure having separate polynucleotide strands comprising sense and antisense regions, wherein the antisense region is about 16 to about 25 (e.g., about 16, 17, 18, 19, 20, 21, 22, 23, 24, or 25) nucleotides in length, wherein the sense region is about 3 to about 18 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) nucleotides in length, wherein the sense region and the antisense region have at least 3 complementary nucleotides, and wherein the siNA can include one or more chemical modifications comprising a structure having any of Formulae I-VII or any combination thereof. For example, an exemplary chemically-modified siNA molecule of the invention comprises an asymmetric double-stranded structure having separate polynucleotide strands comprising sense and antisense regions, wherein the antisense region is about 18 to about 22 (e.g., about 18, 19, 20, 21, or 22) nucleotides in length and wherein the sense region is about 3 to about 15 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15) nucleotides in length, wherein the sense region the antisense region have at least 3 complementary nucleotides, and wherein the siNA can include one or more chemical modifications comprising a structure having any of Formulae I-VII or any combination thereof. In another embodiment, the asymmetric double-stranded siNA molecule can also have a 5′-terminal phosphate group that can be chemically modified as described herein (for example a 5′-terminal phosphate group having Formula IV).
[0085] In another embodiment, an siNA molecule of the invention comprises a circular nucleic acid molecule, wherein the siNA is about 38 to about 70 (e.g., about 38, 40, 45, 50, 55, 60, 65, or 70) nucleotides in length having about 18 to about 23 (e.g., about 18, 19, 20, 21, 22, or 23) base pairs, and wherein the siNA can include a chemical modification, which comprises a structure having any of Formulae I-VII or any combination thereof. For example, an exemplary chemically-modified siNA molecule of the invention comprises a circular oligonucleotide having about 42 to about 50 (e.g., about 42, 43, 44, 45, 46, 47, 48, 49, or 50) nucleotides that is chemically-modified with a chemical modification having any of Formulae I-VII or any combination thereof, wherein the circular oligonucleotide forms a dumbbell shaped structure having about 19 base pairs and 2 loops.
[0086] In another embodiment, a circular siNA molecule of the invention contains two loop motifs, wherein one or both loop portions of the siNA molecule is biodegradable. For example, a circular siNA molecule of the invention is designed such that degradation of the loop portions of the siNA molecule in vivo can generate a double-stranded siNA molecule with 3′-terminal overhangs, such as 3′-terminal nucleotide overhangs comprising about 2 nucleotides.
[0087] In one embodiment, an siNA molecule of the invention comprises at least one (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) abasic moiety, for example a compound having Formula V:
[0000]
[0000] wherein each R3, R4, R5, R6, R7, R8, R10, R11, R12, and R13 is independently H, OH, alkyl, substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SO-alkyl, alkyl-SH, alkyl-OH, O-alkyl-OH, O-alkyl-SH, S-alkyl-OH, S-alkyl-SH, alkyl-5-alkyl, alkyl-O-alkyl, ONO2, NO2, N3, NH2, aminoalkyl, aminoacid, aminoacyl, ONH2, O-aminoalkyl, O-aminoacid, O-aminoacyl, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, or group having Formula I or II; and R9 is O, S, CH2, S═O, CHF, or CF2.
[0088] In one embodiment, an siNA molecule of the invention comprises at least one (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) inverted abasic moiety, for example a compound having Formula VI:
[0000]
[0000] wherein each R3, R4, R5, R6, R7, R8, R10, R11, R12, and R13 is independently H, OH, alkyl, substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SO-alkyl, alkyl-SH, alkyl-OH, O-alkyl-OH, O-alkyl-SH, S-alkyl-OH, S-alkyl-SH, alkyl-5-alkyl, alkyl-O-alkyl, ONO2, NO2, N3, NH2, aminoalkyl, aminoacid, aminoacyl, ONH2, O-aminoalkyl, O-aminoacid, O-aminoacyl, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, or group having Formula I or II; R9 is O, S, CH2, S═O, CHF, or CF2, and either R5, R3, R8 or R13 serves as a point of attachment to the siNA molecule of the invention.
[0089] In another embodiment, an siNA molecule of the invention comprises at least one (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) substituted polyalkyl moieties, for example a compound having Formula VII:
[0000]
[0000] wherein each n is independently an integer from 1 to 12, each R1, R2 and R3 is independently H, OH, alkyl, substituted alkyl, alkaryl or aralkyl, F, Cl, Br, CN, CF3, OCF3, OCN, O-alkyl, S-alkyl, N-alkyl, O-alkenyl, S-alkenyl, N-alkenyl, SO-alkyl, alkyl-SH, alkyl-OH, O-alkyl-OH, O-alkyl-SH, S-alkyl-OH, S-alkyl-SH, alkyl-5-alkyl, alkyl-O-alkyl, ONO2, NO2, N3, NH2, aminoalkyl, aminoacid, aminoacyl, ONH2, O-aminoalkyl, O-aminoacid, O-aminoacyl, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, or a group having Formula I, and R1, R2 or R3 serves as points of attachment to the siNA molecule of the invention.
[0090] In another embodiment, the invention features a compound having Formula VII, wherein R1 and R2 are hydroxyl (OH) groups, n=1, and R3 comprises O and is the point of attachment to the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of one or both strands of a double-stranded siNA molecule of the invention or to a single-stranded siNA molecule of the invention. This modification is referred to herein as “glyceryl” (for example modification 6 in FIG. 10 ).
[0091] In another embodiment, a moiety having any of Formula V, VI or VII of the invention is at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of an siNA molecule of the invention. For example, a moiety having Formula V, VI or VII can be present at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of the antisense strand, the sense strand, or both antisense and sense strands of the siNA molecule. In addition, a moiety having Formula VII can be present at the 3′-end or the 5′-end of a hairpin siNA molecule as described herein.
[0092] In another embodiment, an siNA molecule of the invention comprises an abasic residue having Formula V or VI, wherein the abasic residue having Formula VI or VI is connected to the siNA construct in a 3′-3′,3′-2′,2′-3′, or 5′-5′ configuration, such as at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of one or both siNA strands.
[0093] In one embodiment, an siNA molecule of the invention comprises one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) locked nucleic acid (LNA) nucleotides, for example at the 5′-end, the 3′-end, both of the 5′ and 3′-ends, or any combination thereof, of the siNA molecule.
[0094] In another embodiment, an siNA molecule of the invention comprises one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) acyclic nucleotides, for example at the 5′-end, the 3′-end, both of the 5′ and 3′-ends, or any combination thereof, of the siNA molecule.
[0095] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule of the invention comprising a sense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the sense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more or all) purine nucleotides present in the sense region are 2′-deoxy purine nucleotides (e.g., wherein all purine nucleotides are 2′-deoxy purine nucleotides or alternately a plurality of purine nucleotides are 2′-deoxy purine nucleotides).
[0096] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule of the invention comprising a sense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the sense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more or all) purine nucleotides present in the sense region are 2′-deoxy purine nucleotides (e.g., wherein all purine nucleotides are 2′-deoxy purine nucleotides or alternately a plurality of purine nucleotides are 2′-deoxy purine nucleotides), wherein any nucleotides comprising a 3′-terminal nucleotide overhang that are present in said sense region are 2′-deoxy nucleotides.
[0097] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule of the invention comprising a sense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the sense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more or all) purine nucleotides present in the sense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides).
[0098] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule of the invention comprising a sense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the sense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), wherein any (e.g., one or more or all) purine nucleotides present in the sense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides), and wherein any nucleotides comprising a 3′-terminal nucleotide overhang that are present in said sense region are 2′-deoxy nucleotides.
[0099] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule of the invention comprising an antisense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the antisense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more or all) purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides).
[0100] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule of the invention comprising an antisense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the antisense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), wherein any (e.g., one or more or all) purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides), and wherein any nucleotides comprising a 3′-terminal nucleotide overhang that are present in said antisense region are 2′-deoxy nucleotides.
[0101] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule of the invention comprising an antisense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the antisense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more or all) purine nucleotides present in the antisense region are 2′-deoxy purine nucleotides (e.g., wherein all purine nucleotides are 2′-deoxy purine nucleotides or alternately a plurality of purine nucleotides are 2′-deoxy purine nucleotides).
[0102] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule of the invention comprising an antisense region, wherein any (e.g., one or more or all) pyrimidine nucleotides present in the antisense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and wherein any (e.g., one or more or all) purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides).
[0103] In one embodiment, the invention features a chemically-modified short interfering nucleic acid (siNA) molecule of the invention capable of mediating RNA interference (RNAi) against interleukin and/or interleukin receptor inside a cell or reconstituted in vitro system comprising a sense region, wherein one or more pyrimidine nucleotides present in the sense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and one or more purine nucleotides present in the sense region are 2′-deoxy purine nucleotides (e.g., wherein all purine nucleotides are 2′-deoxy purine nucleotides or alternately a plurality of purine nucleotides are 2′-deoxy purine nucleotides), and an antisense region, wherein one or more pyrimidine nucleotides present in the antisense region are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and one or more purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides). The sense region and/or the antisense region can have a terminal cap modification, such as any modification described herein or shown in FIG. 10 , that is optionally present at the 3′-end, the 5′-end, or both of the 3′ and 5′-ends of the sense and/or antisense sequence. The sense and/or antisense region can optionally further comprise a 3′-terminal nucleotide overhang having about 1 to about 4 (e.g., about 1, 2, 3, or 4) 2′-deoxynucleotides. The overhang nucleotides can further comprise one or more (e.g., about 1, 2, 3, 4 or more) phosphorothioate, phosphonoacetate, and/or thiophosphonoacetate internucleotide linkages. Non-limiting examples of these chemically-modified siNAs are shown in FIGS. 4 and 5 and Tables III and IV herein. In any of these described embodiments, the purine nucleotides present in the sense region are alternatively 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides) and one or more purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides). Also, in any of these embodiments, one or more purine nucleotides present in the sense region are alternatively purine ribonucleotides (e.g., wherein all purine nucleotides are purine ribonucleotides or alternately a plurality of purine nucleotides are purine ribonucleotides) and any purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides). Additionally, in any of these embodiments, one or more purine nucleotides present in the sense region and/or present in the antisense region are alternatively selected from the group consisting of 2′-deoxy nucleotides, locked nucleic acid (LNA) nucleotides, 2′-methoxyethyl nucleotides, 4′-thionucleotides, and 2′-O-methyl nucleotides (e.g., wherein all purine nucleotides are selected from the group consisting of 2′-deoxy nucleotides, locked nucleic acid (LNA) nucleotides, 2′-methoxyethyl nucleotides, 4′-thionucleotides, and 2′-O-methyl nucleotides or alternately a plurality of purine nucleotides are selected from the group consisting of 2′-deoxy nucleotides, locked nucleic acid (LNA) nucleotides, 2′-methoxyethyl nucleotides, 4′-thionucleotides, and 2′-O-methyl nucleotides).
[0104] In another embodiment, any modified nucleotides present in the siNA molecules of the invention, preferably in the antisense strand of the siNA molecules of the invention, but also optionally in the sense and/or both antisense and sense strands, comprise modified nucleotides having properties or characteristics similar to naturally occurring ribonucleotides. For example, the invention features siNA molecules including modified nucleotides having a Northern conformation (e.g., Northern pseudorotation cycle, see for example Saenger, Principles of Nucleic Acid Structure , Springer-Verlag ed., 1984). As such, chemically modified nucleotides present in the siNA molecules of the invention, preferably in the antisense strand of the siNA molecules of the invention, but also optionally in the sense and/or both antisense and sense strands, are resistant to nuclease degradation while at the same time maintaining the capacity to mediate RNAi. Non-limiting examples of nucleotides having a Northern configuration include locked nucleic acid (LNA) nucleotides (e.g., 2′-O, 4′-C-methylene-(D-ribofuranosyl)nucleotides); 2′-methoxyethoxy (MOE) nucleotides; 2′-methyl-thio-ethyl, 2′-deoxy-2′-fluoro nucleotides, 2′-deoxy-2′-chloro nucleotides, 2′-azido nucleotides, and 2′-O-methyl nucleotides.
[0105] In one embodiment, the sense strand of a double-stranded siNA molecule of the invention comprises a terminal cap moiety, (see for example FIG. 10 ) such as an inverted deoxyabasic moiety, at the 3′-end, 5′-end, or both 3′ and 5′-ends of the sense strand.
[0106] In one embodiment, the invention features a chemically-modified short interfering nucleic acid molecule (siNA) capable of mediating RNA interference (RNAi) against interleukin and/or interleukin receptor inside a cell or reconstituted in vitro system, wherein the chemical modification comprises a conjugate covalently attached to the chemically-modified siNA molecule. Non-limiting examples of conjugates contemplated by the invention include conjugates and ligands described in Vargeese et al., U.S. Ser. No. 10/427,160, filed Apr. 30, 2003, incorporated by reference herein in its entirety, including the drawings. In another embodiment, the conjugate is covalently attached to the chemically-modified siNA molecule via a biodegradable linker. In one embodiment, the conjugate molecule is attached at the 3′-end of either the sense strand, the antisense strand, or both strands of the chemically-modified siNA molecule. In another embodiment, the conjugate molecule is attached at the 5′-end of either the sense strand, the antisense strand, or both strands of the chemically-modified siNA molecule. In yet another embodiment, the conjugate molecule is attached both the 3′-end and 5′-end of either the sense strand, the antisense strand, or both strands of the chemically-modified siNA molecule, or any combination thereof. In one embodiment, a conjugate molecule of the invention comprises a molecule that facilitates delivery of a chemically-modified siNA molecule into a biological system, such as a cell. In another embodiment, the conjugate molecule attached to the chemically-modified siNA molecule is a polyethylene glycol, human serum albumin, or a ligand for a cellular receptor that can mediate cellular uptake. Examples of specific conjugate molecules contemplated by the instant invention that can be attached to chemically-modified siNA molecules are described in Vargeese et al., U.S. Ser. No. 10/201,394, filed Jul. 22, 2002 incorporated by reference herein. The type of conjugates used and the extent of conjugation of siNA molecules of the invention can be evaluated for improved pharmacokinetic profiles, bioavailability, and/or stability of siNA constructs while at the same time maintaining the ability of the siNA to mediate RNAi activity. As such, one skilled in the art can screen siNA constructs that are modified with various conjugates to determine whether the siNA conjugate complex possesses improved properties while maintaining the ability to mediate RNAi, for example in animal models as are generally known in the art.
[0107] In one embodiment, the invention features a short interfering nucleic acid (siNA) molecule of the invention, wherein the siNA further comprises a nucleotide, non-nucleotide, or mixed nucleotide/non-nucleotide linker that joins the sense region of the siNA to the antisense region of the siNA. In one embodiment, a nucleotide linker of the invention can be a linker of ≧2 nucleotides in length, for example about 3, 4, 5, 6, 7, 8, 9, or 10 nucleotides in length. In another embodiment, the nucleotide linker can be a nucleic acid aptamer. By “aptamer” or “nucleic acid aptamer” as used herein is meant a nucleic acid molecule that binds specifically to a target molecule wherein the nucleic acid molecule has a sequence that comprises a sequence recognized by the target molecule in its natural setting. Alternately, an aptamer can be a nucleic acid molecule that binds to a target molecule where the target molecule does not naturally bind to a nucleic acid. The target molecule can be any molecule of interest. For example, the aptamer can be used to bind to a ligand-binding domain of a protein, thereby preventing interaction of the naturally occurring ligand with the protein. This is a non-limiting example and those in the art will recognize that other embodiments can be readily generated using techniques generally known in the art. (See, for example, Gold et al., 1995 , Annu. Rev. Biochem., 64, 763; Brody and Gold, 2000 , J. Biotechnol., 74, 5; Sun, 2000 , Curr. Opin. Mol. Ther., 2, 100; Kusser, 2000 , J. Biotechnol., 74, 27; Hermann and Patel, 2000 , Science, 287, 820; and Jayasena, 1999 , Clinical Chemistry, 45, 1628.)
[0108] In yet another embodiment, a non-nucleotide linker of the invention comprises abasic nucleotide, polyether, polyamine, polyamide, peptide, carbohydrate, lipid, polyhydrocarbon, or other polymeric compounds (e.g. polyethylene glycols such as those having between 2 and 100 ethylene glycol units). Specific examples include those described by Seela and Kaiser, Nucleic Acids Res. 1990, 18:6353 and Nucleic Acids Res. 1987, 15:3113; Cload and Schepartz, J. Am. Chem. Soc. 1991, 113:6324; Richardson and Schepartz, J. Am. Chem. Soc. 1991, 113:5109; Ma et al., Nucleic Acids Res. 1993, 21:2585 and Biochemisty 1993, 32:1751; Durand et al., Nucleic Acids Res. 1990, 18:6353; McCurdy et al., Nucleosides & Nucleotides 1991, 10:287; Jschke et al., Tetrahedron Lett. 1993, 34:301; Ono et al., Biochemistry 1991, 30:9914; Arnold et al., International Publication No. WO 89/02439; Usman et al., International Publication No. WO 95/06731; Dudycz et al., International Publication No. WO 95/11910 and Ferentz and Verdine, J. Am. Chem. Soc. 1991, 113:4000, all hereby incorporated by reference herein. A “non-nucleotide” further means any group or compound that can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound can be abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine, for example at the C1 position of the sugar.
[0109] In one embodiment, the invention features a short interfering nucleic acid (siNA) molecule capable of mediating RNA interference (RNAi) inside a cell or reconstituted in vitro system, wherein one or both strands of the siNA molecule that are assembled from two separate oligonucleotides do not comprise any ribonucleotides. For example, an siNA molecule can be assembled from a single oligonucleotide where the sense and antisense regions of the siNA comprise separate oligonucleotides that do not have any ribonucleotides (e.g., nucleotides having a 2′-OH group) present in the oligonucleotides. In another example, an siNA molecule can be assembled from a single oligonucleotide where the sense and antisense regions of the siNA are linked or circularized by a nucleotide or non-nucleotide linker as described herein, wherein the oligonucleotide does not have any ribonucleotides (e.g., nucleotides having a 2′-OH group) present in the oligonucleotide. Applicant has surprisingly found that the presence of ribonucleotides (e.g., nucleotides having a 2′-hydroxyl group) within the siNA molecule is not required or essential to support RNAi activity. As such, in one embodiment, all positions within the siNA can include chemically modified nucleotides and/or non-nucleotides such as nucleotides and or non-nucleotides having Formula I, II, III, IV, V, VI, or VII or any combination thereof to the extent that the ability of the siNA molecule to support RNAi activity in a cell is maintained.
[0110] In one embodiment, an siNA molecule of the invention is a single-stranded siNA molecule that mediates RNAi activity in a cell or reconstituted in vitro system comprising a single-stranded polynucleotide having complementarity to a target nucleic acid sequence. In another embodiment, the single-stranded siNA molecule of the invention comprises a 5′-terminal phosphate group. In another embodiment, the single-stranded siNA molecule of the invention comprises a 5′-terminal phosphate group and a 3′-terminal phosphate group (e.g., a 2′,3′-cyclic phosphate). In another embodiment, the single-stranded siNA molecule of the invention comprises about 19 to about 29 (e.g., about 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, or 29) nucleotides. In yet another embodiment, the single-stranded siNA molecule of the invention comprises one or more chemically modified nucleotides or non-nucleotides described herein. For example, all the positions within the siNA molecule can include chemically-modified nucleotides such as nucleotides having any of Formulae I-VII, or any combination thereof to the extent that the ability of the siNA molecule to support RNAi activity in a cell is maintained.
[0111] In one embodiment, an siNA molecule of the invention is a single-stranded siNA molecule that mediates RNAi activity in a cell or reconstituted in vitro system comprising a single-stranded polynucleotide having complementarity to a target nucleic acid sequence, wherein one or more pyrimidine nucleotides present in the siNA are 2′-deoxy-2′-fluoro pyrimidine nucleotides (e.g., wherein all pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides or alternately a plurality of pyrimidine nucleotides are 2′-deoxy-2′-fluoro pyrimidine nucleotides), and wherein any purine nucleotides present in the antisense region are 2′-O-methyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-O-methyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-O-methyl purine nucleotides), and a terminal cap modification, such as any modification described herein or shown in FIG. 10 , that is optionally present at the 3′-end and/or the 5′-end. The siNA optionally further comprises about 1 to about 4 or more (e.g., about 1, 2, 3, 4 or more) terminal 2′-deoxynucleotides at the 3′-end of the siNA molecule, wherein the terminal nucleotides can further comprise one or more (e.g., 1, 2, 3, 4 or more) phosphorothioate, phosphonoacetate, and/or thiophosphonoacetate internucleotide linkages, and wherein the siNA optionally further comprises a terminal phosphate group, such as a 5′-terminal phosphate group. In any of these embodiments, any purine nucleotides present in the antisense region are alternatively 2′-deoxy purine nucleotides (e.g., wherein all purine nucleotides are 2′-deoxy purine nucleotides or alternately a plurality of purine nucleotides are 2′-deoxy purine nucleotides). Also, in any of these embodiments, any purine nucleotides present in the siNA (i.e., purine nucleotides present in the sense and/or antisense region) can alternatively be locked nucleic acid (LNA) nucleotides (e.g., wherein all purine nucleotides are LNA nucleotides or alternately a plurality of purine nucleotides are LNA nucleotides). Also, in any of these embodiments, any purine nucleotides present in the siNA are alternatively 2′-methoxyethyl purine nucleotides (e.g., wherein all purine nucleotides are 2′-methoxyethyl purine nucleotides or alternately a plurality of purine nucleotides are 2′-methoxyethyl purine nucleotides). In another embodiment, any modified nucleotides present in the single-stranded siNA molecules of the invention comprise modified nucleotides having properties or characteristics similar to naturally occurring ribonucleotides. For example, the invention features siNA molecules including modified nucleotides having a Northern conformation (e.g., Northern pseudorotation cycle, see for example Saenger, Principles of Nucleic Acid Structure , Springer-Verlag ed., 1984). As such, chemically modified nucleotides present in the single-stranded siNA molecules of the invention are preferably resistant to nuclease degradation while at the same time maintaining the capacity to mediate RNAi.
[0112] In one embodiment, the invention features a method for modulating the expression of a interleukin and/or interleukin receptor gene within a cell comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein one of the siNA strands comprises a sequence complementary to RNA of the interleukin and/or interleukin receptor gene; and (b) introducing the siNA molecule into a cell under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the cell.
[0113] In one embodiment, the invention features a method for modulating the expression of a interleukin and/or interleukin receptor gene within a cell comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein one of the siNA strands comprises a sequence complementary to RNA of the interleukin and/or interleukin receptor gene and wherein the sense strand sequence of the siNA comprises a sequence identical or substantially similar to the sequence of the target RNA; and (b) introducing the siNA molecule into a cell under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the cell.
[0114] In another embodiment, the invention features a method for modulating the expression of more than one interleukin and/or interleukin receptor gene within a cell comprising: (a) synthesizing siNA molecules of the invention, which can be chemically-modified, wherein one of the siNA strands comprises a sequence complementary to RNA of the interleukin and/or interleukin receptor genes; and (b) introducing the siNA molecules into a cell under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in the cell.
[0115] In another embodiment, the invention features a method for modulating the expression of two or more interleukin and/or interleukin receptor genes within a cell comprising: (a) synthesizing one or more siNA molecules of the invention, which can be chemically-modified, wherein the siNA strands comprise sequences complementary to RNA of the interleukin and/or interleukin receptor genes and wherein the sense strand sequences of the siNAs comprise sequences identical or substantially similar to the sequences of the target RNAs; and (b) introducing the siNA molecules into a cell under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in the cell.
[0116] In another embodiment, the invention features a method for modulating the expression of more than one interleukin and/or interleukin receptor gene within a cell comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein one of the siNA strands comprises a sequence complementary to RNA of the interleukin and/or interleukin receptor gene and wherein the sense strand sequence of the siNA comprises a sequence identical or substantially similar to the sequences of the target RNAs; and (b) introducing the siNA molecule into a cell under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in the cell.
[0117] In one embodiment, siNA molecules of the invention are used as reagents in ex vivo applications. For example, siNA reagents are introduced into tissue or cells that are transplanted into a subject for therapeutic effect. The cells and/or tissue can be derived from an organism or subject that later receives the explant, or can be derived from another organism or subject prior to transplantation. The siNA molecules can be used to modulate the expression of one or more genes in the cells or tissue, such that the cells or tissue obtain a desired phenotype or are able to perform a function when transplanted in vivo. In one embodiment, certain target cells from a patient are extracted. These extracted cells are contacted with siNAs targeting a specific nucleotide sequence within the cells under conditions suitable for uptake of the siNAs by these cells (e.g. using delivery reagents such as cationic lipids, liposomes and the like or using techniques such as electroporation to facilitate the delivery of siNAs into cells). The cells are then reintroduced back into the same patient or other patients. In one embodiment, the invention features a method of modulating the expression of a interleukin and/or interleukin receptor gene in a tissue explant comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein one of the siNA strands comprises a sequence complementary to RNA of the interleukin and/or interleukin receptor gene; and (b) introducing the siNA molecule into a cell of the tissue explant derived from a particular organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the tissue explant. In another embodiment, the method further comprises introducing the tissue explant back into the organism the tissue was derived from or into another organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in that organism.
[0118] In one embodiment, the invention features a method of modulating the expression of a interleukin and/or interleukin receptor gene in a tissue explant comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein one of the siNA strands comprises a sequence complementary to RNA of the interleukin and/or interleukin receptor gene and wherein the sense strand sequence of the siNA comprises a sequence identical or substantially similar to the sequence of the target RNA; and (b) introducing the siNA molecule into a cell of the tissue explant derived from a particular organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the tissue explant. In another embodiment, the method further comprises introducing the tissue explant back into the organism the tissue was derived from or into another organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in that organism.
[0119] In another embodiment, the invention features a method of modulating the expression of more than one interleukin and/or interleukin receptor gene in a tissue explant comprising: (a) synthesizing siNA molecules of the invention, which can be chemically-modified, wherein one of the siNA strands comprises a sequence complementary to RNA of the interleukin and/or interleukin receptor genes; and (b) introducing the siNA molecules into a cell of the tissue explant derived from a particular organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in the tissue explant. In another embodiment, the method further comprises introducing the tissue explant back into the organism the tissue was derived from or into another organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in that organism.
[0120] In one embodiment, the invention features a method of modulating the expression of a interleukin and/or interleukin receptor gene in an organism comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein one of the siNA strands comprises a sequence complementary to RNA of the interleukin and/or interleukin receptor gene; and (b) introducing the siNA molecule into the organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism. The level of interleukin and/or interleukin receptor protein or RNA can be determined as is known in the art.
[0121] In another embodiment, the invention features a method of modulating the expression of more than one interleukin and/or interleukin receptor gene in an organism comprising: (a) synthesizing siNA molecules of the invention, which can be chemically-modified, wherein one of the siNA strands comprises a sequence complementary to RNA of the interleukin and/or interleukin receptor genes; and (b) introducing the siNA molecules into the organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in the organism. The level of interleukin and/or interleukin receptor protein or RNA can be determined as is known in the art.
[0122] In one embodiment, the invention features a method for modulating the expression of a interleukin and/or interleukin receptor gene within a cell comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein the siNA comprises a single-stranded sequence having complementarity to RNA of the interleukin and/or interleukin receptor gene; and (b) introducing the siNA molecule into a cell under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the cell.
[0123] In another embodiment, the invention features a method for modulating the expression of more than one interleukin and/or interleukin receptor gene within a cell comprising: (a) synthesizing siNA molecules of the invention, which can be chemically-modified, wherein the siNA comprises a single-stranded sequence having complementarity to RNA of the interleukin and/or interleukin receptor gene; and (b) contacting the cell in vitro or in vivo with the siNA molecule under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in the cell.
[0124] In one embodiment, the invention features a method of modulating the expression of a interleukin and/or interleukin receptor gene in a tissue explant comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein the siNA comprises a single-stranded sequence having complementarity to RNA of the interleukin and/or interleukin receptor gene; and (b) contacting the cell of the tissue explant derived from a particular organism with the siNA molecule under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the tissue explant. In another embodiment, the method further comprises introducing the tissue explant back into the organism the tissue was derived from or into another organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in that organism.
[0125] In another embodiment, the invention features a method of modulating the expression of more than one interleukin and/or interleukin receptor gene in a tissue explant comprising: (a) synthesizing siNA molecules of the invention, which can be chemically-modified, wherein the siNA comprises a single-stranded sequence having complementarity to RNA of the interleukin and/or interleukin receptor gene; and (b) introducing the siNA molecules into a cell of the tissue explant derived from a particular organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in the tissue explant. In another embodiment, the method further comprises introducing the tissue explant back into the organism the tissue was derived from or into another organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in that organism.
[0126] In one embodiment, the invention features a method of modulating the expression of a interleukin and/or interleukin receptor gene in an organism comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein the siNA comprises a single-stranded sequence having complementarity to RNA of the interleukin and/or interleukin receptor gene; and (b) introducing the siNA molecule into the organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0127] In another embodiment, the invention features a method of modulating the expression of more than one interleukin and/or interleukin receptor gene in an organism comprising: (a) synthesizing siNA molecules of the invention, which can be chemically-modified, wherein the siNA comprises a single-stranded sequence having complementarity to RNA of the interleukin and/or interleukin receptor gene; and (b) introducing the siNA molecules into the organism under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in the organism.
[0128] In one embodiment, the invention features a method of modulating the expression of a interleukin and/or interleukin receptor gene in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0129] In one embodiment, the invention features a method for treating or preventing a disease, condition, trait, genotype or phenotype in a subject, comprising administering to the subject a composition of the invention under conditions suitable for the treatment or prevention of the disease, condition, trait, genotype or phenotype in the subject, alone or in conjunction with one or more other therapeutic compounds. In yet another embodiment, the invention features a method for reducing or preventing tissue rejection in a subject comprising administering to the subject a composition of the invention under conditions suitable for the reduction or prevention of tissue rejection in the subject.
[0130] In one embodiment, the invention features a method for treating an inflammatory disease or condition in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0131] In one embodiment, the invention features a method for treating or preventing an allergic reaction, disease, or condition in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0132] In one embodiment, the invention features a method for treating or preventing an autoimmune disease or condition in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0133] In one embodiment, the invention features a method for treating or preventing cancer in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0134] In one embodiment, the invention features a method for treating or preventing a respiratory disease or condition in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0135] In one embodiment, the invention features a method for treating or preventing a pulmonary disease or condition in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0136] In one embodiment, the invention features a method for treating or preventing a neurodegenerative or neurological disease or condition in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0137] In one embodiment, the invention features a method for treating or preventing a proliferative disease or condition in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0138] In one embodiment, the invention features a method for treating or preventing a cardiovascular disease or condition in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0139] In one embodiment, the invention features a method for treating or preventing a renal disease or condition in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0140] In one embodiment, the invention features a method for treating or preventing a ocular disease or condition in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0141] In one embodiment, the invention features a method for treating or preventing viral disease or infection in an organism comprising contacting the organism with an siNA molecule of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor gene in the organism.
[0142] The nucleic acid molecules of the instant invention, individually, or in combination or in conjunction with other drugs, can be used to treat diseases or conditions discussed herein (e.g., cancers and other proliferative conditions, viral infection, inflammatory disease, autoimmunity, respiratory disease, pulmonary disease, cardiovascular disease, neurological disease, renal disease, ocular disease, etc.). For example, to treat a particular disease, condition, trait, genotype or phenotype, the siNA molecules can be administered to a subject or can be administered to other appropriate cells evident to those skilled in the art, individually or in combination with one or more drugs under conditions suitable for the treatment.
[0143] In another embodiment, the invention features a method of modulating the expression of more than one interleukin (e.g., any IL-1 through IL-27) and/or interleukin receptor (e.g., any IL-1R through IL-27R) genes in an organism comprising contacting the organism with one or more siNA molecules of the invention under conditions suitable to modulate the expression of the interleukin and/or interleukin receptor genes in the organism.
[0144] The siNA molecules of the invention can be designed to down regulate or inhibit target (e.g., interleukin and/or interleukin receptor) gene expression through RNAi targeting of a variety of RNA molecules. In one embodiment, the siNA molecules of the invention are used to target various RNAs corresponding to a target gene. Non-limiting examples of such RNAs include messenger RNA (mRNA), alternate RNA splice variants of target gene(s), post-transcriptionally modified RNA of target gene(s), pre-mRNA of target gene(s), and/or RNA templates. If alternate splicing produces a family of transcripts that are distinguished by usage of appropriate exons, the instant invention can be used to inhibit gene expression through the appropriate exons to specifically inhibit or to distinguish among the functions of gene family members. For example, a protein that contains an alternatively spliced transmembrane domain can be expressed in both membrane bound and secreted forms. Use of the invention to target the exon containing the transmembrane domain can be used to determine the functional consequences of pharmaceutical targeting of membrane bound as opposed to the secreted form of the protein. Non-limiting examples of applications of the invention relating to targeting these RNA molecules include therapeutic pharmaceutical applications, pharmaceutical discovery applications, molecular diagnostic and gene function applications, and gene mapping, for example using single nucleotide polymorphism mapping with siNA molecules of the invention. Such applications can be implemented using known gene sequences or from partial sequences available from an expressed sequence tag (EST).
[0145] In another embodiment, the siNA molecules of the invention are used to target conserved sequences corresponding to a gene family or gene families such as interleukin and/or interleukin receptor family genes. As such, siNA molecules targeting multiple interleukin and/or interleukin receptor targets can provide increased therapeutic effect. In addition, siNA can be used to characterize pathways of gene function in a variety of applications. For example, the present invention can be used to inhibit the activity of target gene(s) in a pathway to determine the function of uncharacterized gene(s) in gene function analysis, mRNA function analysis, or translational analysis. The invention can be used to determine potential target gene pathways involved in various diseases and conditions toward pharmaceutical development. The invention can be used to understand pathways of gene expression involved in, for example, respiratory disease.
[0146] In one embodiment, siNA molecule(s) and/or methods of the invention are used to down regulate the expression of gene(s) that encode RNA referred to by Genbank Accession Nos., for example interleukin and/or interleukin receptor genes encoding RNA sequence(s) referred to herein by Genbank Accession number, for example, Genbank Accession Nos. shown in Table I.
[0147] In one embodiment, the invention features a method comprising: (a) generating a library of siNA constructs having a predetermined complexity; and (b) assaying the siNA constructs of (a) above, under conditions suitable to determine RNAi target sites within the target RNA sequence. In one embodiment, the siNA molecules of (a) have strands of a fixed length, for example, about 23 nucleotides in length. In another embodiment, the siNA molecules of (a) are of differing length, for example having strands of about 19 to about 25 (e.g., about 19, 20, 21, 22, 23, 24, or 25) nucleotides in length. In one embodiment, the assay can comprise a reconstituted in vitro siNA assay as described herein. In another embodiment, the assay can comprise a cell culture system in which target RNA is expressed. In another embodiment, fragments of target RNA are analyzed for detectable levels of cleavage, for example by gel electrophoresis, Northern blot analysis, or RNAse protection assays, to determine the most suitable target site(s) within the target RNA sequence. The target RNA sequence can be obtained as is known in the art, for example, by cloning and/or transcription for in vitro systems, and by cellular expression in in vivo systems.
[0148] In one embodiment, the invention features a method comprising: (a) generating a randomized library of siNA constructs having a predetermined complexity, such as of 4 N , where N represents the number of base paired nucleotides in each of the siNA construct strands (e.g., for an siNA construct having 21 nucleotide sense and antisense strands with 19 base pairs, the complexity would be 4 19 ); and (b) assaying the siNA constructs of (a) above, under conditions suitable to determine RNAi target sites within the target interleukin and/or interleukin receptor RNA sequence. In another embodiment, the siNA molecules of (a) have strands of a fixed length, for example about 23 nucleotides in length. In yet another embodiment, the siNA molecules of (a) are of differing length, for example having strands of about 19 to about 25 (e.g., about 19, 20, 21, 22, 23, 24, or 25) nucleotides in length. In one embodiment, the assay can comprise a reconstituted in vitro siNA assay as described in Example 6 herein. In another embodiment, the assay can comprise a cell culture system in which target RNA is expressed. In another embodiment, fragments of interleukin and/or interleukin receptor RNA are analyzed for detectable levels of cleavage, for example by gel electrophoresis, Northern blot analysis, or RNAse protection assays, to determine the most suitable target site(s) within the target interleukin and/or interleukin receptor RNA sequence. The target interleukin and/or interleukin receptor RNA sequence can be obtained as is known in the art, for example, by cloning and/or transcription for in vitro systems, and by cellular expression in in vivo systems.
[0149] In another embodiment, the invention features a method comprising: (a) analyzing the sequence of a RNA target encoded by a target gene; (b) synthesizing one or more sets of siNA molecules having sequence complementary to one or more regions of the RNA of (a); and (c) assaying the siNA molecules of (b) under conditions suitable to determine RNAi targets within the target RNA sequence. In one embodiment, the siNA molecules of (b) have strands of a fixed length, for example about 23 nucleotides in length. In another embodiment, the siNA molecules of (b) are of differing length, for example having strands of about 19 to about 25 (e.g., about 19, 20, 21, 22, 23, 24, or 25) nucleotides in length. In one embodiment, the assay can comprise a reconstituted in vitro siNA assay as described herein. In another embodiment, the assay can comprise a cell culture system in which target RNA is expressed. Fragments of target RNA are analyzed for detectable levels of cleavage, for example by gel electrophoresis, Northern blot analysis, or RNAse protection assays, to determine the most suitable target site(s) within the target RNA sequence. The target RNA sequence can be obtained as is known in the art, for example, by cloning and/or transcription for in vitro systems, and by expression in in vivo systems.
[0150] By “target site” is meant a sequence within a target RNA that is “targeted” for cleavage mediated by an siNA construct which contains sequences within its antisense region that are complementary to the target sequence.
[0151] By “detectable level of cleavage” is meant cleavage of target RNA (and formation of cleaved product RNAs) to an extent sufficient to discern cleavage products above the background of RNAs produced by random degradation of the target RNA. Production of cleavage products from 1-5% of the target RNA is sufficient to detect above the background for most methods of detection.
[0152] In one embodiment, the invention features a composition comprising an siNA molecule of the invention, which can be chemically-modified, in a pharmaceutically acceptable carrier or diluent. In another embodiment, the invention features a pharmaceutical composition comprising siNA molecules of the invention, which can be chemically-modified, targeting one or more genes in a pharmaceutically acceptable carrier or diluent. In another embodiment, the invention features a method for diagnosing a disease or condition in a subject comprising administering to the subject a composition of the invention under conditions suitable for the diagnosis of the disease or condition in the subject. In another embodiment, the invention features a method for treating or preventing a disease or condition in a subject, comprising administering to the subject a composition of the invention under conditions suitable for the treatment or prevention of the disease or condition in the subject, alone or in conjunction with one or more other therapeutic compounds. In yet another embodiment, the invention features a method for reducing or preventing, for example, respiratory disease (e.g., asthma) in a subject, comprising administering to the subject a composition of the invention under conditions suitable for the reduction or prevention of the respiratory disease in the subject.
[0153] In another embodiment, the invention features a method for validating a interleukin and/or interleukin receptor gene target, comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein one of the siNA strands includes a sequence complementary to RNA of a interleukin and/or interleukin receptor target gene; (b) introducing the siNA molecule into a cell, tissue, or organism under conditions suitable for modulating expression of the interleukin and/or interleukin receptor target gene in the cell, tissue, or organism; and (c) determining the function of the gene by assaying for any phenotypic change in the cell, tissue, or organism.
[0154] In another embodiment, the invention features a method for validating a interleukin and/or interleukin receptor target comprising: (a) synthesizing an siNA molecule of the invention, which can be chemically-modified, wherein one of the siNA strands includes a sequence complementary to RNA of a interleukin and/or interleukin receptor target gene; (b) introducing the siNA molecule into a biological system under conditions suitable for modulating expression of the interleukin and/or interleukin receptor target gene in the biological system; and (c) determining the function of the gene by assaying for any phenotypic change in the biological system.
[0155] By “biological system” is meant, material, in a purified or unpurified form, from biological sources, including but not limited to human or animal, wherein the system comprises the components required for RNAi activity. The term “biological system” includes, for example, a cell, tissue, or organism, or extract thereof. The term biological system also includes reconstituted RNAi systems that can be used in an in vitro setting.
[0156] By “phenotypic change” is meant any detectable change to a cell that occurs in response to contact or treatment with a nucleic acid molecule of the invention (e.g., siNA). Such detectable changes include, but are not limited to, changes in shape, size, proliferation, motility, protein expression or RNA expression or other physical or chemical changes as can be assayed by methods known in the art. The detectable change can also include expression of reporter genes/molecules such as Green Florescent Protein (GFP) or various tags that are used to identify an expressed protein or any other cellular component that can be assayed.
[0157] In one embodiment, the invention features a kit containing an siNA molecule of the invention, which can be chemically-modified, that can be used to modulate the expression of a interleukin and/or interleukin receptor target gene in a biological system, including, for example, in a cell, tissue, or organism. In another embodiment, the invention features a kit containing more than one siNA molecule of the invention, which can be chemically-modified, that can be used to modulate the expression of more than one interleukin and/or interleukin receptor target gene in a biological system, including, for example, in a cell, tissue, or organism.
[0158] In one embodiment, the invention features a cell containing one or more siNA molecules of the invention, which can be chemically-modified. In another embodiment, the cell containing an siNA molecule of the invention is a mammalian cell. In yet another embodiment, the cell containing an siNA molecule of the invention is a human cell.
[0159] In one embodiment, the synthesis of an siNA molecule of the invention, which can be chemically-modified, comprises: (a) synthesis of two complementary strands of the siNA molecule; (b) annealing the two complementary strands together under conditions suitable to obtain a double-stranded siNA molecule. In another embodiment, synthesis of the two complementary strands of the siNA molecule is by solid phase oligonucleotide synthesis. In yet another embodiment, synthesis of the two complementary strands of the siNA molecule is by solid phase tandem oligonucleotide synthesis.
[0160] In one embodiment, the invention features a method for synthesizing an siNA duplex molecule comprising: (a) synthesizing a first oligonucleotide sequence strand of the siNA molecule, wherein the first oligonucleotide sequence strand comprises a cleavable linker molecule that can be used as a scaffold for the synthesis of the second oligonucleotide sequence strand of the siNA; (b) synthesizing the second oligonucleotide sequence strand of siNA on the scaffold of the first oligonucleotide sequence strand, wherein the second oligonucleotide sequence strand further comprises a chemical moiety than can be used to purify the siNA duplex; (c) cleaving the linker molecule of (a) under conditions suitable for the two siNA oligonucleotide strands to hybridize and form a stable duplex; and (d) purifying the siNA duplex utilizing the chemical moiety of the second oligonucleotide sequence strand.
[0161] In one embodiment, cleavage of the linker molecule in (c) above takes place during deprotection of the oligonucleotide, for example under hydrolysis conditions using an alkylamine base such as methylamine. In one embodiment, the method of synthesis comprises solid phase synthesis on a solid support such as controlled pore glass (CPG) or polystyrene, wherein the first sequence of (a) is synthesized on a cleavable linker, such as a succinyl linker, using the solid support as a scaffold. The cleavable linker in (a) used as a scaffold for synthesizing the second strand can comprise similar reactivity as the solid support derivatized linker, such that cleavage of the solid support derivatized linker and the cleavable linker of (a) takes place concomitantly. In another embodiment, the chemical moiety of (b) that can be used to isolate the attached oligonucleotide sequence comprises a trityl group, for example a dimethoxytrityl group, which can be employed in a trityl-on synthesis strategy as described herein. In yet another embodiment, the chemical moiety, such as a dimethoxytrityl group, is removed during purification, for example, using acidic conditions.
[0162] In a further embodiment, the method for siNA synthesis is a solution phase synthesis or hybrid phase synthesis wherein both strands of the siNA duplex are synthesized in tandem using a cleavable linker attached to the first sequence which acts a scaffold for synthesis of the second sequence. Cleavage of the linker under conditions suitable for hybridization of the separate siNA sequence strands results in formation of the double-stranded siNA molecule.
[0163] In another embodiment, the invention features a method for synthesizing an siNA duplex molecule comprising: (a) synthesizing one oligonucleotide sequence strand of the siNA molecule, wherein the sequence comprises a cleavable linker molecule that can be used as a scaffold for the synthesis of another oligonucleotide sequence; (b) synthesizing a second oligonucleotide sequence having complementarity to the first sequence strand on the scaffold of (a), wherein the second sequence comprises the other strand of the double-stranded siNA molecule and wherein the second sequence further comprises a chemical moiety than can be used to isolate the attached oligonucleotide sequence; (c) purifying the product of (b) utilizing the chemical moiety of the second oligonucleotide sequence strand under conditions suitable for isolating the full-length sequence comprising both siNA oligonucleotide strands connected by the cleavable linker and under conditions suitable for the two siNA oligonucleotide strands to hybridize and form a stable duplex. In one embodiment, cleavage of the linker molecule in (c) above takes place during deprotection of the oligonucleotide, for example under hydrolysis conditions. In another embodiment, cleavage of the linker molecule in (c) above takes place after deprotection of the oligonucleotide. In another embodiment, the method of synthesis comprises solid phase synthesis on a solid support such as controlled pore glass (CPG) or polystyrene, wherein the first sequence of (a) is synthesized on a cleavable linker, such as a succinyl linker, using the solid support as a scaffold. The cleavable linker in (a) used as a scaffold for synthesizing the second strand can comprise similar reactivity or differing reactivity as the solid support derivatized linker, such that cleavage of the solid support derivatized linker and the cleavable linker of (a) takes place either concomitantly or sequentially. In one embodiment, the chemical moiety of (b) that can be used to isolate the attached oligonucleotide sequence comprises a trityl group, for example a dimethoxytrityl group.
[0164] In another embodiment, the invention features a method for making a double-stranded siNA molecule in a single synthetic process comprising: (a) synthesizing an oligonucleotide having a first and a second sequence, wherein the first sequence is complementary to the second sequence, and the first oligonucleotide sequence is linked to the second sequence via a cleavable linker, and wherein a terminal 5′-protecting group, for example, a 5′-O-dimethoxytrityl group (5′-O-DMT) remains on the oligonucleotide having the second sequence; (b) deprotecting the oligonucleotide whereby the deprotection results in the cleavage of the linker joining the two oligonucleotide sequences; and (c) purifying the product of (b) under conditions suitable for isolating the double-stranded siNA molecule, for example using a trityl-on synthesis strategy as described herein.
[0165] In another embodiment, the method of synthesis of siNA molecules of the invention comprises the teachings of Scaringe et al., U.S. Pat. Nos. 5,889,136; 6,008,400; and 6,111,086, incorporated by reference herein in their entirety.
[0166] In one embodiment, the invention features siNA constructs that mediate RNAi against interleukin and/or interleukin receptor, wherein the siNA construct comprises one or more chemical modifications, for example, one or more chemical modifications having any of Formulae I-VII or any combination thereof that increases the nuclease resistance of the siNA construct.
[0167] In another embodiment, the invention features a method for generating siNA molecules with increased nuclease resistance comprising (a) introducing nucleotides having any of Formula I-VII or any combination thereof into an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having increased nuclease resistance.
[0168] In one embodiment, the invention features siNA constructs that mediate RNAi against interleukin and/or interleukin receptor, wherein the siNA construct comprises one or more chemical modifications described herein that modulates the binding affinity between the sense and antisense strands of the siNA construct.
[0169] In another embodiment, the invention features a method for generating siNA molecules with increased binding affinity between the sense and antisense strands of the siNA molecule comprising (a) introducing nucleotides having any of Formula I-VII or any combination thereof into an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having increased binding affinity between the sense and antisense strands of the siNA molecule.
[0170] In one embodiment, the invention features siNA constructs that mediate RNAi against interleukin and/or interleukin receptor, wherein the siNA construct comprises one or more chemical modifications described herein that modulates the binding affinity between the antisense strand of the siNA construct and a complementary target RNA sequence within a cell.
[0171] In one embodiment, the invention features siNA constructs that mediate RNAi against interleukin and/or interleukin receptor, wherein the siNA construct comprises one or more chemical modifications described herein that modulates the binding affinity between the antisense strand of the siNA construct and a complementary target DNA sequence within a cell.
[0172] In another embodiment, the invention features a method for generating siNA molecules with increased binding affinity between the antisense strand of the siNA molecule and a complementary target RNA sequence comprising (a) introducing nucleotides having any of Formula I-VII or any combination thereof into an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having increased binding affinity between the antisense strand of the siNA molecule and a complementary target RNA sequence.
[0173] In another embodiment, the invention features a method for generating siNA molecules with increased binding affinity between the antisense strand of the siNA molecule and a complementary target DNA sequence comprising (a) introducing nucleotides having any of Formula I-VII or any combination thereof into an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having increased binding affinity between the antisense strand of the siNA molecule and a complementary target DNA sequence.
[0174] In one embodiment, the invention features siNA constructs that mediate RNAi against interleukin and/or interleukin receptor, wherein the siNA construct comprises one or more chemical modifications described herein that modulate the polymerase activity of a cellular polymerase capable of generating additional endogenous siNA molecules having sequence homology to the chemically-modified siNA construct.
[0175] In another embodiment, the invention features a method for generating siNA molecules capable of mediating increased polymerase activity of a cellular polymerase capable of generating additional endogenous siNA molecules having sequence homology to a chemically-modified siNA molecule comprising (a) introducing nucleotides having any of Formula I-VII or any combination thereof into an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules capable of mediating increased polymerase activity of a cellular polymerase capable of generating additional endogenous siNA molecules having sequence homology to the chemically-modified siNA molecule.
[0176] In one embodiment, the invention features chemically-modified siNA constructs that mediate RNAi against interleukin and/or interleukin receptor in a cell, wherein the chemical modifications do not significantly effect the interaction of siNA with a target RNA molecule, DNA molecule and/or proteins or other factors that are essential for RNAi in a manner that would decrease the efficacy of RNAi mediated by such siNA constructs.
[0177] In another embodiment, the invention features a method for generating siNA molecules with improved RNAi activity against interleukin and/or interleukin receptor comprising (a) introducing nucleotides having any of Formula I-VII or any combination thereof into an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having improved RNAi activity.
[0178] In yet another embodiment, the invention features a method for generating siNA molecules with improved RNAi activity against interleukin and/or interleukin receptor target RNA comprising (a) introducing nucleotides having any of Formula I-VII or any combination thereof into an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having improved RNAi activity against the target RNA.
[0179] In yet another embodiment, the invention features a method for generating siNA molecules with improved RNAi activity against interleukin and/or interleukin receptor target DNA comprising (a) introducing nucleotides having any of Formula I-VII or any combination thereof into an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having improved RNAi activity against the target DNA.
[0180] In one embodiment, the invention features siNA constructs that mediate RNAi against interleukin and/or interleukin receptor, wherein the siNA construct comprises one or more chemical modifications described herein that modulates the cellular uptake of the siNA construct.
[0181] In another embodiment, the invention features a method for generating siNA molecules against interleukin and/or interleukin receptor with improved cellular uptake comprising (a) introducing nucleotides having any of Formula I-VII or any combination thereof into an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having improved cellular uptake.
[0182] In one embodiment, the invention features siNA constructs that mediate RNAi against interleukin and/or interleukin receptor, wherein the siNA construct comprises one or more chemical modifications described herein that increases the bioavailability of the siNA construct, for example, by attaching polymeric conjugates such as polyethyleneglycol or equivalent conjugates that improve the pharmacokinetics of the siNA construct, or by attaching conjugates that target specific tissue types or cell types in vivo. Non-limiting examples of such conjugates are described in Vargeese et al., U.S. Ser. No. 10/201,394 incorporated by reference herein.
[0183] In one embodiment, the invention features a method for generating siNA molecules of the invention with improved bioavailability, comprising (a) introducing a conjugate into the structure of an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having improved bioavailability. Such conjugates can include ligands for cellular receptors, such as peptides derived from naturally occurring protein ligands; protein localization sequences, including cellular ZIP code sequences; antibodies; nucleic acid aptamers; vitamins and other co-factors, such as folate and N-acetylgalactosamine; polymers, such as polyethyleneglycol (PEG); phospholipids; cholesterol; polyamines, such as spermine or spermidine; and others.
[0184] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that comprises a first nucleotide sequence complementary to a target RNA sequence or a portion thereof, and a second sequence having complementarity to said first sequence, wherein said second sequence is chemically modified in a manner that it can no longer act as a guide sequence for efficiently mediating RNA interference and/or be recognized by cellular proteins that facilitate RNAi.
[0185] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that comprises a first nucleotide sequence complementary to a target RNA sequence or a portion thereof, and a second sequence having complementarity to said first sequence, wherein the second sequence is designed or modified in a manner that prevents its entry into the RNAi pathway as a guide sequence or as a sequence that is complementary to a target nucleic acid (e.g., RNA) sequence. Such design or modifications are expected to enhance the activity of siNA and/or improve the specificity of siNA molecules of the invention. These modifications are also expected to minimize any off-target effects and/or associated toxicity.
[0186] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that comprises a first nucleotide sequence complementary to a target RNA sequence or a portion thereof, and a second sequence having complementarity to said first sequence, wherein said second sequence is incapable of acting as a guide sequence for mediating RNA interference.
[0187] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that comprises a first nucleotide sequence complementary to a target RNA sequence or a portion thereof, and a second sequence having complementarity to said first sequence, wherein said second sequence does not have a terminal 5′-hydroxyl (5′-OH) or 5′-phosphate group.
[0188] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that comprises a first nucleotide sequence complementary to a target RNA sequence or a portion thereof, and a second sequence having complementarity to said first sequence, wherein said second sequence comprises a terminal cap moiety at the 5′-end of said second sequence. In one embodiment, the terminal cap moiety comprises an inverted abasic, inverted deoxy abasic, inverted nucleotide moiety, a group shown in FIG. 10 , an alkyl or cycloalkyl group, a heterocycle, or any other group that prevents RNAi activity in which the second sequence serves as a guide sequence or template for RNAi.
[0189] In one embodiment, the invention features a double-stranded short interfering nucleic acid (siNA) molecule that comprises a first nucleotide sequence complementary to a target RNA sequence or a portion thereof, and a second sequence having complementarity to said first sequence, wherein said second sequence comprises a terminal cap moiety at the 5′-end and 3′-end of said second sequence. In one embodiment, each terminal cap moiety individually comprises an inverted abasic, inverted deoxy abasic, inverted nucleotide moiety, a group shown in FIG. 10 , an alkyl or cycloalkyl group, a heterocycle, or any other group that prevents RNAi activity in which the second sequence serves as a guide sequence or template for RNAi.
[0190] In one embodiment, the invention features a method for generating siNA molecules of the invention with improved specificity for down regulating or inhibiting the expression of a target nucleic acid (e.g., a DNA or RNA such as a gene or its corresponding RNA), comprising (a) introducing one or more chemical modifications into the structure of an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having improved specificity. In another embodiment, the chemical modification used to improve specificity comprises terminal cap modifications at the 5′-end, 3′-end, or both 5′ and 3′-ends of the siNA molecule. The terminal cap modifications can comprise, for example, structures shown in FIG. 10 (e.g. inverted deoxyabasic moieties) or any other chemical modification that renders a portion of the siNA molecule (e.g. the sense strand) incapable of mediating RNA interference against an off target nucleic acid sequence. In a non-limiting example, an siNA molecule is designed such that only the antisense sequence of the siNA molecule can serve as a guide sequence for RISC mediated degradation of a corresponding target RNA sequence. This can be accomplished by rendering the sense sequence of the siNA inactive by introducing chemical modifications to the sense strand that preclude recognition of the sense strand as a guide sequence by RNAi machinery. In one embodiment, such chemical modifications comprise any chemical group at the 5′-end of the sense strand of the siNA, or any other group that serves to render the sense strand inactive as a guide sequence for mediating RNA interference. These modifications, for example, can result in a molecule where the 5′-end of the sense strand no longer has a free 5′-hydroxyl (5′-OH) or a free 5′-phosphate group (e.g., phosphate, diphosphate, triphosphate, cyclic phosphate etc.). Non-limiting examples of such siNA constructs are described herein, such as “Stab 9/10”, “Stab 7/8”, “Stab 7/19”, “Stab 17/22”, “Stab 23/24”, and “Stab 24/25” chemistries and variants thereof (see Table IV) wherein the 5′-end and 3′-end of the sense strand of the siNA do not comprise a hydroxyl group or phosphate group.
[0191] In one embodiment, the invention features a method for generating siNA molecules of the invention with improved specificity for down regulating or inhibiting the expression of a target nucleic acid (e.g., a DNA or RNA such as a gene or its corresponding RNA), comprising introducing one or more chemical modifications into the structure of an siNA molecule that prevent a strand or portion of the siNA molecule from acting as a template or guide sequence for RNAi activity. In one embodiment, the inactive strand or sense region of the siNA molecule is the sense strand or sense region of the siNA molecule, i.e. the strand or region of the siNA that does not have complementarity to the target nucleic acid sequence. In one embodiment, such chemical modifications comprise any chemical group at the 5′-end of the sense strand or region of the siNA that does not comprise a 5′-hydroxyl (5′-OH) or 5′-phosphate group, or any other group that serves to render the sense strand or sense region inactive as a guide sequence for mediating RNA interference. Non-limiting examples of such siNA constructs are described herein, such as “Stab 9/10”, “Stab 7/8”, “Stab 7/19”, “Stab 17/22”, “Stab 23/24”, and “Stab 24/25” chemistries and variants thereof (see Table IV) wherein the 5′-end and 3′-end of the sense strand of the siNA do not comprise a hydroxyl group or phosphate group.
[0192] In one embodiment, the invention features a method for screening siNA molecules that are active in mediating RNA interference against a target nucleic acid sequence comprising (a) generating a plurality of unmodified siNA molecules, (b) screening the siNA molecules of step (a) under conditions suitable for isolating siNA molecules that are active in mediating RNA interference against the target nucleic acid sequence, and (c) introducing chemical modifications (e.g. chemical modifications as described herein or as otherwise known in the art) into the active siNA molecules of (b). In one embodiment, the method further comprises re-screening the chemically modified siNA molecules of step (c) under conditions suitable for isolating chemically modified siNA molecules that are active in mediating RNA interference against the target nucleic acid sequence.
[0193] In one embodiment, the invention features a method for screening chemically modified siNA molecules that are active in mediating RNA interference against a target nucleic acid sequence comprising (a) generating a plurality of chemically modified siNA molecules (e.g. siNA molecules as described herein or as otherwise known in the art), and (b) screening the siNA molecules of step (a) under conditions suitable for isolating chemically modified siNA molecules that are active in mediating RNA interference against the target nucleic acid sequence.
[0194] The term “ligand” refers to any compound or molecule, such as a drug, peptide, hormone, or neurotransmitter, that is capable of interacting with another compound, such as a receptor, either directly or indirectly. The receptor that interacts with a ligand can be present on the surface of a cell or can alternately be an intercellular receptor. Interaction of the ligand with the receptor can result in a biochemical reaction, or can simply be a physical interaction or association.
[0195] In another embodiment, the invention features a method for generating siNA molecules of the invention with improved bioavailability comprising (a) introducing an excipient formulation to an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having improved bioavailability. Such excipients include polymers such as cyclodextrins, lipids, cationic lipids, polyamines, phospholipids, nanoparticles, receptors, ligands, and others.
[0196] In another embodiment, the invention features a method for generating siNA molecules of the invention with improved bioavailability comprising (a) introducing nucleotides having any of Formulae I-VII or any combination thereof into an siNA molecule, and (b) assaying the siNA molecule of step (a) under conditions suitable for isolating siNA molecules having improved bioavailability.
[0197] In another embodiment, polyethylene glycol (PEG) can be covalently attached to siNA compounds of the present invention. The attached PEG can be any molecular weight, preferably from about 2,000 to about 50,000 daltons (Da).
[0198] The present invention can be used alone or as a component of a kit having at least one of the reagents necessary to carry out the in vitro or in vivo introduction of RNA to test samples and/or subjects. For example, preferred components of the kit include an siNA molecule of the invention and a vehicle that promotes introduction of the siNA into cells of interest as described herein (e.g., using lipids and other methods of transfection known in the art, see for example Beigelman et al, U.S. Pat. No. 6,395,713). The kit can be used for target validation, such as in determining gene function and/or activity, or in drug optimization, and in drug discovery (see for example Usman et al., U.S. Ser. No. 60/402,996). Such a kit can also include instructions to allow a user of the kit to practice the invention.
[0199] The term “short interfering nucleic acid”, “siNA”, “short interfering RNA”, “siRNA”, “short interfering nucleic acid molecule”, “short interfering oligonucleotide molecule”, or “chemically-modified short interfering nucleic acid molecule” as used herein refers to any nucleic acid molecule capable of inhibiting or down regulating gene expression or viral replication, for example by mediating RNA interference “RNAi” or gene silencing in a sequence-specific manner; see for example Zamore et al., 2000, Cell, 101, 25-33; Bass, 2001 , Nature, 411, 428-429; Elbashir et al., 2001 , Nature, 411, 494-498; and Kreutzer et al., International PCT Publication No. WO 00/44895; Zernicka-Goetz et al., International PCT Publication No. WO 01/36646; Fire, International PCT Publication No. WO 99/32619; Plaetinck et al., International PCT Publication No. WO 00/01846; Mello and Fire, International PCT Publication No. WO 01/29058; Deschamps-Depaillette, International PCT Publication No. WO 99/07409; and Li et al., International PCT Publication No. WO 00/44914; Allshire, 2002 , Science, 297, 1818-1819; Volpe et al., 2002 , Science, 297, 1833-1837; Jenuwein, 2002 , Science, 297, 2215-2218; and Hall et al., 2002 , Science, 297, 2232-2237; Hutvagner and Zamore, 2002 , Science, 297, 2056-60; McManus et al., 2002 , RNA, 8, 842-850; Reinhart et al., 2002 , Gene & Dev., 16, 1616-1626; and Reinhart & Bartel, 2002 , Science, 297, 1831). Non limiting examples of siNA molecules of the invention are shown in FIGS. 4-6 , and Tables II and III herein. For example the siNA can be a double-stranded polynucleotide molecule comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The siNA can be assembled from two separate oligonucleotides, where one strand is the sense strand and the other is the antisense strand, wherein the antisense and sense strands are self-complementary (i.e. each strand comprises nucleotide sequence that is complementary to nucleotide sequence in the other strand; such as where the antisense strand and sense strand form a duplex or double-stranded structure, for example wherein the double-stranded region is about 19 base pairs); the antisense strand comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense strand comprises nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. Alternatively, the siNA is assembled from a single oligonucleotide, where the self-complementary sense and antisense regions of the siNA are linked by means of a nucleic acid based or non-nucleic acid-based linker(s). The siNA can be a polynucleotide with a duplex, asymmetric duplex, hairpin or asymmetric hairpin secondary structure, having self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a separate target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof. The siNA can be a circular single-stranded polynucleotide having two or more loop structures and a stem comprising self-complementary sense and antisense regions, wherein the antisense region comprises nucleotide sequence that is complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof and the sense region having nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof, and wherein the circular polynucleotide can be processed either in vivo or in vitro to generate an active siNA molecule capable of mediating RNAi. The siNA can also comprise a single-stranded polynucleotide having nucleotide sequence complementary to nucleotide sequence in a target nucleic acid molecule or a portion thereof (for example, where such siNA molecule does not require the presence within the siNA molecule of nucleotide sequence corresponding to the target nucleic acid sequence or a portion thereof), wherein the single-stranded polynucleotide can further comprise a terminal phosphate group, such as a 5′-phosphate (see for example Martinez et al., 2002 , Cell., 110, 563-574 and Schwarz et al., 2002 , Molecular Cell, 10, 537-568), or 5′,3′-diphosphate. In certain embodiments, the siNA molecule of the invention comprises separate sense and antisense sequences or regions, wherein the sense and antisense regions are covalently linked by nucleotide or non-nucleotide linkers molecules as is known in the art, or are alternately non-covalently linked by ionic interactions, hydrogen bonding, van der waals interactions, hydrophobic interactions, and/or stacking interactions. In certain embodiments, the siNA molecules of the invention comprise nucleotide sequence that is complementary to nucleotide sequence of a target gene. In another embodiment, the siNA molecule of the invention interacts with nucleotide sequence of a target gene in a manner that causes inhibition of expression of the target gene. As used herein, siNA molecules need not be limited to those molecules containing only RNA, but further encompasses chemically-modified nucleotides and non-nucleotides. In certain embodiments, the short interfering nucleic acid molecules of the invention lack 2′-hydroxy (2′-OH) containing nucleotides. Applicant describes in certain embodiments short interfering nucleic acids that do not require the presence of nucleotides having a 2′-hydroxy group for mediating RNAi and as such, short interfering nucleic acid molecules of the invention optionally do not include any ribonucleotides (e.g., nucleotides having a 2′-OH group). Such siNA molecules that do not require the presence of ribonucleotides within the siNA molecule to support RNAi can however have an attached linker or linkers or other attached or associated groups, moieties, or chains containing one or more nucleotides with 2′-OH groups. Optionally, siNA molecules can comprise ribonucleotides at about 5, 10, 20, 30, 40, or 50% of the nucleotide positions. The modified short interfering nucleic acid molecules of the invention can also be referred to as short interfering modified oligonucleotides “siMON.” As used herein, the term siNA is meant to be equivalent to other terms used to describe nucleic acid molecules that are capable of mediating sequence specific RNAi, for example short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), short hairpin RNA (shRNA), short interfering oligonucleotide, short interfering nucleic acid, short interfering modified oligonucleotide, chemically-modified siRNA, post-transcriptional gene silencing RNA (ptgsRNA), and others. In addition, as used herein, the term RNAi is meant to be equivalent to other terms used to describe sequence specific RNA interference, such as post transcriptional gene silencing, translational inhibition, or epigenetics. For example, siNA molecules of the invention can be used to epigenetically silence genes at both the post-transcriptional level or the pre-transcriptional level. In a non-limiting example, epigenetic regulation of gene expression by siNA molecules of the invention can result from siNA mediated modification of chromatin structure or methylation pattern to alter gene expression (see, for example, Verdel et al., 2004 , Science, 303, 672-676; Pal-Bhadra et al., 2004 , Science, 303, 669-672; Allshire, 2002 , Science, 297, 1818-1819; Volpe et al., 2002 , Science, 297, 1833-1837; Jenuwein, 2002 , Science, 297, 2215-2218; and Hall et al., 2002 , Science, 297, 2232-2237).
[0200] In one embodiment, an siNA molecule of the invention is a duplex forming oligonucleotide “DFO”, (see for example FIGS. 14-15 and Vaish et al., U.S. Ser. No. 10/727,780 filed Dec. 3, 2003 and McSwiggen et al., PCT/US04/16390, filed May 24, 2004).
[0201] In one embodiment, an siNA molecule of the invention is a multifunctional siNA, (see for example FIGS. 16-22 and Jadhav et al., U.S. Ser. No. 60/543,480 filed Feb. 10, 2004 and McSwiggen et al., PCT/US04/16390, filed May 24, 2004). The multifunctional siNA of the invention can comprise sequence targeting, for example, two regions of interleukin and/or interleukin receptor RNA (see for example target sequences in Tables II and III).
[0202] By “asymmetric hairpin” as used herein is meant a linear siNA molecule comprising an antisense region, a loop portion that can comprise nucleotides or non-nucleotides, and a sense region that comprises fewer nucleotides than the antisense region to the extent that the sense region has enough complementary nucleotides to base pair with the antisense region and form a duplex with loop. For example, an asymmetric hairpin siNA molecule of the invention can comprise an antisense region having length sufficient to mediate RNAi in a cell or in vitro system (e.g. about 19 to about 22, or about 19, 20, 21, or 22 nucleotides) and a loop region comprising about 4 to about 8 (e.g., about 4, 5, 6, 7, or 8) nucleotides, and a sense region having about 3 to about 18 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) nucleotides that are complementary to the antisense region. The asymmetric hairpin siNA molecule can also comprise a 5′-terminal phosphate group that can be chemically modified. The loop portion of the asymmetric hairpin siNA molecule can comprise nucleotides, non-nucleotides, linker molecules, or conjugate molecules as described herein.
[0203] By “asymmetric duplex” as used herein is meant an siNA molecule having two separate strands comprising a sense region and an antisense region, wherein the sense region comprises fewer nucleotides than the antisense region to the extent that the sense region has enough complementary nucleotides to base pair with the antisense region and form a duplex. For example, an asymmetric duplex siNA molecule of the invention can comprise an antisense region having length sufficient to mediate RNAi in a cell or in vitro system e.g. about 19 to about 22 (e.g. about 19, 20, 21, or 22) nucleotides and a sense region having about 3 to about 18 (e.g., about 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, or 18) nucleotides that are complementary to the antisense region.
[0204] By “modulate” is meant that the expression of the gene, or level of RNA molecule or equivalent RNA molecules encoding one or more proteins or protein subunits, or activity of one or more proteins or protein subunits is up regulated or down regulated, such that expression, level, or activity is greater than or less than that observed in the absence of the modulator. For example, the term “modulate” can mean “inhibit,” but the use of the word “modulate” is not limited to this definition.
[0205] By “inhibit”, “down-regulate”, or “reduce”, it is meant that the expression of the gene, or level of RNA molecules or equivalent RNA molecules encoding one or more proteins or protein subunits, or activity of one or more proteins or protein subunits, is reduced below that observed in the absence of the nucleic acid molecules (e.g., siNA) of the invention. In one embodiment, inhibition, down-regulation or reduction with an siNA molecule is below that level observed in the presence of an inactive or attenuated molecule. In another embodiment, inhibition, down-regulation, or reduction with siNA molecules is below that level observed in the presence of, for example, an siNA molecule with scrambled sequence or with mismatches. In another embodiment, inhibition, down-regulation, or reduction of gene expression with a nucleic acid molecule of the instant invention is greater in the presence of the nucleic acid molecule than in its absence.
[0206] By “gene”, or “target gene”, is meant, a nucleic acid that encodes an RNA, for example, nucleic acid sequences including, but not limited to, structural genes encoding a polypeptide. A gene or target gene can also encode a functional RNA (fRNA) or non-coding RNA (ncRNA), such as small temporal RNA (stRNA), micro RNA (miRNA), small nuclear RNA (snRNA), short interfering RNA (siRNA), small nucleolar RNA (snRNA), ribosomal RNA (rRNA), transfer RNA (tRNA) and precursor RNAs thereof. Such non-coding RNAs can serve as target nucleic acid molecules for siNA mediated RNA interference in modulating the activity of fRNA or ncRNA involved in functional or regulatory cellular processes. Aberrant fRNA or ncRNA activity leading to disease can therefore be modulated by siNA molecules of the invention. siNA molecules targeting fRNA and ncRNA can also be used to manipulate or alter the genotype or phenotype of an organism or cell, by intervening in cellular processes such as genetic imprinting, transcription, translation, or nucleic acid processing (e.g., transamination, methylation etc.). The target gene can be a gene derived from a cell, an endogenous gene, a transgene, or exogenous genes such as genes of a pathogen, for example a virus, which is present in the cell after infection thereof. The cell containing the target gene can be derived from or contained in any organism, for example a plant, animal, protozoan, virus, bacterium, or fungus. Non-limiting examples of plants include monocots, dicots, or gymnosperms. Non-limiting examples of animals include vertebrates or invertebrates. Non-limiting examples of fungi include molds or yeasts. For a review, see for example Snyder and Gerstein, 2003 , Science, 300, 258-260.
[0207] By “non-canonical base pair” is meant any non-Watson Crick base pair, such as mismatches and/or wobble base pairs, including flipped mismatches, single hydrogen bond mismatches, trans-type mismatches, triple base interactions, and quadruple base interactions. Non-limiting examples of such non-canonical base pairs include, but are not limited to, AC reverse Hoogsteen, AC wobble, AU reverse Hoogsteen, GU wobble, AA N7 amino, CC 2-carbonyl-amino(H1)-N-3-amino(H2), GA sheared, UC 4-carbonyl-amino, UU imino-carbonyl, AC reverse wobble, AU Hoogsteen, AU reverse Watson Crick, CG reverse Watson Crick, GC N3-amino-amino N3, AA N1-amino symmetric, AA N7-amino symmetric, GA N7-N1 amino-carbonyl, GA+carbonyl-amino N7-N1, GG N1-carbonyl symmetric, GG N3-amino symmetric, CC carbonyl-amino symmetric, CC N3-amino symmetric, UU 2-carbonyl-imino symmetric, UU 4-carbonyl-imino symmetric, AA amino-N3, AA N1-amino, AC amino 2-carbonyl, AC N3-amino, AC N7-amino, AU amino-4-carbonyl, AU N1-imino, AU N3-imino, AU N7-imino, CC carbonyl-amino, GA amino-N1, GA amino-N7, GA carbonyl-amino, GA N3-amino, GC amino-N3, GC carbonyl-amino, GC N3-amino, GC N7-amino, GG amino-N7, GG carbonyl-imino, GG N7-amino, GU amino-2-carbonyl, GU carbonyl-imino, GU imino-2-carbonyl, GU N7-imino, psiU imino-2-carbonyl, UC 4-carbonyl-amino, UC imino-carbonyl, UU imino-4-carbonyl, AC C2-H—N3, GA carbonyl-C2-H, UU imino-4-carbonyl 2 carbonyl-C5-H, AC amino(A) N3(C)-carbonyl, GC imino amino-carbonyl, Gpsi imino-2-carbonyl amino-2-carbonyl, and GU imino amino-2-carbonyl base pairs.
[0208] By “interleukin” is meant, any interleukin (e.g., IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-11, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, and IL-27) polypeptide, protein and/or a polynucleotide encoding an interleukin protein, peptide, or portion thereof (such as polynucleotides referred to by Genbank Accession numbers in Table I or any other interleukin transcript derived from an interleukin gene). The term “interleukin” is also meant to include other interleukin encoding sequence, such as mutant interleukin genes, splice variants of interleukin genes, and interleukin gene polymorphisms, such as those associated with a disease, trait, or condition.
[0209] By “interleukin protein” is meant, any interleukin peptide or protein or a component thereof, wherein the peptide or protein is encoded by an interleukin gene or having interleukin activity.
[0210] By “interleukin receptor” is meant, any interleukin receptor (e.g., IL-1R, IL-2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-8R, IL-9R, IL-10R, IL-11R, IL-12R, IL-13R, IL-14R, IL-15R, IL-16R, IL-17R, IL-18R, IL-19R, IL-20R, IL-21R, IL-22R, IL-23R, IL-24R, IL-25R, IL-26R, and IL-27R) polypeptide, protein and/or a polynucleotide encoding an interleukin receptor protein, peptide, or portion thereof (such as polynucleotides referred to by Genbank Accession numbers in Table I or any other interleukin receptor transcript derived from an interleukin receptor gene). The term “interleukin receptor” is also meant to include other interleukin receptor encoding sequence, such as mutant interleukin receptor genes, splice variants of interleukin receptor genes, and interleukin receptor gene polymorphisms, such as those associated with a disease, trait, or condition.
[0211] By “interleukin receptor protein” is meant, any interleukin receptor peptide or protein or a component thereof, wherein the peptide or protein is encoded by an interleukin receptor gene or having interleukin receptor activity.
[0212] By “homologous sequence” is meant, a nucleotide sequence that is shared by one or more polynucleotide sequences, such as genes, gene transcripts and/or non-coding polynucleotides. For example, a homologous sequence can be a nucleotide sequence that is shared by two or more genes encoding related but different proteins, such as different members of a gene family, different protein epitopes, different protein isoforms or completely divergent genes, such as a cytokine and its corresponding receptors. A homologous sequence can be a nucleotide sequence that is shared by two or more non-coding polynucleotides, such as noncoding DNA or RNA, regulatory sequences, introns, and sites of transcriptional control or regulation. Homologous sequences can also include conserved sequence regions shared by more than one polynucleotide sequence. Homology does not need to be perfect homology (e.g., 100%), as partially homologous sequences are also contemplated by the instant invention (e.g., 99%, 98%, 97%, 96%, 95%, 94%, 93%, 92%, 91%, 90%, 89%, 88%, 87%, 86%, 85%, 84%, 83%, 82%, 81%, 80% etc.).
[0213] By “conserved sequence region” is meant, a nucleotide sequence of one or more regions in a polynucleotide does not vary significantly between generations or from one biological system or organism to another biological system or organism. The polynucleotide can include both coding and non-coding DNA and RNA.
[0214] By “sense region” is meant a nucleotide sequence of an siNA molecule having complementarity to an antisense region of the siNA molecule. In addition, the sense region of an siNA molecule can comprise a nucleic acid sequence having homology with a target nucleic acid sequence.
[0215] By “antisense region” is meant a nucleotide sequence of an siNA molecule having complementarity to a target nucleic acid sequence. In addition, the antisense region of an siNA molecule can optionally comprise a nucleic acid sequence having complementarity to a sense region of the siNA molecule.
[0216] By “target nucleic acid” is meant any nucleic acid sequence whose expression or activity is to be modulated. The target nucleic acid can be DNA or RNA.
[0217] By “complementarity” is meant that a nucleic acid can form hydrogen bond(s) with another nucleic acid sequence by either traditional Watson-Crick or other non-traditional types. In reference to the nucleic molecules of the present invention, the binding free energy for a nucleic acid molecule with its complementary sequence is sufficient to allow the relevant function of the nucleic acid to proceed, e.g., RNAi activity. Determination of binding free energies for nucleic acid molecules is well known in the art (see, e.g., Turner et al., 1987 , CSH Symp. Quant. Biol . LII pp. 123-133; Frier et al., 1986 , Proc. Nat. Acad. Sci. USA 83:9373-9377; Turner et al., 1987 , J. Am. Chem. Soc. 109:3783-3785). A percent complementarity indicates the percentage of contiguous residues in a nucleic acid molecule that can form hydrogen bonds (e.g., Watson-Crick base pairing) with a second nucleic acid sequence (e.g., 5, 6, 7, 8, 9, or 10 nucleotides out of a total of 10 nucleotides in the first oligonucleotide being based paired to a second nucleic acid sequence having 10 nucleotides represents 50%, 60%, 70%, 80%, 90%, and 100% complementary respectively). “Perfectly complementary” means that all the contiguous residues of a nucleic acid sequence will hydrogen bond with the same number of contiguous residues in a second nucleic acid sequence.
[0218] In one embodiment, siNA molecules of the invention that down regulate or reduce interleukin and/or interleukin receptor gene expression are used for preventing or reducing cancers and other proliferative conditions, viral infection, inflammatory disease, autoimmunity, respiratory disease, pulmonary disease, cardiovascular disease, neurological disease, renal disease, ocular disease, liver disease, mitochondrial disease, endocrine disease, prion disease, reproduction related diseases and conditions or any other disease associated with interleukin and/or interleukin receptor gene expression in a subject. In one embodiment, the siNA molecules of the invention that down regulate or reduce interleukin and/or interleukin receptor gene expression are used for treating or preventing asthma, chronic obstructive pulmonary disease or “COPD”, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, cystic fibrosis, pulmonary hypertension, pulmonary vasoconstriction, or emphysema in a subject.
[0219] By “cancer” is meant a group of diseases characterized by uncontrolled growth and spread of abnormal cells.
[0220] By “proliferative disease” or “cancer” is meant, any disease, condition, trait, genotype or phenotype characterized by unregulated cell growth or replication as is known in the art; including AIDS related cancers such as Kaposi's sarcoma; breast cancers; bone cancers such as Osteosarcoma, Chondrosarcomas, Ewing's sarcoma, Fibrosarcomas, Giant cell tumors, Adamantinomas, and Chordomas; Brain cancers such as Meningiomas, Glioblastomas, Lower-Grade Astrocytomas, Oligodendrocytomas, Pituitary Tumors, Schwannomas, and Metastatic brain cancers; cancers of the head and neck including various lymphomas such as mantle cell lymphoma, non-Hodgkins lymphoma, adenoma, squamous cell carcinoma, laryngeal carcinoma, gallbladder and bile duct cancers, cancers of the retina such as retinoblastoma, cancers of the esophagus, gastric cancers, multiple myeloma, ovarian cancer, uterine cancer, thyroid cancer, testicular cancer, endometrial cancer, melanoma, colorectal cancer, lung cancer, bladder cancer, prostate cancer, lung cancer (including non-small cell lung carcinoma), pancreatic cancer, sarcomas, Wilms' tumor, cervical cancer, head and neck cancer, skin cancers, nasopharyngeal carcinoma, liposarcoma, epithelial carcinoma, renal cell carcinoma, gallbladder adeno carcinoma, parotid adenocarcinoma, endometrial sarcoma, multidrug resistant cancers; and proliferative diseases and conditions, such as neovascularization associated with tumor angiogenesis, macular degeneration (e.g., wet/dry AMD), corneal neovascularization, diabetic retinopathy, neovascular glaucoma, myopic degeneration and other proliferative diseases and conditions such as restenosis and polycystic kidney disease, and any other cancer or proliferative disease, condition, trait, genotype or phenotype that can respond to the modulation of disease related gene expression in a cell or tissue, alone or in combination with other therapies.
[0221] By “inflammatory disease” or “inflammatory condition” is meant any disease, condition, trait, genotype or phenotype characterized by an inflammatory or allergic process as is known in the art, such as inflammation, acute inflammation, chronic inflammation, atherosclerosis, restenosis, asthma, allergic rhinitis, atopic dermatitis, psoriasis, septic shock, rheumatoid arthritis, inflammatory bowl disease, inflammatory pelvic disease, pain, ocular inflammatory disease, celiac disease, Leigh Syndrome, Glycerol Kinase Deficiency, Familial eosinophilia (FE), autosomal recessive spastic ataxia, laryngeal inflammatory disease; Tuberculosis, Chronic cholecystitis, Bronchiectasis, Silicosis and other pneumoconiosis, and any other inflammatory disease, condition, trait, genotype or phenotype that can respond to the modulation of disease related gene expression in a cell or tissue, alone or in combination with other therapies.
[0222] By “respiratory disease” is meant, any disease or condition affecting the respiratory tract, such as asthma, chronic obstructive pulmonary disease or “COPD”, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, cystic fibrosis, pulmonary hypertension, pulmonary vasoconstriction, emphysema, and any other respiratory disease, condition, trait, genotype or phenotype that can respond to the modulation of disease related gene expression in a cell or tissue, alone or in combination with other therapies.
[0223] By “autoimmune disease” or “autoimmune condition” is meant, any disease, condition, trait, genotype or phenotype characterized by autoimmunity as is known in the art, such as multiple sclerosis, diabetes mellitus, lupus, celiac disease, Crohn's disease, ulcerative colitis, Guillain-Barre syndrome, scleroderms, Goodpasture's syndrome, Wegener's granulomatosis, autoimmune epilepsy, Rasmussen's encephalitis, Primary biliary sclerosis, Sclerosing cholangitis, Autoimmune hepatitis, Addison's disease, Hashimoto's thyroiditis, Fibromyalgia, Menier's syndrome; transplantation rejection (e.g., prevention of allograft rejection) pernicious anemia, rheumatoid arthritis, systemic lupus erythematosus, dermatomyositis, Sjogren's syndrome, lupus erythematosus, multiple sclerosis, myasthenia gravis, Reiter's syndrome, Grave's disease, and any other autoimmune disease, condition, trait, genotype or phenotype that can respond to the modulation of disease related gene expression in a cell or tissue, alone or in combination with other therapies.
[0224] By “neurological disease” or “neurological disease” is meant any disease, disorder, or condition affecting the central or peripheral nervous system, including ADHD, AIDS—Neurological Complications, Absence of the Septum Pellucidum, Acquired Epileptiform Aphasia, Acute Disseminated Encephalomyelitis, Adrenoleukodystrophy, Agenesis of the Corpus Callosum, Agnosia, Aicardi Syndrome, Alexander Disease, Alpers' Disease, Alternating Hemiplegia, Alzheimer's Disease, Amyotrophic Lateral Sclerosis, Anencephaly, Aneurysm, Angelman Syndrome, Angiomatosis, Anoxia, Aphasia, Apraxia, Arachnoid Cysts, Arachnoiditis, Arnold-Chiari Malformation, Arteriovenous Malformation, Aspartame, Asperger Syndrome, Ataxia Telangiectasia, Ataxia, Attention Deficit-Hyperactivity Disorder, Autism, Autonomic Dysfunction, Back Pain, Barth Syndrome, Batten Disease, Behcet's Disease, Bell's Palsy, Benign Essential Blepharospasm, Benign Focal Amyotrophy, Benign Intracranial Hypertension, Bernhardt-Roth Syndrome, Binswanger's Disease, Blepharospasm, Bloch-Sulzberger Syndrome, Brachial Plexus Birth Injuries, Brachial Plexus Injuries, Bradbury-Eggleston Syndrome, Brain Aneurysm, Brain Injury, Brain and Spinal Tumors, Brown-Sequard Syndrome, Bulbospinal Muscular Atrophy, Canavan Disease, Carpal Tunnel Syndrome, Causalgia, Cavernomas, Cavernous Angioma, Cavernous Malformation, Central Cervical Cord Syndrome, Central Cord Syndrome, Central Pain Syndrome, Cephalic Disorders, Cerebellar Degeneration, Cerebellar Hypoplasia, Cerebral Aneurysm, Cerebral Arteriosclerosis, Cerebral Atrophy, Cerebral Beriberi, Cerebral Gigantism, Cerebral Hypoxia, Cerebral Palsy, Cerebro-Oculo-Facio-Skeletal Syndrome, Charcot-Marie-Tooth Disorder, Chiari Malformation, Chorea, Choreoacanthocytosis, Chronic Inflammatory Demyelinating Polyneuropathy (CIDP), Chronic Orthostatic Intolerance, Chronic Pain, Cockayne Syndrome Type II, Coffin Lowry Syndrome, Coma, including Persistent Vegetative State, Complex Regional Pain Syndrome, Congenital Facial Diplegia, Congenital Myasthenia, Congenital Myopathy, Congenital Vascular Cavernous Malformations, Corticobasal Degeneration, Cranial Arteritis, Craniosynostosis, Creutzfeldt-Jakob Disease, Cumulative Trauma Disorders, Cushing's Syndrome, Cytomegalic Inclusion Body Disease (CIBD), Cytomegalovirus Infection, Dancing Eyes-Dancing Feet Syndrome, Dandy-Walker Syndrome, Dawson Disease, De Morsier's Syndrome, Dejerine-Klumpke Palsy, Dementia—Multi-Infarct, Dementia—Subcortical, Dementia With Lewy Bodies, Dermatomyositis, Developmental Dyspraxia, Devic's Syndrome, Diabetic Neuropathy, Diffuse Sclerosis, Dravet's Syndrome, Dysautonomia, Dysgraphia, Dyslexia, Dysphagia, Dyspraxia, Dystonias, Early Infantile Epileptic Encephalopathy, Empty Sella Syndrome, Encephalitis Lethargica, Encephalitis and Meningitis, Encephaloceles, Encephalopathy, Encephalotrigeminal Angiomatosis, Epilepsy, Erb's Palsy, Erb-Duchenne and Dejerine-Klumpke Palsies, Fabry's Disease, Fahr's Syndrome, Fainting, Familial Dysautonomia, Familial Hemangioma, Familial Idiopathic Basal Ganglia Calcification, Familial Spastic Paralysis, Febrile Seizures (e.g., GEFS and GEFS plus), Fisher Syndrome, Floppy Infant Syndrome, Friedreich's Ataxia, Gaucher's Disease, Gerstmann's Syndrome, Gerstmann-Straussler-Scheinker Disease, Giant Cell Arteritis, Giant Cell Inclusion Disease, Globoid Cell Leukodystrophy, Glossopharyngeal Neuralgia, Guillain-Barre Syndrome, HTLV-1 Associated Myelopathy, Hallervorden-Spatz Disease, Head Injury, Headache, Hemicrania Continua, Hemifacial Spasm, Hemiplegia Alterans, Hereditary Neuropathies, Hereditary Spastic Paraplegia, Heredopathia Atactica Polyneuritiformis, Herpes Zoster Oticus, Herpes Zoster, Hirayama Syndrome, Holoprosencephaly, Huntington's Disease, Hydranencephaly, Hydrocephalus—Normal Pressure, Hydrocephalus, Hydromyelia, Hypercortisolism, Hypersomnia, Hypertonia, Hypotonia, Hypoxia, Immune-Mediated Encephalomyelitis, Inclusion Body Myositis, Incontinentia Pigmenti, Infantile Hypotonia, Infantile Phytanic Acid Storage Disease, Infantile Refsum Disease, Infantile Spasms, Inflammatory Myopathy, Intestinal Lipodystrophy, Intracranial Cysts, Intracranial Hypertension, Isaac's Syndrome, Joubert Syndrome, Kearns-Sayre Syndrome, Kennedy's Disease, Kinsbourne syndrome, Kleine-Levin syndrome, Klippel Feil Syndrome, Klippel-Trenaunay Syndrome (KTS), Kluver-Bucy Syndrome, Korsakoff's Amnesic Syndrome, Krabbe Disease, Kugelberg-Welander Disease, Kuru, Lambert-Eaton Myasthenic Syndrome, Landau-Kleffner Syndrome, Lateral Femoral Cutaneous Nerve Entrapment, Lateral Medullary Syndrome, Learning Disabilities, Leigh's Disease, Lennox-Gastaut Syndrome, Lesch-Nyhan Syndrome, Leukodystrophy, Levine-Critchley Syndrome, Lewy Body Dementia, Lissencephaly, Locked-In Syndrome, Lou Gehrig's Disease, Lupus—Neurological Sequelae, Lyme Disease—Neurological Complications, Machado-Joseph Disease, Macrencephaly, Megalencephaly, Melkersson-Rosenthal Syndrome, Meningitis, Menkes Disease, Meralgia Paresthetica, Metachromatic Leukodystrophy, Microcephaly, Migraine, Miller Fisher Syndrome, Mini-Strokes, Mitochondrial Myopathies, Mobius Syndrome, Monomelic Amyotrophy, Motor Neuron Diseases, Moyamoya Disease, Mucolipidoses, Mucopolysaccharidoses, Multi-Infarct Dementia, Multifocal Motor Neuropathy, Multiple Sclerosis, Multiple System Atrophy with Orthostatic Hypotension, Multiple System Atrophy, Muscular Dystrophy, Myasthenia—Congenital, Myasthenia Gravis, Myelinoclastic Diffuse Sclerosis, Myoclonic Encephalopathy of Infants, Myoclonus, Myopathy—Congenital, Myopathy—Thyrotoxic, Myopathy, Myotonia Congenita, Myotonia, Narcolepsy, Neuroacanthocytosis, Neurodegeneration with Brain Iron Accumulation, Neurofibromatosis, Neuroleptic Malignant Syndrome, Neurological Complications of AIDS, Neurological Manifestations of Pompe Disease, Neuromyelitis Optica, Neuromyotonia, Neuronal Ceroid Lipofuscinosis, Neuronal Migration Disorders, Neuropathy—Hereditary, Neurosarcoidosis, Neurotoxicity, Nevus Cavemosus, Niemann-Pick Disease, O'Sullivan-McLeod Syndrome, Occipital Neuralgia, Occult Spinal Dysraphism Sequence, Ohtahara Syndrome, Olivopontocerebellar Atrophy, Opsoclonus Myoclonus, Orthostatic Hypotension, Overuse Syndrome, Pain—Chronic, Paraneoplastic Syndromes, Paresthesia, Parkinson's Disease, Parmyotonia Congenita, Paroxysmal Choreoathetosis, Paroxysmal Hemicrania, Parry-Romberg, Pelizaeus-Merzbacher Disease, Pena Shokeir II Syndrome, Perineural Cysts, Periodic Paralyses, Peripheral Neuropathy, Periventricular Leukomalacia, Persistent Vegetative State, Pervasive Developmental Disorders, Phytanic Acid Storage Disease, Pick's Disease, Piriformis Syndrome, Pituitary Tumors, Polymyositis, Pompe Disease, Porencephaly, Post-Polio Syndrome, Postherpetic Neuralgia, Postinfectious Encephalomyelitis, Postural Hypotension, Postural Orthostatic Tachycardia Syndrome, Postural Tachycardia Syndrome, Primary Lateral Sclerosis, Prion Diseases, Progressive Hemifacial Atrophy, Progressive Locomotor Ataxia, Progressive Multifocal Leukoencephalopathy, Progressive Sclerosing Poliodystrophy, Progressive Supranuclear Palsy, Pseudotumor Cerebri, Pyridoxine Dependent and Pyridoxine Responsive Siezure Disorders, Ramsay Hunt Syndrome Type I, Ramsay Hunt Syndrome Type II, Rasmussen's Encephalitis and other autoimmune epilepsies, Reflex Sympathetic Dystrophy Syndrome, Refsum Disease—Infantile, Refsum Disease, Repetitive Motion Disorders, Repetitive Stress Injuries, Restless Legs Syndrome, Retrovirus-Associated Myelopathy, Rett Syndrome, Reye's Syndrome, Riley-Day Syndrome, SUNCT Headache, Sacral Nerve Root Cysts, Saint Vitus Dance, Salivary Gland Disease, Sandhoff Disease, Schilder's Disease, Schizencephaly, Seizure Disorders, Septo-Optic Dysplasia, Severe Myoclonic Epilepsy of Infancy (SMEI), Shaken Baby Syndrome, Shingles, Shy-Drager Syndrome, Sjogren's Syndrome, Sleep Apnea, Sleeping Sickness, Soto's Syndrome, Spasticity, Spina Bifida, Spinal Cord Infarction, Spinal Cord Injury, Spinal Cord Tumors, Spinal Muscular Atrophy, Spinocerebellar Atrophy, Steele-Richardson-Olszewski Syndrome, Stiff-Person Syndrome, Striatonigral Degeneration, Stroke, Sturge-Weber Syndrome, Subacute Sclerosing Panencephalitis, Subcortical Arteriosclerotic Encephalopathy, Swallowing Disorders, Sydenham Chorea, Syncope, Syphilitic Spinal Sclerosis, Syringohydromyelia, Syringomyelia, Systemic Lupus Erythematosus, Tabes Dorsalis, Tardive Dyskinesia, Tarlov Cysts, Tay-Sachs Disease, Temporal Arteritis, Tethered Spinal Cord Syndrome, Thomsen Disease, Thoracic Outlet Syndrome, Thyrotoxic Myopathy, Tic Douloureux, Todd's Paralysis, Tourette Syndrome, Transient Ischemic Attack, Transmissible Spongiform Encephalopathies, Transverse Myelitis, Traumatic Brain Injury, Tremor, Trigeminal Neuralgia, Tropical Spastic Paraparesis, Tuberous Sclerosis, Vascular Erectile Tumor, Vasculitis including Temporal Arteritis, Von Economo's Disease, Von Hippel-Lindau disease (VHL), Von Recklinghausen's Disease, Wallenberg's Syndrome, Werdnig-Hoffman Disease, Wernicke-Korsakoff Syndrome, West Syndrome, Whipple's Disease, Williams Syndrome, Wilson's Disease, X-Linked Spinal and Bulbar Muscular Atrophy, and Zellweger Syndrome.
[0225] By “infectious disease” is meant any disease, condition, trait, genotype or phenotype associated with an infectious agent, such as a virus, bacteria, fungus, prion, or parasite. Non-limiting examples of various viral genes that can be targeted using siNA molecules of the invention include Hepatitis C Virus (HCV, for example Genbank Accession Nos: D11168, D50483.1, L38318 and S82227), Hepatitis B Virus (HBV, for example GenBank Accession No. AF100308.1), Human Immunodeficiency Virus type 1 (HIV-1, for example GenBank Accession No. U51188), Human Immunodeficiency Virus type 2 (HIV-2, for example GenBank Accession No. X60667), West Nile Virus (WNV for example GenBank accession No. NC — 001563), cytomegalovirus (CMV for example GenBank Accession No. NC — 001347), respiratory syncytial virus (RSV for example GenBank Accession No. NC — 001781), influenza virus (for example GenBank Accession No. AF037412, rhinovirus (for example, GenBank accession numbers: D00239, X02316, X01087, L24917, M16248, K02121, X01087), papillomavirus (for example GenBank Accession No. NC — 001353), Herpes Simplex Virus (HSV for example GenBank Accession No. NC — 001345), and other viruses such as HTLV (for example GenBank Accession No. AJ430-458). Due to the high sequence variability of many viral genomes, selection of siNA molecules for broad therapeutic applications would likely involve the conserved regions of the viral genome. Nonlimiting examples of conserved regions of the viral genomes include but are not limited to 5′-Non Coding Regions (NCR), 3′-Non Coding Regions (NCR) and/or internal ribosome entry sites (IRES). siNA molecules designed against conserved regions of various viral genomes will enable efficient inhibition of viral replication in diverse patient populations and may ensure the effectiveness of the siNA molecules against viral quasi species which evolve due to mutations in the non-conserved regions of the viral genome. Non-limiting examples of bacterial infections include Actinomycosis, Anthrax, Aspergillosis, Bacteremia, Bacterial Infections and Mycoses, Bartonella Infections, Botulism, Brucellosis, Burkholderia Infections, Campylobacter Infections, Candidiasis, Cat-Scratch Disease, Chlamydia Infections, Cholera, Clostridium Infections, Coccidioidomycosis, Cross Infection, Cryptococcosis, Dermatomycoses, Dermatomycoses, Diphtheria, Ehrlichiosis, Escherichia coli Infections, Fasciitis, Necrotizing, Fusobacterium Infections, Gas Gangrene, Gram-Negative Bacterial Infections, Gram-Positive Bacterial Infections, Histoplasmosis, Impetigo, Klebsiella Infections, Legionellosis, Leprosy, Leptospirosis, Listeria Infections, Lyme Disease, Maduromycosis, Melioidosis, Mycobacterium Infections, Mycoplasma Infections, Mycoses, Nocardia Infections, Onychomycosis, Ornithosis, Plague, Pneumococcal Infections, Pseudomonas Infections, Q Fever, Rat-Bite Fever, Relapsing Fever, Rheumatic Fever, Rickettsia Infections, Rocky Mountain Spotted Fever, Salmonella Infections, Scarlet Fever, Scrub Typhus, Sepsis, Sexually Transmitted Diseases—Bacterial, Bacterial Skin Diseases, Staphylococcal Infections, Streptococcal Infections, Tetanus, Tick-Borne Diseases, Tuberculosis, Tularemia, Typhoid Fever, Typhus, Epidemic Louse-Borne, Vibrio Infections, Yaws, Yersinia Infections, Zoonoses, and Zygomycosis. Non-limiting examples of fungal infections include Aspergillosis, Blastomycosis, Coccidioidomycosis, Cryptococcosis, Fungal Infections of Fingernails and Toenails, Fungal Sinusitis, Histoplasmosis, Histoplasmosis, Mucormycosis, Nail Fungal Infection, Paracoccidioidomycosis, Sporotrichosis, Valley Fever (Coccidioidomycosis), and Mold Allergy.
[0226] By “ocular disease” is meant, any disease, condition, trait, genotype or phenotype of the eye and related structures, such as Cystoid Macular Edema, Asteroid Hyalosis, Pathological Myopia and Posterior Staphyloma, Toxocariasis (Ocular Larva Migrans), Retinal Vein Occlusion, Posterior Vitreous Detachment, Tractional Retinal Tears, Epiretinal Membrane, Diabetic Retinopathy, Lattice Degeneration, Retinal Vein Occlusion, Retinal Artery Occlusion, Macular Degeneration (e.g., age related macular degeneration such as wet AMD or dry AMD), Toxoplasmosis, Choroidal Melanoma, Acquired Retinoschisis, Hollenhorst Plaque, Idiopathic Central Serous Chorioretinopathy, Macular Hole, Presumed Ocular Histoplasmosis Syndrome, Retinal Macroaneursym, Retinitis Pigmentosa, Retinal Detachment, Hypertensive Retinopathy, Retinal Pigment Epithelium (RPE) Detachment, Papillophlebitis, Ocular Ischemic Syndrome, Coats' Disease, Leber's Miliary Aneurysm, Conjunctival Neoplasms, Allergic Conjunctivitis, Vernal Conjunctivitis, Acute Bacterial Conjunctivitis, Allergic Conjunctivitis & Vernal Keratoconjunctivitis, Viral Conjunctivitis, Bacterial Conjunctivitis, Chlamydial & Gonococcal Conjunctivitis, Conjunctival Laceration, Episcleritis, Scleritis, Pingueculitis, Pterygium, Superior Limbic Keratoconjunctivitis (SLK of Theodore), Toxic Conjunctivitis, Conjunctivitis with Pseudomembrane, Giant Papillary Conjunctivitis, Terrien's Marginal Degeneration, Acanthamoeba Keratitis, Fungal Keratitis, Filamentary Keratitis, Bacterial Keratitis, Keratitis Sicca/Dry Eye Syndrome, Bacterial Keratitis, Herpes Simplex Keratitis, Sterile Corneal Infiltrates, Phlyctenulosis, Corneal Abrasion & Recurrent Corneal Erosion, Corneal Foreign Body, Chemical Burs, Epithelial Basement Membrane Dystrophy (EBMD), Thygeson's Superficial Punctate Keratopathy, Corneal Laceration, Salzmann's Nodular Degeneration, Fuchs' Endothelial Dystrophy, Crystalline Lens Subluxation, Ciliary-Block Glaucoma, Primary Open-Angle Glaucoma, Pigment Dispersion Syndrome and Pigmentary Glaucoma, Pseudoexfoliation Syndrom and Pseudoexfoliative Glaucoma, Anterior Uveitis, Primary Open Angle Glaucoma, Uveitic Glaucoma & Glaucomatocyclitic Crisis, Pigment Dispersion Syndrome & Pigmentary Glaucoma, Acute Angle Closure Glaucoma, Anterior Uveitis, Hyphema, Angle Recession Glaucoma, Lens Induced Glaucoma, Pseudoexfoliation Syndrome and Pseudoexfoliative Glaucoma, Axenfeld-Rieger Syndrome, Neovascular Glaucoma, Pars Planitis, Choroidal Rupture, Duane's Retraction Syndrome, Toxic/Nutritional Optic Neuropathy, Aberrant Regeneration of Cranial Nerve III, Intracranial Mass Lesions, Carotid-Cavernous Sinus Fistula, Anterior Ischemic Optic Neuropathy, Optic Disc Edema & Papilledema, Cranial Nerve III Palsy, Cranial Nerve IV Palsy, Cranial Nerve VI Palsy, Cranial Nerve VII (Facial Nerve) Palsy, Horner's Syndrome, Internuclear Opthalmoplegia, Optic Nerve Head Hypoplasia, Optic Pit, Tonic Pupil, Optic Nerve Head Drusen, Demyelinating Optic Neuropathy (Optic Neuritis, Retrobulbar Optic Neuritis), Amaurosis Fugax and Transient Ischemic Attack, Pseudotumor Cerebri, Pituitary Adenoma, Molluscum Contagiosum, Canaliculitis, Verruca and Papilloma, Pediculosis and Pthiriasis, Blepharitis, Hordeolum, Preseptal Cellulitis, Chalazion, Basal Cell Carcinoma, Herpes Zoster Ophthalmicus, Pediculosis & Phthiriasis, Blow-out Fracture, Chronic Epiphora, Dacryocystitis, Herpes Simplex Blepharitis, Orbital Cellulitis, Senile Entropion, and Squamous Cell Carcinoma.
[0227] By “cardiovascular disease” is meant and disease or condition affecting the heart and vasculature, including but not limited to, coronary heart disease (CHD), cerebrovascular disease (CVD), aortic stenosis, peripheral vascular disease, atherosclerosis, arteriosclerosis, myocardial infarction (heart attack), cerebrovascular diseases (stroke), transient ischaemic attacks (TIA), angina (stable and unstable), atrial fibrillation, arrhythmia, valvular disease, and/or congestive heart failure.
[0228] In one embodiment of the present invention, each sequence of an siNA molecule of the invention is independently about 18 to about 24 nucleotides in length, in specific embodiments about 18, 19, 20, 21, 22, 23, or 24 nucleotides in length. In another embodiment, the siNA duplexes of the invention independently comprise about 17 to about 23 base pairs (e.g., about 17, 18, 19, 20, 21, 22, or 23). In yet another embodiment, siNA molecules of the invention comprising hairpin or circular structures are about 35 to about 55 (e.g., about 35, 40, 45, 50 or 55) nucleotides in length, or about 38 to about 44 (e.g., about 38, 39, 40, 41, 42, 43, or 44) nucleotides in length and comprising about 16 to about 22 (e.g., about 16, 17, 18, 19, 20, 21 or 22) base pairs. Exemplary siNA molecules of the invention are shown in Table II. Exemplary synthetic siNA molecules of the invention are shown in Table III and/or FIGS. 4-5 .
[0229] As used herein “cell” is used in its usual biological sense, and does not refer to an entire multicellular organism, e.g., specifically does not refer to a human. The cell can be present in an organism, e.g., birds, plants and mammals such as humans, cows, sheep, apes, monkeys, swine, dogs, and cats. The cell can be prokaryotic (e.g., bacterial cell) or eukaryotic (e.g., mammalian or plant cell). The cell can be of somatic or germ line origin, totipotent or pluripotent, dividing or non-dividing. The cell can also be derived from or can comprise a gamete or embryo, a stem cell, or a fully differentiated cell.
[0230] The siNA molecules of the invention are added directly, or can be complexed with cationic lipids, packaged within liposomes, or otherwise delivered to target cells or tissues. The nucleic acid or nucleic acid complexes can be locally administered to relevant tissues ex vivo, or in vivo through direct dermal application, transdermal application, or injection, with or without their incorporation in biopolymers. In particular embodiments, the nucleic acid molecules of the invention comprise sequences shown in Tables II-III and/or FIGS. 4-5 . Examples of such nucleic acid molecules consist essentially of sequences defined in these tables and figures. Furthermore, the chemically modified constructs described in Table IV can be applied to any siNA sequence of the invention.
[0231] In another aspect, the invention provides mammalian cells containing one or more siNA molecules of this invention. The one or more siNA molecules can independently be targeted to the same or different sites.
[0232] By “RNA” is meant a molecule comprising at least one ribonucleotide residue. By “ribonucleotide” is meant a nucleotide with a hydroxyl group at the 2′ position of a β-D-ribofuranose moiety. The terms include double-stranded RNA, single-stranded RNA, isolated RNA such as partially purified RNA, essentially pure RNA, synthetic RNA, recombinantly produced RNA, as well as altered RNA that differs from naturally occurring RNA by the addition, deletion, substitution and/or alteration of one or more nucleotides. Such alterations can include addition of non-nucleotide material, such as to the end(s) of the siNA or internally, for example at one or more nucleotides of the RNA. Nucleotides in the RNA molecules of the instant invention can also comprise non-standard nucleotides, such as non-naturally occurring nucleotides or chemically synthesized nucleotides or deoxynucleotides. These altered RNAs can be referred to as analogs or analogs of naturally-occurring RNA.
[0233] By “subject” is meant an organism, which is a donor or recipient of explanted cells or the cells themselves. “Subject” also refers to an organism to which the nucleic acid molecules of the invention can be administered. A subject can be a mammal or mammalian cells, including a human or human cells.
[0234] The term “phosphorothioate” as used herein refers to an internucleotide linkage having Formula I, wherein Z and/or W comprise a sulfur atom. Hence, the term phosphorothioate refers to both phosphorothioate and phosphorodithioate internucleotide linkages.
[0235] The term “phosphonoacetate” as used herein refers to an internucleotide linkage having Formula I, wherein Z and/or W comprise an acetyl or protected acetyl group.
[0236] The term “thiophosphonoacetate” as used herein refers to an internucleotide linkage having Formula I, wherein Z comprises an acetyl or protected acetyl group and W comprises a sulfur atom or alternately W comprises an acetyl or protected acetyl group and Z comprises a sulfur atom.
[0237] The term “universal base” as used herein refers to nucleotide base analogs that form base pairs with each of the natural DNA/RNA bases with little discrimination between them. Non-limiting examples of universal bases include C-phenyl, C-naphthyl and other aromatic derivatives, inosine, azole carboxamides, and nitroazole derivatives such as 3-nitropyrrole, 4-nitroindole, 5-nitroindole, and 6-nitroindole as known in the art (see for example Loakes, 2001 , Nucleic Acids Research, 29, 2437-2447).
[0238] The term “acyclic nucleotide” as used herein refers to any nucleotide having an acyclic ribose sugar.
[0239] The nucleic acid molecules of the instant invention, individually, or in combination or in conjunction with other drugs, can be used to for preventing or treating cancers and other proliferative conditions, viral infection, inflammatory disease, autoimmunity, respiratory disease, pulmonary disease, cardiovascular disease, neurological disease, renal disease, ocular disease, liver disease, mitochondrial disease, endocrine disease, prion disease, or reproduction related diseases and conditions in a subject or organism. In one embodiment, siNA molecules of the invention are used in combination with anti-inflammatory agents or bronchodilators as are known in the art to treat or prevent inflammatory and respiratory diseases and/or conditions in a subject or organism.
[0240] For example, the siNA molecules can be administered to a subject or can be administered to other appropriate cells evident to those skilled in the art, individually or in combination with one or more drugs (e.g., statins, hypertensive agents etc.) under conditions suitable for the treatment.
[0241] In one embodiment, the invention features an expression vector comprising a nucleic acid sequence encoding at least one siNA molecule of the invention, in a manner which allows expression of the siNA molecule. For example, the vector can contain sequence(s) encoding both strands of an siNA molecule comprising a duplex. The vector can also contain sequence(s) encoding a single nucleic acid molecule that is self-complementary and thus forms an siNA molecule. Non-limiting examples of such expression vectors are described in Paul et al., 2002 , Nature Biotechnology, 19, 505; Miyagishi and Taira, 2002 , Nature Biotechnology, 19, 497; Lee et al., 2002 , Nature Biotechnology, 19, 500; and Novina et al., 2002 , Nature Medicine , advance online publication doi: 10.1038/nm725.
[0242] In another embodiment, the invention features a mammalian cell, for example, a human cell, including an expression vector of the invention.
[0243] In yet another embodiment, the expression vector of the invention comprises a sequence for an siNA molecule having complementarity to a RNA molecule referred to by a Genbank Accession numbers, for example Genbank Accession Nos. shown in Table I.
[0244] In one embodiment, an expression vector of the invention comprises a nucleic acid sequence encoding two or more siNA molecules, which can be the same or different.
[0245] In another aspect of the invention, siNA molecules that interact with target RNA molecules and down-regulate gene encoding target RNA molecules (for example target RNA molecules referred to by Genbank Accession numbers herein) are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors can be DNA plasmids or viral vectors. siNA expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. The recombinant vectors capable of expressing the siNA molecules can be delivered as described herein, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of siNA molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the siNA molecules bind and down-regulate gene function or expression via RNA interference (RNAi). Delivery of siNA expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from a subject followed by reintroduction into the subject, or by any other means that would allow for introduction into the desired target cell.
[0246] By “vectors” is meant any nucleic acid- and/or viral-based technique used to deliver a desired nucleic acid.
[0247] Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0248] FIG. 1 shows a non-limiting example of a scheme for the synthesis of siNA molecules. The complementary siNA sequence strands, strand 1 and strand 2 , are synthesized in tandem and are connected by a cleavable linkage, such as a nucleotide succinate or abasic succinate, which can be the same or different from the cleavable linker used for solid phase synthesis on a solid support. The synthesis can be either solid phase or solution phase, in the example shown, the synthesis is a solid phase synthesis. The synthesis is performed such that a protecting group, such as a dimethoxytrityl group, remains intact on the terminal nucleotide of the tandem oligonucleotide. Upon cleavage and deprotection of the oligonucleotide, the two siNA strands spontaneously hybridize to form an siNA duplex, which allows the purification of the duplex by utilizing the properties of the terminal protecting group, for example by applying a trityl on purification method wherein only duplexes/oligonucleotides with the terminal protecting group are isolated.
[0249] FIG. 2 shows a MALDI-TOF mass spectrum of a purified siNA duplex synthesized by a method of the invention. The two peaks shown correspond to the predicted mass of the separate siNA sequence strands. This result demonstrates that the siNA duplex generated from tandem synthesis can be purified as a single entity using a simple trityl-on purification methodology.
[0250] FIG. 3 shows a non-limiting proposed mechanistic representation of target RNA degradation involved in RNAi. Double-stranded RNA (dsRNA), which is generated by RNA-dependent RNA polymerase (RdRP) from foreign single-stranded RNA, for example viral, transposon, or other exogenous RNA, activates the DICER enzyme that in turn generates siNA duplexes. Alternately, synthetic or expressed siNA can be introduced directly into a cell by appropriate means. An active siNA complex forms which recognizes a target RNA, resulting in degradation of the target RNA by the RISC endonuclease complex or in the synthesis of additional RNA by RNA-dependent RNA polymerase (RdRP), which can activate DICER and result in additional siNA molecules, thereby amplifying the RNAi response.
[0251] FIG. 4A-F shows non-limiting examples of chemically-modified siNA constructs of the present invention. In the figure, N stands for any nucleotide (adenosine, guanosine, cytosine, uridine, or optionally thymidine, for example thymidine can be substituted in the overhanging regions designated by parenthesis (N N). Various modifications are shown for the sense and antisense strands of the siNA constructs. The antisense strand of constructs A-F comprise sequence complementary to any target nucleic acid sequence of the invention. Furthermore, when a glyceryl moiety (L) is present at the 3′-end of the antisense strand for any construct shown in FIG. 4 A-F, the modified internucleotide linkage is optional.
[0252] FIG. 4A : The sense strand comprises 21 nucleotides wherein the two terminal 3′-nucleotides are optionally base paired and wherein all nucleotides present are ribonucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein. The antisense strand comprises 21 nucleotides, optionally having a 3′-terminal glyceryl moiety wherein the two terminal 3′-nucleotides are optionally complementary to the target RNA sequence, and wherein all nucleotides present are ribonucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein. A modified internucleotide linkage, such as a phosphorothioate, phosphorodithioate or other modified internucleotide linkage as described herein, shown as “s”, optionally connects the (N N) nucleotides in the antisense strand.
[0253] FIG. 4B : The sense strand comprises 21 nucleotides wherein the two terminal 3′-nucleotides are optionally base paired and wherein all pyrimidine nucleotides that may be present are 2′deoxy-2′-fluoro modified nucleotides and all purine nucleotides that may be present are 2′-O-methyl modified nucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein. The antisense strand comprises 21 nucleotides, optionally having a 3′-terminal glyceryl moiety and wherein the two terminal 3′-nucleotides are optionally complementary to the target RNA sequence, and wherein all pyrimidine nucleotides that may be present are 2′-deoxy-2′-fluoro modified nucleotides and all purine nucleotides that may be present are 2′-O-methyl modified nucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein. A modified internucleotide linkage, such as a phosphorothioate, phosphorodithioate or other modified internucleotide linkage as described herein, shown as “s”, optionally connects the (N N) nucleotides in the sense and antisense strand.
[0254] FIG. 4C : The sense strand comprises 21 nucleotides having 5′- and 3′-terminal cap moieties wherein the two terminal 3′-nucleotides are optionally base paired and wherein all pyrimidine nucleotides that may be present are 2′-O-methyl or 2′-deoxy-2′-fluoro modified nucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein. The antisense strand comprises 21 nucleotides, optionally having a 3′-terminal glyceryl moiety and wherein the two terminal 3′-nucleotides are optionally complementary to the target RNA sequence, and wherein all pyrimidine nucleotides that may be present are 2′-deoxy-2′-fluoro modified nucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein. A modified internucleotide linkage, such as a phosphorothioate, phosphorodithioate or other modified internucleotide linkage as described herein, shown as “s”, optionally connects the (N N) nucleotides in the antisense strand.
[0255] FIG. 4D : The sense strand comprises 21 nucleotides having 5′- and 3′-terminal cap moieties wherein the two terminal 3′-nucleotides are optionally base paired and wherein all pyrimidine nucleotides that may be present are 2′-deoxy-2′-fluoro modified nucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein and wherein and all purine nucleotides that may be present are 2′-deoxy nucleotides. The antisense strand comprises 21 nucleotides, optionally having a 3′-terminal glyceryl moiety and wherein the two terminal 3′-nucleotides are optionally complementary to the target RNA sequence, wherein all pyrimidine nucleotides that may be present are 2′-deoxy-2′-fluoro modified nucleotides and all purine nucleotides that may be present are 2′-O-methyl modified nucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein. A modified internucleotide linkage, such as a phosphorothioate, phosphorodithioate or other modified internucleotide linkage as described herein, shown as “s”, optionally connects the (N N) nucleotides in the antisense strand.
[0256] FIG. 4E : The sense strand comprises 21 nucleotides having 5′- and 3′-terminal cap moieties wherein the two terminal 3′-nucleotides are optionally base paired and wherein all pyrimidine nucleotides that may be present are 2′-deoxy-2′-fluoro modified nucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein. The antisense strand comprises 21 nucleotides, optionally having a 3′-terminal glyceryl moiety and wherein the two terminal 3′-nucleotides are optionally complementary to the target RNA sequence, and wherein all pyrimidine nucleotides that may be present are 2′-deoxy-2′-fluoro modified nucleotides and all purine nucleotides that may be present are 2′-O-methyl modified nucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein. A modified internucleotide linkage, such as a phosphorothioate, phosphorodithioate or other modified internucleotide linkage as described herein, shown as “s”, optionally connects the (N N) nucleotides in the antisense strand.
[0257] FIG. 4F : The sense strand comprises 21 nucleotides having 5′- and 3′-terminal cap moieties wherein the two terminal 3′-nucleotides are optionally base paired and wherein all pyrimidine nucleotides that may be present are 2′-deoxy-2′-fluoro modified nucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein and wherein and all purine nucleotides that may be present are 2′-deoxy nucleotides. The antisense strand comprises 21 nucleotides, optionally having a 3′-terminal glyceryl moiety and wherein the two terminal 3′-nucleotides are optionally complementary to the target RNA sequence, and having one 3′-terminal phosphorothioate internucleotide linkage and wherein all pyrimidine nucleotides that may be present are 2′-deoxy-2′-fluoro modified nucleotides and all purine nucleotides that may be present are 2′-deoxy nucleotides except for (N N) nucleotides, which can comprise ribonucleotides, deoxynucleotides, universal bases, or other chemical modifications described herein. A modified internucleotide linkage, such as a phosphorothioate, phosphorodithioate or other modified internucleotide linkage as described herein, shown as “s”, optionally connects the (N N) nucleotides in the antisense strand.
[0258] FIG. 5A-F shows non-limiting examples of specific chemically-modified siNA sequences of the invention. A-F applies the chemical modifications described in FIG. 4A-F to an IL-4R siNA sequence. Such chemical modifications can be applied to any interleukin and/or interleukin receptor sequence and/or interleukin and/or interleukin receptor polymorphism sequence.
[0259] FIG. 6 shows non-limiting examples of different siNA constructs of the invention. The examples shown (constructs 1 , 2 , and 3 ) have 19 representative base pairs; however, different embodiments of the invention include any number of base pairs described herein. Bracketed regions represent nucleotide overhangs, for example comprising about 1, 2, 3, or 4 nucleotides in length, preferably about 2 nucleotides. Constructs 1 and 2 can be used independently for RNAi activity. Construct 2 can comprise a polynucleotide or non-nucleotide linker, which can optionally be designed as a biodegradable linker. In one embodiment, the loop structure shown in construct 2 can comprise a biodegradable linker that results in the formation of construct 1 in vivo and/or in vitro. In another example, construct 3 can be used to generate construct 2 under the same principle wherein a linker is used to generate the active siNA construct 2 in vivo and/or in vitro, which can optionally utilize another biodegradable linker to generate the active siNA construct 1 in vivo and/or in vitro. As such, the stability and/or activity of the siNA constructs can be modulated based on the design of the siNA construct for use in vivo or in vitro and/or in vitro.
[0260] FIG. 7A-C is a diagrammatic representation of a scheme utilized in generating an expression cassette to generate siNA hairpin constructs.
[0261] FIG. 7A : A DNA oligomer is synthesized with a 5′-restriction site (R1) sequence followed by a region having sequence identical (sense region of siNA) to a predetermined interleukin and/or interleukin receptor target sequence, wherein the sense region comprises, for example, about 19, 20, 21, or 22 nucleotides (N) in length, which is followed by a loop sequence of defined sequence (X), comprising, for example, about 3 to about 10 nucleotides.
[0262] FIG. 7B : The synthetic construct is then extended by DNA polymerase to generate a hairpin structure having self-complementary sequence that will result in an siNA transcript having specificity for a interleukin and/or interleukin receptor target sequence and having self-complementary sense and antisense regions.
[0263] FIG. 7C : The construct is heated (for example to about 95° C.) to linearize the sequence, thus allowing extension of a complementary second DNA strand using a primer to the 3′-restriction sequence of the first strand. The double-stranded DNA is then inserted into an appropriate vector for expression in cells. The construct can be designed such that a 3′-terminal nucleotide overhang results from the transcription, for example by engineering restriction sites and/or utilizing a poly-U termination region as described in Paul et al., 2002 , Nature Biotechnology, 29, 505-508.
[0264] FIG. 8A-C is a diagrammatic representation of a scheme utilized in generating an expression cassette to generate double-stranded siNA constructs.
[0265] FIG. 8A : A DNA oligomer is synthesized with a 5′-restriction (R1) site sequence followed by a region having sequence identical (sense region of siNA) to a predetermined interleukin and/or interleukin receptor target sequence, wherein the sense region comprises, for example, about 19, 20, 21, or 22 nucleotides (N) in length, and which is followed by a 3′-restriction site (R2) which is adjacent to a loop sequence of defined sequence (X).
[0266] FIG. 8B : The synthetic construct is then extended by DNA polymerase to generate a hairpin structure having self-complementary sequence.
[0267] FIG. 8C : The construct is processed by restriction enzymes specific to R1 and R2 to generate a double-stranded DNA which is then inserted into an appropriate vector for expression in cells. The transcription cassette is designed such that a U6 promoter region flanks each side of the dsDNA which generates the separate sense and antisense strands of the siNA. Poly T termination sequences can be added to the constructs to generate U overhangs in the resulting transcript.
[0268] FIG. 9A-E is a diagrammatic representation of a method used to determine target sites for siNA mediated RNAi within a particular target nucleic acid sequence, such as messenger RNA.
[0269] FIG. 9A : A pool of siNA oligonucleotides are synthesized wherein the antisense region of the siNA constructs has complementarity to target sites across the target nucleic acid sequence, and wherein the sense region comprises sequence complementary to the antisense region of the siNA.
[0270] FIGS. 9B&C : ( FIG. 9B ) The sequences are pooled and are inserted into vectors such that ( FIG. 9C ) transfection of a vector into cells results in the expression of the siNA.
[0271] FIG. 9D : Cells are sorted based on phenotypic change that is associated with modulation of the target nucleic acid sequence.
[0272] FIG. 9E : The siNA is isolated from the sorted cells and is sequenced to identify efficacious target sites within the target nucleic acid sequence.
[0273] FIG. 10 shows non-limiting examples of different stabilization chemistries (1-10) that can be used, for example, to stabilize the 3′-end of siNA sequences of the invention, including (1) [3-3′]-inverted deoxyribose; (2) deoxyribonucleotide; (3) [5′-3′]-3′-deoxyribonucleotide; (4) [5′-3′]-ribonucleotide; (5) [5′-3′]-3′-O-methyl ribonucleotide; (6) 3′-glyceryl; (7) [3′-5′]-3′-deoxyribonucleotide; (8) [3′-3′]-deoxyribonucleotide; (9) [5′-2′]-deoxyribonucleotide; and (10) [5-3′]-dideoxyribonucleotide. In addition to modified and unmodified backbone chemistries indicated in the figure, these chemistries can be combined with different backbone modifications as described herein, for example, backbone modifications having Formula I. In addition, the 2′-deoxy nucleotide shown 5′ to the terminal modifications shown can be another modified or unmodified nucleotide or non-nucleotide described herein, for example modifications having any of Formulae I-VII or any combination thereof.
[0274] FIG. 11 shows a non-limiting example of a strategy used to identify chemically modified siNA constructs of the invention that are nuclease resistance while preserving the ability to mediate RNAi activity. Chemical modifications are introduced into the siNA construct based on educated design parameters (e.g. introducing 2′-modifications, base modifications, backbone modifications, terminal cap modifications etc). The modified construct in tested in an appropriate system (e.g. human serum for nuclease resistance, shown, or an animal model for PK/delivery parameters). In parallel, the siNA construct is tested for RNAi activity, for example in a cell culture system such as a luciferase reporter assay). Lead siNA constructs are then identified which possess a particular characteristic while maintaining RNAi activity, and can be further modified and assayed once again. This same approach can be used to identify siNA-conjugate molecules with improved pharmacokinetic profiles, delivery, and RNAi activity.
[0275] FIG. 12 shows non-limiting examples of phosphorylated siNA molecules of the invention, including linear and duplex constructs and asymmetric derivatives thereof.
[0276] FIG. 13 shows non-limiting examples of chemically modified terminal phosphate groups of the invention.
[0277] FIG. 14A shows a non-limiting example of methodology used to design self complementary DFO constructs utilizing palindrome and/or repeat nucleic acid sequences that are identified in a target nucleic acid sequence. (i) A palindrome or repeat sequence is identified in a nucleic acid target sequence. (ii) A sequence is designed that is complementary to the target nucleic acid sequence and the palindrome sequence. (iii) An inverse repeat sequence of the non-palindrome/repeat portion of the complementary sequence is appended to the 3′-end of the complementary sequence to generate a self complementary DFO molecule comprising sequence complementary to the nucleic acid target. (iv) The DFO molecule can self-assemble to form a double-stranded oligonucleotide. FIG. 14B shows a non-limiting representative example of a duplex forming oligonucleotide sequence. FIG. 14C shows a non-limiting example of the self assembly schematic of a representative duplex forming oligonucleotide sequence. FIG. 14D shows a non-limiting example of the self assembly schematic of a representative duplex forming oligonucleotide sequence followed by interaction with a target nucleic acid sequence resulting in modulation of gene expression.
[0278] FIG. 15 shows a non-limiting example of the design of self complementary DFO constructs utilizing palindrome and/or repeat nucleic acid sequences that are incorporated into the DFO constructs that have sequence complementary to any target nucleic acid sequence of interest. Incorporation of these palindrome/repeat sequences allow the design of DFO constructs that form duplexes in which each strand is capable of mediating modulation of target gene expression, for example by RNAi. First, the target sequence is identified. A complementary sequence is then generated in which nucleotide or non-nucleotide modifications (shown as X or Y) are introduced into the complementary sequence that generate an artificial palindrome (shown as XYXYXY in the Figure). An inverse repeat of the non-palindrome/repeat complementary sequence is appended to the 3′-end of the complementary sequence to generate a self complementary DFO comprising sequence complementary to the nucleic acid target. The DFO can self-assemble to form a double-stranded oligonucleotide.
[0279] FIG. 16 shows non-limiting examples of multifunctional siNA molecules of the invention comprising two separate polynucleotide sequences that are each capable of mediating RNAi directed cleavage of differing target nucleic acid sequences. FIG. 16A shows a non-limiting example of a multifunctional siNA molecule having a first region that is complementary to a first target nucleic acid sequence (complementary region 1 ) and a second region that is complementary to a second target nucleic acid sequence (complementary region 2 ), wherein the first and second complementary regions are situated at the 3′-ends of each polynucleotide sequence in the multifunctional siNA. The dashed portions of each polynucleotide sequence of the multifunctional siNA construct have complementarity with regard to corresponding portions of the siNA duplex, but do not have complementarity to the target nucleic acid sequences. FIG. 16B shows a non-limiting example of a multifunctional siNA molecule having a first region that is complementary to a first target nucleic acid sequence (complementary region 1 ) and a second region that is complementary to a second target nucleic acid sequence (complementary region 2 ), wherein the first and second complementary regions are situated at the 5′-ends of each polynucleotide sequence in the multifunctional siNA. The dashed portions of each polynucleotide sequence of the multifunctional siNA construct have complementarity with regard to corresponding portions of the siNA duplex, but do not have complementarity to the target nucleic acid sequences.
[0280] FIG. 17 shows non-limiting examples of multifunctional siNA molecules of the invention comprising a single polynucleotide sequence comprising distinct regions that are each capable of mediating RNAi directed cleavage of differing target nucleic acid sequences. FIG. 17A shows a non-limiting example of a multifunctional siNA molecule having a first region that is complementary to a first target nucleic acid sequence (complementary region 1 ) and a second region that is complementary to a second target nucleic acid sequence (complementary region 2 ), wherein the second complementary region is situated at the 3′-end of the polynucleotide sequence in the multifunctional siNA. The dashed portions of each polynucleotide sequence of the multifunctional siNA construct have complementarity with regard to corresponding portions of the siNA duplex, but do not have complementarity to the target nucleic acid sequences. FIG. 17B shows a non-limiting example of a multifunctional siNA molecule having a first region that is complementary to a first target nucleic acid sequence (complementary region 1 ) and a second region that is complementary to a second target nucleic acid sequence (complementary region 2 ), wherein the first complementary region is situated at the 5′-end of the polynucleotide sequence in the multifunctional siNA. The dashed portions of each polynucleotide sequence of the multifunctional siNA construct have complementarity with regard to corresponding portions of the siNA duplex, but do not have complementarity to the target nucleic acid sequences. In one embodiment, these multifunctional siNA constructs are processed in vivo or in vitro to generate multifunctional siNA constructs as shown in FIG. 16 .
[0281] FIG. 18 shows non-limiting examples of multifunctional siNA molecules of the invention comprising two separate polynucleotide sequences that are each capable of mediating RNAi directed cleavage of differing target nucleic acid sequences and wherein the multifunctional siNA construct further comprises a self complementary, palindrome, or repeat region, thus enabling shorter bifunctional siNA constructs that can mediate RNA interference against differing target nucleic acid sequences. FIG. 18A shows a non-limiting example of a multifunctional siNA molecule having a first region that is complementary to a first target nucleic acid sequence (complementary region 1 ) and a second region that is complementary to a second target nucleic acid sequence (complementary region 2 ), wherein the first and second complementary regions are situated at the 3′-ends of each polynucleotide sequence in the multifunctional siNA, and wherein the first and second complementary regions further comprise a self complementary, palindrome, or repeat region. The dashed portions of each polynucleotide sequence of the multifunctional siNA construct have complementarity with regard to corresponding portions of the siNA duplex, but do not have complementarity to the target nucleic acid sequences. FIG. 18B shows a non-limiting example of a multifunctional siNA molecule having a first region that is complementary to a first target nucleic acid sequence (complementary region 1 ) and a second region that is complementary to a second target nucleic acid sequence (complementary region 2 ), wherein the first and second complementary regions are situated at the 5′-ends of each polynucleotide sequence in the multifunctional siNA, and wherein the first and second complementary regions further comprise a self complementary, palindrome, or repeat region. The dashed portions of each polynucleotide sequence of the multifunctional siNA construct have complementarity with regard to corresponding portions of the siNA duplex, but do not have complementarity to the target nucleic acid sequences.
[0282] FIG. 19 shows non-limiting examples of multifunctional siNA molecules of the invention comprising a single polynucleotide sequence comprising distinct regions that are each capable of mediating RNAi directed cleavage of differing target nucleic acid sequences and wherein the multifunctional siNA construct further comprises a self complementary, palindrome, or repeat region, thus enabling shorter bifunctional siNA constructs that can mediate RNA interference against differing target nucleic acid sequences. FIG. 19A shows a non-limiting example of a multifunctional siNA molecule having a first region that is complementary to a first target nucleic acid sequence (complementary region 1 ) and a second region that is complementary to a second target nucleic acid sequence (complementary region 2 ), wherein the second complementary region is situated at the 3′-end of the polynucleotide sequence in the multifunctional siNA, and wherein the first and second complementary regions further comprise a self complementary, palindrome, or repeat region. The dashed portions of each polynucleotide sequence of the multifunctional siNA construct have complementarity with regard to corresponding portions of the siNA duplex, but do not have complementarity to the target nucleic acid sequences. FIG. 19B shows a non-limiting example of a multifunctional siNA molecule having a first region that is complementary to a first target nucleic acid sequence (complementary region 1 ) and a second region that is complementary to a second target nucleic acid sequence (complementary region 2 ), wherein the first complementary region is situated at the 5′-end of the polynucleotide sequence in the multifunctional siNA, and wherein the first and second complementary regions further comprise a self complementary, palindrome, or repeat region. The dashed portions of each polynucleotide sequence of the multifunctional siNA construct have complementarity with regard to corresponding portions of the siNA duplex, but do not have complementarity to the target nucleic acid sequences. In one embodiment, these multifunctional siNA constructs are processed in vivo or in vitro to generate multifunctional siNA constructs as shown in FIG. 18 .
[0283] FIG. 20 shows a non-limiting example of how multifunctional siNA molecules of the invention can target two separate target nucleic acid molecules, such as separate RNA molecules encoding differing proteins, for example a cytokine and its corresponding receptor, differing viral strains, a virus and a cellular protein involved in viral infection or replication, or differing proteins involved in a common or divergent biologic pathway that is implicated in the maintenance of progression of disease. Each strand of the multifunctional siNA construct comprises a region having complementarity to separate target nucleic acid molecules. The multifunctional siNA molecule is designed such that each strand of the siNA can be utilized by the RISC complex to initiate RNA interference mediated cleavage of its corresponding target. These design parameters can include destabilization of each end of the siNA construct (see for example Schwarz et al., 2003 , Cell, 115, 199-208). Such destabilization can be accomplished for example by using guanosine-cytidine base pairs, alternate base pairs (e.g., wobbles), or destabilizing chemically modified nucleotides at terminal nucleotide positions as is known in the art.
[0284] FIG. 21 shows a non-limiting example of how multifunctional siNA molecules of the invention can target two separate target nucleic acid sequences within the same target nucleic acid molecule, such as alternate coding regions of a RNA, coding and non-coding regions of a RNA, or alternate splice variant regions of a RNA. Each strand of the multifunctional siNA construct comprises a region having complementarity to the separate regions of the target nucleic acid molecule. The multifunctional siNA molecule is designed such that each strand of the siNA can be utilized by the RISC complex to initiate RNA interference mediated cleavage of its corresponding target region. These design parameters can include destabilization of each end of the siNA construct (see for example Schwarz et al., 2003 , Cell, 115, 199-208). Such destabilization can be accomplished for example by using guanosine-cytidine base pairs, alternate base pairs (e.g., wobbles), or destabilizing chemically modified nucleotides at terminal nucleotide positions as is known in the art.
[0285] FIG. 22 shows a non-limiting example of reduction of IL-4R mRNA in HeLa cells mediated by siNAs that target IL-4R mRNA. HeLa cells were transfected with 0.25 ug/well of lipid complexed with 25 nM siNA. Active siNA constructs comprising Stab 9/22 stabilization chemistry were compared to matched chemistry irrelevant siNA control constructs (IC), and cells transfected with lipid alone (transfection control). As shown in the figure, the siNA constructs significantly reduce IL-4R RNA expression.
DETAILED DESCRIPTION OF THE INVENTION
Mechanism of Action of Nucleic Acid Molecules of the Invention
[0286] The discussion that follows discusses the proposed mechanism of RNA interference mediated by short interfering RNA as is presently known, and is not meant to be limiting and is not an admission of prior art. Applicant demonstrates herein that chemically-modified short interfering nucleic acids possess similar or improved capacity to mediate RNAi as do siRNA molecules and are expected to possess improved stability and activity in vivo; therefore, this discussion is not meant to be limiting only to siRNA and can be applied to siNA as a whole. By “improved capacity to mediate RNAi” or “improved RNAi activity” is meant to include RNAi activity measured in vitro and/or in vivo where the RNAi activity is a reflection of both the ability of the siNA to mediate RNAi and the stability of the siNAs of the invention. In this invention, the product of these activities can be increased in vitro and/or in vivo compared to an all RNA siRNA or an siNA containing a plurality of ribonucleotides. In some cases, the activity or stability of the siNA molecule can be decreased (i.e., less than ten-fold), but the overall activity of the siNA molecule is enhanced in vitro and/or in vivo.
[0287] RNA interference refers to the process of sequence specific post-transcriptional gene silencing in animals mediated by short interfering RNAs (siRNAs) (Fire et al., 1998 , Nature, 391, 806). The corresponding process in plants is commonly referred to as post-transcriptional gene silencing or RNA silencing and is also referred to as quelling in fungi. The process of post-transcriptional gene silencing is thought to be an evolutionarily-conserved cellular defense mechanism used to prevent the expression of foreign genes which is commonly shared by diverse flora and phyla (Fire et al., 1999 , Trends Genet., 15, 358). Such protection from foreign gene expression may have evolved in response to the production of double-stranded RNAs (dsRNAs) derived from viral infection or the random integration of transposon elements into a host genome via a cellular response that specifically destroys homologous single-stranded RNA or viral genomic RNA. The presence of dsRNA in cells triggers the RNAi response though a mechanism that has yet to be fully characterized. This mechanism appears to be different from the interferon response that results from dsRNA-mediated activation of protein kinase PKR and 2′,5′-oligoadenylate synthetase resulting in non-specific cleavage of mRNA by ribonuclease L.
[0288] The presence of long dsRNAs in cells stimulates the activity of a ribonuclease III enzyme referred to as Dicer. Dicer is involved in the processing of the dsRNA into short pieces of dsRNA known as short interfering RNAs (siRNAs) (Berstein et al., 2001 , Nature, 409, 363). Short interfering RNAs derived from Dicer activity are typically about 21 to about 23 nucleotides in length and comprise about 19 base pair duplexes. Dicer has also been implicated in the excision of 21- and 22-nucleotide small temporal RNAs (stRNAs) from precursor RNA of conserved structure that are implicated in translational control (Hutvagner et al., 2001 , Science, 293, 834). The RNAi response also features an endonuclease complex containing an siRNA, commonly referred to as an RNA-induced silencing complex (RISC), which mediates cleavage of single-stranded RNA having sequence homologous to the siRNA. Cleavage of the target RNA takes place in the middle of the region complementary to the guide sequence of the siRNA duplex (Elbashir et al., 2001 , Genes Dev., 15, 188). In addition, RNA interference can also involve small RNA (e.g., micro-RNA or miRNA) mediated gene silencing, presumably though cellular mechanisms that regulate chromatin structure and thereby prevent transcription of target gene sequences (see for example Allshire, 2002 , Science, 297, 1818-1819; Volpe et al., 2002 , Science, 297, 1833-1837; Jenuwein, 2002 , Science, 297, 2215-2218; and Hall et al., 2002 , Science, 297, 2232-2237). As such, siNA molecules of the invention can be used to mediate gene silencing via interaction with RNA transcripts or alternately by interaction with particular gene sequences, wherein such interaction results in gene silencing either at the transcriptional level or post-transcriptional level.
[0289] RNAi has been studied in a variety of systems. Fire et al., 1998 , Nature, 391, 806, were the first to observe RNAi in C. elegans . Wianny and Goetz, 1999 , Nature Cell Biol., 2, 70, describe RNAi mediated by dsRNA in mouse embryos. Hammond et al., 2000, Nature, 404, 293, describe RNAi in Drosophila cells transfected with dsRNA. Elbashir et al., 2001 , Nature, 411, 494, describe RNAi induced by introduction of duplexes of synthetic 21-nucleotide RNAs in cultured mammalian cells including human embryonic kidney and HeLa cells. Recent work in Drosophila embryonic lysates has revealed certain requirements for siRNA length, structure, chemical composition, and sequence that are essential to mediate efficient RNAi activity. These studies have shown that 21 nucleotide siRNA duplexes are most active when containing two 2-nucleotide 3′-terminal nucleotide overhangs. Furthermore, substitution of one or both siRNA strands with 2′-deoxy or 2′-O-methyl nucleotides abolishes RNAi activity, whereas substitution of 3′-terminal siRNA nucleotides with deoxy nucleotides was shown to be tolerated. Mismatch sequences in the center of the siRNA duplex were also shown to abolish RNAi activity. In addition, these studies also indicate that the position of the cleavage site in the target RNA is defined by the 5′-end of the siRNA guide sequence rather than the 3′-end (Elbashir et al., 2001 , EMBO J., 20, 6877). Other studies have indicated that a 5′-phosphate on the target-complementary strand of an siRNA duplex is required for siRNA activity and that ATP is utilized to maintain the 5′-phosphate moiety on the siRNA (Nykanen et al., 2001 , Cell, 107, 309); however, siRNA molecules lacking a 5′-phosphate are active when introduced exogenously, suggesting that 5′-phosphorylation of siRNA constructs may occur in vivo.
Synthesis of Nucleic Acid Molecules
[0290] Synthesis of nucleic acids greater than 100 nucleotides in length is difficult using automated methods, and the therapeutic cost of such molecules is prohibitive. In this invention, small nucleic acid motifs (“small” refers to nucleic acid motifs no more than 100 nucleotides in length, preferably no more than 80 nucleotides in length, and most preferably no more than 50 nucleotides in length; e.g., individual siNA oligonucleotide sequences or siNA sequences synthesized in tandem) are preferably used for exogenous delivery. The simple structure of these molecules increases the ability of the nucleic acid to invade targeted regions of protein and/or RNA structure. Exemplary molecules of the instant invention are chemically synthesized, and others can similarly be synthesized.
[0291] Oligonucleotides (e.g., certain modified oligonucleotides or portions of oligonucleotides lacking ribonucleotides) are synthesized using protocols known in the art, for example as described in Caruthers et al., 1992 , Methods in Enzymology 211, 3-19, Thompson et al., International PCT Publication No. WO 99/54459, Wincott et al., 1995 , Nucleic Acids Res. 23, 2677-2684, Wincott et al., 1997 , Methods Mol. Bio., 74, 59, Brennan et al., 1998 , Biotechnol Bioeng., 61, 33-45, and Brennan, U.S. Pat. No. 6,001,311. All of these references are incorporated herein by reference. The synthesis of oligonucleotides makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 2.5 min coupling step for 2′-O-methylated nucleotides and a 45 second coupling step for 2′-deoxy nucleotides or 2′-deoxy-2′-fluoro nucleotides. Table V outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be performed on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, Calif.) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M=6.6 μmol) of 2′-O-methyl phosphoramidite and a 105-fold excess of S-ethyl tetrazole (60 μL of 0.25 M=15 μmol) can be used in each coupling cycle of 2′-O-methyl residues relative to polymer-bound 5′-hydroxyl. A 22-fold excess (40 μL of 0.11 M=4.4 μmol) of deoxy phosphoramidite and a 70-fold excess of S-ethyl tetrazole (40 μL of 0.25 M=10 μmol) can be used in each coupling cycle of deoxy residues relative to polymer-bound 5′-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include the following: detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); and oxidation solution is 16.9 mM 12, 49 mM pyridine, 9% water in THF (PerSeptive Biosystems, Inc.). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2-benzodithiol-3-one 1,1-dioxide, 0.05 M in acetonitrile) is used.
[0292] Deprotection of the DNA-based oligonucleotides is performed as follows: the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aqueous methylamine (1 mL) at 65° C. for 10 minutes. After cooling to −20° C., the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H 2 O/3:1:1, vortexed and the supernatant is then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, are dried to a white powder.
[0293] The method of synthesis used for RNA including certain siNA molecules of the invention follows the procedure as described in Usman et al., 1987 , J. Am. Chem. Soc., 109, 7845; Scaringe et al., 1990 , Nucleic Acids Res., 18, 5433; and Wincott et al., 1995 , Nucleic Acids Res. 23, 2677-2684 Wincott et al., 1997 , Methods Mol. Bio., 74, 59, and makes use of common nucleic acid protecting and coupling groups, such as dimethoxytrityl at the 5′-end, and phosphoramidites at the 3′-end. In a non-limiting example, small scale syntheses are conducted on a 394 Applied Biosystems, Inc. synthesizer using a 0.2 μmol scale protocol with a 7.5 min coupling step for alkylsilyl protected nucleotides and a 2.5 min coupling step for 2′-O-methylated nucleotides. Table V outlines the amounts and the contact times of the reagents used in the synthesis cycle. Alternatively, syntheses at the 0.2 μmol scale can be done on a 96-well plate synthesizer, such as the instrument produced by Protogene (Palo Alto, Calif.) with minimal modification to the cycle. A 33-fold excess (60 μL of 0.11 M=6.6 μmol) of 2′-O-methyl phosphoramidite and a 75-fold excess of S-ethyl tetrazole (60 μL of 0.25 M=15 μmol) can be used in each coupling cycle of 2′-O-methyl residues relative to polymer-bound 5′-hydroxyl. A 66-fold excess (120 μL of 0.11 M=13.2 μmol) of alkylsilyl (ribo) protected phosphoramidite and a 150-fold excess of S-ethyl tetrazole (120 μL of 0.25 M=30 μmol) can be used in each coupling cycle of ribo residues relative to polymer-bound 5′-hydroxyl. Average coupling yields on the 394 Applied Biosystems, Inc. synthesizer, determined by colorimetric quantitation of the trityl fractions, are typically 97.5-99%. Other oligonucleotide synthesis reagents for the 394 Applied Biosystems, Inc. synthesizer include the following: detritylation solution is 3% TCA in methylene chloride (ABI); capping is performed with 16% N-methyl imidazole in THF (ABI) and 10% acetic anhydride/10% 2,6-lutidine in THF (ABI); oxidation solution is 16.9 mM 12, 49 mM pyridine, 9% water in THF (PerSeptive Biosystems, Inc.). Burdick & Jackson Synthesis Grade acetonitrile is used directly from the reagent bottle. S-Ethyltetrazole solution (0.25 M in acetonitrile) is made up from the solid obtained from American International Chemical, Inc. Alternately, for the introduction of phosphorothioate linkages, Beaucage reagent (3H-1,2-benzodithiol-3-one 1,1-dioxide, 0.05 M in acetonitrile) is used.
[0294] Deprotection of the RNA is performed using either a two-pot or one-pot protocol. For the two-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 40% aq. methylamine (1 mL) at 65° C. for 10 min. After cooling to −20° C., the supernatant is removed from the polymer support. The support is washed three times with 1.0 mL of EtOH:MeCN:H2O/3:1:1, vortexed and the supernatant is then added to the first supernatant. The combined supernatants, containing the oligoribonucleotide, are dried to a white powder. The base deprotected oligoribonucleotide is resuspended in anhydrous TEA/HF/NMP solution (300 μL of a solution of 1.5 mL N-methylpyrrolidinone, 750 μL TEA and 1 mL TEA·3HF to provide a 1.4 M HF concentration) and heated to 65° C. After 1.5 h, the oligomer is quenched with 1.5 M NH 4 HCO 3 .
[0295] Alternatively, for the one-pot protocol, the polymer-bound trityl-on oligoribonucleotide is transferred to a 4 mL glass screw top vial and suspended in a solution of 33% ethanolic methylamine/DMSO:1/1 (0.8 mL) at 65° C. for 15 minutes. The vial is brought to room temperature TEA·3HF (0.1 mL) is added and the vial is heated at 65° C. for 15 minutes. The sample is cooled at −20° C. and then quenched with 1.5 M NH 4 HCO 3 .
[0296] For purification of the trityl-on oligomers, the quenched NH 4 HCO 3 solution is loaded onto a C-18 containing cartridge that had been prewashed with acetonitrile followed by 50 mM TEAA. After washing the loaded cartridge with water, the RNA is detritylated with 0.5% TFA for 13 minutes. The cartridge is then washed again with water, salt exchanged with 1 M NaCl and washed with water again. The oligonucleotide is then eluted with 30% acetonitrile.
[0297] The average stepwise coupling yields are typically >98% (Wincott et al., 1995 Nucleic Acids Res. 23, 2677-2684). Those of ordinary skill in the art will recognize that the scale of synthesis can be adapted to be larger or smaller than the example described above including but not limited to 96-well format.
[0298] Alternatively, the nucleic acid molecules of the present invention can be synthesized separately and joined together post-synthetically, for example, by ligation (Moore et al., 1992 , Science 256, 9923; Draper et al., International PCT publication No. WO 93/23569; Shabarova et al., 1991 , Nucleic Acids Research 19, 4247; Bellon et al., 1997 , Nucleosides & Nucleotides, 16, 951; Bellon et al., 1997 , Bioconjugate Chem. 8, 204), or by hybridization following synthesis and/or deprotection.
[0299] The siNA molecules of the invention can also be synthesized via a tandem synthesis methodology as described in Example 1 herein, wherein both siNA strands are synthesized as a single contiguous oligonucleotide fragment or strand separated by a cleavable linker which is subsequently cleaved to provide separate siNA fragments or strands that hybridize and permit purification of the siNA duplex. The linker can be a polynucleotide linker or a non-nucleotide linker. The tandem synthesis of siNA as described herein can be readily adapted to both multiwell/multiplate synthesis platforms such as 96 well or similarly larger multi-well platforms. The tandem synthesis of siNA as described herein can also be readily adapted to large scale synthesis platforms employing batch reactors, synthesis columns and the like.
[0300] An siNA molecule can also be assembled from two distinct nucleic acid strands or fragments wherein one fragment includes the sense region and the second fragment includes the antisense region of the RNA molecule.
[0301] The nucleic acid molecules of the present invention can be modified extensively to enhance stability by modification with nuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-fluoro, 2′-O-methyl, 2′-H (for a review see Usman and Cedergren, 1992 , TIBS 17, 34; Usman et al., 1994 , Nucleic Acids Symp. Ser. 31, 163). siNA constructs can be purified by gel electrophoresis using general methods or can be purified by high pressure liquid chromatography (HPLC; see Wincott et al., supra, the totality of which is hereby incorporated herein by reference) and re-suspended in water.
[0302] In another aspect of the invention, siNA molecules of the invention are expressed from transcription units inserted into DNA or RNA vectors. The recombinant vectors can be DNA plasmids or viral vectors. siNA expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. The recombinant vectors capable of expressing the siNA molecules can be delivered as described herein, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of siNA molecules.
Optimizing Activity of the Nucleic Acid Molecule of the Invention.
[0303] Chemically synthesizing nucleic acid molecules with modifications (base, sugar and/or phosphate) can prevent their degradation by serum ribonucleases, which can increase their potency (see e.g., Eckstein et al., International Publication No. WO 92/07065; Perrault et al., 1990 Nature 344, 565; Pieken et al., 1991 , Science 253, 314; Usman and Cedergren, 1992 , Trends in Biochem. Sci. 17, 334; Usman et al., International Publication No. WO 93/15187; and Rossi et al., International Publication No. WO 91/03162; Sproat, U.S. Pat. No. 5,334,711; Gold et al., U.S. Pat. No. 6,300,074; and Burgin et al., supra; all of which are incorporated by reference herein). All of the above references describe various chemical modifications that can be made to the base, phosphate and/or sugar moieties of the nucleic acid molecules described herein. Modifications that enhance their efficacy in cells, and removal of bases from nucleic acid molecules to shorten oligonucleotide synthesis times and reduce chemical requirements are desired.
[0304] There are several examples in the art describing sugar, base and phosphate modifications that can be introduced into nucleic acid molecules with significant enhancement in their nuclease stability and efficacy. For example, oligonucleotides are modified to enhance stability and/or enhance biological activity by modification with nuclease resistant groups, for example, 2′-amino, 2′-C-allyl, 2′-fluoro, 2′-O-methyl, 2′-O-allyl, 2′-H, nucleotide base modifications (for a review see Usman and Cedergren, 1992 , TIBS. 17, 34; Usman et al., 1994 , Nucleic Acids Symp. Ser. 31, 163; Burgin et al., 1996 , Biochemistry, 35, 14090). Sugar modification of nucleic acid molecules have been extensively described in the art (see Eckstein et al., International Publication PCT No. WO 92/07065; Perrault et al. Nature, 1990, 344, 565-568; Pieken et al. Science, 1991, 253, 314-317; Usman and Cedergren, Trends in Biochem. Sci., 1992, 17, 334-339; Usman et al. International Publication PCT No. WO 93/15187; Sproat, U.S. Pat. No. 5,334,711 and Beigelman et al., 1995 , J. Biol. Chem., 270, 25702; Beigelman et al., International PCT publication No. WO 97/26270; Beigelman et al., U.S. Pat. No. 5,716,824; Usman et al., U.S. Pat. No. 5,627,053; Woolf et al., International PCT Publication No. WO 98/13526; Thompson et al., U.S. Ser. No. 60/082,404 which was filed on Apr. 20, 1998; Karpeisky et al., 1998 , Tetrahedron Lett., 39, 1131; Earnshaw and Gait, 1998 , Biopolymers ( Nucleic Acid Sciences ), 48, 39-55; Verma and Eckstein, 1998 , Annu. Rev. Biochem., 67, 99-134; and Burlina et al., 1997 , Bioorg. Med. Chem., 5, 1999-2010; all of the references are hereby incorporated in their totality by reference herein). Such publications describe general methods and strategies to determine the location of incorporation of sugar, base and/or phosphate modifications and the like into nucleic acid molecules without modulating catalysis, and are incorporated by reference herein. In view of such teachings, similar modifications can be used as described herein to modify the siNA nucleic acid molecules of the instant invention so long as the ability of siNA to promote RNAi is cells is not significantly inhibited.
[0305] While chemical modification of oligonucleotide internucleotide linkages with phosphorothioate, phosphorodithioate, and/or 5′-methylphosphonate linkages improves stability, excessive modifications can cause some toxicity or decreased activity. Therefore, when designing nucleic acid molecules, the amount of these internucleotide linkages should be minimized. The reduction in the concentration of these linkages should lower toxicity, resulting in increased efficacy and higher specificity of these molecules.
[0306] Short interfering nucleic acid (siNA) molecules having chemical modifications that maintain or enhance activity are provided. Such a nucleic acid is also generally more resistant to nucleases than an unmodified nucleic acid. Accordingly, the in vitro and/or in vivo activity should not be significantly lowered. In cases in which modulation is the goal, therapeutic nucleic acid molecules delivered exogenously should optimally be stable within cells until translation of the target RNA has been modulated long enough to reduce the levels of the undesirable protein. This period of time varies between hours to days depending upon the disease state. Improvements in the chemical synthesis of RNA and DNA (Wincott et al., 1995 , Nucleic Acids Res. 23, 2677; Caruthers et al., 1992 , Methods in Enzymology 211, 3-19 (incorporated by reference herein)) have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability, as described above.
[0307] In one embodiment, nucleic acid molecules of the invention include one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) G-clamp nucleotides. A G-clamp nucleotide is a modified cytosine analog wherein the modifications confer the ability to hydrogen bond both Watson-Crick and Hoogsteen faces of a complementary guanine within a duplex, see for example Lin and Matteucci, 1998 , J. Am. Chem. Soc., 120, 8531-8532. A single G-clamp analog substitution within an oligonucleotide can result in substantially enhanced helical thermal stability and mismatch discrimination when hybridized to complementary oligonucleotides. The inclusion of such nucleotides in nucleic acid molecules of the invention results in both enhanced affinity and specificity to nucleic acid targets, complementary sequences, or template strands. In another embodiment, nucleic acid molecules of the invention include one or more (e.g., about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) LNA “locked nucleic acid” nucleotides such as a 2′,4′-C methylene bicyclo nucleotide (see for example Wengel et al., International PCT Publication No. WO 00/66604 and WO 99/14226).
[0308] In another embodiment, the invention features conjugates and/or complexes of siNA molecules of the invention. Such conjugates and/or complexes can be used to facilitate delivery of siNA molecules into a biological system, such as a cell. The conjugates and complexes provided by the instant invention can impart therapeutic activity by transferring therapeutic compounds across cellular membranes, altering the pharmacokinetics, and/or modulating the localization of nucleic acid molecules of the invention. The present invention encompasses the design and synthesis of novel conjugates and complexes for the delivery of molecules, including, but not limited to, small molecules, lipids, cholesterol, phospholipids, nucleosides, nucleotides, nucleic acids, antibodies, toxins, negatively charged polymers and other polymers, for example proteins, peptides, hormones, carbohydrates, polyethylene glycols, or polyamines, across cellular membranes. In general, the transporters described are designed to be used either individually or as part of a multi-component system, with or without degradable linkers. These compounds are expected to improve delivery and/or localization of nucleic acid molecules of the invention into a number of cell types originating from different tissues, in the presence or absence of serum (see Sullenger and Cech, U.S. Pat. No. 5,854,038). Conjugates of the molecules described herein can be attached to biologically active molecules via linkers that are biodegradable, such as biodegradable nucleic acid linker molecules.
[0309] The term “biodegradable linker” as used herein, refers to a nucleic acid or non-nucleic acid linker molecule that is designed as a biodegradable linker to connect one molecule to another molecule, for example, a biologically active molecule to an siNA molecule of the invention or the sense and antisense strands of an siNA molecule of the invention. The biodegradable linker is designed such that its stability can be modulated for a particular purpose, such as delivery to a particular tissue or cell type. The stability of a nucleic acid-based biodegradable linker molecule can be modulated by using various chemistries, for example combinations of ribonucleotides, deoxyribonucleotides, and chemically-modified nucleotides, such as 2′-O-methyl, 2′-fluoro, 2′-amino, 2′-O-amino, 2′-C-allyl, 2′-O-allyl, and other 2′-modified or base modified nucleotides. The biodegradable nucleic acid linker molecule can be a dimer, trimer, tetramer or longer nucleic acid molecule, for example, an oligonucleotide of about 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 nucleotides in length, or can comprise a single nucleotide with a phosphorus-based linkage, for example, a phosphoramidate or phosphodiester linkage. The biodegradable nucleic acid linker molecule can also comprise nucleic acid backbone, nucleic acid sugar, or nucleic acid base modifications.
[0310] The term “biodegradable” as used herein, refers to degradation in a biological system, for example enzymatic degradation or chemical degradation.
[0311] The term “biologically active molecule” as used herein, refers to compounds or molecules that are capable of eliciting or modifying a biological response in a system. Non-limiting examples of biologically active siNA molecules either alone or in combination with other molecules contemplated by the instant invention include therapeutically active molecules such as antibodies, cholesterol, hormones, antivirals, peptides, proteins, chemotherapeutics, small molecules, vitamins, co-factors, nucleosides, nucleotides, oligonucleotides, enzymatic nucleic acids, antisense nucleic acids, triplex forming oligonucleotides, 2,5-A chimeras, siNA, dsRNA, allozymes, aptamers, decoys and analogs thereof. Biologically active molecules of the invention also include molecules capable of modulating the pharmacokinetics and/or pharmacodynamics of other biologically active molecules, for example, lipids and polymers such as polyamines, polyamides, polyethylene glycol and other polyethers.
[0312] The term “phospholipid” as used herein, refers to a hydrophobic molecule comprising at least one phosphorus group. For example, a phospholipid can comprise a phosphorus-containing group and saturated or unsaturated alkyl group, optionally substituted with OH, COOH, oxo, amine, or substituted or unsubstituted aryl groups.
[0313] Therapeutic nucleic acid molecules (e.g., siNA molecules) delivered exogenously optimally are stable within cells until reverse transcription of the RNA has been modulated long enough to reduce the levels of the RNA transcript. The nucleic acid molecules are resistant to nucleases in order to function as effective intracellular therapeutic agents. Improvements in the chemical synthesis of nucleic acid molecules described in the instant invention and in the art have expanded the ability to modify nucleic acid molecules by introducing nucleotide modifications to enhance their nuclease stability as described above.
[0314] In yet another embodiment, siNA molecules having chemical modifications that maintain or enhance enzymatic activity of proteins involved in RNAi are provided. Such nucleic acids are also generally more resistant to nucleases than unmodified nucleic acids. Thus, in vitro and/or in vivo the activity should not be significantly lowered.
[0315] Use of the nucleic acid-based molecules of the invention will lead to better treatments by affording the possibility of combination therapies (e.g., multiple siNA molecules targeted to different genes; nucleic acid molecules coupled with known small molecule modulators; or intermittent treatment with combinations of molecules, including different motifs and/or other chemical or biological molecules). The treatment of subjects with siNA molecules can also include combinations of different types of nucleic acid molecules, such as enzymatic nucleic acid molecules (ribozymes), allozymes, antisense, 2,5-A oligoadenylate, decoys, and aptamers.
[0316] In another aspect an siNA molecule of the invention comprises one or more 5′ and/or a 3′-cap structure, for example on only the sense siNA strand, the antisense siNA strand, or both siNA strands.
[0317] By “cap structure” is meant chemical modifications, which have been incorporated at either terminus of the oligonucleotide (see, for example, Adamic et al., U.S. Pat. No. 5,998,203, incorporated by reference herein). These terminal modifications protect the nucleic acid molecule from exonuclease degradation, and may help in delivery and/or localization within a cell. The cap may be present at the 5′-terminus (5′-cap) or at the 3′-terminal (3′-cap) or may be present on both termini. In non-limiting examples, the 5′-cap includes, but is not limited to, glyceryl, inverted deoxy abasic residue (moiety); 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide, 4′-thio nucleotide; carbocyclic nucleotide; 1,5-anhydrohexitol nucleotide; L-nucleotides; alpha-nucleotides; modified base nucleotide; phosphorodithioate linkage; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; acyclic 3,4-dihydroxybutyl nucleotide; acyclic 3,5-dihydroxypentyl nucleotide, 3′-3′-inverted nucleotide moiety; 3′-3′-inverted abasic moiety; 3′-2′-inverted nucleotide moiety; 3′-2′-inverted abasic moiety; 1,4-butanediol phosphate; 3′-phosphoramidate; hexylphosphate; aminohexyl phosphate; 3′-phosphate; 3′-phosphorothioate; phosphorodithioate; or bridging or non-bridging methylphosphonate moiety.
[0318] Non-limiting examples of the 3′-cap include, but are not limited to, glyceryl, inverted deoxy abasic residue (moiety), 4′,5′-methylene nucleotide; 1-(beta-D-erythrofuranosyl) nucleotide; 4′-thio nucleotide, carbocyclic nucleotide; 5′-amino-alkyl phosphate; 1,3-diamino-2-propyl phosphate; 3-aminopropyl phosphate; 6-aminohexyl phosphate; 1,2-aminododecyl phosphate; hydroxypropyl phosphate; 1,5-anhydrohexitol nucleotide; L-nucleotide; alpha-nucleotide; modified base nucleotide; phosphorodithioate; threo-pentofuranosyl nucleotide; acyclic 3′,4′-seco nucleotide; 3,4-dihydroxybutyl nucleotide; 3,5-dihydroxypentyl nucleotide, 5′-5′-inverted nucleotide moiety; 5′-5′-inverted abasic moiety; 5′-phosphoramidate; 5′-phosphorothioate; 1,4-butanediol phosphate; 5′-amino; bridging and/or non-bridging 5′-phosphoramidate, phosphorothioate and/or phosphorodithioate, bridging or non bridging methylphosphonate and 5′-mercapto moieties (for more details see Beaucage and Iyer, 1993 , Tetrahedron 49, 1925; incorporated by reference herein).
[0319] By the term “non-nucleotide” is meant any group or compound which can be incorporated into a nucleic acid chain in the place of one or more nucleotide units, including either sugar and/or phosphate substitutions, and allows the remaining bases to exhibit their enzymatic activity. The group or compound is abasic in that it does not contain a commonly recognized nucleotide base, such as adenosine, guanine, cytosine, uracil or thymine and therefore lacks a base at the 1′-position.
[0320] An “alkyl” group refers to a saturated aliphatic hydrocarbon, including straight-chain, branched-chain, and cyclic alkyl groups. Preferably, the alkyl group has 1 to 12 carbons. More preferably, it is a lower alkyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkyl group can be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, ═O, ═S, NO 2 or N(CH 3 ) 2 , amino, or SH. The term also includes alkenyl groups that are unsaturated hydrocarbon groups containing at least one carbon-carbon double bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkenyl group has 1 to 12 carbons. More preferably, it is a lower alkenyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkenyl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, ═O, ═S, NO 2 , halogen, N(CH 3 ) 2 , amino, or SH. The term “alkyl” also includes alkynyl groups that have an unsaturated hydrocarbon group containing at least one carbon-carbon triple bond, including straight-chain, branched-chain, and cyclic groups. Preferably, the alkynyl group has 1 to 12 carbons. More preferably, it is a lower alkynyl of from 1 to 7 carbons, more preferably 1 to 4 carbons. The alkynyl group may be substituted or unsubstituted. When substituted the substituted group(s) is preferably, hydroxyl, cyano, alkoxy, ═O, ═S, NO 2 or N(CH 3 ) 2 , amino or SH.
[0321] Such alkyl groups can also include aryl, alkylaryl, carbocyclic aryl, heterocyclic aryl, amide and ester groups. An “aryl” group refers to an aromatic group that has at least one ring having a conjugated pi electron system and includes carbocyclic aryl, heterocyclic aryl and biaryl groups, all of which may be optionally substituted. The preferred substituent(s) of aryl groups are halogen, trihalomethyl, hydroxyl, SH, OH, cyano, alkoxy, alkyl, alkenyl, alkynyl, and amino groups. An “alkylaryl” group refers to an alkyl group (as described above) covalently joined to an aryl group (as described above). Carbocyclic aryl groups are groups wherein the ring atoms on the aromatic ring are all carbon atoms. The carbon atoms are optionally substituted. Heterocyclic aryl groups are groups having from 1 to 3 heteroatoms as ring atoms in the aromatic ring and the remainder of the ring atoms are carbon atoms. Suitable heteroatoms include oxygen, sulfur, and nitrogen, and suitable heterocyclic groups include furanyl, thienyl, pyridyl, pyrrolyl, N-lower alkyl pyrrolo, pyrimidyl, pyrazinyl, imidazolyl and the like, all optionally substituted. An “amide” refers to an —C(O)—NH—R, where R is either alkyl, aryl, alkylaryl or hydrogen. An “ester” refers to an —C(O)—OR′, where R is either alkyl, aryl, alkylaryl or hydrogen.
[0322] “Nucleotide” as used herein, and as recognized in the art, includes natural bases (standard), and modified bases well known in the art. Such bases are generally located at the 1′ position of a nucleotide sugar moiety. Nucleotides generally comprise a base, sugar and a phosphate group. The nucleotides can be unmodified or modified at the sugar, phosphate and/or base moiety, (also referred to interchangeably as nucleotide analogs, modified nucleotides, non-natural nucleotides, non-standard nucleotides and other; see, for example, Usman and McSwiggen, supra; Eckstein et al., International PCT Publication No. WO 92/07065; Usman et al., International PCT Publication No. WO 93/15187; Uhlman & Peyman, supra, all are hereby incorporated by reference herein). There are several examples of modified nucleic acid bases known in the art as summarized by Limbach et al., 1994 , Nucleic Acids Res. 22, 2183. Some of the non-limiting examples of base modifications that can be introduced into nucleic acid molecules include, inosine, purine, pyridin-4-one, pyridin-2-one, phenyl, pseudouracil, 2,4,6-trimethoxy benzene, 3-methyl uracil, dihydrouridine, naphthyl, aminophenyl, 5-alkylcytidines (e.g., 5-methylcytidine), 5-alkyluridines (e.g., ribothymidine), 5-halouridine (e.g., 5-bromouridine) or 6-azapyrimidines or 6-alkylpyrimidines (e.g. 6-methyluridine), propyne, and others (Burgin et al., 1996 , Biochemistry, 35, 14090; Uhlman & Peyman, supra). By “modified bases” in this aspect is meant nucleotide bases other than adenine, guanine, cytosine and uracil at 1′ position or their equivalents.
[0323] In one embodiment, the invention features modified siNA molecules, with phosphate backbone modifications comprising one or more phosphorothioate, phosphorodithioate, methylphosphonate, phosphotriester, morpholino, amidate carbamate, carboxymethyl, acetamidate, polyamide, sulfonate, sulfonamide, sulfamate, formacetal, thioformacetal, and/or alkylsilyl, substitutions. For a review of oligonucleotide backbone modifications, see Hunziker and Leumann, 1995 , Nucleic Acid Analogues: Synthesis and Properties, in Modern Synthetic Methods , VCH, 331-417, and Mesmaeker et al., 1994 , Novel Backbone Replacements for Oligonucleotides , in Carbohydrate Modifications in Antisense Research , ACS, 24-39.
[0324] By “abasic” is meant sugar moieties lacking a base or having other chemical groups in place of a base at the 1′ position, see for example Adamic et al., U.S. Pat. No. 5,998,203.
[0325] By “unmodified nucleoside” is meant one of the bases adenine, cytosine, guanine, thymine, or uracil joined to the 1 carbon of β-D-ribo-furanose.
[0326] By “modified nucleoside” is meant any nucleotide base which contains a modification in the chemical structure of an unmodified nucleotide base, sugar and/or phosphate. Non-limiting examples of modified nucleotides are shown by Formulae I-VII and/or other modifications described herein.
[0327] In connection with 2′-modified nucleotides as described for the present invention, by “amino” is meant 2′—NH 2 or 2′-O—NH 2 , which can be modified or unmodified. Such modified groups are described, for example, in Eckstein et al., U.S. Pat. No. 5,672,695 and Matulic-Adamic et al., U.S. Pat. No. 6,248,878, which are both incorporated by reference in their entireties.
[0328] Various modifications to nucleic acid siNA structure can be made to enhance the utility of these molecules. Such modifications will enhance shelf-life, half-life in vitro, stability, and ease of introduction of such oligonucleotides to the target site, e.g., to enhance penetration of cellular membranes, and confer the ability to recognize and bind to targeted cells.
Administration of Nucleic Acid Molecules
[0329] An siNA molecule of the invention can be adapted for use to prevent or treat cancers and other proliferative conditions, viral infection, inflammatory disease, autoimmunity, respiratory disease, pulmonary disease, cardiovascular disease, neurological disease, renal disease, ocular disease, liver disease, mitochondrial disease, endocrine disease, prion disease, reproduction related diseases and conditions, and/or any other trait, disease or condition that is related to or will respond to the levels of interleukin and/or interleukin receptor in a cell or tissue, alone or in combination with other therapies. For example, an siNA molecule can comprise a delivery vehicle, including liposomes, for administration to a subject, carriers and diluents and their salts, and/or can be present in pharmaceutically acceptable formulations. Methods for the delivery of nucleic acid molecules are described in Akhtar et al., 1992 , Trends Cell Bio., 2, 139 ; Delivery Strategies for Antisense Oligonucleotide Therapeutics , ed. Akhtar, 1995, Maurer et al., 1999 , Mol. Membr. Biol., 16, 129-140; Hofland and Huang, 1999 , Handb. Exp. Pharmacol., 137, 165-192; and Lee et al., 2000 , ACS Symp. Ser., 752, 184-192, all of which are incorporated herein by reference. Beigelman et al., U.S. Pat. No. 6,395,713 and Sullivan et al., PCT WO 94/02595 further describe the general methods for delivery of nucleic acid molecules. These protocols can be utilized for the delivery of virtually any nucleic acid molecule. Nucleic acid molecules can be administered to cells by a variety of methods known to those of skill in the art, including, but not restricted to, encapsulation in liposomes, by iontophoresis, or by incorporation into other vehicles, such as biodegradable polymers, hydrogels, cyclodextrins (see for example Gonzalez et al., 1999 , Bioconjugate Chem., 10, 1068-1074; Wang et al., International PCT publication Nos. WO 03/47518 and WO 03/46185), poly(lactic-co-glycolic)acid (PLGA) and PLCA microspheres (see for example U.S. Pat. No. 6,447,796 and US Patent Application Publication No. US 2002130430), biodegradable nanocapsules, and bioadhesive microspheres, or by proteinaceous vectors (O'Hare and Normand, International PCT Publication No. WO 00/53722). In another embodiment, the nucleic acid molecules of the invention can also be formulated or complexed with polyethyleneimine and derivatives thereof, such as polyethyleneimine-polyethyleneglycol-N-acetylgalactosamine (PEI-PEG-GAL) or polyethyleneimine-polyethyleneglycol-tri-N-acetylgalactosamine (PEI-PEG-triGAL) derivatives.
[0330] In one embodiment, an siNA molecule of the invention is complexed with membrane disruptive agents such as those described in U.S. Patent Application Publication No. 20010007666, incorporated by reference herein in its entirety including the drawings. In another embodiment, the membrane disruptive agent or agents and the siNA molecule are also complexed with a cationic lipid or helper lipid molecule, such as those lipids described in U.S. Pat. No. 6,235,310, incorporated by reference herein in its entirety including the drawings.
[0331] In one embodiment, an siNA molecule of the invention is complexed with delivery systems as described in U.S. Patent Application Publication No. 2003077829 and International PCT Publication Nos. WO 00/03683 and WO 02/087541, all incorporated by reference herein in their entirety including the drawings.
[0332] In addition, the invention features the use of methods to deliver the nucleic acid molecules of the instant invention to the central nervous system and/or peripheral nervous system. Experiments have demonstrated the efficient in vivo uptake of nucleic acids by neurons. As an example of local administration of nucleic acids to nerve cells, Sommer et al., 1998 , Antisense Nuc. Acid Drug Dev., 8, 75, describe a study in which a 15mer phosphorothioate antisense nucleic acid molecule to c-fos is administered to rats via microinjection into the brain. Antisense molecules labeled with tetramethylrhodamine-isothiocyanate (TRITC) or fluorescein isothiocyanate (FITC) were taken up by exclusively by neurons thirty minutes post-injection. A diffuse cytoplasmic staining and nuclear staining was observed in these cells. As an example of systemic administration of nucleic acid to nerve cells, Epa et al., 2000 , Antisense Nuc. Acid Drug Dev., 10, 469, describe an in vivo mouse study in which beta-cyclodextrin-adamantane-oligonucleotide conjugates were used to target the p75 neurotrophin receptor in neuronally differentiated PC12 cells. Following a two week course of IP administration, pronounced uptake of p75 neurotrophin receptor antisense was observed in dorsal root ganglion (DRG) cells. In addition, a marked and consistent down-regulation of p75 was observed in DRG neurons. Additional approaches to the targeting of nucleic acid to neurons are described in Broaddus et al., 1998 , J. Neurosurg., 88(4), 734; Karle et al., 1997 , Eur. J. Pharmocol., 340(2/3), 153; Bannai et al., 1998 , Brain Research, 784(1, 2), 304; Rajakumar et al., 1997 , Synapse, 26(3), 199; Wu-pong et al., 1999 , BioPharm, 12(1), 32; Bannai et al., 1998 , Brain Res. Protoc., 3(1), 83; Simantov et al., 1996 , Neuroscience, 74(1), 39. Nucleic acid molecules of the invention are therefore amenable to delivery to and uptake by cells that express repeat expansion allelic variants for modulation of RE gene expression. The delivery of nucleic acid molecules of the invention, targeting RE is provided by a variety of different strategies. Traditional approaches to CNS delivery that can be used include, but are not limited to, intrathecal and intracerebroventricular administration, implantation of catheters and pumps, direct injection or perfusion at the site of injury or lesion, injection into the brain arterial system, or by chemical or osmotic opening of the blood-brain barrier. Other approaches can include the use of various transport and carrier systems, for example though the use of conjugates and biodegradable polymers. Furthermore, gene therapy approaches, for example as described in Kaplitt et al., U.S. Pat. No. 6,180,613 and Davidson, WO 04/013280, can be used to express nucleic acid molecules in the CNS.
[0333] In addition, the invention features the use of methods to deliver the nucleic acid molecules of the instant invention to hematopoietic cells, including monocytes and lymphocytes. These methods are described in detail by Hartmann et al., 1998 , J. Phamacol. Exp. Ther., 285(2), 920-928; Kronenwett et al., 1998 , Blood, 91(3), 852-862; Filion and Phillips, 1997 , Biochim. Biophys. Acta., 1329(2), 345-356; Ma and Wei, 1996 , Leuk. Res., 20(11/12), 925-930; and Bongartz et al., 1994 , Nucleic Acids Research, 22(22), 4681-8. Such methods, as described above, include the use of free oligonucleotide, cationic lipid formulations, liposome formulations including pH sensitive liposomes and immunoliposomes, and bioconjugates including oligonucleotides conjugated to fusogenic peptides, for the transfection of hematopoietic cells with oligonucleotides.
[0334] In one embodiment, a compound, molecule, or composition for the treatment of ocular conditions (e.g., macular degeneration, diabetic retinopathy etc.) is administered to a subject intraocularly or by intraocular means. In another embodiment, a compound, molecule, or composition for the treatment of ocular conditions (e.g., macular degeneration, diabetic retinopathy etc.) is administered to a subject periocularly or by periocular means (see for example Ahlheim et al., International PCT publication No. WO 03/24420). In one embodiment, an siNA molecule and/or formulation or composition thereof is administered to a subject intraocularly or by intraocular means. In another embodiment, an siNA molecule and/or formulation or composition thereof is administered to a subject periocularly or by periocular means. Periocular administration generally provides a less invasive approach to administering siNA molecules and formulation or composition thereof to a subject (see for example Ahlheim et al., International PCT publication No. WO 03/24420). The use of periocular administration also minimizes the risk of retinal detachment, allows for more frequent dosing or administration, provides a clinically relevant route of administration for macular degeneration and other optic conditions, and also provides the possibility of using reservoirs (e.g., implants, pumps or other devices) for drug delivery.
[0335] In one embodiment, the siNA molecules of the invention and formulations or compositions thereof are administered directly or topically (e.g., locally) to the dermis or follicles as is generally known in the art (see for example Brand, 2001 , Curr. Opin. Mol. Ther., 3, 244-8; Regnier et al., 1998 , J. Drug Target, 5, 275-89; Kanikkannan, 2002 , BioDrugs, 16, 339-47; Wraight et al., 2001 , Pharmacol. Ther., 90, 89-104; and Preat and Dujardin, 2001, STP PharmaSciences, 11, 57-68.
[0336] In one embodiment, dermal delivery systems of the invention include, for example, aqueous and nonaqueous gels, creams, multiple emulsions, microemulsions, liposomes, ointments, aqueous and nonaqueous solutions, lotions, aerosols, hydrocarbon bases and powders, and can contain excipients such as solubilizers, permeation enhancers (e.g., fatty acids, fatty acid esters, fatty alcohols and amino acids), and hydrophilic polymers (e.g., polycarbophil and polyvinylpyrolidone). In one embodiment, the pharmaceutically acceptable carrier is a liposome or a transdermal enhancer. Examples of liposomes which can be used in this invention include the following: (1) CellFectin, 1:1.5 (M/M) liposome formulation of the cationic lipid N,NI,NII,NIII-tetramethyl-N,NI,NII,NIII-tetrapalmit-y-spermine and dioleoyl phosphatidylethanolamine (DOPE) (GIBCO BRL); (2) Cytofectin GSV, 2:1 (M/M) liposome formulation of a cationic lipid and DOPE (Glen Research); (3) DOTAP (N-[1-(2,3-dioleoyloxy)-N,N,N-tri-methyl-ammoniummethylsulfate) (Boehringer Manheim); and (4) Lipofectamine, 3:1 (M/M) liposome formulation of the polycationic lipid DOSPA and the neutral lipid DOPE (GIBCO BRL).
[0337] In one embodiment, transmucosal delivery systems of the invention include patches, tablets, suppositories, pessaries, gels and creams, and can contain excipients such as solubilizers and enhancers (e.g., propylene glycol, bile salts and amino acids), and other vehicles (e.g., polyethylene glycol, fatty acid esters and derivatives, and hydrophilic polymers such as hydroxypropylmethylcellulose and hyaluronic acid).
[0338] In one embodiment, nucleic acid molecules of the invention are administered to the central nervous system (CNS) or peripheral nervous system (PNS). Experiments have demonstrated the efficient in vivo uptake of nucleic acids by neurons. As an example of local administration of nucleic acids to nerve cells, Sommer et al., 1998 , Antisense Nuc. Acid Drug Dev., 8, 75, describe a study in which a 15mer phosphorothioate antisense nucleic acid molecule to c-fos is administered to rats via microinjection into the brain. Antisense molecules labeled with tetramethylrhodamine-isothiocyanate (TRITC) or fluorescein isothiocyanate (FITC) were taken up by exclusively by neurons thirty minutes post-injection. A diffuse cytoplasmic staining and nuclear staining was observed in these cells. As an example of systemic administration of nucleic acid to nerve cells, Epa et al., 2000 , Antisense Nuc. Acid Drug Dev., 10, 469, describe an in vivo mouse study in which beta-cyclodextrin-adamantane-oligonucleotide conjugates were used to target the p75 neurotrophin receptor in neuronally differentiated PC12 cells. Following a two week course of IP administration, pronounced uptake of p75 neurotrophin receptor antisense was observed in dorsal root ganglion (DRG) cells. In addition, a marked and consistent down-regulation of p75 was observed in DRG neurons. Additional approaches to the targeting of nucleic acid to neurons are described in Broaddus et al., 1998 , J. Neurosurg., 88(4), 734; Karle et al., 1997 , Eur. J. Pharmocol., 340(2/3), 153; Bannai et al., 1998 , Brain Research, 784(1, 2), 304; Rajakumar et al., 1997 , Synapse, 26(3), 199; Wu-pong et al., 1999 , BioPharm, 12(1), 32; Bannai et al., 1998 , Brain Res. Protoc., 3(1), 83; Simantov et al., 1996 , Neuroscience, 74(1), 39. Nucleic acid molecules of the invention are therefore amenable to delivery to and uptake by cells in the CNS and/or PNS.
[0339] The delivery of nucleic acid molecules of the invention to the CNS is provided by a variety of different strategies. Traditional approaches to CNS delivery that can be used include, but are not limited to, intrathecal and intracerebroventricular administration, implantation of catheters and pumps, direct injection or perfusion at the site of injury or lesion, injection into the brain arterial system, or by chemical or osmotic opening of the blood-brain barrier. Other approaches can include the use of various transport and carrier systems, for example though the use of conjugates and biodegradable polymers. Furthermore, gene therapy approaches, for example as described in Kaplitt et al., U.S. Pat. No. 6,180,613 and Davidson, WO 04/013280, can be used to express nucleic acid molecules in the CNS.
[0340] In one embodiment, the nucleic acid molecules of the invention are administered via pulmonary delivery, such as by inhalation of an aerosol or spray dried formulation administered by an inhalation device or nebulizer, providing rapid local uptake of the nucleic acid molecules into relevant pulmonary tissues. Solid particulate compositions containing respirable dry particles of micronized nucleic acid compositions can be prepared by grinding dried or lyophilized nucleic acid compositions, and then passing the micronized composition through, for example, a 400 mesh screen to break up or separate out large agglomerates. A solid particulate composition comprising the nucleic acid compositions of the invention can optionally contain a dispersant which serves to facilitate the formation of an aerosol as well as other therapeutic compounds. A suitable dispersant is lactose, which can be blended with the nucleic acid compound in any suitable ratio, such as a 1 to 1 ratio by weight.
[0341] Aerosols of liquid particles comprising a nucleic acid composition of the invention can be produced by any suitable means, such as with a nebulizer (see for example U.S. Pat. No. 4,501,729). Nebulizers are commercially available devices which transform solutions or suspensions of an active ingredient into a therapeutic aerosol mist either by means of acceleration of a compressed gas, typically air or oxygen, through a narrow venturi orifice or by means of ultrasonic agitation. Suitable formulations for use in nebulizers comprise the active ingredient in a liquid carrier in an amount of up to 40% w/w preferably less than 20% w/w of the formulation. The carrier is typically water or a dilute aqueous alcoholic solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride or other suitable salts. Optional additives include preservatives if the formulation is not prepared sterile, for example, methyl hydroxybenzoate, anti-oxidants, flavorings, volatile oils, buffering agents and emulsifiers and other formulation surfactants. The aerosols of solid particles comprising the active composition and surfactant can likewise be produced with any solid particulate aerosol generator. Aerosol generators for administering solid particulate therapeutics to a subject produce particles which are respirable, as explained above, and generate a volume of aerosol containing a predetermined metered dose of a therapeutic composition at a rate suitable for human administration. One illustrative type of solid particulate aerosol generator is an insufflator. Suitable formulations for administration by insufflation include finely comminuted powders which can be delivered by means of an insufflator. In the insufflator, the powder, e.g., a metered dose thereof effective to carry out the treatments described herein, is contained in capsules or cartridges, typically made of gelatin or plastic, which are either pierced or opened in situ and the powder delivered by air drawn through the device upon inhalation or by means of a manually-operated pump. The powder employed in the insufflator consists either solely of the active ingredient or of a powder blend comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically comprises from 0.1 to 100 w/w of the formulation. A second type of illustrative aerosol generator comprises a metered dose inhaler. Metered dose inhalers are pressurized aerosol dispensers, typically containing a suspension or solution formulation of the active ingredient in a liquefied propellant. During use these devices discharge the formulation through a valve adapted to deliver a metered volume to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation can additionally contain one or more co-solvents, for example, ethanol, emulsifiers and other formulation surfactants, such as oleic acid or sorbitan trioleate, anti-oxidants and suitable flavoring agents. Other methods for pulmonary delivery are described in, for example US Patent Application No. 20040037780, and U.S. Pat. Nos. 6,592,904; 6,582,728; 6,565,885.
[0342] In one embodiment, siNA molecules of the invention are formulated or complexed with polyethylenimine (e.g., linear or branched PEI) and/or polyethylenimine derivatives, including for example grafted PEIs such as galactose PEI, cholesterol PEI, antibody derivatized PEI, and polyethylene glycol PEI (PEG-PEI) derivatives thereof (see for example Ogris et al., 2001 , AAPA PharmSci, 3, 1-11; Furgeson et al., 2003, Bioconjugate Chem., 14, 840-847; Kunath et al., 2002, Pharmaceutical Research, 19, 810-817; Choi et al., 2001, Bull. Korean Chem. Soc., 22, 46-52; Bettinger et al., 1999, Bioconjugate Chem., 10, 558-561; Peterson et al., 2002, Bioconjugate Chem., 13, 845-854; Erbacher et al., 1999, Journal of Gene Medicine Preprint, 1, 1-18; Godbey et al., 1999., PNAS USA, 96, 5177-5181; Godbey et al., 1999, Journal of Controlled Release, 60, 149-160; Diebold et al., 1999, Journal of Biological Chemistry, 274, 19087-19094; Thomas and Klibanov, 2002, PNAS USA, 99, 14640-14645; and Sagara, U.S. Pat. No. 6,586,524, incorporated by reference herein.
[0343] In one embodiment, an siNA molecule of the invention comprises a bioconjugate, for example a nucleic acid conjugate as described in Vargeese et al., U.S. Ser. No. 10/427,160, filed Apr. 30, 2003; U.S. Pat. No. 6,528,631; U.S. Pat. No. 6,335,434; U.S. Pat. No. 6,235,886; U.S. Pat. No. 6,153,737; U.S. Pat. No. 5,214,136; U.S. Pat. No. 5,138,045, all incorporated by reference herein.
[0344] Thus, the invention features a pharmaceutical composition comprising one or more nucleic acid(s) of the invention in an acceptable carrier, such as a stabilizer, buffer, and the like. The polynucleotides of the invention can be administered (e.g., RNA, DNA or protein) and introduced into a subject by any standard means, with or without stabilizers, buffers, and the like, to form a pharmaceutical composition. When it is desired to use a liposome delivery mechanism, standard protocols for formation of liposomes can be followed. The compositions of the present invention can also be formulated and used as tablets, capsules or elixirs for oral administration, suppositories for rectal administration, sterile solutions, suspensions for injectable administration, and the other compositions known in the art.
[0345] The present invention also includes pharmaceutically acceptable formulations of the compounds described. These formulations include salts of the above compounds, e.g., acid addition salts, for example, salts of hydrochloric, hydrobromic, acetic acid, and benzene sulfonic acid.
[0346] A pharmacological composition or formulation refers to a composition or formulation in a form suitable for administration, e.g., systemic administration, into a cell or subject, including for example a human. Suitable forms, in part, depend upon the use or the route of entry, for example oral, transdermal, or by injection. Such forms should not prevent the composition or formulation from reaching a target cell (i.e., a cell to which the negatively charged nucleic acid is desirable for delivery). For example, pharmacological compositions injected into the blood stream should be soluble. Other factors are known in the art, and include considerations such as toxicity and forms that prevent the composition or formulation from exerting its effect.
[0347] By “systemic administration” is meant in vivo systemic absorption or accumulation of drugs in the blood stream followed by distribution throughout the entire body. Administration routes that lead to systemic absorption include, without limitation: intravenous, subcutaneous, intraperitoneal, inhalation, oral, intrapulmonary and intramuscular. Each of these administration routes exposes the siNA molecules of the invention to an accessible diseased tissue. The rate of entry of a drug into the circulation has been shown to be a function of molecular weight or size. The use of a liposome or other drug carrier comprising the compounds of the instant invention can potentially localize the drug, for example, in certain tissue types, such as the tissues of the reticular endothelial system (RES). A liposome formulation that can facilitate the association of drug with the surface of cells, such as, lymphocytes and macrophages is also useful. This approach can provide enhanced delivery of the drug to target cells by taking advantage of the specificity of macrophage and lymphocyte immune recognition of abnormal cells, such as cancer cells.
[0348] By “pharmaceutically acceptable formulation” is meant a composition or formulation that allows for the effective distribution of the nucleic acid molecules of the instant invention in the physical location most suitable for their desired activity. Non-limiting examples of agents suitable for formulation with the nucleic acid molecules of the instant invention include: P-glycoprotein inhibitors (such as Pluronic P85), which can enhance entry of drugs into the CNS (Jolliet-Riant and Tillement, 1999 , Fundam. Clin. Pharmacol., 13, 16-26); biodegradable polymers, such as poly (DL-lactide-coglycolide) microspheres for sustained release delivery after intracerebral implantation (Emerich, D F et al, 1999 , Cell Transplant, 8, 47-58) (Alkermes, Inc. Cambridge, Mass.); and loaded nanoparticles, such as those made of polybutylcyanoacrylate, which can deliver drugs across the blood brain barrier and can alter neuronal uptake mechanisms ( Prog Neuropsychopharmacol Biol Psychiatry, 23, 941-949, 1999). Other non-limiting examples of delivery strategies for the nucleic acid molecules of the instant invention include material described in Boado et al., 1998 , J. Pharm. Sci., 87, 1308-1315; Tyler et al., 1999 , FEBS Lett., 421, 280-284; Pardridge et al., 1995 , PNAS USA., 92, 5592-5596; Boado, 1995 , Adv. Drug Delivery Rev., 15, 73-107; Aldrian-Herrada et al., 1998 , Nucleic Acids Res., 26, 4910-4916; and Tyler et al., 1999 , PNAS USA., 96, 7053-7058.
[0349] The invention also features the use of the composition comprising surface-modified liposomes containing poly (ethylene glycol) lipids (PEG-modified, or long-circulating liposomes or stealth liposomes). These formulations offer a method for increasing the accumulation of drugs in target tissues. This class of drug carriers resists opsonization and elimination by the mononuclear phagocytic system (MPS or RES), thereby enabling longer blood circulation times and enhanced tissue exposure for the encapsulated drug (Lasic et al. Chem. Rev. 1995, 95, 2601-2627; Ishiwata et al., Chem. Pharm. Bull. 1995, 43, 1005-1011). Such liposomes have been shown to accumulate selectively in tumors, presumably by extravasation and capture in the neovascularized target tissues (Lasic et al., Science 1995, 267, 1275-1276; Oku et al., 1995 , Biochim. Biophys. Acta, 1238, 86-90). The long-circulating liposomes enhance the pharmacokinetics and pharmacodynamics of DNA and RNA, particularly compared to conventional cationic liposomes which are known to accumulate in tissues of the MPS (Liu et al., J. Biol. Chem. 1995, 42, 24864-24870; Choi et al., International PCT Publication No. WO 96/10391; Ansell et al., International PCT Publication No. WO 96/10390; Holland et al., International PCT Publication No. WO 96/10392). Long-circulating liposomes are also likely to protect drugs from nuclease degradation to a greater extent compared to cationic liposomes, based on their ability to avoid accumulation in metabolically aggressive MPS tissues such as the liver and spleen.
[0350] The present invention also includes compositions prepared for storage or administration that include a pharmaceutically effective amount of the desired compounds in a pharmaceutically acceptable carrier or diluent. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington's Pharmaceutical Sciences , Mack Publishing Co. (A. R. Gennaro edit. 1985), hereby incorporated by reference herein. For example, preservatives, stabilizers, dyes and flavoring agents can be provided. These include sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid. In addition, antioxidants and suspending agents can be used.
[0351] A pharmaceutically effective dose is that dose required to prevent, inhibit the occurrence, or treat (alleviate a symptom to some extent, preferably all of the symptoms) of a disease state. The pharmaceutically effective dose depends on the type of disease, the composition used, the route of administration, the type of mammal being treated, the physical characteristics of the specific mammal under consideration, concurrent medication, and other factors that those skilled in the medical arts will recognize. Generally, an amount between 0.1 mg/kg and 100 mg/kg body weight/day of active ingredients is administered dependent upon potency of the negatively charged polymer.
[0352] The nucleic acid molecules of the invention and formulations thereof can be administered orally, topically, parenterally, by inhalation or spray, or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and/or vehicles. The term parenteral as used herein includes percutaneous, subcutaneous, intravascular (e.g., intravenous), intramuscular, or intrathecal injection or infusion techniques and the like. In addition, there is provided a pharmaceutical formulation comprising a nucleic acid molecule of the invention and a pharmaceutically acceptable carrier. One or more nucleic acid molecules of the invention can be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants, and if desired other active ingredients. The pharmaceutical compositions containing nucleic acid molecules of the invention can be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
[0353] Compositions intended for oral use can be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions can contain one or more such sweetening agents, flavoring agents, coloring agents or preservative agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients that are suitable for the manufacture of tablets. These excipients can be, for example, inert diluents; such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia; and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets can be uncoated or they can be coated by known techniques. In some cases such coatings can be prepared by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monosterate or glyceryl distearate can be employed.
[0354] Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
[0355] Aqueous suspensions contain the active materials in a mixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropyl-methylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents can be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions can also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
[0356] Oily suspensions can be formulated by suspending the active ingredients in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions can contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents and flavoring agents can be added to provide palatable oral preparations. These compositions can be preserved by the addition of an anti-oxidant such as ascorbic acid
[0357] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents or suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, can also be present.
[0358] Pharmaceutical compositions of the invention can also be in the form of oil-in-water emulsions. The oily phase can be a vegetable oil or a mineral oil or mixtures of these. Suitable emulsifying agents can be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions can also contain sweetening and flavoring agents.
[0359] Syrups and elixirs can be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol, glucose or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions can be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension can be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents that have been mentioned above. The sterile injectable preparation can also be a sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that can be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
[0360] The nucleic acid molecules of the invention can also be administered in the form of suppositories, e.g., for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient that is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials include cocoa butter and polyethylene glycols.
[0361] Nucleic acid molecules of the invention can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
[0362] Dosage levels of the order of from about 0.1 mg to about 140 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 7 g per subject per day). The amount of active ingredient that can be combined with the carrier materials to produce a single dosage form varies depending upon the host treated and the particular mode of administration. Dosage unit forms generally contain between from about 1 mg to about 500 mg of an active ingredient.
[0363] It is understood that the specific dose level for any particular subject depends upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
[0364] For administration to non-human animals, the composition can also be added to the animal feed or drinking water. It can be convenient to formulate the animal feed and drinking water compositions so that the animal takes in a therapeutically appropriate quantity of the composition along with its diet. It can also be convenient to present the composition as a premix for addition to the feed or drinking water.
[0365] The nucleic acid molecules of the present invention can also be administered to a subject in combination with other therapeutic compounds to increase the overall therapeutic effect. The use of multiple compounds to treat an indication can increase the beneficial effects while reducing the presence of side effects.
[0366] In one embodiment, the invention comprises compositions suitable for administering nucleic acid molecules of the invention to specific cell types. For example, the asialoglycoprotein receptor (ASGPr) (Wu and Wu, 1987 , J. Biol. Chem. 262, 4429-4432) is unique to hepatocytes and binds branched galactose-terminal glycoproteins, such as asialoorosomucoid (ASOR). In another example, the folate receptor is overexpressed in many cancer cells. Binding of such glycoproteins, synthetic glycoconjugates, or folates to the receptor takes place with an affinity that strongly depends on the degree of branching of the oligosaccharide chain, for example, triatennary structures are bound with greater affinity than biatennary or monoatennary chains (Baenziger and Fiete, 1980 , Cell, 22, 611-620; Connolly et al., 1982 , J. Biol. Chem., 257, 939-945). Lee and Lee, 1987 , Glycoconjugate J., 4, 317-328, obtained this high specificity through the use of N-acetyl-D-galactosamine as the carbohydrate moiety, which has higher affinity for the receptor, compared to galactose. This “clustering effect” has also been described for the binding and uptake of mannosyl-terminating glycoproteins or glycoconjugates (Ponpipom et al., 1981 , J. Med. Chem., 24, 1388-1395). The use of galactose, galactosamine, or folate based conjugates to transport exogenous compounds across cell membranes can provide a targeted delivery approach to, for example, the treatment of liver disease, cancers of the liver, or other cancers. The use of bioconjugates can also provide a reduction in the required dose of therapeutic compounds required for treatment. Furthermore, therapeutic bioavailability, pharmacodynamics, and pharmacokinetic parameters can be modulated through the use of nucleic acid bioconjugates of the invention. Non-limiting examples of such bioconjugates are described in Vargeese et al., U.S. Ser. No. 10/201,394, filed Aug. 13, 2001; and Matulic-Adamic et al., U.S. Ser. No. 10/151,116, filed May 17, 2002. In one embodiment, nucleic acid molecules of the invention are complexed with or covalently attached to nanoparticles, such as Hepatitis B virus S, M, or L evelope proteins (see for example Yamado et al., 2003 , Nature Biotechnology, 21, 885). In one embodiment, nucleic acid molecules of the invention are delivered with specificity for human tumor cells, specifically non-apoptotic human tumor cells including for example T-cells, hepatocytes, breast carcinoma cells, ovarian carcinoma cells, melanoma cells, intestinal epithelial cells, prostate cells, testicular cells, non-small cell lung cancers, small cell lung cancers, etc.
[0367] In one embodiment, an siNA molecule of the invention is designed or formulated to specifically target endothelial cells or tumor cells. For example, various formulations and conjugates can be utilized to specifically target endothelial cells or tumor cells, including PEI-PEG-folate, PEI-PEG-RGD, PEI-PEG-biotin, PEI-PEG-cholesterol, and other conjugates known in the art that enable specific targeting to endothelial cells and/or tumor cells.
[0368] Alternatively, certain siNA molecules of the instant invention can be expressed within cells from eukaryotic promoters (e.g., Izant and Weintraub, 1985 , Science, 229, 345; McGarry and Lindquist, 1986 , Proc. Natl. Acad. Sci., USA 83, 399; Scanlon et al., 1991 , Proc. Natl. Acad. Sci. USA, 88, 10591-5; Kashani-Sabet et al., 1992 , Antisense Res. Dev., 2, 3-15; propulic et al., 1992 , J. Virol., 66, 1432-41; Weerasinghe et al., 1991 , J. Virol., 65, 5531-4; Ojwang et al., 1992 , Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al., 1992 , Nucleic Acids Res., 20, 4581-9; Sarver et al., 1990 Science, 247, 1222-1225; Thompson et al., 1995 , Nucleic Acids Res., 23, 2259; Good et al., 1997 , Gene Therapy, 4, 45). Those skilled in the art realize that any nucleic acid can be expressed in eukaryotic cells from the appropriate DNA/RNA vector. The activity of such nucleic acids can be augmented by their release from the primary transcript by a enzymatic nucleic acid (Draper et al., PCT WO 93/23569, and Sullivan et al., PCT WO 94/02595; Ohkawa et al., 1992 , Nucleic Acids Symp. Ser., 27, 15-6; Taira et al., 1991 , Nucleic Acids Res., 19, 5125-30; Ventura et al., 1993 , Nucleic Acids Res., 21, 3249-55; Chowrira et al., 1994 , J. Biol. Chem., 269, 25856).
[0369] In another aspect of the invention, RNA molecules of the present invention can be expressed from transcription units (see for example Couture et al., 1996 , TIG., 12, 510) inserted into DNA or RNA vectors. The recombinant vectors can be DNA plasmids or viral vectors. siNA expressing viral vectors can be constructed based on, but not limited to, adeno-associated virus, retrovirus, adenovirus, or alphavirus. In another embodiment, pol III based constructs are used to express nucleic acid molecules of the invention (see for example Thompson, U.S. Pats. Nos. 5,902,880 and 6,146,886). The recombinant vectors capable of expressing the siNA molecules can be delivered as described above, and persist in target cells. Alternatively, viral vectors can be used that provide for transient expression of nucleic acid molecules. Such vectors can be repeatedly administered as necessary. Once expressed, the siNA molecule interacts with the target mRNA and generates an RNAi response. Delivery of siNA molecule expressing vectors can be systemic, such as by intravenous or intramuscular administration, by administration to target cells ex-planted from a subject followed by reintroduction into the subject, or by any other means that would allow for introduction into the desired target cell (for a review see Couture et al., 1996 , TIG., 12, 510).
[0370] In one aspect the invention features an expression vector comprising a nucleic acid sequence encoding at least one siNA molecule of the instant invention. The expression vector can encode one or both strands of an siNA duplex, or a single self-complementary strand that self hybridizes into an siNA duplex. The nucleic acid sequences encoding the siNA molecules of the instant invention can be operably linked in a manner that allows expression of the siNA molecule (see for example Paul et al., 2002 , Nature Biotechnology, 19, 505; Miyagishi and Taira, 2002 , Nature Biotechnology, 19, 497; Lee et al., 2002 , Nature Biotechnology, 19, 500; and Novina et al., 2002 , Nature Medicine , advance online publication doi: 10.1038/nm725).
[0371] In another aspect, the invention features an expression vector comprising: a) a transcription initiation region (e.g., eukaryotic pol I, II or III initiation region); b) a transcription termination region (e.g., eukaryotic pol I, II or III termination region); and c) a nucleic acid sequence encoding at least one of the siNA molecules of the instant invention, wherein said sequence is operably linked to said initiation region and said termination region in a manner that allows expression and/or delivery of the siNA molecule. The vector can optionally include an open reading frame (ORF) for a protein operably linked on the 5′ side or the 3′-side of the sequence encoding the siNA of the invention; and/or an intron (intervening sequences).
[0372] Transcription of the siNA molecule sequences can be driven from a promoter for eukaryotic RNA polymerase I (pol I), RNA polymerase II (pol II), or RNA polymerase III (pol III). Transcripts from pol II or pol III promoters are expressed at high levels in all cells; the levels of a given pol II promoter in a given cell type depends on the nature of the gene regulatory sequences (enhancers, silencers, etc.) present nearby. Prokaryotic RNA polymerase promoters are also used, providing that the prokaryotic RNA polymerase enzyme is expressed in the appropriate cells (Elroy-Stein and Moss, 1990 , Proc. Natl. Acad. Sci. U S A, 87, 6743-7; Gao and Huang 1993 , Nucleic Acids Res., 21, 2867-72; Lieber et al., 1993 , Methods Enzymol., 217, 47-66; Zhou et al., 1990 , Mol. Cell. Biol., 10, 4529-37). Several investigators have demonstrated that nucleic acid molecules expressed from such promoters can function in mammalian cells (e.g. Kashani-Sabet et al., 1992 , Antisense Res. Dev., 2, 3-15; Ojwang et al., 1992 , Proc. Natl. Acad. Sci. USA, 89, 10802-6; Chen et al., 1992 , Nucleic Acids Res., 20, 4581-9; Yu et al., 1993 , Proc. Natl. Acad. Sci. USA, 90, 6340-4; L'Huillier et al., 1992 , EMBO J., 11, 4411-8; Lisziewicz et al., 1993 , Proc. Natl. Acad. Sci. U.S. A, 90, 8000-4; Thompson et al., 1995 , Nucleic Acids Res., 23, 2259; Sullenger & Cech, 1993 , Science, 262, 1566). More specifically, transcription units such as the ones derived from genes encoding U6 small nuclear (snRNA), transfer RNA (tRNA) and adenovirus VA RNA are useful in generating high concentrations of desired RNA molecules such as siNA in cells (Thompson et al., supra; Couture and Stinchcomb, 1996, supra; Noonberg et al., 1994 , Nucleic Acid Res., 22, 2830; Noonberg et al., U.S. Pat. No. 5,624,803; Good et al., 1997 , Gene Ther., 4, 45; Beigelman et al., International PCT Publication No. WO 96/18736. The above siNA transcription units can be incorporated into a variety of vectors for introduction into mammalian cells, including but not restricted to, plasmid DNA vectors, viral DNA vectors (such as adenovirus or adeno-associated virus vectors), or viral RNA vectors (such as retroviral or alphavirus vectors) (for a review see Couture and Stinchcomb, 1996, supra).
[0373] In another aspect the invention features an expression vector comprising a nucleic acid sequence encoding at least one of the siNA molecules of the invention in a manner that allows expression of that siNA molecule. The expression vector comprises in one embodiment; a) a transcription initiation region; b) a transcription termination region; and c) a nucleic acid sequence encoding at least one strand of the siNA molecule, wherein the sequence is operably linked to the initiation region and the termination region in a manner that allows expression and/or delivery of the siNA molecule.
[0374] In another embodiment the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an open reading frame; and d) a nucleic acid sequence encoding at least one strand of an siNA molecule, wherein the sequence is operably linked to the 3′-end of the open reading frame and wherein the sequence is operably linked to the initiation region, the open reading frame and the termination region in a manner that allows expression and/or delivery of the siNA molecule. In yet another embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; and d) a nucleic acid sequence encoding at least one siNA molecule, wherein the sequence is operably linked to the initiation region, the intron and the termination region in a manner which allows expression and/or delivery of the nucleic acid molecule.
[0375] In another embodiment, the expression vector comprises: a) a transcription initiation region; b) a transcription termination region; c) an intron; d) an open reading frame; and e) a nucleic acid sequence encoding at least one strand of an siNA molecule, wherein the sequence is operably linked to the 3′-end of the open reading frame and wherein the sequence is operably linked to the initiation region, the intron, the open reading frame and the termination region in a manner which allows expression and/or delivery of the siNA molecule.
Interleukin Biology and Biochemistry
[0376] The following discussion is adapted from R&D Systems Mini-Reviews and Tech Notes, Cytokine Mini-Reviews, Copyright©2002 R&D Systems. Interleukin 2 (IL-2) is a lymphokine synthesized and secreted primarily by T helper lymphocytes that have been activated by stimulation with certain mitogens or by interaction of the T cell receptor complex with antigen/MHC complexes on the surfaces of antigen-presenting cells. The response of T helper cells to activation is induction of the expression of IL-2 and receptors for IL-2 and, subsequently, clonal expansion of antigen-specific T cells. At this level IL-2 is an autocrine factor, driving the expansion of the antigen-specific cells. IL-2 also acts as a paracrine factor, influencing the activity of other cells, both within the immune system and outside of it. B cells and natural killer (NK) cells respond, when properly activated, to IL-2. The so-called lymphocyte activated killer, or LAK cells, appear to be derived from NK cells under the influence of IL-2.
[0377] The biological activities of IL-2 are mediated through the binding of IL-2 to a multisubunit cellular receptor. Although three distinct transmembrane glycoprotein subunits contribute to the formation of the high affinity IL-2 receptor, various combinations of receptor subunits (alpha, beta, gamma) are known to occur.
[0378] Interleukin 1 (IL-1) is a general name for two distinct proteins, IL-1a and IL-1b, that are considered the first of a family of regulatory and inflammatory cytokines. Along with IL-1 receptor antagonist (IL-1ra) 2 and IL-18,3 these molecules play important roles in the up- and down-regulation of acute inflammation. In the immune system, the production of IL-1 is typically induced, generally resulting in inflammation. IL-1b and TNF-a are generally thought of as prototypical pro-inflammatory cytokines. The effects of IL-1, however, are not limited to inflammation, as IL-1 has also been associated with bone formation and remodeling, insulin secretion, appetite regulation, fever induction, neuronal phenotype development, and IGF/GH physiology. IL-1 has also been known by a number of alternative names, including lymphocyte activating factor, endogenous pyrogen, catabolin, hemopoietin-1, melanoma growth inhibition factor, and osteoclast activating factor. IL-1a and IL-1b exert their effects by binding to specific receptors. Two distinct IL-1 receptor binding proteins, plus a non-binding signaling accessory protein have been identified to date. Each have three extracellular immunoglobulin-like (Ig-like) domains, qualifying them for membership in the type IV cytokine receptor family.
[0379] Interleukin-4 (IL-4) mediates important pro-inflammatory functions in asthma including induction of the IgE isotype switch, expression of vascular cell adhesion molecule-1 (VCAM-1), promotion of eosinophil transmigration across endothelium, mucus secretion, and differentiation of T helper type 2 lymphocytes leading to cytokine release. Asthma has been linked to polymorphisms in the IL-4 gene promoter and proteins involved in IL-4 signaling. Soluble recombinant IL-4 receptor lacks transmembrane and cytoplasmic activating domains and can therefore sequester IL-4 without mediating cellular activation. Genetic variants within the IL-4 signaling pathway might contribute to the risk of developing asthma in a given individual. A number of polymorphisms have been described within the IL-4 receptor a (IL-4Rα) gene, and in addition, polymorphism occurs in the promoter for the IL-4 gene itself (see for example Hall, 2000 , Respir. Res., 1, 6-8 and Ober et al., 2000 , Am J Hum Genet., 66, 517-526, for a review). The type 2 cytokine IL-13, which shares a receptor component and signaling pathways with IL-4, was found to be necessary and sufficient for the expression of allergic asthma (see Wills-Karp et al., 1998 , Science, 282, 2258-61). IL-13 induces the pathophysiological features of asthma in a manner that is independent of immunoglobulin E and eosinophils. Thus, IL-13 is critical to allergen-induced asthma but operates through mechanisms other than those that are classically implicated in allergic responses.
[0380] Human IL-5 is a 134 amino acid polypeptide with a predicted mass of 12.5 kDa. It is secreted by a restricted number of mesenchymal cell types. In its native state, mature IL-5 is synthesized as a 115 aa, highly glycosylated 22 kDa monomer that forms a 40-50 kDa disulfide-linked homodimer. Although the content of carbohydrate is high, carbohydrate is not needed for bioactivity. Monomeric IL-5 has no activity; a homodimer is required for function. This is in contrast to the receptor-related cytokines IL-3 and GM-CSF, which exist only as monomers. Just as one IL-3 and GM-CSF monomer binds to one receptor, one IL-5 homodimer is able to engage only one IL-5 receptor. It has been suggested that IL-5 (as a dimer) undergoes a general conformational change after binding to one receptor molecule, and this change precludes binding to a second receptor. The receptor for IL-5 consists of a ligand binding a-subunit and a non-ligand binding (common) signal transducing b-subunit that is shared by the receptors for IL-3 and GM-CSF. IL-5 appears to perform a number of functions on eosinophils. These include the down modulation of Mac-1, the upregulation of receptors for IgA and IgG, the stimulation of lipid mediator (leukotriene C4 and PAF) secretion and the induction of granule release. IL-5 also promotes the growth and differentiation of eosinophils.
[0381] Interleukin 6 (IL-6) is considered a prototypic pleiotrophic cytokine. This is reflected in the variety of names originally assigned to IL-6 based on function, including Interferon b2, IL-1-inducible 26 kD Protein, Hepatocyte Stimulating Factor, Cytotoxic T-cell Differentiation Factor, B cell Differentiation Factor (BCDF) and/or B cell Stimulatory Factor 2 (BSF2). A number of cytokines make up an IL-6 cytokine family. Membership in this family is typically based on a helical cytokine structure and receptor subunit makeup. The functional receptor for IL-6 is a complex of two transmembrane glycoproteins (gp130 and IL-6 receptor) that are members of the Class I cytokine receptor superfamily.
[0382] Because of the central role of the interleukin family of cytokines in the mediation of immune and inflammatory responses, modulation of interleukin expression and/or activity can provide important functions in therapeutic and diagnostic applications. The use of small interfering nucleic acid molecules targeting interleukins and their corresponding receptors therefore provides a class of novel therapeutic agents that can be used in the treatment of cancers, proliferative diseases, inflammatory disease, respiratory disease, pulmonary disease, cardiovascular disease, autoimmune disease, infectious disease, prior disease, renal disease, transplant rejection, or any other disease or condition that responds to modulation of interleukin and interleukin receptor genes.
EXAMPLES
[0383] The following are non-limiting examples showing the selection, isolation, synthesis and activity of nucleic acids of the instant invention.
Example 1
Tandem Synthesis of siNA Constructs
[0384] Exemplary siNA molecules of the invention are synthesized in tandem using a cleavable linker, for example, a succinyl-based linker. Tandem synthesis as described herein is followed by a one-step purification process that provides RNAi molecules in high yield. This approach is highly amenable to siNA synthesis in support of high throughput RNAi screening, and can be readily adapted to multi-column or multi-well synthesis platforms.
[0385] After completing a tandem synthesis of an siNA oligo and its complement in which the 5′-terminal dimethoxytrityl (5′-O-DMT) group remains intact (trityl on synthesis), the oligonucleotides are deprotected as described above. Following deprotection, the siNA sequence strands are allowed to spontaneously hybridize. This hybridization yields a duplex in which one strand has retained the 5′-O-DMT group while the complementary strand comprises a terminal 5′-hydroxyl. The newly formed duplex behaves as a single molecule during routine solid-phase extraction purification (Trityl-On purification) even though only one molecule has a dimethoxytrityl group. Because the strands form a stable duplex, this dimethoxytrityl group (or an equivalent group, such as other trityl groups or other hydrophobic moieties) is all that is required to purify the pair of oligos, for example, by using a C18 cartridge.
[0386] Standard phosphoramidite synthesis chemistry is used up to the point of introducing a tandem linker, such as an inverted deoxy abasic succinate or glyceryl succinate linker (see FIG. 1 ) or an equivalent cleavable linker. A non-limiting example of linker coupling conditions that can be used includes a hindered base such as diisopropylethylamine (DIPA) and/or DMAP in the presence of an activator reagent such as Bromotripyrrolidinophosphoniumhexafluororophosphate (PyBrOP). After the linker is coupled, standard synthesis chemistry is utilized to complete synthesis of the second sequence leaving the terminal the 5′-O-DMT intact. Following synthesis, the resulting oligonucleotide is deprotected according to the procedures described herein and quenched with a suitable buffer, for example with 50 mM NaOAc or 1.5M NH 4 H 2 CO 3 .
[0387] Purification of the siNA duplex can be readily accomplished using solid phase extraction, for example using a Waters C18 SepPak 1 g cartridge conditioned with 1 column volume (CV) of acetonitrile, 2 CV H2O, and 2 CV 50 mM NaOAc. The sample is loaded and then washed with 1 CV H2O or 50 mM NaOAc. Failure sequences are eluted with 1 CV 14% ACN (Aqueous with 50 mM NaOAc and 50 mM NaCl). The column is then washed, for example with 1 CV H2O followed by on-column detritylation, for example by passing 1 CV of 1% aqueous trifluoroacetic acid (TFA) over the column, then adding a second CV of 1% aqueous TFA to the column and allowing to stand for approximately 10 minutes. The remaining TFA solution is removed and the column washed with H20 followed by 1 CV 1M NaCl and additional H2O. The siNA duplex product is then eluted, for example, using 1 CV 20% aqueous CAN.
[0388] FIG. 2 provides an example of MALDI-TOF mass spectrometry analysis of a purified siNA construct in which each peak corresponds to the calculated mass of an individual siNA strand of the siNA duplex. The same purified siNA provides three peaks when analyzed by capillary gel electrophoresis (CGE), one peak presumably corresponding to the duplex siNA, and two peaks presumably corresponding to the separate siNA sequence strands. Ion exchange HPLC analysis of the same siNA contract only shows a single peak. Testing of the purified siNA construct using a luciferase reporter assay described below demonstrated the same RNAi activity compared to siNA constructs generated from separately synthesized oligonucleotide sequence strands.
Example 2
Identification of Potential siNA Target Sites in any RNA Sequence
[0389] The sequence of an RNA target of interest, such as a viral or human mRNA transcript, is screened for target sites, for example by using a computer folding algorithm. In a non-limiting example, the sequence of a gene or RNA gene transcript derived from a database, such as Genbank, is used to generate siNA targets having complementarity to the target. Such sequences can be obtained from a database, or can be determined experimentally as known in the art. Target sites that are known, for example, those target sites determined to be effective target sites based on studies with other nucleic acid molecules, for example ribozymes or antisense, or those targets known to be associated with a disease or condition such as those sites containing mutations or deletions, can be used to design siNA molecules targeting those sites. Various parameters can be used to determine which sites are the most suitable target sites within the target RNA sequence. These parameters include but are not limited to secondary or tertiary RNA structure, the nucleotide base composition of the target sequence, the degree of homology between various regions of the target sequence, or the relative position of the target sequence within the RNA transcript. Based on these determinations, any number of target sites within the RNA transcript can be chosen to screen siNA molecules for efficacy, for example by using in vitro RNA cleavage assays, cell culture, or animal models. In a non-limiting example, anywhere from 1 to 1000 target sites are chosen within the transcript based on the size of the siNA construct to be used. High throughput screening assays can be developed for screening siNA molecules using methods known in the art, such as with multi-well or multi-plate assays to determine efficient reduction in target gene expression.
Example 3
Selection of siNA Molecule Target Fites in a RNA
[0390] The following non-limiting steps can be used to carry out the selection of siNAs targeting a given gene sequence or transcript.
[0391] 1. The target sequence is parsed in silico into a list of all fragments or subsequences of a particular length, for example 23 nucleotide fragments, contained within the target sequence. This step is typically carried out using a custom Perl script, but commercial sequence analysis programs such as Oligo, MacVector, or the GCG Wisconsin Package can be employed as well.
[0392] 2. In some instances the siNAs correspond to more than one target sequence; such would be the case for example in targeting different transcripts of the same gene, targeting different transcripts of more than one gene, or for targeting both the human gene and an animal homolog. In this case, a subsequence list of a particular length is generated for each of the targets, and then the lists are compared to find matching sequences in each list. The subsequences are then ranked according to the number of target sequences that contain the given subsequence; the goal is to find subsequences that are present in most or all of the target sequences. Alternately, the ranking can identify subsequences that are unique to a target sequence, such as a mutant target sequence. Such an approach would enable the use of siNA to target specifically the mutant sequence and not effect the expression of the normal sequence.
[0393] 3. In some instances the siNA subsequences are absent in one or more sequences while present in the desired target sequence; such would be the case if the siNA targets a gene with a paralogous family member that is to remain untargeted. As in case 2 above, a subsequence list of a particular length is generated for each of the targets, and then the lists are compared to find sequences that are present in the target gene but are absent in the untargeted paralog.
[0394] 4. The ranked siNA subsequences can be further analyzed and ranked according to GC content. A preference can be given to sites containing 30-70% GC, with a further preference to sites containing 40-60% GC.
[0395] 5. The ranked siNA subsequences can be further analyzed and ranked according to self-folding and internal hairpins. Weaker internal folds are preferred; strong hairpin structures are to be avoided.
[0396] 6. The ranked siNA subsequences can be further analyzed and ranked according to whether they have runs of GGG or CCC in the sequence. GGG (or even more Gs) in either strand can make oligonucleotide synthesis problematic and can potentially interfere with RNAi activity, so it is avoided whenever better sequences are available. CCC is searched in the target strand because that will place GGG in the antisense strand.
[0397] 7. The ranked siNA subsequences can be further analyzed and ranked according to whether they have the dinucleotide UU (uridine dinucleotide) on the 3′-end of the sequence, and/or AA on the 5′-end of the sequence (to yield 3′ UU on the antisense sequence). These sequences allow one to design siNA molecules with terminal TT thymidine dinucleotides.
[0398] 8. Four or five target sites are chosen from the ranked list of subsequences as described above. For example, in subsequences having 23 nucleotides, the right 21 nucleotides of each chosen 23-mer subsequence are then designed and synthesized for the upper (sense) strand of the siNA duplex, while the reverse complement of the left 21 nucleotides of each chosen 23-mer subsequence are then designed and synthesized for the lower (antisense) strand of the siNA duplex (see Tables II and III). If terminal TT residues are desired for the sequence (as described in paragraph 7), then the two 3′ terminal nucleotides of both the sense and antisense strands are replaced by TT prior to synthesizing the oligos.
[0399] 9. The siNA molecules are screened in an in vitro, cell culture or animal model system to identify the most active siNA molecule or the most preferred target site within the target RNA sequence.
[0400] 10. Other design considerations can be used when selecting target nucleic acid sequences, see for example Reynolds et al., 2004 , Nature Biotechnology Advanced Online Publication, 1 Feb. 2004, doi:10.1038/nbt936 and Ui-Tei et al., 2004, Nucleic Acids Research, 32, doi:10.1093/nar/gkh247.
[0401] In an alternate approach, a pool of siNA constructs specific to a interleukin and/or interleukin receptor target sequence is used to screen for target sites in cells expressing interleukin and/or interleukin receptor RNA, such as cultured Jurkat, HeLa, or 293T cells. The general strategy used in this approach is shown in FIG. 9 . A non-limiting example of such is a pool comprising sequences having any of SEQ ID NOS1-1828. Cells expressing interleukin and/or interleukin receptor (e.g., Jurkat, HeLa, or 293T cells) are transfected with the pool of siNA constructs and cells that demonstrate a phenotype associated with interleukin and/or interleukin receptor inhibition are sorted. The pool of siNA constructs can be expressed from transcription cassettes inserted into appropriate vectors (see for example FIG. 7 and FIG. 8 ). The siNA from cells demonstrating a positive phenotypic change (e.g., decreased interleukin and/or interleukin receptor mRNA levels or decreased interleukin and/or interleukin receptor protein expression), are sequenced to determine the most suitable target site(s) within the target interleukin and/or interleukin receptor RNA sequence.
Example 4
Interleukin and Interleukin Receptor Targeted siNA Design
[0402] siNA target sites were chosen by analyzing sequences of the interleukin and/or interleukin receptor RNA target and optionally prioritizing the target sites on the basis of folding (structure of any given sequence analyzed to determine siNA accessibility to the target), by using a library of siNA molecules as described in Example 3, or alternately by using an in vitro siNA system as described in Example 6 herein. siNA molecules were designed that could bind each target and are optionally individually analyzed by computer folding to assess whether the siNA molecule can interact with the target sequence. Varying the length of the siNA molecules can be chosen to optimize activity. Generally, a sufficient number of complementary nucleotide bases are chosen to bind to, or otherwise interact with, the target RNA, but the degree of complementarity can be modulated to accommodate siNA duplexes or varying length or base composition. By using such methodologies, siNA molecules can be designed to target sites within any known RNA sequence, for example those RNA sequences corresponding to the any gene transcript.
[0403] Chemically modified siNA constructs are designed to provide nuclease stability for systemic administration in vivo and/or improved pharmacokinetic, localization, and delivery properties while preserving the ability to mediate RNAi activity. Chemical modifications as described herein are introduced synthetically using synthetic methods described herein and those generally known in the art. The synthetic siNA constructs are then assayed for nuclease stability in serum and/or cellular/tissue extracts (e.g. liver extracts). The synthetic siNA constructs are also tested in parallel for RNAi activity using an appropriate assay, such as a luciferase reporter assay as described herein or another suitable assay that can quantity RNAi activity. Synthetic siNA constructs that possess both nuclease stability and RNAi activity can be further modified and re-evaluated in stability and activity assays. The chemical modifications of the stabilized active siNA constructs can then be applied to any siNA sequence targeting any chosen RNA and used, for example, in target screening assays to pick lead siNA compounds for therapeutic development (see for example FIG. 11 ).
Example 5
Chemical Synthesis and Purification of siNA
[0404] siNA molecules can be designed to interact with various sites in the RNA message, for example, target sequences within the RNA sequences described herein. The sequence of one strand of the siNA molecule(s) is complementary to the target site sequences described above. The siNA molecules can be chemically synthesized using methods described herein. Inactive siNA molecules that are used as control sequences can be synthesized by scrambling the sequence of the siNA molecules such that it is not complementary to the target sequence. Generally, siNA constructs can by synthesized using solid phase oligonucleotide synthesis methods as described herein (see for example Usman et al., U.S. Pat. Nos. 5,804,683; 5,831,071; 5,998,203; 6,117,657; 6,353,098; 6,362,323; 6,437,117; 6,469,158; Scaringe et al., U.S. Pat. Nos. 6,111,086; 6,008,400; 6,111,086 all incorporated by reference herein in their entirety).
[0405] In a non-limiting example, RNA oligonucleotides are synthesized in a stepwise fashion using the phosphoramidite chemistry as is known in the art. Standard phosphoramidite chemistry involves the use of nucleosides comprising any of 5′-O-dimethoxytrityl, 2′-O-tert-butyldimethylsilyl, 3′-O-2-Cyanoethyl N,N-diisopropylphos-phoroamidite groups, and exocyclic amine protecting groups (e.g. N6-benzoyl adenosine, N4 acetyl cytidine, and N2-isobutyryl guanosine). Alternately, 2′-O-Silyl Ethers can be used in conjunction with acid-labile 2′-O-orthoester protecting groups in the synthesis of RNA as described by Scaringe supra. Differing 2′ chemistries can require different protecting groups, for example 2′-deoxy-2′-amino nucleosides can utilize N-phthaloyl protection as described by Usman et al., U.S. Pat. No. 5,631,360, incorporated by reference herein in its entirety).
[0406] During solid phase synthesis, each nucleotide is added sequentially (3′- to 5′-direction) to the solid support-bound oligonucleotide. The first nucleoside at the 3′-end of the chain is covalently attached to a solid support (e.g., controlled pore glass or polystyrene) using various linkers. The nucleotide precursor, a ribonucleoside phosphoramidite, and activator are combined resulting in the coupling of the second nucleoside phosphoramidite onto the 5′-end of the first nucleoside. The support is then washed and any unreacted 5′-hydroxyl groups are capped with a capping reagent such as acetic anhydride to yield inactive 5′-acetyl moieties. The trivalent phosphorus linkage is then oxidized to a more stable phosphate linkage. At the end of the nucleotide addition cycle, the 5′-O-protecting group is cleaved under suitable conditions (e.g., acidic conditions for trityl-based groups and Fluoride for silyl-based groups). The cycle is repeated for each subsequent nucleotide.
[0407] Modification of synthesis conditions can be used to optimize coupling efficiency, for example by using differing coupling times, differing reagent/phosphoramidite concentrations, differing contact times, differing solid supports and solid support linker chemistries depending on the particular chemical composition of the siNA to be synthesized. Deprotection and purification of the siNA can be performed as is generally described in Usman et al., U.S. Pat. No. 5,831,071, U.S. Pat. No. 6,353,098, U.S. Pat. No. 6,437,117, and Bellon et al., U.S. Pat. No. 6,054,576, U.S. Pat. No. 6,162,909, U.S. Pat. No. 6,303,773, or Scaringe supra, incorporated by reference herein in their entireties. Additionally, deprotection conditions can be modified to provide the best possible yield and purity of siNA constructs. For example, applicant has observed that oligonucleotides comprising 2′-deoxy-2′-fluoro nucleotides can degrade under inappropriate deprotection conditions. Such oligonucleotides are deprotected using aqueous methylamine at about 35° C. for 30 minutes. If the 2′-deoxy-2′-fluoro containing oligonucleotide also comprises ribonucleotides, after deprotection with aqueous methylamine at about 35° C. for 30 minutes, TEA-HF is added and the reaction maintained at about 65° C. for an additional 15 minutes.
Example 6
RNAi In Vitro Assay to Assess siNA Activity
[0408] An in vitro assay that recapitulates RNAi in a cell-free system is used to evaluate siNA constructs targeting interleukin and/or interleukin receptor RNA targets. The assay comprises the system described by Tuschl et al., 1999 , Genes and Development, 13, 3191-3197 and Zamore et al., 2000 , Cell, 101, 25-33 adapted for use with interleukin and/or interleukin receptor target RNA. A Drosophila extract derived from syncytial blastoderm is used to reconstitute RNAi activity in vitro. Target RNA is generated via in vitro transcription from an appropriate interleukin and/or interleukin receptor expressing plasmid using T7 RNA polymerase or via chemical synthesis as described herein. Sense and antisense siNA strands (for example 20 uM each) are annealed by incubation in buffer (such as 100 mM potassium acetate, 30 mM HEPES-KOH, pH 7.4, 2 mM magnesium acetate) for 1 minute at 90° C. followed by 1 hour at 37° C., then diluted in lysis buffer (for example 100 mM potassium acetate, 30 mM HEPES-KOH at pH 7.4, 2 mM magnesium acetate). Annealing can be monitored by gel electrophoresis on an agarose gel in TBE buffer and stained with ethidium bromide. The Drosophila lysate is prepared using zero to two-hour-old embryos from Oregon R flies collected on yeasted molasses agar that are dechorionated and lysed. The lysate is centrifuged and the supernatant isolated. The assay comprises a reaction mixture containing 50% lysate [vol/vol], RNA (10-50 pM final concentration), and 10% [vol/vol] lysis buffer containing siNA (10 nM final concentration). The reaction mixture also contains 10 mM creatine phosphate, 10 ug/ml creatine phosphokinase, 100 um GTP, 100 uM UTP, 100 uM CTP, 500 uM ATP, 5 mM DTT, 0.1 U/uL RNasin (Promega), and 100 uM of each amino acid. The final concentration of potassium acetate is adjusted to 100 mM. The reactions are pre-assembled on ice and preincubated at 25° C. for 10 minutes before adding RNA, then incubated at 25° C. for an additional 60 minutes. Reactions are quenched with 4 volumes of 1.25× Passive Lysis Buffer (Promega). Target RNA cleavage is assayed by RT-PCR analysis or other methods known in the art and are compared to control reactions in which siNA is omitted from the reaction.
[0409] Alternately, internally-labeled target RNA for the assay is prepared by in vitro transcription in the presence of [alpha- 32 P] CTP, passed over a G 50 Sephadex column by spin chromatography and used as target RNA without further purification. Optionally, target RNA is 5′- 32 P-end labeled using T4 polynucleotide kinase enzyme. Assays are performed as described above and target RNA and the specific RNA cleavage products generated by RNAi are visualized on an autoradiograph of a gel. The percentage of cleavage is determined by PHOSPHOR IMAGER® (autoradiography) quantitation of bands representing intact control RNA or RNA from control reactions without siNA and the cleavage products generated by the assay.
[0410] In one embodiment, this assay is used to determine target sites the interleukin and/or interleukin receptor RNA target for siNA mediated RNAi cleavage, wherein a plurality of siNA constructs are screened for RNAi mediated cleavage of the interleukin and/or interleukin receptor RNA target, for example, by analyzing the assay reaction by electrophoresis of labeled target RNA, or by Northern blotting, as well as by other methodology well known in the art.
Example 7
Nucleic Acid Inhibition of Interleukin and Interleukin Receptor Target RNA in Vitro
[0411] siNA molecules targeted to the human interleukin and/or interleukin receptor RNA are designed and synthesized as described above. These nucleic acid molecules can be tested for cleavage activity in vivo, for example, using the following procedure. The target sequences and the nucleotide location within the interleukin and/or interleukin receptor RNA are given in Table II and III.
[0412] Two formats are used to test the efficacy of siNAs targeting interleukin and/or interleukin receptor. First, the reagents are tested in cell culture using, for example, Jurkat, HeLa, or 293T cells, to determine the extent of RNA and protein inhibition. siNA reagents (e.g.; see Tables II and III) are selected against the interleukin and/or interleukin receptor target as described herein. RNA inhibition is measured after delivery of these reagents by a suitable transfection agent to, for example, cultured Jurkat, HeLa, or 293T cells. Relative amounts of target RNA are measured versus actin using real-time PCR monitoring of amplification (e.g., ABI 7700 TAQMAN®). A comparison is made to a mixture of oligonucleotide sequences made to unrelated targets or to a randomized siNA control with the same overall length and chemistry, but randomly substituted at each position. Primary and secondary lead reagents are chosen for the target and optimization performed. After an optimal transfection agent concentration is chosen, a RNA time-course of inhibition is performed with the lead siNA molecule. In addition, a cell-plating format can be used to determine RNA inhibition.
[0000] Delivery of siNA to Cells
[0413] Cells (e.g., Jurkat, HeLa, or 293T cells) are seeded, for example, at 1×10 5 cells per well of a six-well dish in EGM-2 (BioWhittaker) the day before transfection. siNA (final concentration, for example 20 nM) and cationic lipid (e.g., final concentration 2 μg/ml) are complexed in EGM basal media (Bio Whittaker) at 37° C. for 30 minutes in polystyrene tubes. Following vortexing, the complexed siNA is added to each well and incubated for the times indicated. For initial optimization experiments, cells are seeded, for example, at 1×10 3 in 96 well plates and siNA complex added as described. Efficiency of delivery of siNA to cells is determined using a fluorescent siNA complexed with lipid. Cells in 6-well dishes are incubated with siNA for 24 hours, rinsed with PBS and fixed in 2% paraformaldehyde for 15 minutes at room temperature. Uptake of siNA is visualized using a fluorescent microscope.
[0000] TAQMAN® (Real-Time PCR Monitoring of Amplification) and Lightcycler Quantification of mRNA
[0414] Total RNA is prepared from cells following siNA delivery, for example, using Qiagen RNA purification kits for 6-well or Rneasy extraction kits for 96-well assays. For TAQMAN® analysis (real-time PCR monitoring of amplification), dual-labeled probes are synthesized with the reporter dye, FAM or JOE, covalently linked at the 5′-end and the quencher dye TAMRA conjugated to the 3′-end. One-step RT-PCR amplifications are performed on, for example, an ABI PRISM 7700 Sequence Detector using 50 μl reactions consisting of 10 μl total RNA, 100 nM forward primer, 900 nM reverse primer, 100 nM probe, 1× TaqMan PCR reaction buffer (PE-Applied Biosystems), 5.5 mM MgCl 2 , 300 μM each dATP, dCTP, dGTP, and dTTP, 10U RNase Inhibitor (Promega), 1.25U AMPLITAQ GOLD® (DNA polymerase) (PE-Applied Biosystems) and 10U M-MLV Reverse Transcriptase (Promega). The thermal cycling conditions can consist of 30 minutes at 48° C., 10 minutes at 95° C., followed by 40 cycles of 15 seconds at 95° C. and 1 minute at 60° C. Quantitation of mRNA levels is determined relative to standards generated from serially diluted total cellular RNA (300, 100, 33, 11 ng/r×n) and normalizing to β-actin or GAPDH mRNA in parallel TAQMAN® reactions (real-time PCR monitoring of amplification). For each gene of interest an upper and lower primer and a fluorescently labeled probe are designed. Real time incorporation of SYBR Green I dye into a specific PCR product can be measured in glass capillary tubes using a lightcyler. A standard curve is generated for each primer pair using control cRNA. Values are represented as relative expression to GAPDH in each sample.
Western Blotting
[0415] Nuclear extracts can be prepared using a standard micro preparation technique (see for example Andrews and Faller, 1991 , Nucleic Acids Research, 19, 2499). Protein extracts from supernatants are prepared, for example using TCA precipitation. An equal volume of 20% TCA is added to the cell supernatant, incubated on ice for 1 hour and pelleted by centrifugation for 5 minutes. Pellets are washed in acetone, dried and resuspended in water. Cellular protein extracts are run on a 10% Bis-Tris NuPage (nuclear extracts) or 4-12% Tris-Glycine (supernatant extracts) polyacrylamide gel and transferred onto nitro-cellulose membranes. Non-specific binding can be blocked by incubation, for example, with 5% non-fat milk for 1 hour followed by primary antibody for 16 hour at 4° C. Following washes, the secondary antibody is applied, for example (1:10,000 dilution) for 1 hour at room temperature and the signal detected with SuperSignal reagent (Pierce).
Example 8
Animal Models Useful to Evaluate the Down-Regulation of Interleukin and/or Interleukin Receptor Gene Expression
[0416] Evaluating the efficacy of anti-interleukin agents in animal models is an important prerequisite to human clinical trials. Allogeneic rejection is the most common cause of corneal graft failure. King et al., 2000, Transplantation, 70, 1225-1233, describe a study investigating the kinetics of cytokine and chemokine mRNA expression before and after the onset of corneal graft rejection. Intracorneal cytokine and chemokine mRNA levels were investigated in the Brown Norway-Lewis inbred rat model, in which rejection onset is observed at 8/9 days after grafting in all animals. Nongrafted corneas and syngeneic (Lewis-Lewis) corneal transplants were used as controls. Donor and recipient cornea were examined by quantitative competitive reverse transcription-polymerase chain reaction (RT-PCR) for hypoxanthine phosphoribosyltransferase (HPRT), CD3, CD25, interleukin (IL)-1beta, IL-IRA, IL-2, IL-6, IL-10, interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), transforming growth factor (TGF)-beta1, and macrophage inflammatory protein (MIP)-2 and by RT-PCR for IL-4, IL-5, IL-12 p40, IL-13, TGF-beta.2, monocyte chemotactic protein-1 (MCP-1), MIP-1alpha, MIP-1beta, and RANTES. A biphasic expression of cytokine and chemokine mRNA was found after transplantation. During the early phase (days 3-9), there was an elevation of the majority of the cytokines examined, including IL-1beta, IL-6, IL-10, IL-12 p40, and MIP-2. There was no difference in cytokine expression patterns between allogeneic or syngeneic recipients at this time. In syngeneic recipients, cytokine levels reduced to pretransplant levels by day 13, whereas levels of all cytokines rose after the rejection onset in the allografts, including TGF-beta.1, TGF-beta.2, and IL-IRA. The T cell-derived cytokines IL-4, IL-13, and IFN-gamma were detected only during the rejection phase in allogeneic recipients. Thus, there appears to be an early cytokine and chemokine response to the transplantation process, evident in syngeneic and allogeneic grafts, that drives angiogenesis, leukocyte recruitment, and affects other leukocyte functions. After an immune response has been generated, allogeneic rejection results in the expression of Th1 cytokines, Th2 cytokines, and anti-inflammatory/Th3 cytokines. This animal model can be used to evaluate the efficacy of nucleic acid molecules of the invention targeting interleukin expression (e.g., phenotypic change, interleukin expression etc.) toward therapeutic use in treating transplant rejection. Similarly, other animal models of transplant rejection as are known in the art can be used to evaluate nucleic acid molecules (e.g., siNA) of the invention toward therapeutic use.
[0417] Other animal models are useful in evaluating the role of interleukins in asthma. For example, Kuperman et al., 2002 , Nature Medicine, 8, 885-9, describe an animal model of IL-13 mediated asthma response animal models of allergic asthma in which blockade of IL-13 markedly inhibits allergen-induced asthma. Venkayya et al., 2002 , Am J Respir Cell Mol Biol., 26, 202-8 and Yang et al., 2001 , Am J Respir Cell Mol Biol., 25, 522-30 describe animal models of airway inflammation and airway hyperresponsiveness (AHR) in which IL-4/IL-4R and IL-13 mediate asthma. These models can be used to evaluate the efficacy of siNA molecules of the invention targeting, for example, IL-4, IL-4R, IL-13, and/or IL-13R for use is treating asthma.
Example 9
RNAi Mediated Inhibition of Interleukin and/or Interleukin Receptor Expression in Cell Culture
[0418] Inhibition of Interleukin and/or Interleukin Receptor RNA Expression Using siNA Targeting Interleukin and/or Interleukin Receptor RNA
[0419] siNA constructs (Table III) are tested for efficacy in reducing interleukin and/or interleukin receptor RNA expression in, for example, Jurkat, HeLa, or 293T cells. Cells are plated approximately 24 hours before transfection in 96-well plates at 5,000-7,500 cells/well, 100 μl/well, such that at the time of transfection cells are 70-90% confluent. For transfection, annealed siNAs are mixed with the transfection reagent (Lipofectamine 2000, Invitrogen) in a volume of 0.5 μl/well and incubated for 20 min. at room temperature. The siNA transfection mixtures are added to cells to give a final siNA concentration of 25 nM in a volume of 150 μl. Each siNA transfection mixture is added to 3 wells for triplicate siNA treatments. Cells are incubated at 37° for 24 h in the continued presence of the siNA transfection mixture. At 24 h, RNA is prepared from each well of treated cells. The supernatants with the transfection mixtures are first removed and discarded, then the cells are lysed and RNA prepared from each well. Target gene expression following treatment is evaluated by RT-PCR for the target gene and for a control gene (36B4, an RNA polymerase subunit) for normalization. The triplicate data is averaged and the standard deviations determined for each treatment. Normalized data are graphed and the percent reduction of target mRNA by active siNAs in comparison to their respective inverted control siNAs is determined.
[0420] In a non-limiting example, chemically modified siNA constructs (Table III) were tested for efficacy as described above in reducing IL-4R RNA expression in HeLa cells. Active siNAs were evaluated compared to a matched chemistry inverted control (IC), and a transfection control. Results are summarized in FIG. 22 . FIG. 22 shows results for Stab 9/22 (Table IV) siNA constructs targeting various sites in IL-4R mRNA. As shown in FIG. 22 , the active siNA constructs provide significant inhibition of IL-4R gene expression in cell culture experiments as determined by levels of IL-4R mRNA when compared to appropriate controls.
Example 10
Indications
[0421] The siNA molecule of the invention can be used to prevent, inhibit or treat cancers and other proliferative conditions, viral infection, inflammatory disease, autoimmunity, respiratory disease, pulmonary disease, cardiovascular disease, neurological disease, renal disease, ocular disease, liver disease, mitochondrial disease, endocrine disease, prion disease, reproduction related diseases and conditions, and/or any other trait, disease or condition that is related to or will respond to the levels of interleukin and/or interleukin receptor in a cell or tissue, alone or in combination with other therapies. Non-limiting examples of respiratory diseases that can be treated using siNA molecules of the invention (e.g., siNA molecules targeting IL-4, IL-4R, IL-13, and/or IL-13R include asthma, chronic obstructive pulmonary disease or “COPD”, allergic rhinitis, sinusitis, pulmonary vasoconstriction, inflammation, allergies, impeded respiration, respiratory distress syndrome, cystic fibrosis, pulmonary hypertension, pulmonary vasoconstriction, emphysema.
[0422] The use of anticholinergic agents, anti-inflammatories, bronchodilators, adenosine inhibitors, adenosine A1 receptor inhibitors, non-selective M3 receptor antagonists such as atropine, ipratropium bromide and selective M3 receptor antagonists such as darifenacin and revatropate are all non-limiting examples of agents that can be combined with or used in conjunction with the nucleic acid molecules (e.g. siNA molecules) of the instant invention. Immunomodulators, chemotherapeutics, anti-inflammatory compounds, and anti-viral compounds are additional non-limiting examples of pharmaceutical agents that can be combined with or used in conjunction with the nucleic acid molecules (e.g. siNA molecules) of the instant invention. Those skilled in the art will recognize that other drugs, compounds and therapies can similarly be readily combined with the nucleic acid molecules of the instant invention (e.g. siRNA molecules) are hence within the scope of the instant invention.
Example 11
Diagnostic Uses
[0423] The siNA molecules of the invention can be used in a variety of diagnostic applications, such as in the identification of molecular targets (e.g., RNA) in a variety of applications, for example, in clinical, industrial, environmental, agricultural and/or research settings. Such diagnostic use of siNA molecules involves utilizing reconstituted RNAi systems, for example, using cellular lysates or partially purified cellular lysates. siNA molecules of this invention can be used as diagnostic tools to examine genetic drift and mutations within diseased cells or to detect the presence of endogenous or exogenous, for example viral, RNA in a cell. The close relationship between siNA activity and the structure of the target RNA allows the detection of mutations in any region of the molecule, which alters the base-pairing and three-dimensional structure of the target RNA. By using multiple siNA molecules described in this invention, one can map nucleotide changes, which are important to RNA structure and function in vitro, as well as in cells and tissues. Cleavage of target RNAs with siNA molecules can be used to inhibit gene expression and define the role of specified gene products in the progression of disease or infection. In this manner, other genetic targets can be defined as important mediators of the disease. These experiments will lead to better treatment of the disease progression by affording the possibility of combination therapies (e.g., multiple siNA molecules targeted to different genes, siNA molecules coupled with known small molecule inhibitors, or intermittent treatment with combinations siNA molecules and/or other chemical or biological molecules). Other in vitro uses of siNA molecules of this invention are well known in the art, and include detection of the presence of mRNAs associated with a disease, infection, or related condition. Such RNA is detected by determining the presence of a cleavage product after treatment with an siNA using standard methodologies, for example, fluorescence resonance emission transfer (FRET).
[0424] In a specific example, siNA molecules that cleave only wild-type or mutant forms of the target RNA are used for the assay. The first siNA molecules (i.e., those that cleave only wild-type forms of target RNA) are used to identify wild-type RNA present in the sample and the second siNA molecules (i.e., those that cleave only mutant forms of target RNA) are used to identify mutant RNA in the sample. As reaction controls, synthetic substrates of both wild-type and mutant RNA are cleaved by both siNA molecules to demonstrate the relative siNA efficiencies in the reactions and the absence of cleavage of the “non-targeted” RNA species. The cleavage products from the synthetic substrates also serve to generate size markers for the analysis of wild-type and mutant RNAs in the sample population. Thus, each analysis requires two siNA molecules, two substrates and one unknown sample, which is combined into six reactions. The presence of cleavage products is determined using an RNase protection assay so that full-length and cleavage fragments of each RNA can be analyzed in one lane of a polyacrylamide gel. It is not absolutely required to quantify the results to gain insight into the expression of mutant RNAs and putative risk of the desired phenotypic changes in target cells. The expression of mRNA whose protein product is implicated in the development of the phenotype (i.e., disease related or infection related) is adequate to establish risk. If probes of comparable specific activity are used for both transcripts, then a qualitative comparison of RNA levels is adequate and decreases the cost of the initial diagnosis. Higher mutant form to wild-type ratios are correlated with higher risk whether RNA levels are compared qualitatively or quantitatively.
[0425] All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. All references cited in this disclosure are incorporated by reference to the same extent as if each reference had been incorporated by reference in its entirety individually.
[0426] One skilled in the art would readily appreciate that the present invention is well adapted to carry out the objects and obtain the ends and advantages mentioned, as well as those inherent therein. The methods and compositions described herein as presently representative of preferred embodiments are exemplary and are not intended as limitations on the scope of the invention. Changes therein and other uses will occur to those skilled in the art, which are encompassed within the spirit of the invention, are defined by the scope of the claims.
[0427] It will be readily apparent to one skilled in the art that varying substitutions and modifications can be made to the invention disclosed herein without departing from the scope and spirit of the invention. Thus, such additional embodiments are within the scope of the present invention and the following claims. The present invention teaches one skilled in the art to test various combinations and/or substitutions of chemical modifications described herein toward generating nucleic acid constructs with improved activity for mediating RNAi activity. Such improved activity can comprise improved stability, improved bioavailability, and/or improved activation of cellular responses mediating RNAi. Therefore, the specific embodiments described herein are not limiting and one skilled in the art can readily appreciate that specific combinations of the modifications described herein can be tested without undue experimentation toward identifying siNA molecules with improved RNAi activity.
[0428] The invention illustratively described herein suitably can be practiced in the absence of any element or elements, limitation or limitations that are not specifically disclosed herein. Thus, for example, in each instance herein any of the terms “comprising”, “consisting essentially of”, and “consisting of” may be replaced with either of the other two terms. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention claimed. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by the description and the appended claims.
[0429] In addition, where features or aspects of the invention are described in terms of Markush groups or other grouping of alternatives, those skilled in the art will recognize that the invention is also thereby described in terms of any individual member or subgroup of members of the Markush group or other group.
[0000]
TABLE I
interleukin and/or interleukin receptor Accession Numbers
Interleukin Family
NM_000575
Homo sapiens interleukin 1, alpha (IL1A), mRNA
NM_000576
Homo sapiens interleukin 1, beta (IL1B), mRNA
NM_012275
Homo sapiens interleukin 1 family, member 5 (delta) (IL1F5), mRNA
NM_014440
Homo sapiens interleukin 1 family, member 6 (epsilon) (IL1F6), mRNA
NM_014439
Homo sapiens interleukin 1 family, member 7 (zeta) (IL1F7), mRNA
NM_014438
Homo sapiens interleukin 1 family, member 8 (eta) (IL1F8), mRNA
NM_019618
Homo sapiens interleukin 1 family, member 9 (IL1F9), mRNA
NM_032556
Homo sapiens interleukin 1 family, member 10 (theta) (IL1F10), mRNA
NM_000586
Homo sapiens interleukin 2 (IL2), mRNA
NM_000588
Homo sapiens interleukin 3 (colony-stimulating factor, multiple) (IL3),
mRNA
NM_000589
Homo sapiens interleukin 4 (IL4), mRNA
NM_000879
Homo sapiens interleukin 5 (colony-stimulating factor, eosinophil) (IL5),
mRNA
NM_000600
Homo sapiens interleukin 6 (interferon, beta 2) (IL6), mRNA
NM_000880
Homo sapiens interleukin 7 (IL7), mRNA
NM_000584
Homo sapiens interleukin 8 (IL8), mRNA
NM_000590
Homo sapiens interleukin 9 (IL9), mRNA
NM_000572
Homo sapiens interleukin 10 (IL10), mRNA
NM_000641
Homo sapiens interleukin 11 (IL11), mRNA
NM_000882
Homo sapiens interleukin 12A (natural killer cell stimulatory factor 1,
cytotoxic lymphocyte maturation factor 1, p35) (IL12A), mRNA
NM_002187
Homo sapiens interleukin 12B (natural killer cell stimulatory factor 2,
cytotoxic lymphocyte maturation factor 2, p40) (IL12B), mRNA
NM_002188
Homo sapiens interleukin 13 (IL13), mRNA
L15344
Homo sapiens interleukin 14 (IL14), mRNA
NM_000585
Homo sapiens interleukin 15 (IL15), mRNA
NM_004513
Homo sapiens interleukin 16 (lymphocyte chemoattractant factor) (IL16),
mRNA
NM_002190
Homo sapiens interleukin 17 (cytotoxic T-lymphocyte-associated serine
esterase 8) (IL17), mRNA
NM_014443
Homo sapiens interleukin 17B (IL17B), mRNA
NM_013278
Homo sapiens interleukin 17C (IL17C), mRNA
NM_138284
Homo sapiens interleukin 17D (IL17D), mRNA
NM_022789
Homo sapiens interleukin 17E (IL17E), mRNA
NM_052872
Homo sapiens interleukin 17F (IL17F), mRNA
NM_001562
Homo sapiens interleukin 18 (interferon-gamma-inducing factor) (IL18),
mRNA
NM_013371
Homo sapiens interleukin 19 (IL19), mRNA
NM_018724
Homo sapiens interleukin 20 (IL20), mRNA
NM_021803
Homo sapiens interleukin 21 (IL21 antisense), mRNA
NM_020525
Homo sapiens interleukin 22 (IL22), mRNA
NM_016584
Homo sapiens interleukin 23, alpha subunit p19 (IL23A), mRNA
NM_006850
Homo sapiens interleukin 24 (IL24), mRNA
NM_018402
Homo sapiens interleukin 26 (IL26), mRNA
AL365373
Homo sapiens interleukin 27 (IL27), mRNA
Interleukin Receptor Family
NM_000877
Homo sapiens interleukin 1 receptor, type I (IL1R1), mRNA
NM_004633
Homo sapiens interleukin 1 receptor, type II (IL1R2), mRNA
NM_016232
Homo sapiens interleukin 1 receptor-like 1 (IL1RL1), mRNA
NM_003856
Homo sapiens interleukin 1 receptor-like 1 (IL1RL1), mRNA
NM_003854
Homo sapiens interleukin 1 receptor-like 2 (IL1RL2), mRNA
NM_000417
Homo sapiens interleukin 2 receptor, alpha (IL2RA), mRNA
NM_000878
Homo sapiens interleukin 2 receptor, beta (IL2RB), mRNA
NM_000206
Homo sapiens interleukin 2 receptor, gamma (severe combined
immunodeficiency) (IL2RG), mRNA
NM_002183
Homo sapiens interleukin 3 receptor, alpha (low affinity) (IL3RA),
mRNA
NM_000418
Homo sapiens interleukin 4 receptor (IL4R), mRNA
NM_000564
Homo sapiens interleukin 5 receptor, alpha (IL5RA), mRNA
NM_000565
Homo sapiens interleukin 6 receptor (IL6R), mRNA
NM_002185
Homo sapiens interleukin 7 receptor (IL7R), mRNA
NM_000634
Homo sapiens interleukin 8 receptor, alpha (IL8RA), mRNA
NM_001557
Homo sapiens interleukin 8 receptor, beta (IL8RB), mRNA
NM_002186
Homo sapiens interleukin 9 receptor (IL9R), mRNA
NM_001558
Homo sapiens interleukin 10 receptor, alpha (IL10RA), mRNA
NM_000628
Homo sapiens interleukin 10 receptor, beta (IL10RB), mRNA
NM_004512
Homo sapiens interleukin 11 receptor, alpha (IL11RA), mRNA
NM_005535
Homo sapiens interleukin 12 receptor, beta 1 (IL12RB1), mRNA
NM_001559
Homo sapiens interleukin 12 receptor, beta 2 (IL12RB2), mRNA
NM_001560
Homo sapiens interleukin 13 receptor, alpha 1 (IL13RA1), mRNA
NM_000640
Homo sapiens interleukin 13 receptor, alpha 2 (IL13RA2), mRNA
NM_002189
Homo sapiens interleukin 15 receptor, alpha (IL15RA), mRNA
NM_014339
Homo sapiens interleukin 17 receptor (IL17R), mRNA
NM_032732
Homo sapiens interleukin 17 receptor C (IL-17RC), mRNA
NM_144640
Homo sapiens interleukin 17 receptor E (IL-17RE), mRNA
NM_018725
Homo sapiens interleukin 17B receptor (IL17BR), mRNA
NM_003855
Homo sapiens interleukin 18 receptor 1 (IL18R1), mRNA
NM_003853
Homo sapiens interleukin 18 receptor accessory protein (IL18RAP),
mRNA
NM_014432
Homo sapiens interleukin 20 receptor, alpha (IL20RA), mRNA
NM_021798
Homo sapiens interleukin 21 receptor (IL21 antisenseR), mRNA
NM_021258
Homo sapiens interleukin 22 receptor (IL22R), mRNA
NM_144701
Homo sapiens interleukin 23 receptor (IL23R), mRNA
Interleukin Associated Proteins
NM_004514
Homo sapiens interleukin enhancer binding factor 1 (ILF1), mRNA
NM_004515
Homo sapiens interleukin enhancer binding factor 2, 45 kD (ILF2), mRNA
NM_012218
Homo sapiens interleukin enhancer binding factor 3, 90 kD (ILF3), mRNA
NM_004516
Homo sapiens interleukin enhancer binding factor 3, 90 kD (ILF3), mRNA
NM_016123
Homo sapiens interleukin-1 receptor associated kinase 4 (IRAK4), mRNA
NM_001569
Homo sapiens interleukin-1 receptor-associated kinase 1 (IRAK1),
mRNA
NM_001570
Homo sapiens interleukin-1 receptor-associated kinase 2 (IRAK2),
mRNA
NM_007199
Homo sapiens interleukin-1 receptor-associated kinase 3 (IRAK3),
mRNA
NM_134470
Homo sapiens interleukin 1 receptor accessory protein (IL1RAP), mRNA
NM_002182
Homo sapiens interleukin 1 receptor accessory protein (IL1RAP), mRNA
NM_014271
Homo sapiens interleukin 1 receptor accessory protein-like 1
(IL1RAPL1), mRNA
NM_017416
Homo sapiens interleukin 1 receptor accessory protein-like 2
(IL1RAPL2), mRNA
NM_000577
Homo sapiens interleukin 1 receptor antagonist (IL1RN), mRNA
NM_002184
Homo sapiens interleukin 6 signal transducer (gp130, oncostatin M
receptor) (IL6ST), mRNA
NM_005699
Homo sapiens interleukin 18 binding protein (IL18BP), mRNA
[0000]
TABLE II
Interleukin and Interleukin receptor siNA and Target Sequences
Seq
Seq
Seq
Pos
Seq
ID
UPos
Upper seq
ID
LPos
Lower seq
ID
IL2RG NM_000206
3
AGAGCAAGCGCCAUGUUGA
1
3
AGAGCAAGCGCCAUGUUGA
1
25
UCAACAUGGCGCUUGCUCU
82
21
AAGCCAUCAUUACCAUUCA
2
21
AAGCCAUCAUUACCAUUCA
2
43
UGAAUGGUAAUGAUGGCUU
83
39
ACAUCCCUCUUAUUCCUGC
3
39
ACAUCCCUCUUAUUCCUGC
3
61
GCAGGAAUAAGAGGGAUGU
84
57
CAGCUGCCCCUGCUGGGAG
4
57
CAGCUGCCCCUGCUGGGAG
4
79
CUCCCAGCAGGGGCAGCUG
85
75
GUGGGGCUGAACACGACAA
5
75
GUGGGGCUGAACACGACAA
5
97
UUGUCGUGUUCAGCCCCAC
86
93
AUUCUGACGCCCAAUGGGA
6
93
AUUCUGACGCCCAAUGGGA
6
115
UCCCAUUGGGCGUCAGAAU
87
111
AAUGAAGACACCACAGCUG
7
111
AAUGAAGACACCACAGCUG
7
133
CAGCUGUGGUGUCUUCAUU
88
129
GAUUUCUUCCUGACCACUA
8
129
GAUUUCUUCCUGACCACUA
8
151
UAGUGGUCAGGAAGAAAUC
89
147
AUGCCCACUGACUCCCUCA
9
147
AUGCCCACUGACUCCCUCA
9
169
UGAGGGAGUCAGUGGGCAU
90
165
AGUGUUUCCACUCUGCCCC
10
165
AGUGUUUCCACUCUGCCCC
10
187
GGGGCAGAGUGGAAACACU
91
183
CUCCCAGAGGUUCAGUGUU
11
183
CUCCCAGAGGUUCAGUGUU
11
205
AACACUGAACCUCUGGGAG
92
201
UUUGUGUUCAAUGUCGAGU
12
201
UUUGUGUUCAAUGUCGAGU
12
223
ACUCGACAUUGAACACAAA
93
219
UACAUGAAUUGCACUUGGA
13
219
UACAUGAAUUGCACUUGGA
13
241
UCCAAGUGCAAUUCAUGUA
94
237
AACAGCAGCUCUGAGCCCC
14
237
AACAGCAGCUCUGAGCCCC
14
259
GGGGCUCAGAGCUGCUGUU
95
255
CAGCCUACCAACCUCACUC
15
255
CAGCCUACCAACCUCACUC
15
277
GAGUGAGGUUGGUAGGCUG
96
273
CUGCAUUAUUGGUACAAGA
16
273
CUGCAUUAUUGGUACAAGA
16
295
UCUUGUACCAAUAAUGCAG
97
291
AACUCGGAUAAUGAUAAAG
17
291
AACUCGGAUAAUGAUAAAG
17
313
CUUUAUCAUUAUCCGAGUU
98
309
GUCCAGAAGUGCAGCCACU
18
309
GUCCAGAAGUGCAGCCACU
18
331
AGUGGCUGCACUUCUGGAC
99
327
UAUCUAUUCUCUGAAGAAA
19
327
UAUCUAUUCUCUGAAGAAA
19
349
UUUCUUCAGAGAAUAGAUA
100
345
AUCACUUCUGGCUGUCAGU
20
345
AUCACUUCUGGCUGUCAGU
20
367
ACUGACAGCCAGAAGUGAU
101
363
UUGCAAAAAAAGGAGAUCC
21
363
UUGCAAAAAAAGGAGAUCC
21
385
GGAUCUCCUUUUUUUGCAA
102
381
CACCUCUACCAAACAUUUG
22
381
CACCUCUACCAAACAUUUG
22
403
CAAAUGUUUGGUAGAGGUG
103
399
GUUGUUCAGCUCCAGGACC
23
399
GUUGUUCAGCUCCAGGACC
23
421
GGUCCUGGAGCUGAACAAC
104
417
CCACGGGAACCCAGGAGAC
24
417
CCACGGGAACCCAGGAGAC
24
439
GUCUCCUGGGUUCCCGUGG
105
435
CAGGCCACACAGAUGCUAA
25
435
CAGGCCACACAGAUGCUAA
25
457
UUAGCAUCUGUGUGGCCUG
106
453
AAACUGCAGAAUCUGGUGA
26
453
AAACUGCAGAAUCUGGUGA
26
475
UCACCAGAUUCUGCAGUUU
107
471
AUCCCCUGGGCUCCAGAGA
27
471
AUCCCCUGGGCUCCAGAGA
27
493
UCUCUGGAGCCCAGGGGAU
108
489
AACCUAACACUUCACAAAC
28
489
AACCUAACACUUCACAAAC
28
511
GUUUGUGAAGUGUUAGGUU
109
507
CUGAGUGAAUCCCAGCUAG
29
507
CUGAGUGAAUCCCAGCUAG
29
529
CUAGCUGGGAUUCACUCAG
110
525
GAACUGAACUGGAACAACA
30
525
GAACUGAACUGGAACAACA
30
547
UGUUGUUCCAGUUCAGUUC
111
543
AGAUUCUUGAACCACUGUU
31
543
AGAUUCUUGAACCACUGUU
31
565
AACAGUGGUUCAAGAAUCU
112
561
UUGGAGCACUUGGUGCAGU
32
561
UUGGAGCACUUGGUGCAGU
32
583
ACUGCACCAAGUGCUCCAA
113
579
UACCGGACUGACUGGGACC
33
579
UACCGGACUGACUGGGACC
33
601
GGUCCCAGUCAGUCCGGUA
114
597
CACAGCUGGACUGAACAAU
34
597
CACAGCUGGACUGAACAAU
34
619
AUUGUUCAGUCCAGCUGUG
115
615
UCAGUGGAUUAUAGACAUA
35
615
UCAGUGGAUUAUAGACAUA
35
637
UAUGUCUAUAAUCCACUGA
116
633
AAGUUCUCCUUGCCUAGUG
36
633
AAGUUCUCCUUGCCUAGUG
36
655
CACUAGGCAAGGAGAACUU
117
651
GUGGAUGGGCAGAAACGCU
37
651
GUGGAUGGGCAGAAACGCU
37
673
AGCGUUUCUGCCCAUCCAC
118
669
UACACGUUUCGUGUUCGGA
38
669
UACACGUUUCGUGUUCGGA
38
691
UCCGAACACGAAACGUGUA
119
687
AGCCGCUUUAACCCACUCU
39
687
AGCCGCUUUAACCCACUCU
39
709
AGAGUGGGUUAAAGCGGCU
120
705
UGUGGAAGUGCUCAGCAUU
40
705
UGUGGAAGUGCUCAGCAUU
40
727
AAUGCUGAGCACUUCCACA
121
723
UGGAGUGAAUGGAGCCACC
41
723
UGGAGUGAAUGGAGCCACC
41
745
GGUGGCUCCAUUCACUCCA
122
741
CCAAUCCACUGGGGGAGCA
42
741
CCAAUCCACUGGGGGAGCA
42
763
UGCUCCCCCAGUGGAUUGG
123
759
AAUACUUCAAAAGAGAAUC
43
759
AAUACUUCAAAAGAGAAUC
43
781
GAUUCUCUUUUGAAGUAUU
124
777
CCUUUCCUGUUUGCAUUGG
44
777
CCUUUCCUGUUUGCAUUGG
44
799
CCAAUGCAAACAGGAAAGG
125
795
GAAGCCGUGGUUAUCUCUG
45
795
GAAGCCGUGGUUAUCUCUG
45
817
CAGAGAUAACCACGGCUUC
126
813
GUUGGCUCCAUGGGAUUGA
46
813
GUUGGCUCCAUGGGAUUGA
46
835
UCAAUCCCAUGGAGCCAAC
127
831
AUUAUCAGCCUUCUCUGUG
47
831
AUUAUCAGCCUUCUCUGUG
47
853
CACAGAGAAGGCUGAUAAU
128
849
GUGUAUUUCUGGCUGGAAC
48
849
GUGUAUUUCUGGCUGGAAC
48
871
GUUCCAGCCAGAAAUACAC
129
867
CGGACGAUGCCCCGAAUUC
49
867
CGGACGAUGCCCCGAAUUC
49
889
GAAUUCGGGGCAUCGUCCG
130
885
CCCACCCUGAAGAACCUAG
50
885
CCCACCCUGAAGAACCUAG
50
907
CUAGGUUCUUCAGGGUGGG
131
903
GAGGAUCUUGUUACUGAAU
51
903
GAGGAUCUUGUUACUGAAU
51
925
AUUCAGUAACAAGAUCCUC
132
921
UACCACGGGAACUUUUCGG
52
921
UACCACGGGAACUUUUCGG
52
943
CCGAAAAGUUCCCGUGGUA
133
939
GCCUGGAGUGGUGUGUCUA
53
939
GCCUGGAGUGGUGUGUCUA
53
961
UAGACACACCACUCCAGGC
134
957
AAGGGACUGGCUGAGAGUC
54
957
AAGGGACUGGCUGAGAGUC
54
979
GACUCUCAGCCAGUCCCUU
135
975
CUGCAGCCAGACUACAGUG
55
975
CUGCAGCCAGACUACAGUG
55
997
CACUGUAGUCUGGCUGCAG
136
993
GAACGACUCUGCCUCGUCA
56
993
GAACGACUCUGCCUCGUCA
56
1015
UGACGAGGCAGAGUCGUUC
137
1011
AGUGAGAUUCCCCCAAAAG
57
1011
AGUGAGAUUCCCCCAAAAG
57
1033
CUUUUGGGGGAAUCUCACU
138
1029
GGAGGGGCCCUUGGGGAGG
58
1029
GGAGGGGCCCUUGGGGAGG
58
1051
CCUCCCCAAGGGCCCCUCC
139
1047
GGGCCUGGGGCCUCCCCAU
59
1047
GGGCCUGGGGCCUCCCCAU
59
1069
AUGGGGAGGCCCCAGGCCC
140
1065
UGCAACCAGCAUAGCCCCU
60
1065
UGCAACCAGCAUAGCCCCU
60
1087
AGGGGCUAUGCUGGUUGCA
141
1083
UACUGGGCCCCCCCAUGUU
61
1083
UACUGGGCCCCCCCAUGUU
61
1105
AACAUGGGGGGGCCCAGUA
142
1101
UACACCCUAAAGCCUGAAA
62
1101
UACACCCUAAAGCCUGAAA
62
1123
UUUCAGGCUUUAGGGUGUA
143
1119
ACCUGAACCCCAAUCCUCU
63
1119
ACCUGAACCCCAAUCCUCU
63
1141
AGAGGAUUGGGGUUCAGGU
144
1137
UGACAGAAGAACCCCAGGG
64
1137
UGACAGAAGAACCCCAGGG
64
1159
CCCUGGGGUUCUUCUGUCA
145
1155
GUCCUGUAGCCCUAAGUGG
65
1155
GUCCUGUAGCCCUAAGUGG
65
1177
CCACUUAGGGCUACAGGAC
146
1173
GUACUAACUUUCCUUCAUU
66
1173
GUACUAACUUUCCUUCAUU
66
1195
AAUGAAGGAAAGUUAGUAC
147
1191
UCAACCCACCUGCGUCUCA
67
1191
UCAACCCACCUGCGUCUCA
67
1213
UGAGACGCAGGUGGGUUGA
148
1209
AUACUCACCUCACCCCACU
68
1209
AUACUCACCUCACCCCACU
68
1231
AGUGGGGUGAGGUGAGUAU
149
1227
UGUGGCUGAUUUGGAAUUU
69
1227
UGUGGCUGAUUUGGAAUUU
69
1249
AAAUUCCAAAUCAGCCACA
150
1245
UUGUGCCCCCAUGUAAGCA
70
1245
UUGUGCCCCCAUGUAAGCA
70
1267
UGCUUACAUGGGGGCACAA
151
1263
ACCCCUUCAUUUGGCAUUC
71
1263
ACCCCUUCAUUUGGCAUUC
71
1285
GAAUGCCAAAUGAAGGGGU
152
1281
CCCCACUUGAGAAUUACCC
72
1281
CCCCACUUGAGAAUUACCC
72
1303
GGGUAAUUCUCAAGUGGGG
153
1299
CUUUUGCCCCGAACAUGUU
73
1299
CUUUUGCCCCGAACAUGUU
73
1321
AACAUGUUCGGGGCAAAAG
154
1317
UUUUCUUCUCCCUCAGUCU
74
1317
UUUUCUUCUCCCUCAGUCU
74
1339
AGACUGAGGGAGAAGAAAA
155
1335
UGGCCCUUCCUUUUCGCAG
75
1335
UGGCCCUUCCUUUUCGCAG
75
1357
CUGCGAAAAGGAAGGGCCA
156
1353
GGAUUCUUCCUCCCUCCCU
76
1353
GGAUUCUUCCUCCCUCCCU
76
1375
AGGGAGGGAGGAAGAAUCC
157
1371
UCUUUCCCUCCCUUCCUCU
77
1371
UCUUUCCCUCCCUUCCUCU
77
1393
AGAGGAAGGGAGGGAAAGA
158
1389
UUUCCAUCUACCCUCCGAU
78
1389
UUUCCAUCUACCCUCCGAU
78
1411
AUCGGAGGGUAGAUGGAAA
159
1407
UUGUUCCUGAACCGAUGAG
79
1407
UUGUUCCUGAACCGAUGAG
79
1429
CUCAUCGGUUCAGGAACAA
160
1425
GAAAUAAAGUUUCUGUUGA
80
1425
GAAAUAAAGUUUCUGUUGA
80
1447
UCAACAGAAACUUUAUUUC
161
1431
AAGUUUCUGUUGAUAAUCA
81
1431
AAGUUUCUGUUGAUAAUCA
81
1453
UGAUUAUCAACAGAAACUU
162
IL4 NM_000589
3
CUAUGCAAAGCAAAAAGCC
163
3
CUAUGCAAAGCAAAAAGCC
163
25
GGCUUUUUGCUUUGCAUAG
214
21
CAGCAGCAGCCCCAAGCUG
164
21
CAGCAGCAGCCCCAAGCUG
164
43
CAGCUUGGGGCUGCUGCUG
215
39
GAUAAGAUUAAUCUAAAGA
165
39
GAUAAGAUUAAUCUAAAGA
165
61
UCUUUAGAUUAAUCUUAUC
216
57
AGCAAAUUAUGGUGUAAUU
166
57
AGCAAAUUAUGGUGUAAUU
166
79
AAUUACACCAUAAUUUGCU
217
75
UUCCUAUGCUGAAACUUUG
167
75
UUCCUAUGCUGAAACUUUG
167
97
CAAAGUUUCAGCAUAGGAA
218
93
GUAGUUAAUUUUUUAAAAA
168
93
GUAGUUAAUUUUUUAAAAA
168
115
UUUUUAAAAAAUUAACUAC
219
111
AGGUUUCAUUUUCCUAUUG
169
111
AGGUUUCAUUUUCCUAUUG
169
133
CAAUAGGAAAAUGAAACCU
220
129
GGUCUGAUUUCACAGGAAC
170
129
GGUCUGAUUUCACAGGAAC
170
151
GUUCCUGUGAAAUCAGACC
221
147
CAUUUUACCUGUUUGUGAG
171
147
CAUUUUACCUGUUUGUGAG
171
169
CUCACAAACAGGUAAAAUG
222
165
GGCAUUUUUUCUCCUGGAA
172
165
GGCAUUUUUUCUCCUGGAA
172
187
UUCCAGGAGAAAAAAUGCC
223
183
AGAGAGGUGCUGAUUGGCC
173
183
AGAGAGGUGCUGAUUGGCC
173
205
GGCCAAUCAGCACCUCUCU
224
201
CCCAAGUGACUGACAAUCU
174
201
CCCAAGUGACUGACAAUCU
174
223
AGAUUGUCAGUCACUUGGG
225
219
UGGUGUAACGAAAAUUUCC
175
219
UGGUGUAACGAAAAUUUCC
175
241
GGAAAUUUUCGUUACACCA
226
237
CAAUGUAAACUCAUUUUCC
176
237
CAAUGUAAACUCAUUUUCC
176
259
GGAAAAUGAGUUUACAUUG
227
255
CCUCGGUUUCAGCAAUUUU
177
255
CCUCGGUUUCAGCAAUUUU
177
277
AAAAUUGCUGAAACCGAGG
228
273
UAAAUCUAUAUAUAGAGAU
178
273
UAAAUCUAUAUAUAGAGAU
178
295
AUCUCUAUAUAUAGAUUUA
229
291
UAUCUUUGUCAGCAUUGCA
179
291
UAUCUUUGUCAGCAUUGCA
179
313
UGCAAUGCUGACAAAGAUA
230
309
AUCGUUAGCUUCUCCUGAU
180
309
AUCGUUAGCUUCUCCUGAU
180
331
AUCAGGAGAAGCUAACGAU
231
327
UAAACUAAUUGCCUCACAU
181
327
UAAACUAAUUGCCUCACAU
181
349
AUGUGAGGCAAUUAGUUUA
232
345
UUGUCACUGCAAAUCGACA
182
345
UUGUCACUGCAAAUCGACA
182
367
UGUCGAUUUGCAGUGACAA
233
363
ACCUAUUAAUGGGUCUCAC
183
363
ACCUAUUAAUGGGUCUCAC
183
385
GUGAGACCCAUUAAUAGGU
234
381
CCUCCCAACUGCUUCCCCC
184
381
CCUCCCAACUGCUUCCCCC
184
403
GGGGGAAGCAGUUGGGAGG
235
399
CUCUGUUCUUCCUGCUAGC
185
399
CUCUGUUCUUCCUGCUAGC
185
421
GCUAGCAGGAAGAACAGAG
236
417
CAUGUGCCGGCAACUUUGU
186
417
CAUGUGCCGGCAACUUUGU
186
439
ACAAAGUUGCCGGCACAUG
237
435
UCCACGGACACAAGUGCGA
187
435
UCCACGGACACAAGUGCGA
187
457
UCGCACUUGUGUCCGUGGA
238
453
AUAUCACCUUACAGGAGAU
188
453
AUAUCACCUUACAGGAGAU
188
475
AUCUCCUGUAAGGUGAUAU
239
471
UCAUCAAAACUUUGAACAG
189
471
UCAUCAAAACUUUGAACAG
189
493
CUGUUCAAAGUUUUGAUGA
240
489
GCCUCACAGAGCAGAAGAC
190
489
GCCUCACAGAGCAGAAGAC
190
511
GUCUUCUGCUCUGUGAGGC
241
507
CUCUGUGCACCGAGUUGAC
191
507
CUCUGUGCACCGAGUUGAC
191
529
GUCAACUCGGUGCACAGAG
242
525
CCGUAACAGACAUCUUUGC
192
525
CCGUAACAGACAUCUUUGC
192
547
GCAAAGAUGUCUGUUACGG
243
543
CUGCCUCCAAGAACACAAC
193
543
CUGCCUCCAAGAACACAAC
193
565
GUUGUGUUCUUGGAGGCAG
244
561
CUGAGAAGGAAACCUUCUG
194
561
CUGAGAAGGAAACCUUCUG
194
583
CAGAAGGUUUCCUUCUCAG
245
579
GCAGGGCUGCGACUGUGCU
195
579
GCAGGGCUGCGACUGUGCU
195
601
AGCACAGUCGCAGCCCUGC
246
597
UCCGGCAGUUCUACAGCCA
196
597
UCCGGCAGUUCUACAGCCA
196
619
UGGCUGUAGAACUGCCGGA
247
615
ACCAUGAGAAGGACACUCG
197
615
ACCAUGAGAAGGACACUCG
197
637
CGAGUGUCCUUCUCAUGGU
248
633
GCUGCCUGGGUGCGACUGC
198
633
GCUGCCUGGGUGCGACUGC
198
655
GCAGUCGCACCCAGGCAGC
249
651
CACAGCAGUUCCACAGGCA
199
651
CACAGCAGUUCCACAGGCA
199
673
UGCCUGUGGAACUGCUGUG
250
669
ACAAGCAGCUGAUCCGAUU
200
669
ACAAGCAGCUGAUCCGAUU
200
691
AAUCGGAUCAGCUGCUUGU
251
687
UCCUGAAACGGCUCGACAG
201
687
UCCUGAAACGGCUCGACAG
201
709
CUGUCGAGCCGUUUCAGGA
252
705
GGAACCUCUGGGGCCUGGC
202
705
GGAACCUCUGGGGCCUGGC
202
727
GCCAGGCCCCAGAGGUUCC
253
723
CGGGCUUGAAUUCCUGUCC
203
723
CGGGCUUGAAUUCCUGUCC
203
745
GGACAGGAAUUCAAGCCCG
254
741
CUGUGAAGGAAGCCAACCA
204
741
CUGUGAAGGAAGCCAACCA
204
763
UGGUUGGCUUCCUUCACAG
255
759
AGAGUACGUUGGAAAACUU
205
759
AGAGUACGUUGGAAAACUU
205
781
AAGUUUUCCAACGUACUCU
256
777
UCUUGGAAAGGCUAAAGAC
206
777
UCUUGGAAAGGCUAAAGAC
206
799
GUCUUUAGCCUUUCCAAGA
257
795
CGAUCAUGAGAGAGAAAUA
207
795
CGAUCAUGAGAGAGAAAUA
207
817
UAUUUCUCUCUCAUGAUCG
258
813
AUUCAAAGUGUUCGAGCUG
208
813
AUUCAAAGUGUUCGAGCUG
208
835
CAGCUCGAACACUUUGAAU
259
831
GAAUAUUUUAAUUUAUGAG
209
831
GAAUAUUUUAAUUUAUGAG
209
853
CUCAUAAAUUAAAAUAUUC
260
849
GUUUUUGAUAGCUUUAUUU
210
849
GUUUUUGAUAGCUUUAUUU
210
871
AAAUAAAGCUAUCAAAAAC
261
867
UUUUAAGUAUUUAUAUAUU
211
867
UUUUAAGUAUUUAUAUAUU
211
889
AAUAUAUAAAUACUUAAAA
262
885
UUAUAACUCAUCAUAAAAU
212
885
UUAUAACUCAUCAUAAAAU
212
907
AUUUUAUGAUGAGUUAUAA
263
901
AAUAAAGUAUAUAUAGAAU
213
901
AAUAAAGUAUAUAUAGAAU
213
923
AUUCUAUAUAUACUUUAUU
264
IL4R NM_000418
3
CGAAUGGAGCAGGGGCGCG
265
3
CGAAUGGAGCAGGGGCGCG
265
25
CGCGCCCCUGCUCCAUUCG
465
21
GCAGAUAAUUAAAGAUUUA
266
21
GCAGAUAAUUAAAGAUUUA
266
43
UAAAUCUUUAAUUAUCUGC
466
39
ACACACAGCUGGAAGAAAU
267
39
ACACACAGCUGGAAGAAAU
267
61
AUUUCUUCCAGCUGUGUGU
467
57
UCAUAGAGAAGCCGGGCGU
268
57
UCAUAGAGAAGCCGGGCGU
268
79
ACGCCCGGCUUCUCUAUGA
468
75
UGGUGGCUCAUGCCUAUAA
269
75
UGGUGGCUCAUGCCUAUAA
269
97
UUAUAGGCAUGAGCCACCA
469
93
AUCCCAGCACUUUUGGAGG
270
93
AUCCCAGCACUUUUGGAGG
270
115
CCUCCAAAAGUGCUGGGAU
470
111
GCUGAGGCGGGCAGAUCAC
271
111
GCUGAGGCGGGCAGAUCAC
271
133
GUGAUCUGCCCGCCUCAGC
471
129
CUUGAGAUCAGGAGUUCGA
272
129
CUUGAGAUCAGGAGUUCGA
272
151
UCGAACUCCUGAUCUCAAG
472
147
AGACCAGCCUGGUGCCUUG
273
147
AGACCAGCCUGGUGCCUUG
273
169
CAAGGCACCAGGCUGGUCU
473
165
GGCAUCUCCCAAUGGGGUG
274
165
GGCAUCUCCCAAUGGGGUG
274
187
CACCCCAUUGGGAGAUGCC
474
183
GGCUUUGCUCUGGGCUCCU
275
183
GGCUUUGCUCUGGGCUCCU
275
205
AGGAGCCCAGAGCAAAGCC
475
201
UGUUCCCUGUGAGCUGCCU
276
201
UGUUCCCUGUGAGCUGCCU
276
223
AGGCAGCUCACAGGGAACA
476
219
UGGUCCUGCUGCAGGUGGC
277
219
UGGUCCUGCUGCAGGUGGC
277
241
GCCACCUGCAGCAGGACCA
477
237
CAAGCUCUGGGAACAUGAA
278
237
CAAGCUCUGGGAACAUGAA
278
259
UUCAUGUUCCCAGAGCUUG
478
255
AGGUCUUGCAGGAGCCCAC
279
255
AGGUCUUGCAGGAGCCCAC
279
277
GUGGGCUCCUGCAAGACCU
479
273
CCUGCGUCUCCGACUACAU
280
273
CCUGCGUCUCCGACUACAU
280
295
AUGUAGUCGGAGACGCAGG
480
291
UGAGCAUCUCUACUUGCGA
281
291
UGAGCAUCUCUACUUGCGA
281
313
UCGCAAGUAGAGAUGCUCA
481
309
AGUGGAAGAUGAAUGGUCC
282
309
AGUGGAAGAUGAAUGGUCC
282
331
GGACCAUUCAUCUUCCACU
482
327
CCACCAAUUGCAGCACCGA
283
327
CCACCAAUUGCAGCACCGA
283
349
UCGGUGCUGCAAUUGGUGG
483
345
AGCUCCGCCUGUUGUACCA
284
345
AGCUCCGCCUGUUGUACCA
284
367
UGGUACAACAGGCGGAGCU
484
363
AGCUGGUUUUUCUGCUCUC
285
363
AGCUGGUUUUUCUGCUCUC
285
385
GAGAGCAGAAAAACCAGCU
485
381
CCGAAGCCCACACGUGUAU
286
381
CCGAAGCCCACACGUGUAU
286
403
AUACACGUGUGGGCUUCGG
486
399
UCCCUGAGAACAACGGAGG
287
399
UCCCUGAGAACAACGGAGG
287
421
CCUCCGUUGUUCUCAGGGA
487
417
GCGCGGGGUGCGUGUGCCA
288
417
GCGCGGGGUGCGUGUGCCA
288
439
UGGCACACGCACCCCGCGC
488
435
ACCUGCUCAUGGAUGACGU
289
435
ACCUGCUCAUGGAUGACGU
289
457
ACGUCAUCCAUGAGCAGGU
489
453
UGGUCAGUGCGGAUAACUA
290
453
UGGUCAGUGCGGAUAACUA
290
475
UAGUUAUCCGCACUGACCA
490
471
AUACACUGGACCUGUGGGC
291
471
AUACACUGGACCUGUGGGC
291
493
GCCCACAGGUCCAGUGUAU
491
489
CUGGGCAGCAGCUGCUGUG
292
489
CUGGGCAGCAGCUGCUGUG
292
511
CACAGCAGCUGCUGCCCAG
492
507
GGAAGGGCUCCUUCAAGCC
293
507
GGAAGGGCUCCUUCAAGCC
293
529
GGCUUGAAGGAGCCCUUCC
493
525
CCAGCGAGCAUGUGAAACC
294
525
CCAGCGAGCAUGUGAAACC
294
547
GGUUUCACAUGCUCGCUGG
494
543
CCAGGGCCCCAGGAAACCU
295
543
CCAGGGCCCCAGGAAACCU
295
565
AGGUUUCCUGGGGCCCUGG
495
561
UGACAGUUCACACCAAUGU
296
561
UGACAGUUCACACCAAUGU
296
583
ACAUUGGUGUGAACUGUCA
496
579
UCUCCGACACUCUGCUGCU
297
579
UCUCCGACACUCUGCUGCU
297
601
AGCAGCAGAGUGUCGGAGA
497
597
UGACCUGGAGCAACCCGUA
298
597
UGACCUGGAGCAACCCGUA
298
619
UACGGGUUGCUCCAGGUCA
498
615
AUCCCCCUGACAAUUACCU
299
615
AUCCCCCUGACAAUUACCU
299
637
AGGUAAUUGUCAGGGGGAU
499
633
UGUAUAAUCAUCUCACCUA
300
633
UGUAUAAUCAUCUCACCUA
300
655
UAGGUGAGAUGAUUAUACA
500
651
AUGCAGUCAACAUUUGGAG
301
651
AUGCAGUCAACAUUUGGAG
301
673
CUCCAAAUGUUGACUGCAU
501
669
GUGAAAACGACCCGGCAGA
302
669
GUGAAAACGACCCGGCAGA
302
691
UCUGCCGGGUCGUUUUCAC
502
687
AUUUCAGAAUCUAUAACGU
303
687
AUUUCAGAAUCUAUAACGU
303
709
ACGUUAUAGAUUCUGAAAU
503
705
UGACCUACCUAGAACCCUC
304
705
UGACCUACCUAGAACCCUC
304
727
GAGGGUUCUAGGUAGGUCA
504
723
CCCUCCGCAUCGCAGCCAG
305
723
CCCUCCGCAUCGCAGCCAG
305
745
CUGGCUGCGAUGCGGAGGG
505
741
GCACCCUGAAGUCUGGGAU
306
741
GCACCCUGAAGUCUGGGAU
306
763
AUCCCAGACUUCAGGGUGC
506
759
UUUCCUACAGGGCACGGGU
307
759
UUUCCUACAGGGCACGGGU
307
781
ACCCGUGCCCUGUAGGAAA
507
777
UGAGGGCCUGGGCUCAGUG
308
777
UGAGGGCCUGGGCUCAGUG
308
799
CACUGAGCCCAGGCCCUCA
508
795
GCUAUAACACCACCUGGAG
309
795
GCUAUAACACCACCUGGAG
309
817
CUCCAGGUGGUGUUAUAGC
509
813
GUGAGUGGAGCCCCAGCAC
310
813
GUGAGUGGAGCCCCAGCAC
310
835
GUGCUGGGGCUCCACUCAC
510
831
CCAAGUGGCACAACUCCUA
311
831
CCAAGUGGCACAACUCCUA
311
853
UAGGAGUUGUGCCACUUGG
511
849
ACAGGGAGCCCUUCGAGCA
312
849
ACAGGGAGCCCUUCGAGCA
312
871
UGCUCGAAGGGCUCCCUGU
512
867
AGCACCUCCUGCUGGGCGU
313
867
AGCACCUCCUGCUGGGCGU
313
889
ACGCCCAGCAGGAGGUGCU
513
885
UCAGCGUUUCCUGCAUUGU
314
885
UCAGCGUUUCCUGCAUUGU
314
907
ACAAUGCAGGAAACGCUGA
514
903
UCAUCCUGGCCGUCUGCCU
315
903
UCAUCCUGGCCGUCUGCCU
315
925
AGGCAGACGGCCAGGAUGA
515
921
UGUUGUGCUAUGUCAGCAU
316
921
UGUUGUGCUAUGUCAGCAU
316
943
AUGCUGACAUAGCACAACA
516
939
UCACCAAGAUUAAGAAAGA
317
939
UCACCAAGAUUAAGAAAGA
317
961
UCUUUCUUAAUCUUGGUGA
517
957
AAUGGUGGGAUCAGAUUCC
318
957
AAUGGUGGGAUCAGAUUCC
318
979
GGAAUCUGAUCCCACCAUU
518
975
CCAACCCAGCCCGCAGCCG
319
975
CCAACCCAGCCCGCAGCCG
319
997
CGGCUGCGGGCUGGGUUGG
519
993
GCCUCGUGGCUAUAAUAAU
320
993
GCCUCGUGGCUAUAAUAAU
320
1015
AUUAUUAUAGCCACGAGGC
520
1011
UCCAGGAUGCUCAGGGGUC
321
1011
UCCAGGAUGCUCAGGGGUC
321
1033
GACCCCUGAGCAUCCUGGA
521
1029
CACAGUGGGAGAAGCGGUC
322
1029
CACAGUGGGAGAAGCGGUC
322
1051
GACCGCUUCUCCCACUGUG
522
1047
CCCGAGGCCAGGAACCAGC
323
1047
CCCGAGGCCAGGAACCAGC
323
1069
GCUGGUUCCUGGCCUCGGG
523
1065
CCAAGUGCCCACACUGGAA
324
1065
CCAAGUGCCCACACUGGAA
324
1087
UUCCAGUGUGGGCACUUGG
524
1083
AGAAUUGUCUUACCAAGCU
325
1083
AGAAUUGUCUUACCAAGCU
325
1105
AGCUUGGUAAGACAAUUCU
525
1101
UCUUGCCCUGUUUUCUGGA
326
1101
UCUUGCCCUGUUUUCUGGA
326
1123
UCCAGAAAACAGGGCAAGA
526
1119
AGCACAACAUGAAAAGGGA
327
1119
AGCACAACAUGAAAAGGGA
327
1141
UCCCUUUUCAUGUUGUGCU
527
1137
AUGAAGAUCCUCACAAGGC
328
1137
AUGAAGAUCCUCACAAGGC
328
1159
GCCUUGUGAGGAUCUUCAU
528
1155
CUGCCAAAGAGAUGCCUUU
329
1155
CUGCCAAAGAGAUGCCUUU
329
1177
AAAGGCAUCUCUUUGGCAG
529
1173
UCCAGGGCUCUGGAAAAUC
330
1173
UCCAGGGCUCUGGAAAAUC
330
1195
GAUUUUCCAGAGCCCUGGA
530
1191
CAGCAUGGUGCCCAGUGGA
331
1191
CAGCAUGGUGCCCAGUGGA
331
1213
UCCACUGGGCACCAUGCUG
531
1209
AGAUCAGCAAGACAGUCCU
332
1209
AGAUCAGCAAGACAGUCCU
332
1231
AGGACUGUCUUGCUGAUCU
532
1227
UCUGGCCAGAGAGCAUCAG
333
1227
UCUGGCCAGAGAGCAUCAG
333
1249
CUGAUGCUCUCUGGCCAGA
533
1245
GCGUGGUGCGAUGUGUGGA
334
1245
GCGUGGUGCGAUGUGUGGA
334
1267
UCCACACAUCGCACCACGC
534
1263
AGUUGUUUGAGGCCCCGGU
335
1263
AGUUGUUUGAGGCCCCGGU
335
1285
ACCGGGGCCUCAAACAACU
535
1281
UGGAGUGUGAGGAGGAGGA
336
1281
UGGAGUGUGAGGAGGAGGA
336
1303
UCCUCCUCCUCACACUCCA
536
1299
AGGAGGUAGAGGAAGAAAA
337
1299
AGGAGGUAGAGGAAGAAAA
337
1321
UUUUCUUCCUCUACCUCCU
537
1317
AAGGGAGCUUCUGUGCAUC
338
1317
AAGGGAGCUUCUGUGCAUC
338
1339
GAUGCACAGAAGCUCCCUU
538
1335
CGCCUGAGAGCAGCAGGGA
339
1335
CGCCUGAGAGCAGCAGGGA
339
1357
UCCCUGCUGCUCUCAGGCG
539
1353
AUGACUUCCAGGAGGGAAG
340
1353
AUGACUUCCAGGAGGGAAG
340
1375
CUUCCCUCCUGGAAGUCAU
540
1371
GGGAGGGCAUUGUGGCCCG
341
1371
GGGAGGGCAUUGUGGCCCG
341
1393
CGGGCCACAAUGCCCUCCC
541
1389
GGCUAACAGAGAGCCUGUU
342
1389
GGCUAACAGAGAGCCUGUU
342
1411
AACAGGCUCUCUGUUAGCC
542
1407
UCCUGGACCUGCUCGGAGA
343
1407
UCCUGGACCUGCUCGGAGA
343
1429
UCUCCGAGCAGGUCCAGGA
543
1425
AGGAGAAUGGGGGCUUUUG
344
1425
AGGAGAAUGGGGGCUUUUG
344
1447
CAAAAGCCCCCAUUCUCCU
544
1443
GCCAGCAGGACAUGGGGGA
345
1443
GCCAGCAGGACAUGGGGGA
345
1465
UCCCCCAUGUCCUGCUGGC
545
1461
AGUCAUGCCUUCUUCCACC
346
1461
AGUCAUGCCUUCUUCCACC
346
1483
GGUGGAAGAAGGCAUGACU
546
1479
CUUCGGGAAGUACGAGUGC
347
1479
CUUCGGGAAGUACGAGUGC
347
1501
GCACUCGUACUUCCCGAAG
547
1497
CUCACAUGCCCUGGGAUGA
348
1497
CUCACAUGCCCUGGGAUGA
348
1519
UCAUCCCAGGGCAUGUGAG
548
1515
AGUUCCCAAGUGCAGGGCC
349
1515
AGUUCCCAAGUGCAGGGCC
349
1537
GGCCCUGCACUUGGGAACU
549
1533
CCAAGGAGGCACCUCCCUG
350
1533
CCAAGGAGGCACCUCCCUG
350
1555
CAGGGAGGUGCCUCCUUGG
550
1551
GGGGCAAGGAGCAGCCUCU
351
1551
GGGGCAAGGAGCAGCCUCU
351
1573
AGAGGCUGCUCCUUGCCCC
551
1569
UCCACCUGGAGCCAAGUCC
352
1569
UCCACCUGGAGCCAAGUCC
352
1591
GGACUUGGCUCCAGGUGGA
552
1587
CUCCUGCCAGCCCGACCCA
353
1587
CUCCUGCCAGCCCGACCCA
353
1609
UGGGUCGGGCUGGCAGGAG
553
1605
AGAGUCCAGACAACCUGAC
354
1605
AGAGUCCAGACAACCUGAC
354
1627
GUCAGGUUGUCUGGACUCU
554
1623
CUUGCACAGAGACGCCCCU
355
1623
CUUGCACAGAGACGCCCCU
355
1645
AGGGGCGUCUCUGUGCAAG
555
1641
UCGUCAUCGCAGGCAACCC
356
1641
UCGUCAUCGCAGGCAACCC
356
1663
GGGUUGCCUGCGAUGACGA
556
1659
CUGCUUACCGCAGCUUCAG
357
1659
CUGCUUACCGCAGCUUCAG
357
1681
CUGAAGCUGCGGUAAGCAG
557
1677
GCAACUCCCUGAGCCAGUC
358
1677
GCAACUCCCUGAGCCAGUC
358
1699
GACUGGCUCAGGGAGUUGC
558
1695
CACCGUGUCCCAGAGAGCU
359
1695
CACCGUGUCCCAGAGAGCU
359
1717
AGCUCUCUGGGACACGGUG
559
1713
UGGGUCCAGACCCACUGCU
360
1713
UGGGUCCAGACCCACUGCU
360
1735
AGCAGUGGGUCUGGACCCA
560
1731
UGGCCAGACACCUGGAGGA
361
1731
UGGCCAGACACCUGGAGGA
361
1753
UCCUCCAGGUGUCUGGCCA
561
1749
AAGUAGAACCCGAGAUGCC
362
1749
AAGUAGAACCCGAGAUGCC
362
1771
GGCAUCUCGGGUUCUACUU
562
1767
CCUGUGUCCCCCAGCUCUC
363
1767
CCUGUGUCCCCCAGCUCUC
363
1789
GAGAGCUGGGGGACACAGG
563
1785
CUGAGCCAACCACUGUGCC
364
1785
CUGAGCCAACCACUGUGCC
364
1807
GGCACAGUGGUUGGCUCAG
564
1803
CCCAACCUGAGCCAGAAAC
365
1803
CCCAACCUGAGCCAGAAAC
365
1825
GUUUCUGGCUCAGGUUGGG
565
1821
CCUGGGAGCAGAUCCUCCG
366
1821
CCUGGGAGCAGAUCCUCCG
366
1843
CGGAGGAUCUGCUCCCAGG
566
1839
GCCGAAAUGUCCUCCAGCA
367
1839
GCCGAAAUGUCCUCCAGCA
367
1861
UGCUGGAGGACAUUUCGGC
567
1857
AUGGGGCAGCUGCAGCCCC
368
1857
AUGGGGCAGCUGCAGCCCC
368
1879
GGGGCUGCAGCUGCCCCAU
568
1875
CCGUCUCGGCCCCCACCAG
369
1875
CCGUCUCGGCCCCCACCAG
369
1897
CUGGUGGGGGCCGAGACGG
569
1893
GUGGCUAUCAGGAGUUUGU
370
1893
GUGGCUAUCAGGAGUUUGU
370
1915
ACAAACUCCUGAUAGCCAC
570
1911
UACAUGCGGUGGAGCAGGG
371
1911
UACAUGCGGUGGAGCAGGG
371
1933
CCCUGCUCCACCGCAUGUA
571
1929
GUGGCACCCAGGCCAGUGC
372
1929
GUGGCACCCAGGCCAGUGC
372
1951
GCACUGGCCUGGGUGCCAC
572
1947
CGGUGGUGGGCUUGGGUCC
373
1947
CGGUGGUGGGCUUGGGUCC
373
1969
GGACCCAAGCCCACCACCG
573
1965
CCCCAGGAGAGGCUGGUUA
374
1965
CCCCAGGAGAGGCUGGUUA
374
1987
UAACCAGCCUCUCCUGGGG
574
1983
ACAAGGCCUUCUCAAGCCU
375
1983
ACAAGGCCUUCUCAAGCCU
375
2005
AGGCUUGAGAAGGCCUUGU
575
2001
UGCUUGCCAGCAGUGCUGU
376
2001
UGCUUGCCAGCAGUGCUGU
376
2023
ACAGCACUGCUGGCAAGCA
576
2019
UGUCCCCAGAGAAAUGUGG
377
2019
UGUCCCCAGAGAAAUGUGG
377
2041
CCACAUUUCUCUGGGGACA
577
2037
GGUUUGGGGCUAGCAGUGG
378
2037
GGUUUGGGGCUAGCAGUGG
378
2059
CCACUGCUAGCCCCAAACC
578
2055
GGGAAGAGGGGUAUAAGCC
379
2055
GGGAAGAGGGGUAUAAGCC
379
2077
GGCUUAUACCCCUCUUCCC
579
2073
CUUUCCAAGACCUCAUUCC
380
2073
CUUUCCAAGACCUCAUUCC
380
2095
GGAAUGAGGUCUUGGAAAG
580
2091
CUGGCUGCCCUGGGGACCC
381
2091
CUGGCUGCCCUGGGGACCC
381
2113
GGGUCCCCAGGGCAGCCAG
581
2109
CUGCCCCAGUCCCUGUCCC
382
2109
CUGCCCCAGUCCCUGUCCC
382
2131
GGGACAGGGACUGGGGCAG
582
2127
CCUUGUUCACCUUUGGACU
383
2127
CCUUGUUCACCUUUGGACU
383
2149
AGUCCAAAGGUGAACAAGG
583
2145
UGGACAGGGAGCCACCUCG
384
2145
UGGACAGGGAGCCACCUCG
384
2167
CGAGGUGGCUCCCUGUCCA
584
2163
GCAGUCCGCAGAGCUCACA
385
2163
GCAGUCCGCAGAGCUCACA
385
2185
UGUGAGCUCUGCGGACUGC
585
2181
AUCUCCCAAGCAGCUCCCC
386
2181
AUCUCCCAAGCAGCUCCCC
386
2203
GGGGAGCUGCUUGGGAGAU
586
2199
CAGAGCACCUGGGUCUGGA
387
2199
CAGAGCACCUGGGUCUGGA
387
2221
UCCAGACCCAGGUGCUCUG
587
2217
AGCCGGGGGAAAAGGUAGA
388
2217
AGCCGGGGGAAAAGGUAGA
388
2239
UCUACCUUUUCCCCCGGCU
588
2235
AGGACAUGCCAAAGCCCCC
389
2235
AGGACAUGCCAAAGCCCCC
389
2257
GGGGGCUUUGGCAUGUCCU
589
2253
CACUUCCCCAGGAGCAGGC
390
2253
CACUUCCCCAGGAGCAGGC
390
2275
GCCUGCUCCUGGGGAAGUG
590
2271
CCACAGACCCCCUUGUGGA
391
2271
CCACAGACCCCCUUGUGGA
391
2293
UCCACAAGGGGGUCUGUGG
591
2289
ACAGCCUGGGCAGUGGCAU
392
2289
ACAGCCUGGGCAGUGGCAU
392
2311
AUGCCACUGCCCAGGCUGU
592
2307
UUGUCUACUCAGCCCUUAC
393
2307
UUGUCUACUCAGCCCUUAC
393
2329
GUAAGGGCUGAGUAGACAA
593
2325
CCUGCCACCUGUGCGGCCA
394
2325
CCUGCCACCUGUGCGGCCA
394
2347
UGGCCGCACAGGUGGCAGG
594
2343
ACCUGAAACAGUGUCAUGG
395
2343
ACCUGAAACAGUGUCAUGG
395
2365
CCAUGACACUGUUUCAGGU
595
2361
GCCAGGAGGAUGGUGGCCA
396
2361
GCCAGGAGGAUGGUGGCCA
396
2383
UGGCCACCAUCCUCCUGGC
596
2379
AGACCCCUGUCAUGGCCAG
397
2379
AGACCCCUGUCAUGGCCAG
397
2401
CUGGCCAUGACAGGGGUCU
597
2397
GUCCUUGCUGUGGCUGCUG
398
2397
GUCCUUGCUGUGGCUGCUG
398
2419
CAGCAGCCACAGCAAGGAC
598
2415
GCUGUGGAGACAGGUCCUC
399
2415
GCUGUGGAGACAGGUCCUC
399
2437
GAGGACCUGUCUCCACAGC
599
2433
CGCCCCCUACAACCCCCCU
400
2433
CGCCCCCUACAACCCCCCU
400
2455
AGGGGGGUUGUAGGGGGCG
600
2451
UGAGGGCCCCAGACCCCUC
401
2451
UGAGGGCCCCAGACCCCUC
401
2473
GAGGGGUCUGGGGCCCUCA
601
2469
CUCCAGGUGGGGUUCCACU
402
2469
CUCCAGGUGGGGUUCCACU
402
2491
AGUGGAACCCCACCUGGAG
602
2487
UGGAGGCCAGUCUGUGUCC
403
2487
UGGAGGCCAGUCUGUGUCC
403
2509
GGACACAGACUGGCCUCCA
603
2505
CGGCCUCCCUGGCACCCUC
404
2505
CGGCCUCCCUGGCACCCUC
404
2527
GAGGGUGCCAGGGAGGCCG
604
2523
CGGGCAUCUCAGAGAAGAG
405
2523
CGGGCAUCUCAGAGAAGAG
405
2545
CUCUUCUCUGAGAUGCCCG
605
2541
GUAAAUCCUCAUCAUCCUU
406
2541
GUAAAUCCUCAUCAUCCUU
406
2563
AAGGAUGAUGAGGAUUUAC
606
2559
UCCAUCCUGCCCCUGGCAA
407
2559
UCCAUCCUGCCCCUGGCAA
407
2581
UUGCCAGGGGCAGGAUGGA
607
2577
AUGCUCAGAGCUCAAGCCA
408
2577
AUGCUCAGAGCUCAAGCCA
408
2599
UGGCUUGAGCUCUGAGCAU
608
2595
AGACCCCCAAAAUCGUGAA
409
2595
AGACCCCCAAAAUCGUGAA
409
2617
UUCACGAUUUUGGGGGUCU
609
2613
ACUUUGUCUCCGUGGGACC
410
2613
ACUUUGUCUCCGUGGGACC
410
2635
GGUCCCACGGAGACAAAGU
610
2631
CCACAUACAUGAGGGUCUC
411
2631
CCACAUACAUGAGGGUCUC
411
2653
GAGACCCUCAUGUAUGUGG
611
2649
CUUAGGUGCAUGUCCUCUU
412
2649
CUUAGGUGCAUGUCCUCUU
412
2671
AAGAGGACAUGCACCUAAG
612
2667
UGUUGCUGAGUCUGCAGAU
413
2667
UGUUGCUGAGUCUGCAGAU
413
2689
AUCUGCAGACUCAGCAACA
613
2685
UGAGGACUAGGGCUUAUCC
414
2685
UGAGGACUAGGGCUUAUCC
414
2707
GGAUAAGCCCUAGUCCUCA
614
2703
CAUGCCUGGGAAAUGCCAC
415
2703
CAUGCCUGGGAAAUGCCAC
415
2725
GUGGCAUUUCCCAGGCAUG
615
2721
CCUCCUGGAAGGCAGCCAG
416
2721
CCUCCUGGAAGGCAGCCAG
416
2743
CUGGCUGCCUUCCAGGAGG
616
2739
GGCUGGCAGAUUUCCAAAA
417
2739
GGCUGGCAGAUUUCCAAAA
417
2761
UUUUGGAAAUCUGCCAGCC
617
2757
AGACUUGAAGAACCAUGGU
418
2757
AGACUUGAAGAACCAUGGU
418
2779
ACCAUGGUUCUUCAAGUCU
618
2775
UAUGAAGGUGAUUGGCCCC
419
2775
UAUGAAGGUGAUUGGCCCC
419
2797
GGGGCCAAUCACCUUCAUA
619
2793
CACUGACGUUGGCCUAACA
420
2793
CACUGACGUUGGCCUAACA
420
2815
UGUUAGGCCAACGUCAGUG
620
2811
ACUGGGCUGCAGAGACUGG
421
2811
ACUGGGCUGCAGAGACUGG
421
2833
CCAGUCUCUGCAGCCCAGU
621
2829
GACCCCGCCCAGCAUUGGG
422
2829
GACCCCGCCCAGCAUUGGG
422
2851
CCCAAUGCUGGGCGGGGUC
622
2847
GCUGGGCUCGCCACAUCCC
423
2847
GCUGGGCUCGCCACAUCCC
423
2869
GGGAUGUGGCGAGCCCAGC
623
2865
CAUGAGAGUAGAGGGCACU
424
2865
CAUGAGAGUAGAGGGCACU
424
2887
AGUGCCCUCUACUCUCAUG
624
2883
UGGGUCGCCGUGCCCCACG
425
2883
UGGGUCGCCGUGCCCCACG
425
2905
CGUGGGGCACGGCGACCCA
625
2901
GGCAGGCCCCUGCAGGAAA
426
2901
GGCAGGCCCCUGCAGGAAA
426
2923
UUUCCUGCAGGGGCCUGCC
626
2919
AACUGAGGCCCUUGGGCAC
427
2919
AACUGAGGCCCUUGGGCAC
427
2941
GUGCCCAAGGGCCUCAGUU
627
2937
CCUCGACUUGUGAACGAGU
428
2937
CCUCGACUUGUGAACGAGU
428
2959
ACUCGUUCACAAGUCGAGG
628
2955
UUGUUGGCUGCUCCCUCCA
429
2955
UUGUUGGCUGCUCCCUCCA
429
2977
UGGAGGGAGCAGCCAACAA
629
2973
ACAGCUUCUGCAGCAGACU
430
2973
ACAGCUUCUGCAGCAGACU
430
2995
AGUCUGCUGCAGAAGCUGU
630
2991
UGUCCCUGUUGUAACUGCC
431
2991
UGUCCCUGUUGUAACUGCC
431
3013
GGCAGUUACAACAGGGACA
631
3009
CCAAGGCAUGUUUUGCCCA
432
3009
CCAAGGCAUGUUUUGCCCA
432
3031
UGGGCAAAACAUGCCUUGG
632
3027
ACCAGAUCAUGGCCCACGU
433
3027
ACCAGAUCAUGGCCCACGU
433
3049
ACGUGGGCCAUGAUCUGGU
633
3045
UGGAGGCCCACCUGCCUCU
434
3045
UGGAGGCCCACCUGCCUCU
434
3067
AGAGGCAGGUGGGCCUCCA
634
3063
UGUCUCACUGAACUAGAAG
435
3063
UGUCUCACUGAACUAGAAG
435
3085
CUUCUAGUUCAGUGAGACA
635
3081
GCCGAGCCUAGAAACUAAC
436
3081
GCCGAGCCUAGAAACUAAC
436
3103
GUUAGUUUCUAGGCUCGGC
636
3099
CACAGCCAUCAAGGGAAUG
437
3099
CACAGCCAUCAAGGGAAUG
437
3121
CAUUCCCUUGAUGGCUGUG
637
3117
GACUUGGGCGGCCUUGGGA
438
3117
GACUUGGGCGGCCUUGGGA
438
3139
UCCCAAGGCCGCCCAAGUC
638
3135
AAAUCGAUGAGAAAUUGAA
439
3135
AAAUCGAUGAGAAAUUGAA
439
3157
UUCAAUUUCUCAUCGAUUU
639
3153
ACUUCAGGGAGGGUGGUCA
440
3153
ACUUCAGGGAGGGUGGUCA
440
3175
UGACCACCCUCCCUGAAGU
640
3171
AUUGCCUAGAGGUGCUCAU
441
3171
AUUGCCUAGAGGUGCUCAU
441
3193
AUGAGCACCUCUAGGCAAU
641
3189
UUCAUUUAACAGAGCUUCC
442
3189
UUCAUUUAACAGAGCUUCC
442
3211
GGAAGCUCUGUUAAAUGAA
642
3207
CUUAGGUUGAUGCUGGAGG
443
3207
CUUAGGUUGAUGCUGGAGG
443
3229
CCUCCAGCAUCAACCUAAG
643
3225
GCAGAAUCCCGGCUGUCAA
444
3225
GCAGAAUCCCGGCUGUCAA
444
3247
UUGACAGCCGGGAUUCUGC
644
3243
AGGGGUGUUCAGUUAAGGG
445
3243
AGGGGUGUUCAGUUAAGGG
445
3265
CCCUUAACUGAACACCCCU
645
3261
GGAGCAACAGAGGACAUGA
446
3261
GGAGCAACAGAGGACAUGA
446
3283
UCAUGUCCUCUGUUGCUCC
646
3279
AAAAAUUGCUAUGACUAAA
447
3279
AAAAAUUGCUAUGACUAAA
447
3301
UUUAGUCAUAGCAAUUUUU
647
3297
AGCAGGGACAAUUUGCUGC
448
3297
AGCAGGGACAAUUUGCUGC
448
3319
GCAGCAAAUUGUCCCUGCU
648
3315
CCAAACACCCAUGCCCAGC
449
3315
CCAAACACCCAUGCCCAGC
449
3337
GCUGGGCAUGGGUGUUUGG
649
3333
CUGUAUGGCUGGGGGCUCC
450
3333
CUGUAUGGCUGGGGGCUCC
450
3355
GGAGCCCCCAGCCAUACAG
650
3351
CUCGUAUGCAUGGAACCCC
451
3351
CUCGUAUGCAUGGAACCCC
451
3373
GGGGUUCCAUGCAUACGAG
651
3369
CCAGAAUAAAUAUGCUCAG
452
3369
CCAGAAUAAAUAUGCUCAG
452
3391
CUGAGCAUAUUUAUUCUGG
652
3387
GCCACCCUGUGGGCCGGGC
453
3387
GCCACCCUGUGGGCCGGGC
453
3409
GCCCGGCCCACAGGGUGGC
653
3405
CAAUCCAGACAGCAGGCAU
454
3405
CAAUCCAGACAGCAGGCAU
454
3427
AUGCCUGCUGUCUGGAUUG
654
3423
UAAGGCACCAGUUACCCUG
455
3423
UAAGGCACCAGUUACCCUG
455
3445
CAGGGUAACUGGUGCCUUA
655
3441
GCAUGUUGGCCCAGACCUC
456
3441
GCAUGUUGGCCCAGACCUC
456
3463
GAGGUCUGGGCCAACAUGC
656
3459
CAGGUGCUAGGGAAGGCGG
457
3459
CAGGUGCUAGGGAAGGCGG
457
3481
CCGCCUUCCCUAGCACCUG
657
3477
GGAACCUUGGGUUGAGUAA
458
3477
GGAACCUUGGGUUGAGUAA
458
3499
UUACUCAACCCAAGGUUCC
658
3495
AUGCUCGUCUGUGUGUUUU
459
3495
AUGCUCGUCUGUGUGUUUU
459
3517
AAAACACACAGACGAGCAU
659
3513
UAGUUUCAUCACCUGUUAU
460
3513
UAGUUUCAUCACCUGUUAU
460
3535
AUAACAGGUGAUGAAACUA
660
3531
UCUGUGUUUGCUGAGGAGA
461
3531
UCUGUGUUUGCUGAGGAGA
461
3553
UCUCCUCAGCAAACACAGA
661
3549
AGUGGAACAGAAGGGGUGG
462
3549
AGUGGAACAGAAGGGGUGG
462
3571
CCACCCCUUCUGUUCCACU
662
3567
GAGUUUUGUAUAAAUAAAG
463
3567
GAGUUUUGUAUAAAUAAAG
463
3589
CUUUAUUUAUACAAAACUC
663
3577
UAAAUAAAGUUUCUUUGUC
464
3577
UAAAUAAAGUUUCUUUGUC
464
3599
GACAAAGAAACUUUAUUUA
664
IL13 NM_002188
3
GCCACCCAGCCUAUGCAUC
665
3
GCCACCCAGCCUAUGCAUC
665
25
GAUGCAUAGGCUGGGUGGC
736
21
CCGCUCCUCAAUCCUCUCC
666
21
CCGCUCCUCAAUCCUCUCC
666
43
GGAGAGGAUUGAGGAGCGG
737
39
CUGUUGGCACUGGGCCUCA
667
39
CUGUUGGCACUGGGCCUCA
667
61
UGAGGCCCAGUGCCAACAG
738
57
AUGGCGCUUUUGUUGACCA
668
57
AUGGCGCUUUUGUUGACCA
668
79
UGGUCAACAAAAGCGCCAU
739
75
ACGGUCAUUGCUCUCACUU
669
75
ACGGUCAUUGCUCUCACUU
669
97
AAGUGAGAGCAAUGACCGU
740
93
UGCCUUGGCGGCUUUGCCU
670
93
UGCCUUGGCGGCUUUGCCU
670
115
AGGCAAAGCCGCCAAGGCA
741
111
UCCCCAGGCCCUGUGCCUC
671
111
UCCCCAGGCCCUGUGCCUC
671
133
GAGGCACAGGGCCUGGGGA
742
129
CCCUCUACAGCCCUCAGGG
672
129
CCCUCUACAGCCCUCAGGG
672
151
CCCUGAGGGCUGUAGAGGG
743
147
GAGCUCAUUGAGGAGCUGG
673
147
GAGCUCAUUGAGGAGCUGG
673
169
CCAGCUCCUCAAUGAGCUC
744
165
GUCAACAUCACCCAGAACC
674
165
GUCAACAUCACCCAGAACC
674
187
GGUUCUGGGUGAUGUUGAC
745
183
CAGAAGGCUCCGCUCUGCA
675
183
CAGAAGGCUCCGCUCUGCA
675
205
UGCAGAGCGGAGCCUUCUG
746
201
AAUGGCAGCAUGGUAUGGA
676
201
AAUGGCAGCAUGGUAUGGA
676
223
UCCAUACCAUGCUGCCAUU
747
219
AGCAUCAACCUGACAGCUG
677
219
AGCAUCAACCUGACAGCUG
677
241
CAGCUGUCAGGUUGAUGCU
748
237
GGCAUGUACUGUGCAGCCC
678
237
GGCAUGUACUGUGCAGCCC
678
259
GGGCUGCACAGUACAUGCC
749
255
CUGGAAUCCCUGAUCAACG
679
255
CUGGAAUCCCUGAUCAACG
679
277
CGUUGAUCAGGGAUUCCAG
750
273
GUGUCAGGCUGCAGUGCCA
680
273
GUGUCAGGCUGCAGUGCCA
680
295
UGGCACUGCAGCCUGACAC
751
291
AUCGAGAAGACCCAGAGGA
681
291
AUCGAGAAGACCCAGAGGA
681
313
UCCUCUGGGUCUUCUCGAU
752
309
AUGCUGAGCGGAUUCUGCC
682
309
AUGCUGAGCGGAUUCUGCC
682
331
GGCAGAAUCCGCUCAGCAU
753
327
CCGCACAAGGUCUCAGCUG
683
327
CCGCACAAGGUCUCAGCUG
683
349
CAGCUGAGACCUUGUGCGG
754
345
GGGCAGUUUUCCAGCUUGC
684
345
GGGCAGUUUUCCAGCUUGC
684
367
GCAAGCUGGAAAACUGCCC
755
363
CAUGUCCGAGACACCAAAA
685
363
CAUGUCCGAGACACCAAAA
685
385
UUUUGGUGUCUCGGACAUG
756
381
AUCGAGGUGGCCCAGUUUG
686
381
AUCGAGGUGGCCCAGUUUG
686
403
CAAACUGGGCCACCUCGAU
757
399
GUAAAGGACCUGCUCUUAC
687
399
GUAAAGGACCUGCUCUUAC
687
421
GUAAGAGCAGGUCCUUUAC
758
417
CAUUUAAAGAAACUUUUUC
688
417
CAUUUAAAGAAACUUUUUC
688
439
GAAAAAGUUUCUUUAAAUG
759
435
CGCGAGGGACAGUUCAACU
689
435
CGCGAGGGACAGUUCAACU
689
457
AGUUGAACUGUCCCUCGCG
760
453
UGAAACUUCGAAAGCAUCA
690
453
UGAAACUUCGAAAGCAUCA
690
475
UGAUGCUUUCGAAGUUUCA
761
471
AUUAUUUGCAGAGACAGGA
691
471
AUUAUUUGCAGAGACAGGA
691
493
UCCUGUCUCUGCAAAUAAU
762
489
ACCUGACUAUUGAAGUUGC
692
489
ACCUGACUAUUGAAGUUGC
692
511
GCAACUUCAAUAGUCAGGU
763
507
CAGAUUCAUUUUUCUUUCU
693
507
CAGAUUCAUUUUUCUUUCU
693
529
AGAAAGAAAAAUGAAUCUG
764
525
UGAUGUCAAAAAUGUCUUG
694
525
UGAUGUCAAAAAUGUCUUG
694
547
CAAGACAUUUUUGACAUCA
765
543
GGGUAGGCGGGAAGGAGGG
695
543
GGGUAGGCGGGAAGGAGGG
695
565
CCCUCCUUCCCGCCUACCC
766
561
GUUAGGGAGGGGUAAAAUU
696
561
GUUAGGGAGGGGUAAAAUU
696
583
AAUUUUACCCCUCCCUAAC
767
579
UCCUUAGCUUAGACCUCAG
697
579
UCCUUAGCUUAGACCUCAG
697
601
CUGAGGUCUAAGCUAAGGA
768
597
GCCUGUGCUGCCCGUCUUC
698
597
GCCUGUGCUGCCCGUCUUC
698
619
GAAGACGGGCAGCACAGGC
769
615
CAGCCUAGCCGACCUCAGC
699
615
CAGCCUAGCCGACCUCAGC
699
637
GCUGAGGUCGGCUAGGCUG
770
633
CCUUCCCCUUGCCCAGGGC
700
633
CCUUCCCCUUGCCCAGGGC
700
655
GCCCUGGGCAAGGGGAAGG
771
651
CUCAGCCUGGUGGGCCUCC
701
651
CUCAGCCUGGUGGGCCUCC
701
673
GGAGGCCCACCAGGCUGAG
772
669
CUCUGUCCAGGGCCCUGAG
702
669
CUCUGUCCAGGGCCCUGAG
702
691
CUCAGGGCCCUGGACAGAG
773
687
GCUCGGUGGACCCAGGGAU
703
687
GCUCGGUGGACCCAGGGAU
703
709
AUCCCUGGGUCCACCGAGC
774
705
UGACAUGUCCCUACACCCC
704
705
UGACAUGUCCCUACACCCC
704
727
GGGGUGUAGGGACAUGUCA
775
723
CUCCCCUGCCCUAGAGCAC
705
723
CUCCCCUGCCCUAGAGCAC
705
745
GUGCUCUAGGGCAGGGGAG
776
741
CACUGUAGCAUUACAGUGG
706
741
CACUGUAGCAUUACAGUGG
706
763
CCACUGUAAUGCUACAGUG
777
759
GGUGCCCCCCUUGCCAGAC
707
759
GGUGCCCCCCUUGCCAGAC
707
781
GUCUGGCAAGGGGGGCACC
778
777
CAUGUGGUGGGACAGGGAC
708
777
CAUGUGGUGGGACAGGGAC
708
799
GUCCCUGUCCCACCACAUG
779
795
CCCACUUCACACACAGGCA
709
795
CCCACUUCACACACAGGCA
709
817
UGCCUGUGUGUGAAGUGGG
780
813
AACUGAGGCAGACAGCAGC
710
813
AACUGAGGCAGACAGCAGC
710
835
GCUGCUGUCUGCCUCAGUU
781
831
CUCAGGCACACUUCUUCUU
711
831
CUCAGGCACACUUCUUCUU
711
853
AAGAAGAAGUGUGCCUGAG
782
849
UGGUCUUAUUUAUUAUUGU
712
849
UGGUCUUAUUUAUUAUUGU
712
871
ACAAUAAUAAAUAAGACCA
783
867
UGUGUUAUUUAAAUGAGUG
713
867
UGUGUUAUUUAAAUGAGUG
713
889
CACUCAUUUAAAUAACACA
784
885
GUGUUUGUCACCGUUGGGG
714
885
GUGUUUGUCACCGUUGGGG
714
907
CCCCAACGGUGACAAACAC
785
903
GAUUGGGGAAGACUGUGGC
715
903
GAUUGGGGAAGACUGUGGC
715
925
GCCACAGUCUUCCCCAAUC
786
921
CUGCUAGCACUUGGAGCCA
716
921
CUGCUAGCACUUGGAGCCA
716
943
UGGCUCCAAGUGCUAGCAG
787
939
AAGGGUUCAGAGACUCAGG
717
939
AAGGGUUCAGAGACUCAGG
717
961
CCUGAGUCUCUGAACCCUU
788
957
GGCCCCAGCACUAAAGCAG
718
957
GGCCCCAGCACUAAAGCAG
718
979
CUGCUUUAGUGCUGGGGCC
789
975
GUGGACACCAGGAGUCCCU
719
975
GUGGACACCAGGAGUCCCU
719
997
AGGGACUCCUGGUGUCCAC
790
933
UGGUAAUAAGUACUGUGUA
720
993
UGGUAAUAAGUACUGUGUA
720
1015
UACACAGUACUUAUUACCA
791
1011
ACAGAAUUCUGCUACCUCA
721
1011
ACAGAAUUCUGCUACCUCA
721
1033
UGAGGUAGCAGAAUUCUGU
792
1029
ACUGGGGUCCUGGGGCCUC
722
1029
ACUGGGGUCCUGGGGCCUC
722
1051
GAGGCCCCAGGACCCCAGU
793
1047
CGGAGCCUCAUCCGAGGCA
723
1047
CGGAGCCUCAUCCGAGGCA
723
1069
UGCCUCGGAUGAGGCUCCG
794
1065
AGGGUCAGGAGAGGGGCAG
724
1065
AGGGUCAGGAGAGGGGCAG
724
1087
CUGCCCCUCUCCUGACCCU
795
1083
GAACAGCCGCUCCUGUCUG
725
1083
GAACAGCCGCUCCUGUCUG
725
1105
CAGACAGGAGCGGCUGUUC
796
1101
GCCAGCCAGCAGCCAGCUC
726
1101
GCCAGCCAGCAGCCAGCUC
726
1123
GAGCUGGCUGCUGGCUGGC
797
1119
CUCAGCCAACGAGUAAUUU
727
1119
CUCAGCCAACGAGUAAUUU
727
1141
AAAUUACUCGUUGGCUGAG
798
1137
UAUUGUUUUUCCUUGUAUU
728
1137
UAUUGUUUUUCCUUGUAUU
728
1159
AAUACAAGGAAAAACAAUA
799
1155
UUAAAUAUUAAAUAUGUUA
729
1155
UUAAAUAUUAAAUAUGUUA
729
1177
UAACAUAUUUAAUAUUUAA
800
1173
AGCAAAGAGUUAAUAUAUA
730
1173
AGCAAAGAGUUAAUAUAUA
730
1195
UAUAUAUUAACUCUUUGCU
801
1191
AGAAGGGUACCUUGAACAC
731
1191
AGAAGGGUACCUUGAACAC
731
1213
GUGUUCAAGGUACCCUUCU
802
1209
CUGGGGGAGGGGACAUUGA
732
1209
CUGGGGGAGGGGACAUUGA
732
1231
UCAAUGUCCCCUCCCCCAG
803
1227
AACAAGUUGUUUCAUUGAC
733
1227
AACAAGUUGUUUCAUUGAC
733
1249
GUCAAUGAAACAACUUGUU
804
1245
CUAUCAAACUGAAGCCAGA
734
1245
CUAUCAAACUGAAGCCAGA
734
1267
UCUGGCUUCAGUUUGAUAG
805
1262
GAAAUAAAGUUGGUGACAG
735
1262
GAAAUAAAGUUGGUGACAG
735
1284
CUGUCACCAACUUUAUUUC
806
IL 13RA1 NM_001560
3
CCAAGGCUCCAGCCCGGCC
807
3
CCAAGGCUCCAGCCCGGCC
807
25
GGCCGGGCUGGAGCCUUGG
1030
21
CGGGCUCCGAGGCGAGAGG
808
21
CGGGCUCCGAGGCGAGAGG
808
43
CCUCUCGCCUCGGAGCCCG
1031
39
GCUGCAUGGAGUGGCCGGC
809
39
GCUGCAUGGAGUGGCCGGC
809
61
GCCGGCCACUCCAUGCAGC
1032
57
CGCGGCUCUGCGGGCUGUG
810
57
CGCGGCUCUGCGGGCUGUG
810
79
CACAGCCCGCAGAGCCGCG
1033
75
GGGCGCUGCUGCUCUGCGC
811
75
GGGCGCUGCUGCUCUGCGC
811
97
GCGCAGAGCAGCAGCGCCC
1034
93
CCGGCGGCGGGGGCGGGGG
812
93
CCGGCGGCGGGGGCGGGGG
812
115
CCCCCGCCCCCGCCGCCGG
1035
111
GCGGGGGCGCCGCGCCUAC
813
111
GCGGGGGCGCCGCGCCUAC
813
133
GUAGGCGCGGCGCCCCCGC
1036
129
CGGAAACUCAGCCACCUGU
814
129
CGGAAACUCAGCCACCUGU
814
151
ACAGGUGGCUGAGUUUCCG
1037
147
UGACAAAUUUGAGUGUCUC
815
147
UGACAAAUUUGAGUGUCUC
815
169
GAGACACUCAAAUUUGUCA
1038
165
CUGUUGAAAACCUCUGCAC
816
165
CUGUUGAAAACCUCUGCAC
816
187
GUGCAGAGGUUUUCAACAG
1039
183
CAGUAAUAUGGACAUGGAA
817
183
CAGUAAUAUGGACAUGGAA
817
205
UUCCAUGUCCAUAUUACUG
1040
201
AUCCACCCGAGGGAGCCAG
818
201
AUCCACCCGAGGGAGCCAG
818
223
CUGGCUCCCUCGGGUGGAU
1041
219
GCUCAAAUUGUAGUCUAUG
819
219
GCUCAAAUUGUAGUCUAUG
819
241
CAUAGACUACAAUUUGAGC
1042
237
GGUAUUUUAGUCAUUUUGG
820
237
GGUAUUUUAGUCAUUUUGG
820
259
CCAAAAUGACUAAAAUACC
1043
255
GCGACAAACAAGAUAAGAA
821
255
GCGACAAACAAGAUAAGAA
821
277
UUCUUAUCUUGUUUGUCGC
1044
273
AAAUAGCUCCGGAAACUCG
822
273
AAAUAGCUCCGGAAACUCG
822
295
CGAGUUUCCGGAGCUAUUU
1045
291
GUCGUUCAAUAGAAGUACC
823
291
GUCGUUCAAUAGAAGUACC
823
313
GGUACUUCUAUUGAACGAC
1046
309
CCCUGAAUGAGAGGAUUUG
824
309
CCCUGAAUGAGAGGAUUUG
824
331
CAAAUCCUCUCAUUCAGGG
1047
327
GUCUGCAAGUGGGGUCCCA
825
327
GUCUGCAAGUGGGGUCCCA
825
349
UGGGACCCCACUUGCAGAC
1048
345
AGUGUAGCACCAAUGAGAG
826
345
AGUGUAGCACCAAUGAGAG
826
367
CUCUCAUUGGUGCUACACU
1049
363
GUGAGAAGCCUAGCAUUUU
827
363
GUGAGAAGCCUAGCAUUUU
827
385
AAAAUGCUAGGCUUCUCAC
1050
381
UGGUUGAAAAAUGCAUCUC
828
381
UGGUUGAAAAAUGCAUCUC
828
403
GAGAUGCAUUUUUCAACCA
1051
399
CACCCCCAGAAGGUGAUCC
829
399
CACCCCCAGAAGGUGAUCC
829
421
GGAUCACCUUCUGGGGGUG
1052
417
CUGAGUCUGCUGUGACUGA
830
417
CUGAGUCUGCUGUGACUGA
830
439
UCAGUCACAGCAGACUCAG
1053
435
AGCUUCAAUGCAUUUGGCA
831
435
AGCUUCAAUGCAUUUGGCA
831
457
UGCCAAAUGCAUUGAAGCU
1054
453
ACAACCUGAGCUACAUGAA
832
453
ACAACCUGAGCUACAUGAA
832
475
UUCAUGUAGCUCAGGUUGU
1055
471
AGUGUUCUUGGCUCCCUGG
833
471
AGUGUUCUUGGCUCCCUGG
833
493
CCAGGGAGCCAAGAACACU
1056
489
GAAGGAAUACCAGUCCCGA
834
489
GAAGGAAUACCAGUCCCGA
834
511
UCGGGACUGGUAUUCCUUC
1057
507
ACACUAACUAUACUCUCUA
835
507
ACACUAACUAUACUCUCUA
835
529
UAGAGAGUAUAGUUAGUGU
1058
525
ACUAUUGGCACAGAAGCCU
836
525
ACUAUUGGCACAGAAGCCU
836
547
AGGCUUCUGUGCCAAUAGU
1059
543
UGGAAAAAAUUCAUCAAUG
837
543
UGGAAAAAAUUCAUCAAUG
837
565
CAUUGAUGAAUUUUUUCCA
1060
561
GUGAAAACAUCUUUAGAGA
838
561
GUGAAAACAUCUUUAGAGA
838
583
UCUCUAAAGAUGUUUUCAC
1061
579
AAGGCCAAUACUUUGGUUG
839
579
AAGGCCAAUACUUUGGUUG
839
601
CAACCAAAGUAUUGGCCUU
1062
597
GUUCCUUUGAUCUGACCAA
840
597
GUUCCUUUGAUCUGACCAA
840
619
UUGGUCAGAUCAAAGGAAC
1063
615
AAGUGAAGGAUUCCAGUUU
841
615
AAGUGAAGGAUUCCAGUUU
841
637
AAACUGGAAUCCUUCACUU
1064
633
UUGAACAACACAGUGUCCA
842
633
UUGAACAACACAGUGUCCA
842
655
UGGACACUGUGUUGUUCAA
1065
651
AAAUAAUGGUCAAGGAUAA
843
651
AAAUAAUGGUCAAGGAUAA
843
673
UUAUCCUUGACCAUUAUUU
1066
669
AUGCAGGAAAAAUUAAACC
844
669
AUGCAGGAAAAAUUAAACC
844
691
GGUUUAAUUUUUCCUGCAU
1067
687
CAUCCUUCAAUAUAGUGCC
845
687
CAUCCUUCAAUAUAGUGCC
845
709
GGCACUAUAUUGAAGGAUG
1068
705
CUUUAACUUCCCGUGUGAA
846
705
CUUUAACUUCCCGUGUGAA
846
727
UUCACACGGGAAGUUAAAG
1069
723
AACCUGAUCCUCCACAUAU
847
723
AACCUGAUCCUCCACAUAU
847
745
AUAUGUGGAGGAUCAGGUU
1070
741
UUAAAAACCUCUCCUUCCA
848
741
UUAAAAACCUCUCCUUCCA
848
763
UGGAAGGAGAGGUUUUUAA
1071
759
ACAAUGAUGACCUAUAUGU
849
759
ACAAUGAUGACCUAUAUGU
849
781
ACAUAUAGGUCAUCAUUGU
1072
777
UGCAAUGGGAGAAUCCACA
850
777
UGCAAUGGGAGAAUCCACA
850
799
UGUGGAUUCUCCCAUUGCA
1073
795
AGAAUUUUAUUAGCAGAUG
851
795
AGAAUUUUAUUAGCAGAUG
851
817
CAUCUGCUAAUAAAAUUCU
1074
813
GCCUAUUUUAUGAAGUAGA
852
813
GCCUAUUUUAUGAAGUAGA
852
835
UCUACUUCAUAAAAUAGGC
1075
831
AAGUCAAUAACAGCCAAAC
853
831
AAGUCAAUAACAGCCAAAC
853
853
GUUUGGCUGUUAUUGACUU
1076
849
CUGAGACACAUAAUGUUUU
854
849
CUGAGACACAUAAUGUUUU
854
871
AAAACAUUAUGUGUCUCAG
1077
867
UCUACGUCCAAGAGGCUAA
855
867
UCUACGUCCAAGAGGCUAA
855
889
UUAGCCUCUUGGACGUAGA
1078
885
AAUGUGAGAAUCCAGAAUU
856
885
AAUGUGAGAAUCCAGAAUU
856
907
AAUUCUGGAUUCUCACAUU
1079
903
UUGAGAGAAAUGUGGAGAA
857
903
UUGAGAGAAAUGUGGAGAA
857
925
UUCUCCACAUUUCUCUCAA
1080
921
AUACAUCUUGUUUCAUGGU
858
921
AUACAUCUUGUUUCAUGGU
858
943
ACCAUGAAACAAGAUGUAU
1081
939
UCCCUGGUGUUCUUCCUGA
859
939
UCCCUGGUGUUCUUCCUGA
859
961
UCAGGAAGAACACCAGGGA
1082
957
AUACUUUGAACACAGUCAG
860
957
AUACUUUGAACACAGUCAG
860
979
CUGACUGUGUUCAAAGUAU
1083
975
GAAUAAGAGUCAAAACAAA
861
975
GAAUAAGAGUCAAAACAAA
861
997
UUUGUUUUGACUCUUAUUC
1084
993
AUAAGUUAUGCUAUGAGGA
862
993
AUAAGUUAUGCUAUGAGGA
862
1015
UCCUCAUAGCAUAACUUAU
1085
1011
AUGACAAACUCUGGAGUAA
863
1011
AUGACAAACUCUGGAGUAA
863
1033
UUACUCCAGAGUUUGUCAU
1086
1029
AUUGGAGCCAAGAAAUGAG
864
1029
AUUGGAGCCAAGAAAUGAG
864
1051
CUCAUUUCUUGGCUCCAAU
1087
1047
GUAUAGGUAAGAAGCGCAA
865
1047
GUAUAGGUAAGAAGCGCAA
865
1069
UUGCGCUUCUUACCUAUAC
1088
1065
AUUCCACACUCUACAUAAC
866
1065
AUUCCACACUCUACAUAAC
866
1087
GUUAUGUAGAGUGUGGAAU
1089
1083
CCAUGUUACUCAUUGUUCC
867
1083
CCAUGUUACUCAUUGUUCC
867
1105
GGAACAAUGAGUAACAUGG
1090
1101
CAGUCAUCGUCGCAGGUGC
868
1101
CAGUCAUCGUCGCAGGUGC
868
1123
GCACCUGCGACGAUGACUG
1091
1119
CAAUCAUAGUACUCCUGCU
869
1119
CAAUCAUAGUACUCCUGCU
869
1141
AGCAGGAGUACUAUGAUUG
1092
1137
UUUACCUAAAAAGGCUCAA
870
1137
UUUACCUAAAAAGGCUCAA
870
1159
UUGAGCCUUUUUAGGUAAA
1093
1155
AGAUUAUUAUAUUCCCUCC
871
1155
AGAUUAUUAUAUUCCCUCC
871
1177
GGAGGGAAUAUAAUAAUCU
1094
1173
CAAUUCCUGAUCCUGGCAA
872
1173
CAAUUCCUGAUCCUGGCAA
872
1195
UUGCCAGGAUCAGGAAUUG
1095
1191
AGAUUUUUAAAGAAAUGUU
873
1191
AGAUUUUUAAAGAAAUGUU
873
1213
AACAUUUCUUUAAAAAUCU
1096
1209
UUGGAGACCAGAAUGAUGA
874
1209
UUGGAGACCAGAAUGAUGA
874
1231
UCAUCAUUCUGGUCUCCAA
1097
1227
AUACUCUGCACUGGAAGAA
875
1227
AUACUCUGCACUGGAAGAA
875
1249
UUCUUCCAGUGCAGAGUAU
1098
1245
AGUACGACAUCUAUGAGAA
876
1245
AGUACGACAUCUAUGAGAA
876
1267
UUCUCAUAGAUGUCGUACU
1099
1263
AGCAAACCAAGGAGGAAAC
877
1263
AGCAAACCAAGGAGGAAAC
877
1285
GUUUCCUCCUUGGUUUGCU
1100
1281
CCGACUCUGUAGUGCUGAU
878
1281
CCGACUCUGUAGUGCUGAU
878
1303
AUCAGCACUACAGAGUCGG
1101
1299
UAGAAAACCUGAAGAAAGC
879
1299
UAGAAAACCUGAAGAAAGC
879
1321
GCUUUCUUCAGGUUUUCUA
1102
1317
CCUCUCAGUGAUGGAGAUA
880
1317
CCUCUCAGUGAUGGAGAUA
880
1339
UAUCUCCAUCACUGAGAGG
1103
1335
AAUUUAUUUUUACCUUCAC
881
1335
AAUUUAUUUUUACCUUCAC
881
1357
GUGAAGGUAAAAAUAAAUU
1104
1353
CUGUGACCUUGAGAAGAUU
882
1353
CUGUGACCUUGAGAAGAUU
882
1375
AAUCUUCUCAAGGUCACAG
1105
1371
UCUUCCCAUUCUCCAUUUG
883
1371
UCUUCCCAUUCUCCAUUUG
883
1393
CAAAUGGAGAAUGGGAAGA
1106
1389
GUUAUCUGGGAACUUAUUA
884
1389
GUUAUCUGGGAACUUAUUA
884
1411
UAAUAAGUUCCCAGAUAAC
1107
1407
AAAUGGAAACUGAAACUAC
885
1407
AAAUGGAAACUGAAACUAC
885
1429
GUAGUUUCAGUUUCCAUUU
1108
1425
CUGCACCAUUUAAAAACAG
886
1425
CUGCACCAUUUAAAAACAG
886
1447
CUGUUUUUAAAUGGUGCAG
1109
1443
GGCAGCUCAUAAGAGCCAC
887
1443
GGCAGCUCAUAAGAGCCAC
887
1465
GUGGCUCUUAUGAGCUGCC
1110
1461
CAGGUCUUUAUGUUGAGUC
888
1461
CAGGUCUUUAUGUUGAGUC
888
1483
GACUCAACAUAAAGACCUG
1111
1479
CGCGCACCGAAAAACUAAA
889
1479
CGCGCACCGAAAAACUAAA
889
1501
UUUAGUUUUUCGGUGCGCG
1112
1497
AAAUAAUGGGCGCUUUGGA
890
1497
AAAUAAUGGGCGCUUUGGA
890
1519
UCCAAAGCGCCCAUUAUUU
1113
1515
AGAAGAGUGUGGAGUCAUU
891
1515
AGAAGAGUGUGGAGUCAUU
891
1537
AAUGACUCCACACUCUUCU
1114
1533
UCUCAUUGAAUUAUAAAAG
892
1533
UCUCAUUGAAUUAUAAAAG
892
1555
CUUUUAUAAUUCAAUGAGA
1115
1551
GCCAGCAGGCUUCAAACUA
893
1551
GCCAGCAGGCUUCAAACUA
893
1573
UAGUUUGAAGCCUGCUGGC
1116
1569
AGGGGACAAAGCAAAAAGU
894
1569
AGGGGACAAAGCAAAAAGU
894
1591
ACUUUUUGCUUUGUCCCCU
1117
1587
UGAUGAUAGUGGUGGAGUU
895
1587
UGAUGAUAGUGGUGGAGUU
895
1609
AACUCCACCACUAUCAUCA
1118
1605
UAAUCUUAUCAAGAGUUGU
896
1605
UAAUCUUAUCAAGAGUUGU
896
1627
ACAACUCUUGAUAAGAUUA
1119
1623
UGACAACUUCCUGAGGGAU
897
1623
UGACAACUUCCUGAGGGAU
897
1645
AUCCCUCAGGAAGUUGUCA
1120
1641
UCUAUACUUGCUUUGUGUU
898
1641
UCUAUACUUGCUUUGUGUU
898
1663
AACACAAAGCAAGUAUAGA
1121
1659
UCUUUGUGUCAACAUGAAC
899
1659
UCUUUGUGUCAACAUGAAC
899
1681
GUUCAUGUUGACACAAAGA
1122
1677
CAAAUUUUAUUUGUAGGGG
900
1677
CAAAUUUUAUUUGUAGGGG
900
1699
CCCCUACAAAUAAAAUUUG
1123
1695
GAACUCAUUUGGGGUGCAA
901
1695
GAACUCAUUUGGGGUGCAA
901
1717
UUGCACCCCAAAUGAGUUC
1124
1713
AAUGCUAAUGUCAAACUUG
902
1713
AAUGCUAAUGUCAAACUUG
902
1735
CAAGUUUGACAUUAGCAUU
1125
1731
GAGUCACAAAGAACAUGUA
903
1731
GAGUCACAAAGAACAUGUA
903
1753
UACAUGUUCUUUGUGACUC
1126
1749
AGAAAACAAAAUGGAUAAA
904
1749
AGAAAACAAAAUGGAUAAA
904
1771
UUUAUCCAUUUUGUUUUCU
1127
1767
AAUCUGAUAUGUAUUGUUU
905
1767
AAUCUGAUAUGUAUUGUUU
905
1789
AAACAAUACAUAUCAGAUU
1128
1785
UGGGAUCCUAUUGAACCAU
906
1785
UGGGAUCCUAUUGAACCAU
906
1807
AUGGUUCAAUAGGAUCCCA
1129
1803
UGUUUGUGGCUAUUAAAAC
907
1803
UGUUUGUGGCUAUUAAAAC
907
1825
GUUUUAAUAGCCACAAACA
1130
1821
CUCUUUUAACAGUCUGGGC
908
1821
CUCUUUUAACAGUCUGGGC
908
1843
GCCCAGACUGUUAAAAGAG
1131
1839
CUGGGUCCGGUGGCUCACG
909
1839
CUGGGUCCGGUGGCUCACG
909
1861
CGUGAGCCACCGGACCCAG
1132
1857
GCCUGUAAUCCCAGCAAUU
910
1857
GCCUGUAAUCCCAGCAAUU
910
1879
AAUUGCUGGGAUUACAGGC
1133
1875
UUGGGAGUCCGAGGCGGGC
911
1875
UUGGGAGUCCGAGGCGGGC
911
1897
GCCCGCCUCGGACUCCCAA
1134
1893
CGGAUCACUCGAGGUCAGG
912
1893
CGGAUCACUCGAGGUCAGG
912
1915
CCUGACCUCGAGUGAUCCG
1135
1911
GAGUUCCAGACCAGCCUGA
913
1911
GAGUUCCAGACCAGCCUGA
913
1933
UCAGGCUGGUCUGGAACUC
1136
1929
ACCAAAAUGGUGAAACCUC
914
1929
ACCAAAAUGGUGAAACCUC
914
1951
GAGGUUUCACCAUUUUGGU
1137
1947
CCUCUCUACUAAAACUACA
915
1947
CCUCUCUACUAAAACUACA
915
1969
UGUAGUUUUAGUAGAGAGG
1138
1965
AAAAAUUAACUGGGUGUGG
916
1965
AAAAAUUAACUGGGUGUGG
916
1987
CCACACCCAGUUAAUUUUU
1139
1983
GUGGCGCGUGCCUGUAAUC
917
1983
GUGGCGCGUGCCUGUAAUC
917
2005
GAUUACAGGCACGCGCCAC
1140
2001
CCCAGCUACUCGGGAAGCU
918
2001
CCCAGCUACUCGGGAAGCU
918
2023
AGCUUCCCGAGUAGCUGGG
1141
2019
UGAGGCAGGUGAAUUGUUU
919
2019
UGAGGCAGGUGAAUUGUUU
919
2041
AAACAAUUCACCUGCCUCA
1142
2037
UGAACCUGGGAGGUGGAGG
920
2037
UGAACCUGGGAGGUGGAGG
920
2059
CCUCCACCUCCCAGGUUCA
1143
2055
GUUGCAGUGAGCAGAGAUC
921
2055
GUUGCAGUGAGCAGAGAUC
921
2077
GAUCUCUGCUCACUGCAAC
1144
2073
CACACCACUGCACUCUAGC
922
2073
CACACCACUGCACUCUAGC
922
2095
GCUAGAGUGCAGUGGUGUG
1145
2091
CCUGGGUGACAGAGCAAGA
923
2091
CCUGGGUGACAGAGCAAGA
923
2113
UCUUGCUCUGUCACCCAGG
1146
2109
ACUCUGUCUAAAAAACAAA
924
2109
ACUCUGUCUAAAAAACAAA
924
2131
UUUGUUUUUUAGACAGAGU
1147
2127
AACAAAACAAAACAAAACA
925
2127
AACAAAACAAAACAAAACA
925
2149
UGUUUUGUUUUGUUUUGUU
1148
2145
AAAAAAACCUCUUAAUAUU
926
2145
AAAAAAACCUCUUAAUAUU
926
2167
AAUAUUAAGAGGUUUUUUU
1149
2163
UCUGGAGUCAUCAUUCCCU
927
2163
UCUGGAGUCAUCAUUCCCU
927
2185
AGGGAAUGAUGACUCCAGA
1150
2181
UUCGACAGCAUUUUCCUCU
928
2181
UUCGACAGCAUUUUCCUCU
928
2203
AGAGGAAAAUGCUGUCGAA
1151
2199
UGCUUUGAAAGCCCCAGAA
929
2199
UGCUUUGAAAGCCCCAGAA
929
2221
UUCUGGGGCUUUCAAAGCA
1152
2217
AAUCAGUGUUGGCCAUGAU
930
2217
AAUCAGUGUUGGCCAUGAU
930
2239
AUCAUGGCCAACACUGAUU
1153
2235
UGACAACUACAGAAAAACC
931
2235
UGACAACUACAGAAAAACC
931
2257
GGUUUUUCUGUAGUUGUCA
1154
2253
CAGAGGCAGCUUCUUUGCC
932
2253
CAGAGGCAGCUUCUUUGCC
932
2275
GGCAAAGAAGCUGCCUCUG
1155
2271
CAAGACCUUUCAAAGCCAU
933
2271
CAAGACCUUUCAAAGCCAU
933
2293
AUGGCUUUGAAAGGUCUUG
1156
2289
UUUUAGGCUGUUAGGGGCA
934
2289
UUUUAGGCUGUUAGGGGCA
934
2311
UGCCCCUAACAGCCUAAAA
1157
2307
AGUGGAGGUAGAAUGACUC
935
2307
AGUGGAGGUAGAAUGACUC
935
2329
GAGUCAUUCUACCUCCACU
1158
2325
CCUUGGGUAUUAGAGUUUC
936
2325
CCUUGGGUAUUAGAGUUUC
936
2347
GAAACUCUAAUACCCAAGG
1159
2343
CAACCAUGAAGUCUCUAAC
937
2343
CAACCAUGAAGUCUCUAAC
937
2365
GUUAGAGACUUCAUGGUUG
1160
2361
CAAUGUAUUUUCUUCACCU
938
2361
CAAUGUAUUUUCUUCACCU
938
2383
AGGUGAAGAAAAUACAUUG
1161
2379
UCUGCUACUCAAGUAGCAU
939
2379
UCUGCUACUCAAGUAGCAU
939
2401
AUGCUACUUGAGUAGCAGA
1162
2397
UUUACUGUGUCUUUGGUUU
940
2397
UUUACUGUGUCUUUGGUUU
940
2419
AAACCAAAGACACAGUAAA
1163
2415
UGUGCUAGGCCCCCGGGUG
941
2415
UGUGCUAGGCCCCCGGGUG
941
2437
CACCCGGGGGCCUAGCACA
1164
2433
GUGAAGCACAGACCCCUUC
942
2433
GUGAAGCACAGACCCCUUC
942
2455
GAAGGGGUCUGUGCUUCAC
1165
2451
CCAGGGGUUUACAGUCUAU
943
2451
CCAGGGGUUUACAGUCUAU
943
2473
AUAGACUGUAAACCCCUGG
1166
2469
UUUGAGACUCCUCAGUUCU
944
2469
UUUGAGACUCCUCAGUUCU
944
2491
AGAACUGAGGAGUCUCAAA
1167
2487
UUGCCACUUUUUUUUUUAA
945
2487
UUGCCACUUUUUUUUUUAA
945
2509
UUAAAAAAAAAAGUGGCAA
1168
2505
AUCUCCACCAGUCAUUUUU
946
2505
AUCUCCACCAGUCAUUUUU
946
2527
AAAAAUGACUGGUGGAGAU
1169
2523
UCAGACCUUUUAACUCCUC
947
2523
UCAGACCUUUUAACUCCUC
947
2545
GAGGAGUUAAAAGGUCUGA
1170
2541
CAAUUCCAACACUGAUUUC
948
2541
CAAUUCCAACACUGAUUUC
948
2563
GAAAUCAGUGUUGGAAUUG
1171
2559
CCCCUUUUGCAUUCUCCCU
949
2559
CCCCUUUUGCAUUCUCCCU
949
2581
AGGGAGAAUGCAAAAGGGG
1172
2577
UCCUUCCCUUCCUUGUAGC
950
2577
UCCUUCCCUUCCUUGUAGC
950
2599
GCUACAAGGAAGGGAAGGA
1173
2595
CCUUUUGACUUUCAUUGGA
951
2595
CCUUUUGACUUUCAUUGGA
951
2617
UCCAAUGAAAGUCAAAAGG
1174
2613
AAAUUAGGAUGUAAAUCUG
952
2613
AAAUUAGGAUGUAAAUCUG
952
2635
CAGAUUUACAUCCUAAUUU
1175
2631
GCUCAGGAGACCUGGAGGA
953
2631
GCUCAGGAGACCUGGAGGA
953
2653
UCCUCCAGGUCUCCUGAGC
1176
2649
AGCAGAGGAUAAUUAGCAU
954
2649
AGCAGAGGAUAAUUAGCAU
954
2671
AUGCUAAUUAUCCUCUGCU
1177
2667
UCUCAGGUUAAGUGUGAGU
955
2667
UCUCAGGUUAAGUGUGAGU
955
2689
ACUCACACUUAACCUGAGA
1178
2685
UAAUCUGAGAAACAAUGAC
956
2685
UAAUCUGAGAAACAAUGAC
956
2707
GUCAUUGUUUCUCAGAUUA
1179
2703
CUAAUUCUUGCAUAUUUUG
957
2703
CUAAUUCUUGCAUAUUUUG
957
2725
CAAAAUAUGCAAGAAUUAG
1180
2721
GUAACUUCCAUGUGAGGGU
958
2721
GUAACUUCCAUGUGAGGGU
958
2743
ACCCUCACAUGGAAGUUAC
1181
2739
UUUUCAGCAUUGAUAUUUG
959
2739
UUUUCAGCAUUGAUAUUUG
959
2761
CAAAUAUCAAUGCUGAAAA
1182
2757
GUGCAUUUUCUAAACAGAG
960
2757
GUGCAUUUUCUAAACAGAG
960
2779
CUCUGUUUAGAAAAUGCAC
1183
2775
GAUGAGGUGGUAUCUUCAC
961
2775
GAUGAGGUGGUAUCUUCAC
961
2797
GUGAAGAUACCACCUCAUC
1184
2793
CGUAGAACAUUGGUAUUCG
962
2793
CGUAGAACAUUGGUAUUCG
962
2815
CGAAUACCAAUGUUCUACG
1185
2811
GCUUGAGAAAAAAAGAAUA
963
2811
GCUUGAGAAAAAAAGAAUA
963
2833
UAUUCUUUUUUUCUCAAGC
1186
2829
AGUUGAACCUAUUUCUCUU
964
2829
AGUUGAACCUAUUUCUCUU
964
2851
AAGAGAAAUAGGUUCAACU
1187
2847
UUCUUUACAAGAUGGGUCC
965
2847
UUCUUUACAAGAUGGGUCC
965
2869
GGACCCAUCUUGUAAAGAA
1188
2865
CAGGAUUCCUCUUUUCUCU
966
2865
CAGGAUUCCUCUUUUCUCU
966
2887
AGAGAAAAGAGGAAUCCUG
1189
2883
UGCCAUAAAUGAUUAAUUA
967
2883
UGCCAUAAAUGAUUAAUUA
967
2905
UAAUUAAUCAUUUAUGGCA
1190
2901
AAAUAGCUUUUGUGUCUUA
968
2901
AAAUAGCUUUUGUGUCUUA
968
2923
UAAGACACAAAAGCUAUUU
1191
2919
ACAUUGGUAGCCAGCCAGC
969
2919
ACAUUGGUAGCCAGCCAGC
969
2941
GCUGGCUGGCUACCAAUGU
1192
2937
CCAAGGCUCUGUUUAUGCU
970
2937
CCAAGGCUCUGUUUAUGCU
970
2959
AGCAUAAACAGAGCCUUGG
1193
2955
UUUUGGGGGGCAUAUAUUG
971
2955
UUUUGGGGGGCAUAUAUUG
971
2977
CAAUAUAUGCCCCCCAAAA
1194
2973
GGGUUCCAUUCUCACCUAU
972
2973
GGGUUCCAUUCUCACCUAU
972
2995
AUAGGUGAGAAUGGAACCC
1195
2991
UCCACACAACAUAUCCGUA
973
2991
UCCACACAACAUAUCCGUA
973
3013
UACGGAUAUGUUGUGUGGA
1196
3009
AUAUAUCCCCUCUACUCUU
974
3009
AUAUAUCCCCUCUACUCUU
974
3031
AAGAGUAGAGGGGAUAUAU
1197
3027
UACUUCCCCCAAAUUUAAA
975
3027
UACUUCCCCCAAAUUUAAA
975
3049
UUUAAAUUUGGGGGAAGUA
1198
3045
AGAAGUAUGGGAAAUGAGA
976
3045
AGAAGUAUGGGAAAUGAGA
976
3067
UCUCAUUUCCCAUACUUCU
1199
3063
AGGCAUUUCCCCCACCCCA
977
3063
AGGCAUUUCCCCCACCCCA
977
3085
UGGGGUGGGGGAAAUGCCU
1200
3081
AUUUCUCUCCUCACACACA
978
3081
AUUUCUCUCCUCACACACA
978
3103
UGUGUGUGAGGAGAGAAAU
1201
3099
AGACUCAUAUUACUGGUAG
979
3099
AGACUCAUAUUACUGGUAG
979
3121
CUACCAGUAAUAUGAGUCU
1202
3117
GGAACUUGAGAACUUUAUU
980
3117
GGAACUUGAGAACUUUAUU
980
3139
AAUAAAGUUCUCAAGUUCC
1203
3135
UUCCAAGUUGUUCAAACAU
981
3135
UUCCAAGUUGUUCAAACAU
981
3157
AUGUUUGAACAACUUGGAA
1204
3153
UUUACCAAUCAUAUUAAUA
982
3153
UUUACCAAUCAUAUUAAUA
982
3175
UAUUAAUAUGAUUGGUAAA
1205
3171
ACAAUGAUGCUAUUUGCAA
983
3171
ACAAUGAUGCUAUUUGCAA
983
3193
UUGCAAAUAGCAUCAUUGU
1206
3189
AUUCCUGCUCCUAGGGGAG
984
3189
AUUCCUGCUCCUAGGGGAG
984
3211
CUCCCCUAGGAGCAGGAAU
1207
3207
GGGGAGAUAAGAAACCCUC
985
3207
GGGGAGAUAAGAAACCCUC
985
3229
GAGGGUUUCUUAUCUCCCC
1208
3225
CACUCUCUACAGGUUUGGG
986
3225
CACUCUCUACAGGUUUGGG
986
3247
CCCAAACCUGUAGAGAGUG
1209
3243
GUACAAGUGGCAACCUGCU
987
3243
GUACAAGUGGCAACCUGCU
987
3265
AGCAGGUUGCCACUUGUAC
1210
3261
UUCCAUGGCCGUGUAGAAG
988
3261
UUCCAUGGCCGUGUAGAAG
988
3283
CUUCUACACGGCCAUGGAA
1211
3279
GCAUGGUGCCCUGGCUUCU
989
3279
GCAUGGUGCCCUGGCUUCU
989
3301
AGAAGCCAGGGCACCAUGC
1212
3297
UCUGAGGAAGCUGGGGUUC
990
3297
UCUGAGGAAGCUGGGGUUC
990
3319
GAACCCCAGCUUCCUCAGA
1213
3315
CAUGACAAUGGCAGAUGUA
991
3315
CAUGACAAUGGCAGAUGUA
991
3337
UACAUCUGCCAUUGUCAUG
1214
3333
AAAGUUAUUCUUGAAGUCA
992
3333
AAAGUUAUUCUUGAAGUCA
992
3355
UGACUUCAAGAAUAACUUU
1215
3351
AGAUUGAGGCUGGGAGACA
993
3351
AGAUUGAGGCUGGGAGACA
993
3373
UGUCUCCCAGCCUCAAUCU
1216
3369
AGCCGUAGUAGAUGUUCUA
994
3369
AGCCGUAGUAGAUGUUCUA
994
3391
UAGAACAUCUACUACGGCU
1217
3387
ACUUUGUUCUGCUGUUCUC
995
3387
ACUUUGUUCUGCUGUUCUC
995
3409
GAGAACAGCAGAACAAAGU
1218
3405
CUAGAAAGAAUAUUUGGUU
996
3405
CUAGAAAGAAUAUUUGGUU
996
3427
AACCAAAUAUUCUUUCUAG
1219
3423
UUUCCUGUAUAGGAAUGAG
997
3423
UUUCCUGUAUAGGAAUGAG
997
3445
CUCAUUCCUAUACAGGAAA
1220
3441
GAUUAAUUCCUUUCCAGGU
998
3441
GAUUAAUUCCUUUCCAGGU
998
3463
ACCUGGAAAGGAAUUAAUC
1221
3459
UAUUUUAUAAUUCUGGGAA
999
3459
UAUUUUAUAAUUCUGGGAA
999
3481
UUCCCAGAAUUAUAAAAUA
1222
3477
AGCAAAACCCAUGCCUCCC
1000
3477
AGCAAAACCCAUGCCUCCC
1000
3499
GGGAGGCAUGGGUUUUGCU
1223
3495
CCCUAGCCAUUUUUACUGU
1001
3495
CCCUAGCCAUUUUUACUGU
1001
3517
ACAGUAAAAAUGGCUAGGG
1224
3513
UUAUCCUAUUUAGAUGGCC
1002
3513
UUAUCCUAUUUAGAUGGCC
1002
3535
GGCCAUCUAAAUAGGAUAA
1225
3531
CAUGAAGAGGAUGCUGUGA
1003
3531
CAUGAAGAGGAUGCUGUGA
1003
3553
UCACAGCAUCCUCUUCAUG
1226
3549
AAAUUCCCAACAAACAUUG
1004
3549
AAAUUCCCAACAAACAUUG
1004
3571
CAAUGUUUGUUGGGAAUUU
1227
3567
GAUGCUGACAGUCAUGCAG
1005
3567
GAUGCUGACAGUCAUGCAG
1005
3589
CUGCAUGACUGUCAGCAUC
1228
3585
GUCUGGGAGUGGGGAAGUG
1006
3585
GUCUGGGAGUGGGGAAGUG
1006
3607
CACUUCCCCACUCCCAGAC
1229
3603
GAUCUUUUGUUCCCAUCCU
1007
3603
GAUCUUUUGUUCCCAUCCU
1007
3625
AGGAUGGGAACAAAAGAUC
1230
3621
UCUUCUUUUAGCAGUAAAA
1008
3621
UCUUCUUUUAGCAGUAAAA
1008
3643
UUUUACUGCUAAAAGAAGA
1231
3639
AUAGCUGAGGGAAAAGGGA
1009
3639
AUAGCUGAGGGAAAAGGGA
1009
3661
UCCCUUUUCCCUCAGCUAU
1232
3657
AGGGAAAAGGAAGUUAUGG
1010
3657
AGGGAAAAGGAAGUUAUGG
1010
3679
CCAUAACUUCCUUUUCCCU
1233
3675
GGAAUACCUGUGGUGGUUG
1011
3675
GGAAUACCUGUGGUGGUUG
1011
3697
CAACCACCACAGGUAUUCC
1234
3693
GUGAUCCCUAGGUCUUGGG
1012
3693
GUGAUCCCUAGGUCUUGGG
1012
3715
CCCAAGACCUAGGGAUCAC
1235
3711
GAGCUCUUGGAGGUGUCUG
1013
3711
GAGCUCUUGGAGGUGUCUG
1013
3733
CAGACACCUCCAAGAGCUC
1236
3729
GUAUCAGUGGAUUUCCCAU
1014
3729
GUAUCAGUGGAUUUCCCAU
1014
3751
AUGGGAAAUCCACUGAUAC
1237
3747
UCCCCUGUGGGAAAUUAGU
1015
3747
UCCCCUGUGGGAAAUUAGU
1015
3769
ACUAAUUUCCCACAGGGGA
1238
3765
UAGGCUCAUUUACUGUUUU
1016
3765
UAGGCUCAUUUACUGUUUU
1016
3787
AAAACAGUAAAUGAGCCUA
1239
3783
UAGGUCUAGCCUAUGUGGA
1017
3783
UAGGUCUAGCCUAUGUGGA
1017
3805
UCCACAUAGGCUAGACCUA
1240
3801
AUUUUUUCCUAACAUACCU
1018
3801
AUUUUUUCCUAACAUACCU
1018
3823
AGGUAUGUUAGGAAAAAAU
1241
3819
UAAGCAAACCCAGUGUCAG
1019
3819
UAAGCAAACCCAGUGUCAG
1019
3841
CUGACACUGGGUUUGCUUA
1242
3837
GGAUGGUAAUUCUUAUUCU
1020
3837
GGAUGGUAAUUCUUAUUCU
1020
3859
AGAAUAAGAAUUACCAUCC
1243
3855
UUUCGUUCAGUUAAGUUUU
1021
3855
UUUCGUUCAGUUAAGUUUU
1021
3877
AAAACUUAACUGAACGAAA
1244
3873
UUCCCUUCAUCUGGGCACU
1022
3873
UUCCCUUCAUCUGGGCACU
1022
3895
AGUGCCCAGAUGAAGGGAA
1245
3891
UGAAGGGAUAUGUGAAACA
1023
3891
UGAAGGGAUAUGUGAAACA
1023
3913
UGUUUCACAUAUCCCUUCA
1246
3909
AAUGUUAACAUUUUUGGUA
1024
3909
AAUGUUAACAUUUUUGGUA
1024
3931
UACCAAAAAUGUUAACAUU
1247
3927
AGUCUUCAACCAGGGAUUG
1025
3927
AGUCUUCAACCAGGGAUUG
1025
3949
CAAUCCCUGGUUGAAGACU
1248
3945
GUUUCUGUUUAACUUCUUA
1026
3945
GUUUCUGUUUAACUUCUUA
1026
3967
UAAGAAGUUAAACAGAAAC
1249
3963
AUAGGAAAGCUUGAGUAAA
1027
3963
AUAGGAAAGCUUGAGUAAA
1027
3985
UUUACUCAAGCUUUCCUAU
1250
3981
AAUAAAUAUUGUCUUUUUG
1028
3981
AAUAAAUAUUGUCUUUUUG
1028
4003
CAAAAAGACAAUAUUUAUU
1251
3986
AUAUUGUCUUUUUGUAUGU
1029
3986
AUAUUGUCUUUUUGUAUGU
1029
4008
ACAUACAAAAAGACAAUAU
1252
The 3′-ends of the Upper sequence and the Lower sequence of the siNA construct can include an overhang sequence, for example about 1, 2, 3, or 4 nucleotides in length, preferably 2 nucleotides in length, wherein the overhanging sequence of the lower sequence is optionally complementary to a portion of the target sequence. The upper sequence is also referred to as the sense strand, whereas the lower sequence is also referred to as the antisense strand. The upper and lower sequences in the Table can further comprise a chemical modification having Formulae I-VII or any combination thereof.
[0000]
TABLE III
Interleukin and Interleukin receptor Synthetic Modified siNA constructs
Target
Seq
Seq
Pos
Target
ID
Cmpd#
Aliases
Sequence
ID
IL2RG
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:120U21 sense siNA
ACCACAGCUGAUUUCUUCCTT
1311
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:132U21 sense siNA
UUCUUCCUGACCACUAUGCTT
1312
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:140U21 sense siNA
GACCACUAUGCCCACUGACTT
1313
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:157U21 sense siNA
ACUCCCUCAGUGUUUCCACTT
1314
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:264U21 sense siNA
AACCUCACUCUGCAUUAUUTT
1315
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:304U21 sense siNA
AUAAAGUCCAGAAGUGCAGTT
1316
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:305U21 sense siNA
UAAAGUCCAGAAGUGCAGCTT
1317
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:346U21 sense siNA
UCACUUCUGGCUGUCAGUUTT
1318
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:138L21 antisense siNA
GGAAGAAAUCAGCUGUGGUTT
1319
(120C)
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:150L21 antisense siNA
GCAUAGUGGUCAGGAAGAATT
1320
(132C)
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:158L21 antisense siNA
GUCAGUGGGCAUAGUGGUCTT
1321
(140C)
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:175L21 antisense siNA
GUGGAAACACUGAGGGAGUTT
1322
(157C)
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:282L21 antisense siNA
AAUAAUGCAGAGUGAGGUUTT
1323
(264C)
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:322L21 antisense siNA
CUGCACUUCUGGACUUUAUTT
1324
(304C)
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:323L21 antisense siNA
GCUGCACUUCUGGACUUUATT
1325
(305C)
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:364L21 antisense siNA
AACUGACAGCCAGAAGUGATT
1326
(346C)
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:120U21 sense siNA
B AccAcAGcuGAuuucuuccTT B
1327
stab04
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:132U21 sense siNA
B uucuuccuGAccAcuAuGcTT B
1328
stab04
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:140U21 sense siNA
B GAccAcuAuGcccAcuGAcTT B
1329
stab04
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:157U21 sense siNA
B AcucccucAGuGuuuccAcTT B
1330
stab04
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:264U21 sense siNA
B AAccucAcucuGcAuuAuuTT B
1331
stab04
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:304U21 sense siNA
B AuAAAGuccAGAAGuGcAGTT B
1332
stab04
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:305U21 sense siNA
B uAAAGuccAGAAGuGcAGcTT B
1333
stab04
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:346U21 sense siNA
B ucAcuucuGGcuGucAGuuTT B
1334
stab04
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:138L21 antisense siNA
GGAAGAAAucAGcuGuGGuTsT
1335
(120C) stab05
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:150L21 antisense siNA
GcAuAGuGGucAGGAAGAATsT
1336
(132C) stab05
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:158L21 antisense siNA
GucAGuGGGcAuAGuGGucTsT
1337
(140C) stab05
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:175L21 antisense siNA
GuGGAAAcAcuGAGGGAGuTsT
1338
(157C) stab05
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:282L21 antisense siNA
AAuAAuGcAGAGuGAGGuuTsT
1339
(264C) stab05
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:322L21 antisense siNA
cuGcAcuucuGGAcuuuAuTsT
1340
(304C) stab05
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:323L21 antisense siNA
GcuGcAcuucuGGAcuuuATsT
1341
(305C) stab05
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:364L21 antisense siNA
AAcuGAcAGccAGAAGuGATsT
1342
(346C) stab05
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:120U21 sense siNA
B AccAcAG cu GA uuucuuccTT B
1343
stab07
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:132U21 sense siNA
B uucuuccu GA cc A cu A u G cTT B
1344
stab07
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:140U21 sense siNA
B GA cc A cu A u G ccc A cu GA cTT B
1345
stab07
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:157U21 sense siNA
B A cucccuc AG u G uuucc A cTT B
1346
stab07
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:264U21 sense siNA
B AA ccuc A cucu G c A uu A uuTT B
1347
stab07
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:304U21 sense siNA
B A u AAAG ucc AGAAG u G c AG TT B
1348
stab07
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:305U21 sense siNA
B u AAAG ucc AGAAG u G c AG cTT B
1349
stab07
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:346U21 sense siNA
B uc A cuucu GG cu G uc AG uuTT B
1350
stab07
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:138L21 antisense siNA
GGAAGAAA uc AG cu G u GG uTsT
1351
(120C) stab11
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:150L21 antisense siNA
G c A u AG u GG uc AGGAAGAA TsT
1352
(132C) stab11
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:158L21 antisense siNA
G uc AG u GGG c A u AG u GG ucTsT
1353
(140C) stab11
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:175L21 antisense siNA
G u GGAAA c A cu GAGGGAG uTsT
1354
(157C) stab11
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:282L21 antisense siNA
AA u AA u G c AGAG u GAGG uuTsT
1355
(264C) stab11
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:322L21 antisense siNA
cu G c A cuucu GGA cuuu A uTsT
1356
(304C) stab11
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:323L21 antisense siNA
G cu G c A cuucu GGA cuuu A TsT
1357
(305C) stab11
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:364L21 antisense siNA
AA cu GA c AG cc AGAAG u GA TsT
1358
(346C) stab11
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:120U21 sense siNA
B AccAcAGcuGAuuucuuccTT B
1359
stab18
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:132U21 sense siNA
B uucuuccuGAccAcuAuGcTT B
1360
stab18
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:140U21 sense siNA
B GAccAcuAuGcccAcuGAcTT B
1361
stab18
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:157U21 sense siNA
B AcucccucAGuGuuuccAcTT B
1362
stab18
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:264U21 sense siNA
B AAccucAcucuGcAuuAuuTT B
1363
stab18
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:304U21 sense siNA
B AuAAAGuccAGAAGuGcAGTT B
1364
stab18
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:305U21 sense siNA
B uAAAGuccAGAAGuGcAGcTT B
1365
stab18
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:346U21 sense siNA
B ucAcuucuGGcuGucAGuuTT B
1366
stab18
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:138L21 antisense siNA
GGAAGAAAucAGcuGuGGuTsT
1367
(120C) stab08
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:150L21 antisense siNA
GcAuAGuGGucAGGAAGAATsT
1368
(132C) stab08
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:158L21 antisense siNA
GucAGuGGGcAuAGuGGucTsT
1369
(140C) stab08
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:175L21 antisense siNA
GuGGAAAcAcuGAGGGAGuTsT
1370
(157C) stab08
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:282L21 antisense siNA
AAuAAuGcAGAGuGAGGuuTsT
1371
(264C) stab08
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:322L21 antisense siNA
cuGcAcuucuGGAcuuuAuTsT
1372
(304C) stab08
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:323L21 antisense siNA
GcuGcAcuucuGGAcuuuATsT
1373
(305C) stab08
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:364L21 antisense siNA
AAcuGAcAGccAGAAGuGATsT
1374
(346C) stab08
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:120U21 sense siNA
B ACCACAGCUGAUUUCUUCCTT B
1375
stab09
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:132U21 sense siNA
B UUCUUCCUGACCACUAUGCTT B
1376
stab09
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:140U21 sense siNA
B GACCACUAUGCCCACUGACTT B
1377
stab09
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:157U21 sense siNA
B ACUCCCUCAGUGUUUCCACTT B
1378
stab09
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:264U21 sense siNA
B AACCUCACUCUGCAUUAUUTT B
1379
stab09
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:304U21 sense siNA
B AUAAAGUCCAGAAGUGCAGTT B
1380
stab09
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:305U21 sense siNA
B UAAAGUCCAGAAGUGCAGCTT B
1381
stab09
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:346U21 sense siNA
B UCACUUCUGGCUGUCAGUUTT B
1382
stab09
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:138L21 antisense siNA
GGAAGAAAUCAGCUGUGGUTsT
1383
(120C) stab10
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:150L21 antisense siNA
GCAUAGUGGUCAGGAAGAATsT
1384
(132C) stab10
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:158L21 antisense siNA
GUCAGUGGGCAUAGUGGUCTsT
1385
(140C) stab10
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:175L21 antisense siNA
GUGGAAACACUGAGGGAGUTsT
1386
(157C) stab10
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:282L21 antisense siNA
AAUAAUGCAGAGUGAGGUUTsT
1387
(264C) stab10
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:322L21 antisense siNA
CUGCACUUCUGGACUUUAUTsT
1388
(304C) stab10
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:323L21 antisense siNA
GCUGCACUUCUGGACUUUATsT
1389
(305C) stab10
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:364L21 antisense siNA
AACUGACAGCCAGAAGUGATsT
1390
(346C) stab10
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:138L21 antisense siNA
GGAAGAAAucAGcuGuGGuTT B
1391
(120C) stab19
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:150L21 antisense siNA
GcAuAGuGGucAGGAAGAATT B
1392
(132C) stab19
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:158L21 antisense siNA
GucAGuGGGcAuAGuGGucTT B
1393
(140C) stab19
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:175L21 antisense siNA
GuGGAAAcAcuGAGGGAGuTT B
1394
(157C) stab19
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:282L21 antisense siNA
AAuAAuGcAGAGuGAGGuuTT B
1395
(264C) stab19
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:322L21 antisense siNA
cuGcAcuucuGGAcuuuAuTT B
1396
(304C) stab19
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:323L21 antisense siNA
GcuGcAcuucuGGAcuuuATT B
1397
(305C) stab19
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:364L21 antisense siNA
AAcuGAcAGccAGAAGuGATT B
1398
(346C) stab19
118
ACACCACAGCUGAUUUCUUCCUG
1253
IL2RG:138L21 antisense siNA
GGAAGAAAUCAGCUGUGGUTT B
1399
(120C) stab22
130
AUUUCUUCCUGACCACUAUGCCC
1254
IL2RG:150L21 antisense siNA
GCAUAGUGGUCAGGAAGAATT B
1400
(132C) stab22
138
CUGACCACUAUGCCCACUGACUC
1255
IL2RG:158L21 antisense siNA
GUCAGUGGGCAUAGUGGUCTT B
1401
(140C) stab22
155
UGACUCCCUCAGUGUUUCCACUC
1256
IL2RG:175L21 antisense siNA
GUGGAAACACUGAGGGAGUTT B
1402
(157C) stab22
262
CCAACCUCACUCUGCAUUAUUGG
1257
IL2RG:282L21 antisense siNA
AAUAAUGCAGAGUGAGGUUTT B
1403
(264C) stab22
302
UGAUAAAGUCCAGAAGUGCAGCC
1258
IL2RG:322L21 antisense siNA
CUGCACUUCUGGACUUUAUTT B
1404
(304C) stab22
303
GAUAAAGUCCAGAAGUGCAGCCA
1259
IL2RG:323L21 antisense siNA
GCUGCACUUCUGGACUUUATT B
1405
(305C) stab22
344
AAUCACUUCUGGCUGUCAGUUGC
1260
IL2RG:364L21 antisense siNA
AACUGACAGCCAGAAGUGATT B
1406
(346C) stab22
IL4
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:489U21 sense siNA
GCCUCACAGAGCAGAAGACTT
1407
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:491U21 sense siNA
CUCACAGAGCAGAAGACUCTT
1408
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:518U21 sense siNA
GAGUUGACCGUAACAGACATT
1409
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:528U21 sense siNA
UAACAGACAUCUUUGCUGCTT
1410
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:547U21 sense siNA
CUCCAAGAACACAACUGAGTT
1411
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:608U21 sense siNA
UACAGCCACCAUGAGAAGGTT
1412
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:730U21 sense siNA
GAAUUCCUGUCCUGUGAAGTT
1413
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:747U21 sense siNA
AGGAAGCCAACCAGAGUACTT
1414
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:507L21 antisense siNA
GUCUUCUGCUCUGUGAGGCTT
1415
(489C)
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:509L21 antisense siNA
GAGUCUUCUGCUCUGUGAGTT
1416
(491C)
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:536L21 antisense siNA
UGUCUGUUACGGUCAACUCTT
1417
(518C)
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:546L21 antisense siNA
GCAGCAAAGAUGUCUGUUATT
1418
(528C)
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:565L21 antisense siNA
CUCAGUUGUGUUCUUGGAGTT
1419
(547C)
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:626L21 antisense siNA
CCUUCUCAUGGUGGCUGUATT
1420
(608C)
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:748L21 antisense siNA
CUUCACAGGACAGGAAUUCTT
1421
(730C)
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:765L21 antisense siNA
GUACUCUGGUUGGCUUCCUTT
1422
(747C)
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:489U21 sense siNA
B GccucAcAGAGcAGAAGAcTT B
1423
stab04
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:491U21 sense siNA
B cucAcAGAGcAGAAGAcucTT B
1424
stab04
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:518U21 sense siNA
B GAGuuGAccGuAAcAGAcATT B
1425
stab04
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:528U21 sense siNA
B uAAcAGAcAucuuuGcuGcTT B
1426
stab04
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:547U21 sense siNA
B cuccAAGAAcAcAAcuGAGTT B
1427
stab04
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:608U21 sense siNA
B uAcAGccAccAuGAGAAGGTT B
1428
stab04
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:730U21 sense siNA
B GAAuuccuGuccuGuGAAGTT B
1429
stab04
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:747U21 sense siNA
B AGGAAGccAAccAGAGuAcTT B
1430
stab04
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:507L21 antisense siNA
GucuucuGcucuGuGAGGcTsT
1431
(489C) stab05
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:509L21 antisense siNA
GAGucuucuGcucuGuGAGTsT
1432
(491C) stab05
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:536L21 antisense siNA
uGucuGuuAcGGucAAcucTsT
1433
(518C) stab05
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:546L21 antisense siNA
GcAGcAAAGAuGucuGuuATsT
1434
(528C) stab05
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:565L21 antisense siNA
cucAGuuGuGuucuuGGAGTsT
1435
(547C) stab05
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:626L21 antisense siNA
ccuucucAuGGuGGcuGuATsT
1436
(608C) stab05
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:748L21 antisense siNA
cuucAcAGGAcAGGAAuucTsT
1437
(730C) stab05
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:765L21 antisense siNA
GuAcucuGGuuGGcuuccuTsT
1438
(747C) stab05
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:489U21 sense siNA
B G ccuc A c AGAG c AGAAGA cTT B
1439
stab07
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:491U21 sense siNA
B cuc A c AGAG c AGAAGA cucTT B
1440
stab07
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:518U21 sense siNA
B GAG uu GA cc G u AA c AGA c A TT B
1441
stab07
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:528U21 sense siNA
B u AA c AGA c A ucuuu G cu G cTT B
1442
stab07
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:547U21 sense siNA
B cucc AAGAA c A c AA cu GAG TT B
1443
stab07
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:608U21 sense siNA
B u A c AG cc A cc A u GAGAAGG TT B
1444
stab07
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:730U21 sense siNA
B GAA uuccu G uccu G u GAAG TT B
1445
stab07
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:747U21 sense siNA
B AGGAAG cc AA cc AGAG u A cTT B
1446
stab07
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:507L21 antisense siNA
G ucuucu G cucu G u GAGG cTsT
1447
(489C) stab11
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:509L21 antisense siNA
GAG ucuucu G cucu G u GAG TsT
1448
(491C) stab11
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:536L21 antisense siNA
u G ucu G uu A c GG uc AA cucTsT
1449
(518C) stab11
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:546L21 antisense siNA
G c AG c AAAGA u G ucu G uu A TsT
1450
(528C) stab11
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:565L21 antisense siNA
cuc AG uu G u G uucuu GGAG TsT
1451
(547C) stab11
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:626L21 antisense siNA
ccuucuc A u GG u GG cu G u A TsT
1452
(608C) stab11
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:748L21 antisense siNA
cuuc A c AGGA c AGGAA uucTsT
1453
(730C) stab11
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:765L21 antisense siNA
G u A cucu GG uu GG cuuccuTsT
1454
(747C)stab11
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:489U21 sense siNA
B GccucAcAGAGcAGAAGAcTT B
1455
stab18
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:491U21 sense siNA
B cucAcAGAGcAGAAGAcucTT B
1456
stab18
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:518U21 sense siNA
B GAGuuGAccGuAAcAGAcATT B
1457
stab18
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:528U21 sense siNA
B uAAcAGAcAucuuuGcuGcTT B
1458
stab18
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:547U21 sense siNA
B cuccAAGAAcAcAAcuGAGTT B
1459
stab18
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:608U21 sense siNA
B uAcAGccAccAuGAGAAGGTT B
1460
stab18
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:730U21 sense siNA
B GAAuuccuGuccuGuGAAGTT B
1461
stab18
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:747U21 sense siNA
B AGGAAGccAAccAGAGuAcTT B
1462
stab18
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:507L21 antisense siNA
GucuucuGcucuGuGAGGcTsT
1463
(489C) stab08
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:509L21 antisense siNA
GAGucuucuGcucuGuGAGTsT
1464
(491C) stab08
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:536L21 antisense siNA
uGucuGuuAcGGucAAcucTsT
1465
(518C) stab08
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:546L21 antisense siNA
GcAGcAAAGAuGucuGuuATsT
1466
(528C) stab08
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:565L21 antisense siNA
cucAGuuGuGuucuuGGAGTsT
1467
(547C) stab08
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:626L21 antisense siNA
ccuucucAuGGuGGcuGuATsT
1468
(608C) stab08
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:748L21 antisense siNA
cuucAcAGGAcAGGAAuucTsT
1469
(730C) stabo8
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:765L21 antisense siNA
GuAcucuGGuuGGcuuccuTsT
1470
(747C) stab08
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:489U21 sense siNA
B GCCUCACAGAGCAGAAGACTT B
1471
stab09
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:491U21 sense siNA
B CUCACAGAGCAGAAGACUCTT B
1472
stab09
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:518U21 sense siNA
B GAGUUGACCGUAACAGACATT B
1473
stab09
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:528U21 sense siNA
B UAACAGACAUCUUUGCUGCTT B
1474
stab09
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:547U21 sense siNA
B CUCCAAGAACACAACUGAGTT B
1475
stab09
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:608U21 sense siNA
B UACAGCCACCAUGAGAAGGTT B
1476
stab09
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:730U21 sense siNA
B GAAUUCCUGUCCUGUGAAGTT B
1477
stab09
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:747U21 sense siNA
B AGGAAGCCAACCAGAGUACTT B
1478
stab09
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:507L21 antisense siNA
GUCUUCUGCUCUGUGAGGCTsT
1479
(489C) stab10
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:509L21 antisense siNA
GAGUCUUCUGCUCUGUGAGTsT
1480
(491C) stab10
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:536L21 antisense siNA
UGUCUGUUACGGUCAACUCTsT
1481
(518C) stab10
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:546L21 antisense siNA
GCAGCAAAGAUGUCUGUUATsT
1482
(528C) stab10
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:565L21 antisense siNA
CUCAGUUGUGUUCUUGGAGTsT
1483
(547C) stab10
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:626L21 antisense siNA
CCUUCUCAUGGUGGCUGUATsT
1484
(608C) stab10
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:748L21 antisense siNA
CUUCACAGGACAGGAAUUCTsT
1485
(730C) stab10
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:765L21 antisense siNA
GUACUCUGGUUGGCUUCCUTsT
1486
(747C) stab10
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:507L21 antisense siNA
GucuucuGcucuGuGAGGcTT B
1487
(489C) stab19
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:509L21 antisense siNA
GAGucuucuGcucuGuGAGTT B
1488
(491C) stab19
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:536L21 antisense siNA
uGucuGuuAcGGucAAcucTT B
1489
(518C) stab19
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:546L21 antisense siNA
GcAGcAAAGAuGucuGuuATT B
1490
(528C) stab19
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:565L21 antisense siNA
cucAGuuGuGuucuuGGAGTT B
1491
(547C) stab19
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:626L21 antisense siNA
ccuucucAuGGuGGcuGuATT B
1492
(6C8C) stab19
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:748L21 antisense siNA
cuucAcAGGAcAGGAAuucTT B
1493
(730C) stab19
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:765L21 antisense siNA
GuAcucuGGuuGGcuuccuTT B
1494
(747C) stab19
487
CAGCCUCACAGAGCAGAAGACUC
1269
IL4:507L21 antisense siNA
GUCUUCUGCUCUGUGAGGCTT B
1495
(489C) stab22
489
GCCUCACAGAGCAGAAGACUCUG
1270
IL4:509L21 antisense siNA
GAGUCUUCUGCUCUGUGAGTT B
1496
(491C) stab22
516
CCGAGUUGACCGUAACAGACAUC
1271
IL4:536L21 antisense siNA
UGUCUGUUACGGUCAACUCTT B
1497
(518C) stab22
526
CGUAACAGACAUCUUUGCUGCCU
1272
IL4:546L21 antisense siNA
GCAGCAAAGAUGUCUGUUATT B
1498
(528C) stab22
545
GCCUCCAAGAACACAACUGAGAA
1273
IL4:565L21 antisense siNA
CUCAGUUGUGUUCUUGGAGTT B
1499
(547C) stab22
606
UCUACAGCCACCAUGAGAAGGAC
1274
IL4:626L21 antisense siNA
CCUUCUCAUGGUGGCUGUATT B
1500
(608C) stab22
728
UUGAAUUCCUGUCCUGUGAAGGA
1275
IL4:748L21 antisense siNA
CUUCACAGGACAGGAAUUCTT B
1501
(730C) stab22
745
GAAGGAAGCCAACCAGAGUACGU
1276
IL4:765L21 antisense siNA
GUACUCUGGUUGGCUUCCUTT B
1502
(747C) stab22
IL4R
469
CUAUACACUGGACCUGUGGGCUG
1277
IL4R:471U21 sense siNA
AUACACUGGACCUGUGGGCTT
1503
551
CCAGGAAACCUGACAGUUCACAC
1278
IL4R:553U21 sense siNA
AGGAAACCUGACAGUUCACTT
1504
1119
AGCACAACAUGAAAAGGGAUGAA
1279
IL4R:1121U21 sense siNA
CACAACAUGAAAAGGGAUGTT
1505
1120
GCACAACAUGAAAAGGGAUGAAG
1280
IL4R:1122U21 sense siNA
ACAACAUGAAAAGGGAUGATT
1506
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
IL4R:1134U21 sense siNA
GGGAUGAAGAUCCUCACAATT
1507
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
IL4R:3132U21 sense siNA
GGGAAAUCGAUGAGAAAUUTT
1508
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
IL4R:3133U21 sense siNA
GGAAAUCGAUGAGAAAUUGTT
1509
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
IL4R:3171U21 sense siNA
AUUGCCUAGAGGUGCUCAUTT
1510
469
CUAUACACUGGACCUGUGGGCUG
1277
IL4R:489L21 antisense siNA
GCCCACAGGUCCAGUGUAUTT
1511
(471C)
551
CCAGGAAACCUGACAGUUCACAC
1278
IL4R:57IL21 antisense siNA
GUGAACUGUCAGGUUUCCUTT
1512
(553C)
1119
AGCACAACAUGAAAAGGGAUGAA
1279
IL4R:1139L21 antisense siNA
CAUCCCUUUUCAUGUUGUGTT
1513
(1121C)
1120
GCACAACAUGAAAAGGGAUGAAG
1280
IL4R:1140L21 antisense siNA
UCAUCCCUUUUCAUGUUGUTT
1514
(1122C)
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
IL4R:1152L21 antisense siNA
UUGUGAGGAUCUUCAUCCCTT
1515
(1134C)
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
IL4R:3150L21 antisense siNA
AAUUUCUCAUCGAUUUCCCTT
1516
(3132C)
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
IL4R:315IL21 antisense siNA
CAAUUUCUCAUCGAUUUCCTT
1517
(3133C)
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
IL4R:3189L21 antisense siNA
AUGAGCACCUCUAGGCAAUTT
1518
(3171C)
469
CUAUACACUGGACCUGUGGGCUG
1277
IL4R:471U21 sense siNA
B AuAcAcuGGAccuGuGGGcTT B
1519
stab04
551
CCAGGAAACCUGACAGUUCACAC
1278
IL4R:553U21 sense siNA
B AGGAAAccuGAcAGuucAcTT B
1520
stab04
1119
AGCACAACAUGAAAAGGGAUGAA
1279
IL4R:1121U21 sense siNA
B cAcAAcAuGAAAAGGGAuGTT B
1521
stab04
1120
GCACAACAUGAAAAGGGAUGAAG
1280
IL4R:1122U21 sense siNA
B AcAAcAuGAAAAGGGAuGATT B
1522
stab04
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
IL4R:1134U21 sense siNA
B GGGAuGAAGAuccucAcAATT B
1523
stab04
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
IL4R:3132U21 sense siNA
B GGGAAAucGAuGAGAAAuuTT B
1524
stab04
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
IL4R:3133U21 sense siNA
B GGAAAucGAuGAGAAAuuGTT B
1525
stab04
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
IL4R:3171U21 sense siNA
B AuuGccuAGAGGuGcucAuTT B
1526
stab04
469
CUAUACACUGGACCUGUGGGCUG
1277
IL4R:489L21 antisense siNA
GcccAcAGGuccAGuGuAuTsT
1527
(471C) stab05
551
CCAGGAAACCUGACAGUUCACAC
1278
IL4R:571L21 antisense siNA
GuGAAcuGucAGGuuuccuTsT
1528
(553C) stab05
1119
AGCACAACAUGAAAAGGGAUGAA
1279
IL4R:1139L21 antisense siNA
cAucccuuuucAuGuuGuGTsT
1529
(1121C) stab05
1120
GCACAACAUGAAAAGGGAUGAAG
1280
IL4R:1140L21 antisense siNA
ucAucccuuuucAuGuuGuTsT
1530
(1122C) stab05
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
IL4R:1152L21 antisense siNA
uuGuGAGGAucuucAucccTsT
1531
(1134C) stab05
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
IL4R:3150L21 antisense siNA
AAuuucucAucGAuuucccTsT
1532
(3132C) stab05
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
IL4R:315IL21 antisense siNA
cAAuuucucAucGAuuuccTsT
1533
(3133C) stab05
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
IL4R:3189L21 antisense siNA
AuGAGcAccucuAGGcAAuTsT
1534
(3171C) stab05
469
CUAUACACUGGACCUGUGGGCUG
1277
IL4R:471U21 sense siNA
B A u A c A cu GGA ccu G u GGG cTT B
1535
stab07
551
CCAGGAAACCUGACAGUUCACAC
1278
IL4R:553U21 sense siNA
B AGGAAA ccu GA c AG uuc A cTT B
1536
stab07
1119
AGCACAACAUGAAAAGGGAUGAA
1279
IL4R:1121U21 sense siNA
B c A c AA c A u GAAAAGGGA u G TT B
1537
stab07
1120
GCACAACAUGAAAAGGGAUGAAG
1280
IL4R:1122U21 sense siNA
B A c AA c A u GAAAAGGGA u GA TT B
1538
stab07
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
IL4R:1134U21 sense siNA
B GGGA u GAAGA uccuc A c AA TT B
1539
stab07
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
IL4R:3132U21 sense siNA
B GGGAAA uc GA u GAGAAA uuTT B
1540
stab07
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
IL4R:3133U21 sense siNA
B GGAAA uc GA u GAGAAA uu G TT B
1541
stab07
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
IL4R:3171U21 sense siNA
B A uu G ccu AGAGG u G cuc A uTT B
1542
stab07
469
CUAUACACUGGACCUGUGGGCUG
1277
IL4R:489L21 antisense siNA
G ccc A c AGG ucc AG u G u A uTsT
1543
(471C) stab11
551
CCAGGAAACCUGACAGUUCACAC
1278
IL4R:571L21 antisense siNA
G u GAA cu G uc AGG uuuccuTsT
1544
(553C) stab11
1119
AGCACAACAUGAAAAGGGAUGAA
1279
IL4R:1139L21 antisense siNA
c A ucccuuuuc A u G uu G u G TsT
1545
(1121C) stab11
1120
GCACAACAUGAAAAGGGAUGAAG
1280
IL4R:1140L21 antisense siNA
uc A ucccuuuuc A u G uu G uTsT
1546
(1122C) stab11
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
IL4R:1152L21 antisense siNA
uu G u GAGGA ucuuc A ucccTsT
1547
(1134C) stab11
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
IL4R:3150L21 antisense siNA
AA uuucuc Al uc GA uuucccTsT
1548
(3132C) stab11
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
IL4R:315IL21 antisense siNA
c AA uuucuc A uc GA uuuccTsT
1549
(3133C) stab11
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
IL4R:3189L21 antisense siNA
A u GAG c A ccucu AGG c AA uTsT
1550
(3171C) stab11
469
CUAUACACUGGACCUGUGGGCUG
1277
IL4R:471U21 sense siNA
B AuAcAcuGGAccuGuGGGcTTB
1551
stab18
551
CCAGGAAACCUGACAGUUCACAC
1278
IL4R:553U21 sense siNA
B AGGAAAccuGAcAGuucAcTT B
1552
stab18
1119
AGCACAACAUGAAAAGGGAUGAA
1279
IL4R:1121U21 sense siNA
B cAcAAcAuGAAAAGGGAuGTT B
1553
stab18
1120
GCACAACAUGAAAAGGGAUGAAG
1280
IL4R:1122U21 sense siNA
B AcAAcAuGAAAAGGGAuGATT B
1554
stab18
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
IL4R:1134U21 sense siNA
B GGGAuGAAGAuccucAcAATT B
1555
stab18
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
IL4R:3132U21 sense siNA
B GGGAAAucGAuGAGAAAuuTT B
1556
stab18
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
IL4R:3133U21 sense siNA
B GGAAAucGAuGAGAAAuuGTT B
1557
stab18
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
IL4R:3171U21 sense siNA
B AuuGccuAGAGGuGcucAuTT B
1558
stab18
469
CUAUACACUGGACCUGUGGGCUG
1277
IL4R:489L21 antisense siNA
GcccAcAGGuccAGuGuAuTsT
1559
(471C) stab08
551
CCAGGAAACCUGACAGUUCACAC
1278
IL4R:571L21 antisense siNA
GuGAAcuGucAGGuuuccuTsT
1560
(553C) stab08
1119
AGCACAACAUGAAAAGGGAUGAA
1279
IL4R:1139L21 antisense siNA
cAucccuuuucAuGuuGuGTsT
1561
(1121C) stab08
1120
GCACAACAUGAAAAGGGAUGAAG
1280
IL4R:1140L21 antisense siNA
ucAucccuuuucAuGuuGuTsT
1562
(1122C) stab08
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
IL4R:1152L21 antisense siNA
uuGuGAGGAucuucAucccTsT
1563
(1134C) stab08
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
IL4R:3150L21 antisense siNA
AAuuucucAucGAuuucccTsT
1564
(3132C) stab08
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
IL4R:315IL21 antisense siNA
cAAuuucucAucGAuuuccTsT
1565
(3133C) stab08
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
IL4R:3189L21 antisense siNA
AuGAGcAccucuAGGcAAuTsT
1566
(3171C) stab08
469
CUAUACACUGGACCUGUGGGCUG
1277
36729
IL4R:471U21 sense siNA
B AUACACUGGACCUGUGGGCTT B
1567
stab09
551
CCAGGAAACCUGACAGUUCACAC
1278
36730
IL4R:553U21 sense siNA
B AGGAAACCUGACAGUUCACTT B
1568
stab09
1119
AGCACAACAUGAAAAGGGAUGAA
1279
36731
IL4R:1121U21 sense siNA
B CACAACAUGAAAAGGGAUGTT B
1569
stab09
1120
GCACAACAUGAAAAGGGAUGAAG
1280
36732
IL4R:1122U21 sense siNA
B ACAACAUGAAAAGGGAUGATT B
1570
stab09
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
36733
IL4R:1134U21 sense siNA
B GGGAUGAAGAUCCUCACAATT B
1571
stab09
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
36734
IL4R:3132U21 sense siNA
B GGGAAAUCGAUGAGAAAUUTT B
1572
stab09
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
36735
IL4R:3133U21 sense siNA
B GGAAAUCGAUGAGAAAUUGTT B
1573
stab09
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
36736
IL4R:3171U21 sense siNA
B AUUGCCUAGAGGUGCUCAUTT B
1574
stab09
469
CUAUACACUGGACCUGUGGGCUG
1277
IL4R:489L21 antisense siNA
GCCCACAGGUCCAGUGUAUTsT
1575
(471C) stab10
551
CCAGGAAACCUGACAGUUCACAC
1278
IL4R:571L21 antisense siNA
GUGAACUGUCAGGUUUCCUTsT
1576
(553C) stab10
1119
AGCACAACAUGAAAAGGGAUGAA
1279
IL4R:1139L21 antisense siNA
CAUCCCUUUUCAUGUUGUGTsT
1577
(1121C) stab10
1120
GCACAACAUGAAAAGGGAUGAAG
1280
IL4R:1140L21 antisense siNA
UCAUCCCUUUUCAUGUUGUTsT
1578
(1122C) stab10
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
IL4R:1152L21 antisense siNA
UUGUGAGGAUCUUCAUCCCTsT
1579
(1134C) stab10
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
IL4R:3150L21 antisense siNA
AAUUUCUCAUCGAUUUCCCTsT
1580
(3132C) stab10
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
IL4R:315IL21 antisense siNA
CAAUUUCUCAUCGAUUUCCTsT
1581
(3133C) stab10
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
IL4R:3189L21 antisense siNA
AUGAGCACCUCUAGGCAAUTsT
1582
(3171C) stab10
469
CUAUACACUGGACCUGUGGGCUG
1277
36737
IL4R:489L21 antisense siNA
GcccAcAGGuccAGuGuAuTT B
1583
(471C) stab19
551
CCAGGAAACCUGACAGUUCACAC
1278
36738
IL4R:571L21 antisense siNA
GuGAAcuGucAGGuuuccuTT B
1584
(553C) stab19
1119
AGCACAACAUGAAAAGGGAUGAA
1279
36739
IL4R:1139L21 antisense siNA
cAucccuuuucAuGuuGuGTT B
1585
(1121C) stab19
1120
GCACAACAUGAAAAGGGAUGAAG
1280
36740
IL4R:1140L21 antisense siNA
ucAucccuuuucAuGuuGuTT B
1586
(1122C) stab19
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
36741
IL4R:1152L21 antisense siNA
uuGuGAGGAucuucAucccTT B
1587
(1134C) stab19
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
36742
IL4R:3150L21 antisense siNA
AAuuucucAucGAuuucccTT B
1588
(3132C) stab19
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
36743
IL4R:315IL21 antisense siNA
cAAuuucucAucGAuuuccTT B
1589
(3133C) stab19
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
36744
IL4R:3189L21 antisense siNA
AuGAGcAccucuAGGcAAuTT B
1590
(3171C) stab19
469
CUAUACACUGGACCUGUGGGCUG
1277
36745
IL4R:489L21 antisense siNA
GCCCACAGGUCCAGUGUAUTT B
1591
(471C) stab22
551
CCAGGAAACCUGACAGUUCACAC
1278
36746
IL4R:571L21 antisense siNA
GUGAACUGUCAGGUUUCCUTT B
1592
(553C) stab22
1119
AGCACAACAUGAAAAGGGAUGAA
1279
36747
IL4R:1139L21 antisense siNA
CAUCCCUUUUCAUGUUGUGTTB
1593
(1121C) stab22
1120
GCACAACAUGAAAAGGGAUGAAG
1280
36748
IL4R:1140L21 antisense siNA
UCAUCCCUUUUCAUGUUGUTT B
1594
(1122C) stab22
1132
AAGGGAUGAAGAUCCUCACAAGG
1281
36749
IL4R:1152L21 antisense siNA
UUGUGAGGAUCUUCAUCCCTT B
1595
(1134C) stab22
3130
UUGGGAAAUCGAUGAGAAAUUGA
1282
36750
IL4R:3150L21 antisense siNA
AAUUUCUCAUCGAUUUCCCTT B
1596
(3132C) stab22
3131
UGGGAAAUCGAUGAGAAAUUGAA
1283
36751
IL4R:315IL21 antisense siNA
CAAUUUCUCAUCGAUUUCCTT B
1597
(3133C) stab22
3169
UCAUUGCCUAGAGGUGCUCAUUC
1284
36752
IL4R:3189L21 antisense siNA
AUGAGCACCUCUAGGCAAUTT B
1598
(3171C) stab22
IL13
391
CCCAGUUUGUAAAGGACCUGCUC
1285
IL13:393U21 sense siNA
CAGUUUGUAAAGGACCUGCTT
1599
797
CACUUCACACACAGGCAACUGAG
1286
IL13:799U21 sense siNA
CUUCACACACAGGCAACUGTT
1600
832
UCAGGCACACUUCUUCUUGGUCU
1287
IL13:834U21 sense siNA
AGGCACACUUCUUCUUGGUTT
1601
911
AAGACUGUGGCUGCUAGCACUUG
1288
IL13:913U21 sense siNA
GACUGUGGCUGCUAGCACUTT
1602
963
AGCACUAAAGCAGUGGACACCAG
1289
IL13:965U21 sense siNA
CACUAAAGCAGUGGACACCTT
1603
965
CACUAAAGCAGUGGACACCAGGA
1290
IL13:967U21 sense siNA
CUAAAGCAGUGGACACCAGTT
1604
968
UAAAGCAGUGGACACCAGGAGUC
1291
IL13:970U21 sense siNA
AAGCAGUGGACACCAGGAGTT
1605
1191
AGAAGGGUACCUUGAACACUGGG
1292
IL13:1193U21 sense siNA
AAGGGUACCUUGAACACUGTT
1606
391
CCCAGUUUGUAAAGGACCUGCUC
1285
IL13:411L21 antisense siNA
GCAGGUCCUUUACAAACUGTT
1607
(393C)
797
CACUUCACACACAGGCAACUGAG
1286
IL13:817L21 antisense siNA
CAGUUGCCUGUGUGUGAAGTT
1608
(799C)
832
UCAGGCACACUUCUUCUUGGUCU
1287
IL13:852L21 antisense siNA
ACCAAGAAGAAGUGUGCCUTT
1609
(834C)
911
AAGACUGUGGCUGCUAGCACUUG
1288
IL13:931L21 antisense siNA
AGUGCUAGCAGCCACAGUCTT
1610
(913C)
963
AGCACUAAAGCAGUGGACACCAG
1289
IL13:983L21 antisense siNA
GGUGUCCACUGCUUUAGUGTT
1611
(965C)
965
CACUAAAGCAGUGGACACCAGGA
1290
IL13:985L21 antisense siNA
CUGGUGUCCACUGCUUUAGTT
1612
(967C)
968
UAAAGCAGUGGACACCAGGAGUC
1291
IL13:988L21 antisense siNA
CUCCUGGUGUCCACUGCUUTT
1613
(970C)
1191
AGAAGGGUACCUUGAACACUGGG
1292
IL13:121IL21 antisense siNA
CAGUGUUCAAGGUACCCUUTT
1614
(1193C)
391
CCCAGUUUGUAAAGGACCUGCUC
1285
IL13:393U21 sense siNA
B cAGuuuGuAAAGGAccuGcTT B
1615
stab04
797
CACUUCACACACAGGCAACUGAG
1286
IL13:799U21 sense siNA
B cuucAcAcAcAGGcAAcuGTT B
1616
stab04
832
UCAGGCACACUUCUUCUUGGUCU
1287
IL13:834U21 sense siNA
B AGGcAcAcuucuucuuGGuTT B
1617
stab04
911
AAGACUGUGGCUGCUAGCACUUG
1288
IL13:913U21 sense siNA
B GAcuGuGGcuGcuAGcAcuTT B
1618
stab04
963
AGCACUAAAGCAGUGGACACCAG
1289
IL13:965U21 sense siNA
B cAcuAAAGcAGuGGAcAccTT B
1619
stab04
965
CACUAAAGCAGUGGACACCAGGA
1290
IL13:967U21 sense siNA
B cuAAAGcAGuGGAcAccAGTT B
1620
stab04
968
UAAAGCAGUGGACACCAGGAGUC
1291
IL13:970U21 sense siNA
B AAGcAGuGGAcAccAGGAGTT B
1621
stab04
1191
AGAAGGGUACCUUGAACACUGGG
1292
IL13:1193U21 sense siNA
B AAGGGuAccuuGAAcAcuGTT B
1622
stab04
391
CCCAGUUUGUAAAGGACCUGCUC
1285
IL13:411L21 antisense siNA
GcAGGuccuuuAcAAAcuGTsT
1623
(393C) stab05
797
CACUUCACACACAGGCAACUGAG
1286
IL13:817L21 antisense siNA
cAGuuGccuGuGuGuGAAGTsT
1624
(799C) stab05
832
UCAGGCACACUUCUUCUUGGUCU
1287
IL13:852L21 antisense siNA
AccAAGAAGAAGuGuGccuTsT
1625
(834C) stab05
911
AAGACUGUGGCUGCUAGCACUUG
1288
IL13:931L21 antisense siNA
AGuGcuAGcAGccAcAGucTsT
1626
(913C) stab05
963
AGCACUAAAGCAGUGGACACCAG
1289
IL13:983L21 antisense siNA
GGuGuccAcuGcuuuAGuGTsT
1627
(965C) stab05
965
CACUAAAGCAGUGGACACCAGGA
1290
IL13:985L21 antisense siNA
cuGGuGuccAcuGcuuuAGTsT
1628
(967C) stab05
968
UAAAGCAGUGGACACCAGGAGUC
1291
IL13:988L21 antisense siNA
cuccuGGuGuccAcuGcuuTsT
1629
(970C) stab05
1191
AGAAGGGUACCUUGAACACUGGG
1292
IL13:121IL21 antisense siNA
cAGuGuucAAGGuAcccuuTsT
1630
(1193C) stab05
864
UAUUGUGUGUUAUUUAAAUGAGU
1293
33355
IL13:864U21 sense siNA
B uu G u G u G uu A uuu AAA u GA TT B
1631
stab07
865
AUUGUGUGUUAUUUAAAUGAGUG
1294
33356
IL13:865U21 sense siNA
B u G u G u G uu A uuu AAA u GAG TT B
1632
stab07
866
UUGUGUGUUAUUUAAAUGAGUGU
1295
33357
IL13:866U21 sense siNA
B G u G u G uu A uuu AAA u GAG uTT B
1633
stab07
863
UUAUUGUGUGUUAUUUAAAUGAG
1296
33358
IL13:863U21 sense siNA
B A uu G u G u G uu A uuu AAA u G TT B
1634
stab07
200
UGCAAUGGCAGCAUGGUAUGGAG
1297
33359
IL13:200U21 sense siNA
B c AA u GG c AG c A u GG u A u GG TT B
1635
stab07
201
GCAAUGGCAGCAUGGUAUGGAGC
1298
33360
IL13:201U21 sense siNA
B AA u GG c AG c A u GG u A u GGA TT B
1636
stab07
202
CAAUGGCAGCAUGGUAUGGAGCA
1299
33361
IL13:202U21 sense siNA
B A u GG c AG c A u GG u A u GGAG TT B
1637
stab07
860
UUAUUAUUGUGUGUUAUUUAAAU
1300
33362
IL13:860U21 sense siNA
B A uu A uu G u G u G uu A uuu AA TT B
1638
stab07
861
UAUUAUUGUGUGUUAUUUAAAUG
1301
33363
IL13:861U21 sense siNA
B uu A uu G u G u G uu A uuu AAA TT B
1639
stab07
862
AUUAUUGUGUGUUAUUUAAAUGA
1302
33364
IL13:862U21 sense siNA
B u A uu G u G u G uu A uuu AAA uTT B
1640
stab07
391
CCCAGUUUGUAAAGGACCUGCUC
1285
IL13:393U21 sense siNA
B c AG uuu G u AAAGGA ccu G cTT B
1641
stab07
797
CACUUCACACACAGGCAACUGAG
1286
IL13:799U21 sense siNA
B cuuc A c A c A c AGG c AA cu G TT B
1642
stab07
832
UCAGGCACACUUCUUCUUGGUCU
1287
IL13:834U21 sense siNA
B AGG c A c A cuucuucuu GG uTT B
1643
stab07
911
AAGACUGUGGCUGCUAGCACUUG
1288
IL13:913U21 sense siNA
B GA cu G u GG cu G cu AG c A cuTT B
1644
stab07
963
AGCACUAAAGCAGUGGACACCAG
1289
IL13:965U21 sense siNA
B c A cu AAAG c AG u GGA c A ccTT B
1645
stab07
965
CACUAAAGCAGUGGACACCAGGA
1290
IL13:967U21 sense siNA
B cu AAAG c AG u GGA c A cc AG TT B
1646
stab07
968
UAAAGCAGUGGACACCAGGAGUC
1291
IL13:970U21 sense siNA
B AAG c AG u GGA c A cc AGGAG TT B
1647
stab07
1191
AGAAGGGUACCUUGAACACUGGG
1292
IL13:1193U21 sense siNA
B AAGGG u A ccuu GAA c A cu G TT B
1648
stab07
391
CCCAGUUUGUAAAGGACCUGCUC
1285
IL13:411L21 antisense siNA
G c AGG uccuuu A c AAA cu G TsT
1649
(393C) stab11
797
CACUUCACACACAGGCAACUGAG
1286
IL13:817L21 antisense siNA
c AG uu G ccu G u G u G u GAAG TsT
1650
(799C) stab11
832
UCAGGCACACUUCUUCUUGGUCU
1287
IL13:852L21 antisense siNA
A cc AAGAAGAAG u G u G ccuTsT
1651
(834C) stab11
911
AAGACUGUGGCUGCUAGCACUUG
1288
IL13:931L21 antisense siNA
AG u G cu AG c AG cc A c AG ucTsT
1652
(913C) stab11
963
AGCACUAAAGCAGUGGACACCAG
1289
IL13:983L21 antisense siNA
GG u G ucc A cu G cuuu AG u G TsT
1653
(965C) stab11
965
CACUAAAGCAGUGGACACCAGGA
1290
IL13:985L21 antisense siNA
cu GG u G ucc A cu G cuuu AG TsT
1654
(967C) stab11
968
UAAAGCAGUGGACACCAGGAGUC
1291
IL13:988L21 antisense siNA
cuccu GG u G ucc A cu G cuuTsT
1655
(970C) stab11
1191
AGAAGGGUACCUUGAACACUGGG
1292
IL13:121IL21 antisense siNA
c AG u G uuc AAGG u A cccuuTsT
1656
(1193C) stab11
391
CCCAGUUUGUAAAGGACCUGCUC
1285
IL13:393U21 sense siNA
B cAGuuuGuAAAGGAccuGcTT B
1657
stab18
797
CACUUCACACACAGGCAACUGAG
1286
IL13:799U21 sense siNA
B cuucAcAcAcAGGcAAcuGTT B
1658
stab18
832
UCAGGCACACUUCUUCUUGGUCU
1287
IL13:834U21 sense siNA
B AGGcAcAcuucuucuuGGuTT B
1659
stab18
911
AAGACUGUGGCUGCUAGCACUUG
1288
IL13:913U21 sense siNA
B GAcuGuGGcuGcuAGcAcuTT B
1660
stab18
963
AGCACUAAAGCAGUGGACACCAG
1289
IL13:965U21 sense siNA
B cAcuAAAGcAGuGGAcAccTT B
1661
stab18
965
CACUAAAGCAGUGGACACCAGGA
1290
IL13:967U21 sense siNA
B cuAAAGcAGuGGAcAccAGTT B
1662
stab18
968
UAAAGCAGUGGACACCAGGAGUC
1291
IL13:970U21 sense siNA
B AAGcAGuGGAcAccAGGAGTT B
1663
stab18
1191
AGAAGGGUACCUUGAACACUGGG
1292
IL13:1193U21 sense siNA
B AAGGGuAccuuGAAcAcuGTT B
1664
stab18
864
UAUUGUGUGUUAUUUAAAUGAGU
1293
33375
IL13:882L21 antisense siNA
ucAuuuAAAuAAcAcAcAATsT
1665
(864C) stab08
865
AUUGUGUGUUAUUUAAAUGAGUG
1294
33376
IL13:883L21 antisense siNA
cucAuuuAAAuAAcAcAcATsT
1666
(865C) stab08
866
UUGUGUGUUAUUUAAAUGAGUGU
1295
33377
IL13:884L21 antisense siNA
AcucAuuuAAAuAAcAcAcTsT
1667
(866C) stab08
863
UUAUUGUGUGUUAUUUAAAUGAG
1296
33378
IL13:88IL21 antisense siNA
cAuuuAAAuAAcAcAcAAuTsT
1668
(863C) stab08
200
UGCAAUGGCAGCAUGGUAUGGAG
1297
33379
IL13:218L21 antisense siNA
ccAuAccAuGcuGccAuuGTsT
1669
(200C) stab08
201
GCAAUGGCAGCAUGGUAUGGAGC
1298
33380
IL13:219L21 antisense siNA
uccAuAccAuGcuGccAuuTsT
1670
(201C) stab08
202
CAAUGGCAGCAUGGUAUGGAGCA
1299
33381
IL13:220L21 antisense siNA
cuccAuAccAuGcuGccAuTsT
1671
(202C) stab08
860
UUAUUAUUGUGUGUUAUUUAAAU
1300
33382
IL13:878L21 antisense siNA
uuAAAuAAcAcAcAAuAAuTsT
1672
(860C) stab08
861
UAUUAUUGUGUGUUAUUUAAAUG
1301
33383
IL13:879L21 antisense siNA
uuuAAAuAAcAcAcAAuAATsT
1673
(861C) stab08
862
AUUAUUGUGUGUUAUUUAAAUGA
1302
33384
IL13:880L21 antisense siNA
AuuuAAAuAAcAcAcAAuATsT
1674
(862C) stab08
391
CCCAGUUUGUAAAGGACCUGCUC
1285
IL13:411L21 antisense siNA
GcAGGuccuuuAcAAAcuGTsT
1675
(393C) stab08
797
CACUUCACACACAGGCAACUGAG
1286
IL13:817L21 antisense siNA
cAGuuGccuGuGuGuGAAGTsT
1676
(799C) stab08
832
UCAGGCACACUUCUUCUUGGUCU
1287
IL13:852L21 antisense siNA
AccAAGAAGAAGuGuGccuTsT
1677
(834C) stab08
911
AAGACUGUGGCUGCUAGCACUUG
1288
IL13:931L21 antisense siNA
AGuGcuAGcAGccAcAGucTsT
1678
(913C) stab08
963
AGCACUAAAGCAGUGGACACCAG
1289
IL13:983L21 antisense siNA
GGuGuccAcuGcuuuAGuGTsT
1679
(965C) stab08
965
CACUAAAGCAGUGGACACCAGGA
1290
IL13:985L21 antisense siNA
cuGGuGuccAcuGcuuuAGTsT
1680
(967C) stab08
968
UAAAGCAGUGGACACCAGGAGUC
1291
IL13:988L21 antisense siNA
cuccuGGuGuccAcuGcuuTsT
1681
(970C) stab08
1191
AGAAGGGUACCUUGAACACUGGG
1292
IL13:121IL21 antisense siNA
cAGuGuucAAGGuAcccuuTsT
1682
(1193C) stab08
391
CCCAGUUUGUAAAGGACCUGCUC
1285
36890
IL13:393U21 sense siNA
B CAGUUUGUAAAGGACCUGCTT B
1683
stab09
797
CACUUCACACACAGGCAACUGAG
1286
36891
IL13:799U21 sense siNA
B CUUCACACACAGGCAACUGTT B
1684
stab09
832
UCAGGCACACUUCUUCUUGGUCU
1287
36892
IL13:834U21 sense siNA
B AGGCACACUUCUUCUUGGUTT B
1685
stab09
911
AAGACUGUGGCUGCUAGCACUUG
1288
36893
IL13:913U21 sense siNA
B GACUGUGGCUGCUAGCACUTT B
1686
stab09
963
AGCACUAAAGCAGUGGACACCAG
1289
36894
IL13:965U21 sense siNA
B CACUAAAGCAGUGGACACCTT B
1687
stab09
965
CACUAAAGCAGUGGACACCAGGA
1290
36895
IL13:967U21 sense siNA
B CUAAAGCAGUGGACACCAGTT B
1688
stab09
968
UAAAGCAGUGGACACCAGGAGUC
1291
36896
IL13:970U21 sense siNA
B AAGCAGUGGACACCAGGAGTT B
1689
stab09
1191
AGAAGGGUACCUUGAACACUGGG
1292
36897
IL13:1193U21 sense siNA
B AAGGGUACCUUGAACACUGTT B
1690
stab09
391
CCCAGUUUGUAAAGGACCUGCUC
1285
IL13:411L21 antisense siNA
GCAGGUCCUUUACAAACUGTsT
1691
(393C) stab10
797
CACUUCACACACAGGCAACUGAG
1286
IL13:817L21 antisense siNA
CAGUUGCCUGUGUGUGAAGTsT
1692
(799C) stab10
832
UCAGGCACACUUCUUCUUGGUCU
1287
IL13:852L21 antisense siNA
ACCAAGAAGAAGUGUGCCUTsT
1693
(834C) stab10
911
AAGACUGUGGCUGCUAGCACUUG
1288
IL13:931L21 antisense siNA
AGUGCUAGCAGCCACAGUCTsT
1694
(913C) stab10
963
AGCACUAAAGCAGUGGACACCAG
1289
IL13:983L21 antisense siNA
GGUGUCCACUGCUUUAGUGTsT
1695
(965C) stab10
965
CACUAAAGCAGUGGACACCAGGA
1290
IL13:985L21 antisense siNA
CUGGUGUCCACUGCUUUAGTsT
1696
(967C) stab10
968
UAAAGCAGUGGACACCAGGAGUC
1291
IL13:988L21 antisense siNA
CUCCUGGUGUCCACUGCUUTsT
1697
(970C) stab10
1191
AGAAGGGUACCUUGAACACUGGG
1292
IL13:121IL21 antisense siNA
CCAGUGUUCAAGGUACCCUUTsT
1698
(1193C) stab10
391
CCCAGUUUGUAAAGGACCUGCUC
1285
IL13:411L21 antisense siNA
GcAGGuccuuuAcAAAcuGTT B
1699
(393C) stab19
797
CACUUCACACACAGGCAACUGAG
1286
IL13:817L21 antisense siNA
cAGuuGccuGuGuGuGAAGTT B
1700
(799C) stab19
832
UCAGGCACACUUCUUCUUGGUCU
1287
IL13:852L21 antisense siNA
AccAAGAAGAAGuGuGccuTT B
1701
(834C) stab19
911
AAGACUGUGGCUGCUAGCACUUG
1288
IL13:931L21 antisense siNA
AGuGcuAGcAGccAcAGucTT B
1702
(913C) stab19
963
AGCACUAAAGCAGUGGACACCAG
1289
IL13:983L21 antisense siNA
GGuGuccAcuGcuuuAGuGTT B
1703
(965C) stab19
965
CACUAAAGCAGUGGACACCAGGA
1290
IL13:985L21 antisense siNA
cuGGuGuccAcuGcuuuAGTT B
1704
(967C) stab19
968
UAAAGCAGUGGACACCAGGAGUC
1291
IL13:988L21 antisense siNA
cuccuGGuGuccAcuGcuuTT B
1705
(970C) stab19
1191
AGAAGGGUACCUUGAACACUGGG
1292
IL13:121IL21 antisense siNA
cAGuGuucAAGGuAcccuuTT B
1706
(1193C) stab19
391
CCCAGUUUGUAAAGGACCUGCUC
1285
36898
IL13:411L21 antisense siNA
GCAGGUCCUUUACAAACUGTT B
1707
(393C) stab22
797
CACUUCACACACAGGCAACUGAG
1286
36899
IL13:817L21 antisense siNA
CAGUUGCCUGUGUGUGAAGTT B
1708
(799C) stab22
832
UCAGGCACACUUCUUCUUGGUCU
1287
36900
IL13:852L21 antisense siNA
ACCAAGAAGAAGUGUGCCUTT B
1709
(834C) stab22
911
AAGACUGUGGCUGCUAGCACUUG
1288
36901
IL13:931L21 antisense siNA
AGUGCUAGCAGCCACAGUCTTB
1710
(913C) stab22
963
AGCACUAAAGCAGUGGACACCAG
1289
36902
IL13:983L21 antisense siNA
GGUGUCCACUGCUUUAGUGTT B
1711
(965C) stab22
965
CACUAAAGCAGUGGACACCAGGA
1290
36903
IL13:985L21 antisense siNA
CUGGUGUCCACUGCUUUAGTT B
1712
(967C) stab22
968
UAAAGCAGUGGACACCAGGAGUC
1291
36904
IL13:988L21 antisense siNA
CUCCUGGUGUCCACUGCUUTT B
1713
(970C) stab22
1191
AGAAGGGUACCUUGAACACUGGG
1292
36905
IL13:121IL21 antisense siNA
CAGUGUUCAAGGUACCCUUTT B
1714
(1193C) stab22
IL13R
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
IL13RA1:410U21 sense siNA
GGUGAUCCUGAGUCUGCUGTT
1715
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
IL13RA1:659U21 sense siNA
GUCAAGGAUAAUGCAGGAATT
1716
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
IL13RA1:873U21 sense siNA
UCCAAGAGGCUAAAUGUGATT
1717
1276
GGAAACCGACUCUGUAGUGCUGA
1306
IL13RA1:1278U21 sense siNA
AAACCGACUCUGUAGUGCUTT
1718
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
IL13RA1:1310U21 sense siNA
AAGAAAGCCUCUCAGUGAUTT
1719
1424
ACUGCACCAUUUAAAAACAGGCA
1308
IL13RA1:1426U21 sense siNA
UGCACCAUUUAAAAACAGGTT
1720
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
IL13RA1:2188U21 sense siNA
GCAUUUUCCUCUGCUUUGATT
1721
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
IL13RA1:2272U21 sense siNA
AAGACCUUUCAAAGCCAUUTT
1722
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
IL13RA1:428L21 antisense
CAGCAGACUCAGGAUCACCTT
1723
siNA (410C)
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
IL13RA1:677L21 antisense
UUCCUGCAUUAUCCUUGACTT
1724
siNA (659C)
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
IL13RA1:89IL21 antisense
UCACAUUUAGCCUCUUGGATT
1725
siNA (873C)
1276
GGAAACCGACUCUGUAGUGCUGA
1306
IL13RA1:1296L21 antisense
AGCACUACAGAGUCGGUUUTT
1726
siNA (1278C)
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
IL13RA1:1328L21 antisense
AUCACUGAGAGGCUUUCUUTT
1727
siNA (1310C)
1424
ACUGCACCAUUUAAAAACAGGCA
1308
IL13RA1:1444L21 antisense
CCUGUUUUUAAAUGGUGCATT
1728
siNA (1426C)
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
IL13RA1:2206L21 antisense
UCAAAGCAGAGGAAAAUGCTT
1729
siNA (2188C)
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
IL13RA1:2290L21 antisense
AAUGGCUUUGAAAGGUCUUTT
1730
siNA (2272C)
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
IL13RA1:410U21 sense siNA
B GGuGAuccuGAGucuGcuGTT B
1731
stab04
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
IL13RA1:659U21 sense siNA
B GucAAGGAuAAuGcAGGAATT B
1732
stab04
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
IL13RA1:873U21 sense siNA
B uccAAGAGGcuAAAuGuGATT B
1733
stab04
1276
GGAAACCGACUCUGUAGUGCUGA
1306
IL13RA1:1278U21 sense siNA
B AAAccGAcucuGuAGuGcuTT B
1734
stab04
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
IL13RA1:1310U21 sense siNA
B AAGAAAGccucucAGuGAuTT B
1735
stab04
1424
ACUGCACCAUUUAAAAACAGGCA
1308
IL13RA1:1426U21 sense siNA
B uGcAccAuuuAAAAAcAGGTT B
1736
stab04
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
IL13RA1:2188U21 sense siNA
B GcAuuuuccucuGcuuuGATT B
1737
stab04
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
IL13RA1:2272U21 sense siNA
B AAGAccuuucAAAGccAuuTT B
1738
stab04
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
IL13RA1:428L21 antisense
cAGcAGAcucAGGAucAccTsT
1739
siNA (410C) stab05
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
IL13RA1:677L21 antisense
uuccuGcAuuAuccuuGAcTsT
1740
siNA (659C) stab05
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
IL13RA1:891L21 antisense
ucAcAuuuAGccucuuGGATsT
1741
siNA (873C) stab05
1276
GGAAACCGACUCUGUAGUGCUGA
1306
IL13RA1:1296L21 antisense
AGcAcuAcAGAGucGGuuuTsT
1742
siNA (1278C) stab05
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
IL13RA1:1328L21 antisense
AucAcuGAGAGGcuuucuuTsT
1743
siNA (1310C) stab05
1424
ACUGCACCAUUUAAAAACAGGCA
1308
IL13RA1:1444L21 antisense
ccuGuuuuuAAAuGGuGcATsT
1744
siNA (1426C) stab05
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
IL13RA1:2206L21 antisense
ucAAAGcAGAGGAAAAuGcTsT
1745
siNA (2188C) stab05
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
IL13RA1:2290L21 antisense
AAuGGcuuuGAAAGGucuuTsT
1746
siNA (2272C) stab05
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
IL13RA1:410U21 sense siNA
B GG u GA uccu GAG ucu G cu G TT B
1747
stab07
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
IL13RA1:659U21 sense siNA
B G uc AAGGA u AA u G c AGGAA TT B
1748
stab07
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
IL13RA1:873U21 sense siNA
B ucc AAGAGG cu AAA u G u GA TT B
1749
stab07
1276
GGAAACCGACUCUGUAGUGCUGA
1306
IL13RA1:1278U21 sense siNA
B AAA cc GA cucu G uA G u G cuTT B
1750
stab07
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
IL13RA1:1310U21 sense siNA
B AAGAAAG ccucuc AG u GA uTT B
1751
stab07
1424
ACUGCACCAUUUAAAAACAGGCA
1308
IL13RA1:1426U21 sense siNA
B u G c A cc A uuu AAAAA c AGG TT B
1752
stab07
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
IL13RA1:2188U21 sense siNA
B G c A uuuuccucu G cuuu GA TT B
1753
stab07
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
IL13RA1:2272U21 sense siNA
B AAGA ccuuuc AAAG cc A uuTT B
1754
stab07
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
IL13RA1:428L21 antisense
c AG c AGA cuc AGGA uc A ccTsT
1755
siNA (410C) stab11
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
IL13RA1:677L21 antisense
uuccu G c A uu A uccuu GA cTsT
1756
siNA (659C) stab11
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
IL13RA1:891L21 antisense
uc A c A uuu AG ccucuu GGA TsT
1757
siNA (873C) stab11
1276
GGAAACCGACUCUGUAGUGCUGA
1306
IL13RA1:1296L21 antisense
AG c A cu A c AGAG uc GG uuuTsT
1758
siNA (1278C) stab11
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
IL13RA1:1328L21 antisense
A uc A cu GAGAGG cuuucuuTsT
1759
siNA (1310C) stab11
1424
ACUGCACCAUUUAAAAACAGGCA
1308
IL13RA1:1444L21 antisense
ccu G uuuuu AAA u GG u G c A TsT
1760
siNA (1426C) stab11
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
IL13RA1:2206L21 antisense
uc AAAG c AGAGGAAAA u G cTsT
1761
siNA (2188C) stab11
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
IL13RA1:2290L21 antisense
AA u GG cuuu GAAAGG ucuuTsT
1762
siNA (2272C) stab11
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
IL13RA1:410U21 sense siNA
B GGuGAuccuGAGucuGcuGTT B
1763
stab18
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
IL13RA1:659U21 sense siNA
B GucAAGGAuAAuGcAGGAATT B
1764
stab18
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
IL13RA1:873U21 sense siNA
B uccAAGAGGcuAAAuGuGATT B
1765
stab18
1276
GGAAACCGACUCUGUAGUGCUGA
1306
IL13RA1:1278U21 sense siNA
B AAAccGAcucuGuAGuGcuTT B
1766
stab18
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
IL13RA1:1310U21 sense siNA
B AAGAAAGccucucAGuGAuTT B
1767
stab18
1424
ACUGCACCAUUUAAAAACAGGCA
1308
ILl3RAl:1426U21 sense siNA
B uGcAccAuuuAAAAAcAGGTT B
1768
stab18
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
IL13RA1:2188U21 sense siNA
B GcAuuuuccucuGcuuuGATT B
1769
stab18
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
IL13RA1:2272U21 sense siNA
B AAGAccuuucAAAGccAuuTT B
1770
stab18
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
IL13RA1:428L21 antisense
cAGcAGAcucAGGAucAccTsT
1771
siNA (410C) stab08
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
IL13RA1:677L21 antisense
uuccuGcAuuAuccuuGAcTsT
1772
siNA (659C) stab08
871
0GU00AAGAGG0UAAAUGUGAGA
1305
L13RA1:891L21 antisense
ucAcAuuuAGccucuuGGATsT
1773
siNA (873C) stab08
1276
GGAAACCGACUCUGUAGUGCUGA
1306
IL13RA1:1296L21 antisense
AGcAcuAcAGAGucGGuuuTsT
1774
siNA (1278C) stab08
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
IL13RA1:1328L21 antisense
AucAcuGAGAGGcuuucuuTsT
1775
siNA (1310C) stab08
1424
ACUGCACCAUUUAAAAACAGGCA
1308
IL13RA1:1444L21 antisense
ccuGuuuuuAAAuGGuGcATsT
1776
siNA (1426C) stab08
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
IL13RA1:2206L21 antisense
ucAAAGcAGAGGAAAAuGcTsT
1777
siNA (2188C) stab08
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
IL13RA1:2290L21 antisense
AAuGGcuuuGAAAGGucuuTsT
1778
siNA (2272C) stab08
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
36906
IL13RA1:410U21 sense siNA
B GGUGAUCCUGAGUCUGCUGTT B
1779
stab09
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
36907
IL13RA1:659U21 sense siNA
B GUCAAGGAUAAUGCAGGAATT B
1780
stab09
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
36908
IL13RA1:873U21 sense siNA
B UCCAAGAGGCUAAAUGUGATT B
1781
stab09
1276
GGAAACCGACUCUGUAGUGCUGA
1306
36909
IL13RA1:1278U21 sense siNA
B AAACCGACUCUGUAGUGCUTT B
1782
stab09
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
36910
IL13RA1:1310U21 sense siNA
B AAGAAAGCCUCUCAGUGAUTT B
1783
stab09
1424
ACUGCACCAUUUAAAAACAGGCA
1308
36911
IL13RA1:1426U21 sense siNA
B UGCACCAUUUAAAAACAGGTT B
1784
stab09
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
36912
IL13RA1:2188U21 sense siNA
B GCAUUUUCCUCUGCUUUGATT B
1785
stab09
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
36913
IL13RA1:2272U21 sense siNA
B AAGACCUUUCAAAGCCAUUTT B
1786
stab09
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
IL13RA1:428L21 antisense
CAGCAGACUCAGGAUCACCTsT
1787
siNA (410C) stab10
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
IL13RA1:677L21 antisense
UUCCUGCAUUAUCCUUGACTsT
1788
siNA (659C) stab10
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
IL13RA1:891L21 antisense
UCACAUUUAGCCUCUUGGATsT
1789
siNA (873C) stab10
1276
GGAAACCGACUCUGUAGUGCUGA
1306
IL13RA1:1296L21 antisense
AGCACUACAGAGUCGGUUUTsT
1790
siNA (1278C) stab10
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
IL13RA1:1328L21 antisense
AUCACUGAGAGGCUUUCUUTsT
1791
siNA (1310C) stab10
1424
ACUGCACCAUUUAAAAACAGGCA
1308
IL13RA1:1444L21 antisense
CCUGUUUUUAAAUGGUGCATsT
1792
siNA (1426C) stab10
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
IL13RA1:2206L21 antisense
UCAAAGCAGAGGAAAAUGCTsT
1793
siNA (2188C) stab10
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
IL13RA1:2290L21 antisense
AAUGGCUUUGAAAGGUCUUTsT
1794
siNA (2272C) stab10
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
IL13RA1:428L21 antisense
cAGcAGAcucAGGAucAccTT B
1795
siNA (410C) stab19
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
IL13RA1:677L21 antisense
uuccuGcAuuAuccuuGAcTT B
1796
siNA (659C) stab19
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
IL13RA1:891L21 antisense
ucAcAuuuAGccucuuGGATT B
1797
siNA (873C) stab19
1276
GGAAACCGACUCUGUAGUGCUGA
1306
IL13RA1:1296L21 antisense
AGcAcuAcAGAGucGGuuuTT B
1798
siNA (1278C) stab19
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
IL13RA1:1328L21 antisense
AucAcuGAGAGGcuuucuuTT B
1799
siNA (1310C) stab19
1424
ACUGCACCAUUUAAAAACAGGCA
1308
IL13RA1:1444L21 antisense
ccuGuuuuuAAAuGGuGcATT B
1800
siNA (1426C) stab19
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
IL13RA1:2206L21 antisense
ucAAAGcAGAGGAAAAuGcTT B
1801
siNA (2188C) stab19
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
IL13RA1:2290L21 antisense
AAuGGcuuuGAAAGGucuuTT B
1802
siNA (2272C) stab19
408
AAGGUGAUCCUGAGUCUGCUGUG
1303
36914
IL13RA1:428L21 antisense
CAGCAGACUCAGGAUCACCTT B
1803
siNA (410C) stab22
657
UGGUCAAGGAUAAUGCAGGAAAA
1304
36915
IL13RA1:677L21 antisense
UUCCUGCAUUAUCCUUGACTT B
1804
siNA (659C) stab22
871
CGUCCAAGAGGCUAAAUGUGAGA
1305
36916
IL13RA1:891L21 antisense
UCACAUUUAGCCUCUUGGATT B
1805
siNA (873C) stab22
1276
GGAAACCGACUCUGUAGUGCUGA
1306
36917
IL13RA1:1296L21 antisense
AGCACUACAGAGUCGGUUUTT B
1806
siNA (1278C) stab22
1308
UGAAGAAAGCCUCUCAGUGAUGG
1307
36918
IL13RA1:1328L21 antisense
AUCACUGAGAGGCUUUCUUTT B
1807
siNA (1310C) stab22
1424
ACUGCACCAUUUAAAAACAGGCA
1308
36919
IL13RA1:1444L21 antisense
CCUGUUUUUAAAUGGUGCATT B
1808
siNA (1426C) stab22
2186
CAGCAUUUUCCUCUGCUUUGAAA
1309
36920
IL13RA1:2206L21 antisense
UCAAAGCAGAGGAAAAUGCTT B
1809
siNA (2188C) stab22
2270
CCAAGACCUUUCAAAGCCAUUUU
1310
36921
IL13RA1:2290L21 antisense
AAUGGCUUUGAAAGGUCUUTT B
1810
siNA (2272C) stab22
Uppercase = ribonucleotide
u, c = 2′-deoxy-2′-fluoro U, C
T = thymidine
B = inverted deoxy abasic
s = phosphorothioate linkage
A = deoxy Adenosine
G = deoxy Guanosine
G = 2′-O-methyl Guanosine
A = 2′-O-methyl Adenosine
[0000]
TABLE IV
Non-limiting examples of Stabilization Chemistries for
chemically modified siNA constructs
Chemistry
pyrimidine
Purine
cap
p = S
Strand
“Stab 00”
Ribo
Ribo
TT at
S/AS
3′-ends
“Stab 1”
Ribo
Ribo
—
5 at 5′-end
S/AS
1 at 3′-end
“Stab 2”
Ribo
Ribo
—
All
Usually AS
linkages
“Stab 3”
2′-fluoro
Ribo
—
4 at 5′-end
Usually S
4 at 3′-end
“Stab 4”
2′-fluoro
Ribo
5′ and
—
Usually S
3′-ends
“Stab 5”
2′-fluoro
Ribo
—
1 at 3′-end
Usually AS
“Stab 6”
2′-O-Methyl
Ribo
5′ and
—
Usually S
3′-ends
“Stab 7”
2′-fluoro
2′-deoxy
5′ and
—
Usually S
3′-ends
“Stab 8”
2′-fluoro
2′-O-
—
1 at 3′-end
Usually AS
Methyl
“Stab 9”
Ribo
Ribo
5′ and
—
Usually S
3′-ends
“Stab 10”
Ribo
Ribo
—
1 at 3′-end
Usually AS
“Stab 11”
2′-fluoro
2′-deoxy
—
1 at 3′-end
Usually AS
“Stab 12”
2′-fluoro
LNA
5′ and
Usually S
3′-ends
“Stab 13”
2′-fluoro
LNA
1 at 3′-end
Usually AS
“Stab 14”
2′-fluoro
2′-deoxy
2 at 5′-end
Usually AS
1 at 3′-end
“Stab 15”
2′-deoxy
2′-deoxy
2 at 5′-end
Usually AS
1 at 3′-end
“Stab 16”
Ribo
2′-O-
5′ and
Usually S
Methyl
3′-ends
“Stab 17”
2′-O-Methyl
2′-O-
5′ and
Usually S
Methyl
3′-ends
“Stab 18”
2′-fluoro
2′-O-
5′ and
1 at 3′-end
Usually S
Methyl
3′-ends
“Stab 19”
2′-fluoro
2′-O-
3′-end
Usually AS
Methyl
“Stab 20”
2′-fluoro
2′-deoxy
3′-end
Usually AS
“Stab 21”
2′-fluoro
Ribo
3′-end
Usually AS
“Stab 22”
Ribo
Ribo
3′-end -
Usually AS
“Stab 23”
2′-fluoro*
2′-deoxy*
5′ and
Usually S
3′-ends
“Stab 24”
2′-fluoro*
2′-O-
—
1 at 3′-end
Usually AS
Methyl*
“Stab 25”
2′-fluoro*
2′-O-
—
1 at 3′-end
Usually AS
Methyl*
CAP = any terminal cap, see for example FIG. 10.
All Stab 1-25 chemistries can comprise 3′-terminal thymidine (TT) residues
All Stab 1-25 chemistries typically comprise about 21 nucleotides, but can vary as described herein.
S = sense strand
AS = antisense strand
*Stab 23 has single ribonucleotide adjacent to 3′-CAP
*Stab 24 has single ribonucleotide at 5′-terminus
*Stab 25 has three ribonucleotides at 5′-terminus
[0000]
TABLE V
Reagent
Equivalents
Amount
Wait Time* DNA
Wait Time* 2′-O-methyl
Wait Time* RNA
A. 2.5 μmol Synthesis Cycle ABI 394 Instrument
Phosphoramidites
6.5
163
μL
45
sec
2.5
min
7.5
min
S-Ethyl Tetrazole
23.8
238
μL
45
sec
2.5
min
7.5
min
Acetic Anhydride
100
233
μL
5
sec
5
sec
5
sec
N-Methyl
186
233
μL
5
sec
5
sec
5
sec
Imidazole
TCA
176
2.3
mL
21
sec
21
sec
21
sec
Iodine
11.2
1.7
mL
45
sec
45
sec
45
sec
Beaucage
12.9
645
μL
100
sec
300
sec
300
sec
Acetonitrile
NA
6.67
mL
NA
NA
NA
B. 0.2 μmol Synthesis Cycle ABI 394 Instrument
Phosphoramidites
15
31
μL
45
sec
233
sec
465
sec
S-Ethyl Tetrazole
38.7
31
μL
45
sec
233
min
465
sec
Acetic Anhydride
655
124
μL
5
sec
5
sec
5
sec
N-Methyl
1245
124
μL
5
sec
5
sec
5
sec
Imidazole
TCA
700
732
μL
10
sec
10
sec
10
sec
Iodine
20.6
244
μL
15
sec
15
sec
15
sec
Beaucage
7.7
232
μL
100
sec
300
sec
300
sec
Acetonitrile
NA
2.64
mL
NA
NA
NA
C. 0.2 μmol Synthesis Cycle 96 well Instrument
Equivalents: DNA/
Amount: DNA/2′-O-
Wait Time* 2′-O-
Reagent
2′-O-methyl/Ribo
methyl/Ribo
Wait Time* DNA
methyl
Wait Time* Ribo
Phosphoramidites
22/33/66
40/60/120
μL
60 sec
180
sec
360
sec
S-Ethyl Tetrazole
70/105/210
40/60/120
μL
60 sec
180
min
360
sec
Acetic Anhydride
265/265/265
50/50/50
μL
10 sec
10
sec
10
sec
N-Methyl
502/502/502
50/50/50
μL
10 sec
10
sec
10
sec
Imidazole
TCA
238/475/475
250/500/500
μL
15 sec
15
sec
15
sec
Iodine
6.8/6.8/6.8
80/80/80
μL
30 sec
30
sec
30
sec
Beaucage
34/51/51
80/120/120
100 sec
200
sec
200
sec
Acetonitrile
NA
1150/1150/1150
μL
NA
NA
NA
Wait time does not include contact time during delivery.
Tandem synthesis utilizes double coupling of linker molecule
|
This invention relates to compounds, compositions, and methods useful for modulating interleukin and/or interleukin receptor gene expression using short interfering nucleic acid (siNA) molecules. This invention also relates to compounds, compositions, and methods useful for modulating the expression and activity of other genes involved in pathways of interleukin and/or interleukin receptor gene expression and/or activity by RNA interference (RNAi) using small nucleic acid molecules. In particular, the instant invention features small nucleic acid molecules, such as short interfering nucleic acid (siNA), short interfering RNA (siRNA), double-stranded RNA (dsRNA), micro-RNA (miRNA), and short hairpin RNA (shRNA) molecules and methods used to modulate the expression of interleukin and/or interleukin receptor genes such as IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-1, IL-12, IL-13, IL-14, IL-15, IL-16, IL-17, IL-18, IL-19, IL-20, IL-21, IL-22, IL-23, IL-24, IL-25, IL-26, and IL-27 genes and IL-1R, IL-2R, IL-3R, IL-4R, IL-5R, IL-6R, IL-7R, IL-8R, IL-9R, IL-10R, IL- 11 R, IL-12R, IL-13R, IL-14R, IL-15R, IL-16R, IL-17R, IL-18R, IL-19R, IL-20R, IL-21R, 1L-22R, IL-23R, IL-24R, IL-25R, IL-26R, and IL-27R genes.
| 0
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BACKGROUND OF THE INVENTION
The present invention relates in general to filter circuits and in particular to a low-pass filter circuit having a high slew rate.
Analog data acquisition systems often simultaneously acquire waveform data from several different analog signals by sampling the signals in rapid succession, employing digitally controlled multiplexers to successively connect each analog signal to the input of an analog-to-digital (A/D) converter. The A/D converter converts the DC voltage level of each waveform into digital data of proportional magnitude for storage by the acquisition system in a random access memory. When a sampled waveform contains noise, it is desirable to filter out high frequency components in the multiplexer output with a low-pass filter circuit typically having attenuation of 60 db or more at frequencies of 60 Hz or higher, but such filters normally require up to 300 milli-seconds to slew and settle in response to a relatively large voltage difference between two successively sampled signals. The scanning rate at which the multiplexer can be switched from channel to channel is therefore typically limited by the filter slew rate to about three channels per second, a rate which is much too slow to provide adequate sampling of most AC waveforms. What is needed is a low-pass filter with a high slew rate which would permit the multiplexer to sample multiple waveforms at a much higher scanning rate.
SUMMARY OF THE INVENTION
According to one aspect of the invention, the bandwidth and slew rate of an active, low-pass filter are determined by an input RC network having series resistance and shunt capacitance elements, the output voltage of the filter being determined by the charge on the capacitance elements. Means are provided to temporarily short the series resistance elements of the network in response to a change in input voltage, thereby permitting rapid charging or discharging of the shunt capacitance element to a steady state level and allowing the filter output to quickly adjust to the change in filter input. The resistance elements are then unshorted to permit normal filtering action. When used in conjunction with a filter circuit having, for example a 60 dB attenuation at 60 Hz requiring a nominal slew time of 300 milliseconds for output stability, the temporary shunting of the resistance elements can typically decrease the slew time to 500 microseconds or less.
According to another aspect of the invention, a multiplexer is adapted to sample multiple analog waveform signals to provide a sequence of analog sample input voltages for an analog data acquisition system. The output of the multiplexer is filtered by a low-pass filter. As the multiplexer switches state to sample a new analog signal, series filter resistance elements are temporarily shorted, to rapidly slew the output voltage, and then unshorted to permit normal low-pass filter operation. Latch means then apply the filtered output to the data acquisition system input. Control means are provided for switching the multiplexer, shorting and unshorting the resistance elements and operating the latch means in timed sequence according to an applied clock signal. For a typical filter circuit permitting a nominal multiplexer input signal scanning rate of, for instance 3 channels per second, temporarily short circuiting the resistance elements permits a multiplexer scanning rate of several hundred channels per second or more.
According to a further aspect of the invention, switch means are also provided for selectively open circuiting the shunt capacitance elements of the filter circuit when the resistance elements are short circuited, thereby increasing the bandwidth of the filter, allowing it to pass higher frequency input signals while still retaining the high input impedance of the filter. When the filter is used in conjunction with a multiplexer input data acquisition system, this feature permits the system to alternately sample high and low frequency signals with the filter operating in a low-pass mode only when sampling low frequency signals and in an "all-pass" mode when sampling higher frequency signals.
It is accordingly an object of the present invention to provide a new and improved low-pass filter circuit having a high slew rate.
It is another object of the present invention to provide a new and improved filter circuit having selectively either low-pass or all-pass characteristics.
It is still another object of the present invention to provide a new and improved apparatus for rapidly scanning and filtering a plurality of voltage input signals wherein low frequency input signals are selectively low-pass filtered while high frequency signals are high-pass filtered.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic diagram of a low-pass filter circuit of the prior art;
FIG. 2 is a schematic diagram of a rapid slewing, low-pass filter according to the present invention;
FIG. 3 is a block diagram of an apparatus according to the present invention for rapidly scanning and filtering a plurality of input voltage signals; and
FIG. 4 is a block diagram of the control circuit of FIG. 3.
DETAILED DESCRIPTION
Referring to FIG. 1, a well known Butterworth (Sallen-Key) filter 10 of the prior art, depicted in schematic diagram form, is adapted to provide a low-pass filtered output voltage Vo in response to an input voltage Vi. The filter 10 comprises a high gain operational amplifier 12, having a non-inverting input for receiving the filter input signal Vi through an RC network including a pair of series resistors R1 and R2 and a shunt capacitor C1, coupling the non-inverting amplifier input to ground. The output of the filter 10 comprises the output voltage Vo of amplifier 12 which is fed back to its inverting input through resistors R3 and R4, the resistance of resistor R4 being adjustable.
When C1 is charged to a steady state voltage, a small input current passing through R1 and R2 causes a small offset voltage drop (Voff=V1+V2) across R1 and R2 such that the voltage across C1 at the non-inverting input of amplifier 12 is Vi-Voff. The resistance of feedback resistor R4 is adjusted such that a steady state current, passing into the inverting input of amplifier 12 through resistors R3 and R4, causes a similar offset voltage drop across R3 and R4. If the input impedance of the amplifier 12 is large compared to R3+R4, and if the nominal gain of amplifier 12 is large, a steady state voltage at the inverting input of amplifier 12 will substantially equal a steady state voltage at the non-inverting input, and the steady state DC output voltage Vo of the filter will substantially equal the input voltage Vi.
The amplifier 12 output is also coupled to the junction between resistors R1 and R2 through a capacitor C2. The transfer function of the filter circuit 10 can be determined by dividing the output impedance (Xo) of the circuit by its input impedance (Xin) as follows:
Xo/Xin=[(R1R2C2)C1)].sup.-1
x[S.sup.2 +((R1+R2)/(R1R2C2))S+(1/(R1R2C2)C1)].sup.-1
This is equivalent to the transfer function of an RLC filter of the form:
Vo/Vin=[1/LC]/[S.sup.2 +(Ro/L)S+(1/LC)]
where Ro=R1+R2, L=(R1R2C2), and C=C1=C2. Attenuation is 40 db/decade or 12 db/octave, and the bandwidth of the circuit, the frequency at which -3 db attenuation (i.e. Vo=0.707Vin) occurs is:
ω.sub.p =(1/LC).sup.1/2 [1-(RoRoC/4L)].sup.1/2 rad/s.[1]
or by substitution of the definitions of Ro, L and C into equation [1],
ω.sub.p =[1/R1R2C1C2].sup.1/2 [(R1+R2).sup.2 C1/4(R1R2C2)].sup.1/2 rad/s. [2]
When the filter input voltage Vi changes from one DC level to another, currents flow through resistors R1 and R2 to charge or discharge C1 and through resistor R1 to charge or discharge capacitor C2. Since these capacitors take time to charge or discharge, the resulting change in Vo lags the change in Vi. When the input voltage Vi is maintained at a steady state DC level for a sufficient time to permit the output voltage to reach a corresponding steady state level, the voltage across capacitor C1 will be maintained at Vi-Voff, while the voltage across capacitor C2 will settle to V1.
When the input voltage Vi changes abruptly from a first DC voltage level to a second DC voltage level, the output voltage Vo rises or falls to a level matching the second DC level at a slew rate determined by a time constant R1C1. In a typical application, wherein the values of R1 and C1 are chosen for a 60 dB attenuation at 60 Hz, the output voltage requires on the order of 300 milliseconds to slew and settle to a magnitude which is stable to within 1 part in 4096.
Referring to FIG. 2, there is depicted in schematic diagram form a low-pass filter 20 adapted according to the present invention to provide a substantially increased slew rate in response to a change in input voltage Vi. The filter 20 comprises an operational amplifier 12, resistors R1R4, and capacitors C1 and C2 interconnected in a manner similar to the corresponding elements of the prior art Butterworth filter 10 of FIG. 1. However, in addition to these elements, the filter 20 of the present invention also comprises first switch means SW1 to selectively shunt resistor R1 with a small resistance R5, along with second switch means SW2 to selectively shunt both resistors R1 and R2 through another small resistor R6. Filter 20 further includes switch means S3 to selectively connect the amplifier 12 output Vo directly to its inverting input to shunt resistors R3 and R4, and switch means S4 to selectively disconnect capacitor C1 from the inverting input of amplifier 12. Switch means SW1-4 are preferably high speed electronic switches having switching states controlled according to applied digital signals, switches SW1-3 closing when a terminal A is driven low and switch SW4 closing when a terminal B is driven low.
When terminal A is high and terminal B is low, switches SW1-3 are open and switch SW4 is closed. In this state the filter 20 operates as a low-pass filter in a fashion similar to that of the Butterworth filter 10 of FIG. 1 and has a relatively low slew rate. When terminal A is then driven low, switches SW1-3 also close, and capacitors C1 and C2 will quickly charge or discharge in response to any step change in input voltage level, assuming resistors R5 and R6 are negligibly small compared to resistors R1 and R2, since comparatively large charging or discharging currents, no longer limited by R1 and R2, are applied to the capacitors C1 and C2. When the capacitors C1 and C2 have charged or discharged to a steady state voltage level, the input voltage Vi, less a negligible drop across resistor R6, will appear at the non-inverting input of amplifier 12.
The slew rate of the filter circuit 20 is increased by many orders of magnitude when switches S1-3 are closed, but at the same time the bandwidth of the filter circuit 10 is also increased by many orders of magnitude (to approximately 1/R6C1), and circuit 20 will not block high frequency signals. However if S1-S3 are reopened after the output voltage Vo reaches its steady state value in response to a change in input voltage, the circuit 20 will again operate as a low-pass filter. Thus if the switches S1-S3 are briefly closed immediately after a change in input voltage magnitude, and then reopened, the filter circuit will rapidly adjust its output to the input voltage change and then continue to operate as a low-pass filter.
If switches SW1-3 remain closed long enough for the output voltage Vo to reach a steady state DC level in response to a change DC input voltage Vi, the amplifier 12 output voltage Vo will exhibit little transient response when the switches SW1-3 are reopened because there will be only a small change in voltage across capacitors C1 and C2. With the switches S1-S3 closed, the steady state output voltage Vo and the voltage across C1 will equal Vi and the voltage across C2 will be substantially 0. With switches S1-S3 opened, the steady state output voltage will also be Vi and the voltage across capacitor C1 will be maintained at Vi-Voff, while the voltage across capacitor C2 will settle to V1, matching voltage across R1. If Voff and V1 are relatively small, then very little fluctuation in voltages across capacitors C1 and C will occur after switches SW1-3 are opened and therefore very little fluctuation in output voltage Vo will occur.
In the preferred embodiment of the present invention, switches SW1-4 comprise high speed, low leakage, optically isolated MOSFET switches, although in other embodiments the switches may comprise other switch means such as relays. Resistors R5 and R6 are provided to damp any ringing due to any small inherent capacitances associated with switches SW1 and SW2.
Thus the circuit 20 of the present invention can be operated in a rapid slewing mode in response to a change in input voltage by temporarily applying a low control voltage to terminal A, thereby closing switches SW1-3, and may be operated in a low-pass filter mode by applying a high control signal voltage to terminal A, thereby reopening switches SW1-3 when the output voltage reaches steady state. In addition, switch SW4, which selectively disconnects capacitor C1 from the inverting input of amplifier 12, may be opened by applying a high control voltage to terminal B. If switches SW1-3 are closed while switch SW4 is opened, circuit 20 will operate in an "all pass" mode wherein the circuit has a very wide bandwidth. In this all-pass mode, the input voltage Vi is applied directly to the non-inverting input of amplifier 12 while the amplifier output voltage Vo is applied directly to the inverting input to maintain the gain of the circuit 20 at unity. Thus, switch SW4 allows the bandwidth of the circuit to be selectively increased.
Referring to FIG. 3, there is depicted in block diagram form a circuit 30 according to the present invention adapted to sequentially sample and filter a plurality of input voltage signals Vin; circuit 30 includes a set of buffering amplifiers 32, each providing a buffered output signal according to a separate input signal Vi, each buffered output signal being applied as a separate input of a multiplexer 34. The output of multiplexer 34, being a selected one of the buffered inputs, is applied as an input Vi to a filter circuit 20, similar to the filter circuit 20 of FIG. 2. The output Vo of filter circuit 20 is applied to an input of a sample and hold circuit 36. In a typical application, the latch output Vo' may be applied as an input to a data acquisition system 40, including means for converting the latch output signal Vo' to a digital signal of representative magnitude and means for storing the digital signal output of the converting means.
A control circuit 38 provides signals for operating the switching control input of multiplexer 34, the A and B control inputs of filter circuit 20, the sampling control input of sample and hold circuit 36, and an input enabling control of DAC 40 in timed response to a clock signal Vc and an all-pass mode control signal Vs. In operation, control circuit 38 advances the switching state of multiplexer 34 on the trailing edge of each input clock signal Vc pulse so that the multiplexer scans each input signal in turn, sequentially transmitting each input signal or "channel" to the filter circuit 20 input. The Vc input signal is also applied to the A input of filter circuit 20. When the all-pass signal Vs is low, the control circuit 38 maintains the B input terminal of filter circuit 20 in a low state and applies the Vc input signal to the A input terminal of the filter circuit. As described hereinabove, when the A terminal is driven low and the filter circuit 20 enters the rapid slew mode wherein the output Vo of the filter circuit rapidly adjusts to a change in input voltage level, and when the A terminal is driven high the filter enters the low-pass filter mode. Therefore, on receipt of a negative-going edge of the Vc signal the filter circuit 20 rapidly slews, while on receipt of a positive going edge of the Vc signal the filter circuit low-pass filters the input signals. The length of each negative-going Vc signal pulse is adjusted to allow the filter circuit 20 to fully slew in response to any anticipated step change in input voltage magnitude caused by multiplexer 34 channel switching.
The sample and hold circuit 36 samples the output voltage Vo of the filter circuit 20 and holds it as its output Vo' on receipt of a negative-going pulse edge at its clock input. Such sample and hold circuits are commonly known in the art and are not further detailed herein. Control circuit 38 delays the Vc signal pulse by a time sufficient to permit the filter circuit to slew in response to a change in input and then utilizes the delayed Vc signal to clock the sample and hold circuit 36. The control circuit 38 further delays the Vc signal by an amount sufficient to ensure that the sample and hold circuit 36 has sampled the Vo signal and applies the further delayed Vc signal to an enable EN input terminal of the DAC 40, the negative-going edge of each delayed clock signal pulse enabling the DAC to sample, convert and store its current input signal Vo'.
Thus when the B input to the filter circuit 20 is held low, the sample and hold circuit 36 output Vo' transmitted to the DAC circuit 40 comprises a sequence of DC voltage levels, each level representative of a sampled magnitude of one low-pass filtered multiplexer 34 input signal. The sampling rate of the multiplexer can be comparatively high since it is not limited by the slew rate of filter 20 in the low-pass mode but rather by the slew rate of the filter in the rapid slew mode, which is several orders of magnitude faster than the low-pass mode slew rate.
When the A input terminal of the filter circuit 20 is driven low while the B input terminal is driven high, the filter circuit enters the the all-pass mode. When the control signal Vs is high, control circuit 38 maintains the A terminal low and the B terminal high regardless of the state of the clock input signal, thereby maintaining the filter circuit 20 in the all pass mode. The all-pass mode may be utilized when the input signals Vi are high frequency and the low-pass filtering operation of the filter 20 is not desired, but wherein the high input impedance of the filter circuit 20 is to be maintained. If the all-pass control signal Vs is driven high whenever the input signal Vi is of a frequency higher than the cut-off frequency of the filter, and is driven low whenever the input signal is higher than the filter cut-off frequency, then the filtering action of the filter 20 can be activated or deactivated as the multiplexer 34 scans from signal to signal as necessary to block high frequency noise in low frequency input signals or to pass high frequency input signals. Thus circuit 30 can be used to simultaneously scan and selectively low-pass filter a mixed set of high and low frequency input signals by appropriately controlling the all-pass signal Vs.
Referring to FIG. 4 an embodiment of the control circuit 38 of FIG. 3, depicted in block diagram form, comprises a counter 42 for generating a digitally encoded count of the trailing edges of Vc clock signal pulses, the count being applied as the switching control signal input to the multiplexer circuit 34. The control circuit also includes first signal time delay means 44 for producing the delayed Vc signal to the sample control input of sample and hold circuit 36 and second signal delay means 46 for producing the further delayed Vc signal to the enabling input of the DAC system 40. A multiplexer circuit 48 selectively applies either the Vc signal or a logical 0 (low) signal to the A input of filter circuit 20 depending on whether the applied all-pass signal Vs connected to the control input of multiplexer 48 is low or low or high. The all-pass control signal Vs is also directly connected to the B input of filter circuit 20.
Thus filter circuit 20 has three modes of operation. In a "rapid slewing" mode of operation it responds rapidly to a change in magnitude of input signal Vi to produce an output signal Vo of comparable magnitude. In a "low pass" mode of operation it acts like a low pass filter with a relatively low cutoff frequency but responds less quickly to changes in Vi. In an "all pass" mode, the filter has a relatively high bandwidth. The mode of operation of the circuit is determined by the state of the binary control signal applied to terminal A for controlling switches SW1-SW3 and by the binary control signal applied to terminal B which controls switch SW4. The circuit operates in the all pass mode when terminal A is driven low and terminal B is driven high. When terminals A and B are low, the circuit operates in the rapid slewing mode, and when B is low and A is high, the circuit operates in the low pass filter mode. The Vs signal at terminal B of the filter controls switch SW4 which connects a capacitor C1 to the input of amplifier 12. When Vs is driven high, SW4 opens, thereby disconnecting C1 from the amplifier input. When Vs is driven high it also switches multiplexer 48 of FIG. 4 so that the multiplexer passes a logical "0" to terminal A, thereby causing switches SW1-SW3 to close. Switch SW3 connects the output of amplifier 42 to its input so that it has unity gain. Switches SW1 and SW2 remove the high resistances R1 and R2 from the input signal path. With R1, R2 and C1 removed from the input signal path, the filter operates in the all pass mode and does not filter the input signal. This mode is suitable when the input signal is high frequency and no filtering is desired, but when the high input impedance of the amplifier is desired.
When the Vs signal is driven low, the filter circuit 20 operates in either the rapid slewing mode or in the low pass filter mode depending on the state of clock signal Vc. As clock signal Vc goes low, counter 42 changes the switching state of multiplexer 34 so that a new input signal is applied to filter 20. At the same time, clock signal Vc closes switches SW1-SW3 so as to put filter 20 in its high slew rate mode. The filter stays in that mode as long as Vc is low and then, when Vc goes high, opens SW1-SW3 so that the filter begins to operate in its low bandpass mode. Some time thereafter, as determined by delay circuit 44, sample and hold circuit 36 samples the filtered output signal of filter 20. The period of time during which the filter is in its high slew rate mode is determined by the width of the negative portion of each pulse of a typical square wave clock signal Vc. In order to provide for proper operation of the filter circuit, the length of the negative pulse of clock signal Vc should be sufficient to ensure that, for the maximum expected abrupt change in filter input signal magnitude, the high slew rate mode continues until the filter input and output voltages equalize.
While a preferred embodiment of the present invention has been shown and described, it will be apparent to those skilled in the art that many changes and modifications may be made without departing from the invention in its broader aspects. For instance, many low-pass filters employing various series resistor and shunt capacitor networks to set the passband characteristics of the filter are known in the art and the slew rate of many of these filters may be increased by selectively shorting the series resistance elements in a manner according to the present invention to permit the shunt capacitance elements to rapidly charge or discharge in response to a change in filter input voltage. The appended claims are therefore intended to cover all such changes and modifications as fall within the true spirit and scope of the invention.
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A multiplexer samples multiple analog waveform signals to provide a sequence of input signals to an active low-pass filter. The bandwidth of the filter is determined by an input RC network having series resistance and shunt capacitance elements. As the multiplexer switches state to sample a different analog signal, the resistance elements of the filter are temporarily shorted to allow the filter input signal to rapidly charge or discharge the shunt capacitance element to a steady state voltage in response to any change in input signal voltage. The resistance elements are then unshorted to permit normal low-pass filter operation. Switch means are also provided to selectively disconnect the shunt capacitance element from the network when the resistance elements are shunted, thereby selectively widening the bandwidth of the filter to pass higher frequency input signals.
| 7
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to gift wrapping and in particular to an ornament assembly which expands to form an ornamental design, figure or shape which resembles either indicia which is printed on gift wrapping paper or is otherwise simulative of a 3 dimensional object.
2. Description of the Prior Art
The use of paper for wrapping gifts is known in the prior art, as is the use of ornaments or bows for decoration of a gift-wrapped object. More specifically, ornaments and bows heretofore devised and utilized for the purpose of decorating gift-wrapped objects are known to consist basically of familiar, expected, and obvious structural configurations, notwithstanding the myriad of designs encompassed by the crowded prior art which has been developed for the fulfillment of countless objectives and requirements.
By way of example, the prior art discloses various means for making and arranging various shaped bows and ribbons on packages. In particular, U.S. Pat. No. 4,374,877 to Cole discloses an automatically expanding pop-up decoration for use in connection with gift-wrapping a package having an elastic cord secured to the decoration and used to fasten the decoration to the package.
With regards to prior art disclosing various shaped bows and ribbons, U.S. Pat. No. 5,240,750 to Cheng discloses a three-dimensional, heart shaped decorative bow and a method of making the bow.
U.S. Pat. No. 5,026,578 to Iname discloses a flower shaped ribbon comprising pairs of overlapping strips with strings placed between and along the strips.
U.S. Pat. No. 4,937,106 to Eliason discloses a collapsible decorative bow assembly.
In all of the cited references, however, there has been no discussion of the paper on which the decorative items will be placed. Neither does the prior art teach the use of such decorative items in combination with wrapping paper on which there are indicia which resemble the decorative item in overall shape, color or design. The coordination between the objects, symbols or words on the wrapping paper and the decorative ornament is considered to be a main object of the invention and provides a means whereby a gift can be wrapped so that the appearance of the wrapped gift is aesthetically appealing.
Furthermore, the prior art does not teach the use of supports for maintaining the decorative ornament or bow in an upright open position. In addition, the decorative bows of the prior art are formed of a single material which significantly limits the variety of forms and shapes which are possible to create therewith. Moreover, the prior art bows contemplate only the formation of a single shape with each unit.
In this regard, the instant invention substantially departs from the conventional concepts and designs of the prior art, and in doing so provides an apparatus primarily developed for the purpose of providing an ornament or bow which expands to form an ornamental design, figure or shape resembling either indicia on wrapping paper which is included therewith or is otherwise representative of at least one 3 dimensional object. The ornament assembly further includes means for supporting supplementary indicia which may be connected therewith. Additionally, the ornament assembly may include supports which are adapted to maintain the ornament in an upright, 3-dimensional configuration.
Therefore, it can be appreciated that there exists a continuing need for a new and improved expansible ornament assembly which can be used for the purpose of providing an ornament assembly which expands to form an ornament, figure or shape resembling either the indicia on wrapping paper or another three dimensional object whereby the ornament further includes supports which serve to provide stability to the ornament in use. Furthermore, there exists a need for a gift wrapping ornament or decoration which includes both primary and supplementary indicia within the same assembly so as to form an aesthetically pleasing, personalized, or customized decoration for a special gift. In this regard, the present invention substantially fulfills this need.
SUMMARY OF THE INVENTION
In view of the foregoing disadvantages inherent in the known types of ornament assemblies now present in the prior art, the present invention provides a decorative ornament constructed of an expansible paper form of lightweight construction wherein the form may be and most preferably is simulative of an object. The expansible form preferably includes supports disposed within the form such that in use the supports serve to hold the form in a fixed configuration. Additionally, the combined ornament, in a preferred embodiment, includes secondary decorative members formed of a paper or the like which is substantially heavier than the expansible form. The decorative members are folded within the expansible form and upon opening, will extend outwardly therefrom. The combined ornament is adapted to be used in combination with a coordinated gift wrapping sheet.
As such, the general purpose of the present invention, which will be described subsequently in greater detail, is to provide a new and improved wrapping paper and ornament assembly and method which has all the advantages of the prior art and none of the disadvantages.
To attain this, the present invention in a preferred embodiment essentially comprises a decorative ornament including an expansible form of a first lightweight material comprised of tissue-paper or the like. It is contemplated that the assembly is used in combination with a sheet of paper or other material suitable for wrapping having an outer portion including first indicia. The expansible form has two ends, each of which are attached to a base having an outside face. The ornament also includes attachment means for attaching the outside face of the base to a sheet of wrapping material.
The ornament may further include one or more decorative members formed of a second material, the second material being different from and of a substantially heavier weight than the first lightweight material. The decorative members are arranged between the two ends of the expansible tissue form.
In use, the expansible form and decorative members display a primary and supplementary indicia wherein the primary and supplementary indicia resembles or coordinates with the first indicia on the outer portion of the sheet of paper. Alternatively, the expansible form and decorative members may employed without wrapping paper and as such, may be simulative of any desired 3 dimensional object or figure.
There has thus been outlined, rather broadly, the more important features of the invention in order that the detailed description thereof that follows may be better understood and in order that the present contribution to the art may be better appreciated. There are, of course, additional features of the invention that will be described hereinafter and which will form the subject matter of the claims appended hereto.
In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of descriptions and should not be regarded as limiting.
As such, those skilled in the art will appreciate that the conception, upon which this disclosure is based, may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the present invention.
Further, the purpose of the foregoing abstract is to enable the U.S. Patent and Trademark Office and the public generally, and especially the scientists, engineers and practitioners in the art who are not familiar with patent of legal terms or phraseology, to determine quickly from a cursory inspection the nature and essence of the technical disclosure of the application. The abstract is neither intended to define the invention of the application, which is measured by the claims, nor is it intended to be limiting as to the scope of the invention in any way.
It is therefore an object of the present invention to provide a gift wrapping decoration which expands to form an ornament, figure or shape resembling either the indicia on wrapping paper or another three dimensional object.
It is a further object to provide a gift wrapping ornament which includes supports which serve to provide stability to the ornament in use.
Furthermore, it is another important object of the present invention to provide a gift wrapping ornament or decoration which is adapted to include both primary and supplementary indicia within the same assembly so as to form an aesthetically pleasing, personalized, or customized decoration for a special gift.
It is a further object of the present invention to provide new and improved wrapping paper and expansible ornament assembly which have all the advantages of the prior art and none of the disadvantages.
It is another object of the present invention to provide new and improved wrapping paper and expansible ornament assembly which may be easily and efficiently manufactured and marketed.
It is further object of the present invention to provide a new and improved expansible gift wrapping ornament assembly which is of durable and reliable constructions.
An even further object of the present invention is to provide a new and improved expansible gift wrapping ornament assembly which is susceptible of a low cost of manufacture with regard to both materials and labor, and which accordingly is then susceptible of low prices of sale to the consuming public, thereby making such wrapping paper and expansible ornament assemblies economically available to the buying public.
Still yet another object of the present invention is to provide a new and improved expansible ornament assembly which provide in the apparatuses and methods of the prior art some of the advantages thereof, while simultaneously overcoming some of the disadvantages normally associated therewith.
These together with other objects of the invention, along with the various features of novelty which characterize the invention, are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its operating advantages and the specific objects attained by its uses, reference should be had to the accompanying drawings and descriptive matter in which there is illustrated preferred embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be better understood and objects other than those set forth above will become apparent when consideration is given to the following detailed description thereof. Such description makes reference to the annexed drawings wherein:
FIG. 1 is a perspective view of the preferred embodiment of the expansible ornament assembly constructed in accordance with the principles of the present invention.
FIG. 2A is a view in partial cutaway of the expansible ornament assembly according to the present invention in a compressed state.
FIG. 2B is a view in partial cutaway of a second embodiment of an expansible ornament assembly according to the present invention in a compressed state.
FIG. 3 is a perspective view detailing the base members of the expansible ornament assembly.
FIG. 4 is a side elevational view of the expansible ornament assembly.
The same reference numerals refer to the same parts through the various Figures.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Reference now will be made in detail to the present preferred embodiments of the present invention, examples of which are illustrated in the accompanying drawings.
The preferred embodiment of the ornament assembly is shown in FIG. 1 and generally designated by the numeral 10.
The ornament assembly 10 of the present invention is preferably used in conjunction with wrapping material 20 preferably having some sort of indicia 20a formed thereon. The gift wrapping material 20 is preferably any type of paper but may also be comprised of any other such suitable material, such as foil, lightweight plastic sheet material or of any other construction used by those knowledgeable in the art to provide an aesthetically appealing wrapping for a gift or similar item.
The ornament assembly itself 10 is comprised of an expansible form 30 constructed of lightweight paper such as tissue paper. Both the indicia on the paper 20a and the shape of the expansible form 30 may be chosen to substantially resemble or coordinate with each other in design and/or color. The configuration of the expansible form 30 may such that when expanded, the contours of the form 30 resemble various shapes or indicia such as a square, a car, an animal, a panoramic scene, a letter, words, phrases, and the like.
FIG. 2A illustrates the ornament assembly 10 of the present invention in a compressed state, prior to being expanded. The expansible form 30, made up of multiple layers of lightweight paper 40 such as tissue paper, is adhered together by means of an adhesive along adhesion lines 41. The adhesion lines 41 are generally parallel on each layer of tissue paper and serve to connect the layers of tissue paper together. It should be noted that the adhesion lines on one layer of tissue paper are offset from those on adjacent upper and lower layers of tissue paper. This arrangement serves the purpose of creating cavities 50 when the expansible tissue paper form 30 is fully expanded.
FIG. 2B illustrates a second embodiment of the expansible tissue form 30' used in the present invention. The tissue paper layers 40' are adhered together along adhesion lines 41' in a manner substantially identical to that described by the first embodiment. The tissue paper layers of the second embodiment include metallic strips 42 adhered to the tissue paper. The strips 42 may be multi-colored and may provide additional ornamental features to the decorative ornament assembly of the present invention.
It should be noted that the expansible tissue forms of FIG. 2A and FIG. 2B may be cut in any desired shape or form so as to provide an expansible form 30,30' which, when expanded, forms indicia which resembles the indicia 20a provided on the wrapping paper 20. Therefore, the co-ordination between the indicia 20a on the wrapping paper 20 and the indicia of the expansible ornament assembly 30 is achieved and provides a means whereby a gift can be wrapped so that the appearance of the wrapped gift is aesthetically appealing. However, the ornament assembly 10 may be employed without wrapping paper and as such, may be simulative of any desired 3-dimensional object or figure.
As shown in FIG. 4, the expansible form 30 includes a plurality of cavities 50 when expanded. The cavities 50 are of generally quadrilateral cross section and provide recesses which retain support members 60a, and supplemental decorative members 60b which are formed of a material which is different and of heavier construction than that of the expansible form 30.
Since the expansible form 30 is generally constructed from tissue paper and is therefore non-rigid and not self-supporting, in order to provide a means of maintaining the form in an upright and expanded configuration, support members 60a may be provided. The support members 60a comprise generally rigid longitudinal elements of cardboard or other similar material and have a quadrilateral cross-section. The quadrilateral cross-section of the support members is sized and configured such that the support members 60a may be inserted within the generally quadrilateral cavities 50 of the expansible form 30.
The support members 60a may be secured inside the cavities 50 by means of adhesive such that when the form is compressed or unopened, the supports 60a are disposed completely within the confines of the recesses formed by the cavities 50. In a compressed orientation, the supports 60a may be either folded or unfold depending on the shape and design of the form.
Further, in an expanded orientation, the support members 60a extend in a generally downward direction with respect to the wrapping paper 20 so that the ornament 10 is raised thereabove. After expansion of the form 30, the support members 60a may optionally be secured to the wrapping paper 20 or other surface by means of an adhesive provided on the terminal end of the members 60a.
Supplemental or secondary decorative members 60b may also be provided and are disposed within the cavities 50 of the expansible form 30 in a manner similar to that of the supports 60a. The supplemental decorative members 60b comprise generally rigid longitudinal elements of cardboard or other similar material and have a quadrilateral cross-section. The quadrilateral cross-section of the supplemental decorative members 60b is sized and configured such that the members 60b may be inserted within the generally quadrilateral cavities 50 of the expansible form 30. The supplemental decorative members 60b may be maintained within the cavities 50 of the form 30 in a folded or unfolded configuration. However, upon expansion of the form 30, it is to be understood that the decorative members 60b will extend outwardly from the form 30 so as to be visible upon casual observation.
In the event that the decorative members 60b and supports 60a are maintained in a folded orientation within the cavities 50, upon expansion of the form 30, it may be necessary for a user to manually extend both the decorative members 60b and supports 60a outwardly or downwardly therefrom.
The supplemental decorative members 60b include supplemental decorations 70 which may include objects, shapes or messages intended to accompany the expansible form 30 and also possibly the wrapping paper 20. The decorations 70 resemble and/or coordinate with the shape of the expansible form 30 and also optionally with the indicia 20a formed on the wrapping paper if there is any. The decorations 70 provide a means for complementing the aesthetic features of the expansible form 30 and/or the wrapping paper 20 and thus allows for a fully functional decorative assembly which can be custom-designed by a user.
As best shown in FIG. 3, the assembly 10 includes base members 35 at each end of the expansible form 30 which provide a means for securing the assembly 10 to the wrapping paper 20 or other planar surface. The base members 35 have outside edges 37 covered with an adhesive layer 38 which permits securement of the base members 35, and thus the complete assembly 10, to the wrapping paper 20 or other surface in any position desired by the user.
Each base member 35 is constructed from cardboard, plastic, or or any other acceptable material and includes an inner side 36 and an outer side 37. The inner side 36 of each base member 35 is secured to an end of the expansible form 30 as shown in FIG. 2, by means of an adhesive. Thus, when the expansible form 30 is compressed for storage or packaging, the base members 35 sandwich the paper layers 40 of the form 30 together. This provides a compact package and by virtue of their generally rigid construction, the base members 35 provide protection to the delicate compressed paper layers 40.
On the outer side 37 of each base member 35 is a layer of adhesive 38. This adhesive layer 38 is covered by a removable foil or plastic strip 39. As shown in FIG. 1, when the foil or plastic strip is removed, the adhesive layer 38 serves to secure the base members 35 in position on the wrapping paper 20 or other surface.
The support members 60a and decorative members 60b are positioned in the cavities 50 between the base members 35 of the expansible ornament assembly 30 in such a way as to provide a secure support for both the expansible form 30 and the various object, shapes or messages 70 secured on the decorative members 60b. The support members 60a and decorative members 60b may be inserted between and adhered to the tissue paper layers 40 of the expansible form 30 during fabrication, thereby creating a prepared support structure for the expansible ornament assembly 10.
Alternately, the support members 60a and/or the decorative members 60b may be provided separately to the user to be inserted into the cavities 50 after the expansion of ornament assembly 10. This latter arrangement provides the user with a means to support the expansible ornament in any position that he or she chooses, thus giving the user substantially complete choice and control over the position and design of the entire ornament assembly.
Therefore, by means of the wrapping paper 20 and combined expansible form 30, the support members 60a, decorative members 60b and various objects, shapes or messages 70, the user of the present invention is able to custom design an unlimited number of aesthetically pleasing ornamental assemblies. The user of the present invention is additionally able to personalize the outer presentation of a package by selecting an expandable ornament having an object, shape or message which appeals to the gift recipient. The user may secure various objects, shapes or messages 70 to the decorative members 60b secured in cavities 50 in the expansible form 30, thereby adding to the uniqueness of the wrapping presentation.
For example, an expansible form 30 with the contours of a musical note could be combined with wrapping paper 20 having musical notes as indicia 20a on the paper and cardboard cut-outs of musical notes as the decorations 70 on the decorative members 60b. In a similar manner, bright, multi-colored birthday paper could be used in conjunction with an expansible form 30 which expands out and supports a message such as "Happy Birthday." Furthermore, a wrapping paper 20 displaying a desert scene could have an expansible form 30 with the shape of a sun or a mountain wherein the decorations 70 are cactus or animal shapes or similar indicia, so as to create a desert scene.
All of these examples are meant to display the unlimited number of ways whereby the aesthetic appearance of the wrapped gift can be enhanced. The variations afforded by the present invention are extremely varied and are in a large part dependant upon the imagination of the person wrapping the gift. The invention provides for a wrapping paper and expansible ornament assembly which affords the person wrapping the gift a variety of ways to create a scene in which the wrapping paper 20, the expansible form 30 and various objects, shapes or messages 70 secured thereto inter-relate thematically with each other.
As to the manner of usage and operation of the present invention, the same should be apparent from the above description. Accordingly, no further discussion relating to the manner of usage and operation will be provided.
With respect to the above description then, it is to be realized that the optimum dimensional relationships for the parts of the invention, to include variations in size, materials, shape, form, function and manner of operation, assembly and use, are deemed readily apparent and obvious to one skilled in the art, and all equivalent relationships to those illustrated in the drawings and described in the specification are intended to be encompassed by the present invention.
Therefore, the foregoing is considered as illustrative only of the principles of the invention. Further, since numerous modifications and changes will readily occur to those skilled in the art, it is not desired to limit the invention to the exact construction and operation shown and described, and accordingly, all suitable modifications and equivalents may be resorted to, falling within the scope of the invention.
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An expansible ornament assembly comprising an expansible form having an open position and a closed position and constructed of a lightweight material such as tissue paper. The form has cavities formed therein and includes two ends wherein each of the two ends is attached to at least one base. The assembly includes means for attaching each base at each end thereof to a flat planar surface. When in the open position, the expansible ornament assembly is adapted to display a three dimensional object or another simulative representation such as a letter, phrase, or the like. The ornament assembly may be used in combination with a gift wrapping sheet which coordinates in some respect with the displayed three dimensional object.
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BACKGROUND OF THE INVENTION
The present invention relates to electric appliances and, more specifically, to electric irons.
An electric iron consists essentially of a heating element and a means for controlling the application of electric power to the heating element. Thermostatic controls are conventionally employed to maintain a sole-plate temperature in a selectable range.
One of the long-felt problems of electric irons is a perceived danger of fire or injury resulting from an electric iron inadvertently being left energized for an extended period. One solution to this problem, disclosed in U.S. patent application Ser. Nos. 687,842 and 678,843, includes a timer and a motion sensor connected to cut off electric power to the heating element if the electric iron remains stationary for a predetermined period such as, for example, about 10 minutes.
Although the 10-minute cutoff cycle is appropriate for avoiding long-term operation of an electric iron in the absence of motion, if the soleplate of an electric iron remains stationary in contact with a fabric, or other material susceptible to heat damage, marking, charring, or other damage may occur long before the expiration of the 10-minute timing period. Reducing the timing period to a short enough value to avoid such damage interferes with normal usage of the electric iron which may be rested on its heel for several minutes while other tasks are undertaken by the operator.
The electronic and electro-mechanical components for operating an electric iron are conventionally contained in a hollow handle and a hollow forward pedestal. Modern styling of electric irons tends toward narrower and more angled designs, thereby reducing the amount of space available for the electronic and electro-mechanical components. Thus, more compact elements are desireable. Furthermore, it is desireable to reduce the manufacturing cost of such elements. One area of present interest for size and cost reduction is a relay switch used for breaking the power to the electric iron if the timer reaches the end of its cycle without being reset by the motion sensor.
OBJECTS AND SUMMARY OF THE INVENTION
It is an object of the invention to provide an electric iron which overcomes the drawbacks of the prior art.
It is a further object of the invention to provide an electric iron having first and second timing cycles. A first timing cycle turns off power to the heating element of the electric iron unless reset by motion of the electric iron before the end of a first time period. A second timing cycle, shorter than the first time period, turns off power to the heating element of the electric iron unless reset by motion of the electric iron. The second timing cycle is effective when the soleplate of the electric iron is in a horizontal position.
It is a further object of the invention to provide a solenoid actuator for turning off power to an electric iron in response to a signal representing an end of a timing cycle.
It is a still further object of the invention to provide a solenoid actuator for an electric iron having a wedge-shaped actuator driven by a solenoid for unlatching a switch feeding power to the electric iron.
Briefly stated, the present invention provides an automatic-cutoff electric iron employing two timing cycles for turning off power to the electric iron upon the absence of motion for two different discrete time periods. A motion sensor includes an angle sensor to enable a short timing cycle for cutting of power to the electric iron after the electric iron is motionless with its sole plate in a horizontal orientation. The longer timing cycle is enabled when the electric iron is motionless with its sole plate tilted from the horizontal. The cutoff function is performed by a wedge-shaped actuator driven by a solenoid which releases a spring-urged shaft along with one of the electrical contacts feeding power to the electric iron. The power is turned on by mechanical actuation of the shaft whereby a latch member is engaged behind a cam boss on the shaft. A manual cutoff is also disclosed.
According to an embodiment of the invention, there is provided a dual-cutoff electric iron comprising: a heating element, a sole plate heatable by the heating element, mechanically actuatable means for feeding electric power to the heating element, means for producing first and second timing signals, the first timing signal having a first timing period, the second timing signal having a second timing period, the first timing period being substantially shorter than the second timing period, a motion sensor, the motion sensor including means for producing a change in an output thereof in response to motion of the electric iron, the means for producing including means responsive to the change for resetting without producing the first and second timing signals, the motion sensor having means for producing a first quiescent output responsive to the electric iron being motionless with its sole plate in a generally horizontal orientation and for producing a second quiescent output responsive to the electric iron being motionless with its sole plate in an orientation other than generally horizontal, means responsive to the second timing signal for electrically opening the mechanically actuatable means, whereby power to at least the heating element is cut off, and means responsive to the first quiescent output for enabling the means for electrically opening to be responsive to the first timing signal for electrically opening the mechanically actuatable means, whereby different cutoff times are achieved in response to the first and second quiescent outputs.
According to a feature of the invention, there is provided a switching device comprising: a stationary electrical contact, a movable electrical contact, a shaft, means on the shaft for manually urging the movable electrical contact into electrical engagement with the stationary electrical contact, first resilient means for urging the movable electrical contact away from the stationary electrical contact, a latch member, second resilient means for urging the latch member toward the shaft, means on the shaft for camming engagement with the latch member whereby the latch member is movable against the urging of the second resilient means, the means on the shaft and the latch member further including stable engagement means engageable for retaining the shaft in a position wherein the movable electrical contact is in electrical contact with the stationary electrical contact, an electrical solenoid having an armature, an actuator head connected to the armature, the actuator head having a first inclined cam surface, a hole in the latch member, a second inclined cam surface in the hole having an angle substantially matching an angle of the first inclined surface, and the first and second inclined surfaces being effective, when the solenoid is energized, for moving the latch member out of the position whereby the shaft and the movable contact are movable by the resilient means to positions breaking the electrical contact.
The above, and other objects, features and advantages of the present invention will become apparent from the following description read in conjunction with the accompanying drawings, in which like reference numerals designate the same elements.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side view of an electric iron to which the present invention may be applied.
FIG. 2 is a block and schematic diagram of an electrical control system according to an embodiment of the invention.
FIG. 3 is a partial cross section taken along III--III in FIG. 1, showing a manually actuated, electrically deactuated switch in its deactuated condition.
FIG. 4 is a partial cross section corresponding to FIG. 3 in the engaged condition with its electrical contacts stably engaged.
FIG. 5 is a cross section corresponding to FIGS. 3 and 4 with the manually actuated, electrically deactuated switch in the process of opening its electrical contacts.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring to FIG. 1, an electric iron is shown, generally at 10. A metallic sole plate 12 is heated by an electric heater element (not shown in FIG. 1). A heat barrier 14, preferably of a heat-resistant material such as, for example, phenolic, is disposed above metallic sole plate 12. A housing 16, preferably of a thermoplastic material such as, for example, polypropylene, is disposed atop heat barrier 14.
Housing 16 includes a body 18 which may contain the heating element and a water reservoir (not shown) suitable for containing water whose level is discernible through a transparent sight gauge 20. A forward pedestal 22 rises near the front of housing 16 and a rear pedestal 24 rises near the rear of housing 16. A handle lower shell 26 joins facing portions of forward pedestal 22 and rear pedestal 24. A handle upper shell and control cover 28 closes the top of handle lower shell 26 and forward pedestal 22. An electric cord 30, entering through rear pedestal 24, provides electric power to interior components of electric iron 10. A conventional heel plate 32 and a heel rest 34 are disposed at the rear end of electric iron 10. As is conventional, electric iron 10 may be rested on a horizontal surface upon heel plate 32 and heel rest 34 with metallic sole plate 12 inclined at a substantial upward angle out of contact with the horizontal surface.
Handle lower shell 26 and handle upper shell and control cover 28, as well as forward pedestal 22, are hollow whereby space is provided for mechanical actuators, control valves, electronics and electro-mechanical devices required for operation of electric iron 10. An ON pushbutton 36 is disposed above forward pedestal 22. Other conventional controls are visible in FIG. 1 but are not identified or described since they are not considered to form an inventive part of the present disclosure.
Referring now to FIG. 2, there is shown, generally at 38, an electrical control system according to an embodiment of the invention. A manually actuated, electrically deactuated switch 40 includes a switch 42 in series between one conductor of electric cord 30 and a thermostatic switch 44. A heater element 46 is connected between thermostatic switch 44 and the other conductor of electric cord 30. Switch 42 is manually closeable by actuation of ON pushbutton 36, and remains closed in a manner to be described, until released by actuation of a solenoid 48.
One terminal of solenoid 48 is connected to the switched side of switch 42. The other terminal of solenoid 48 is connected to an anode terminal of a power-switching device 50 such as, for example, a silicon-controlled rectifier, a power transistor, or a disk. For purposes of description, power-switching device 50 is assumed to be a silicon-controlled rectifier. One skilled in the art, with access to the present disclosure would be fully enabled to substitute alternative devices, such as those listed above, as well as others not listed.
A cathode terminal of power-switching device 50 is connected to ground. As is well known, a silicon-controlled rectifier remains in a non-conducting condition until a gate terminal thereof is given a voltage more positive than its anode terminal. Once the gate terminal is made more positive than the anode terminal, the silicon-controlled rectifier is driven into full conduction, regardless of subsequent changes in the gate voltage. Conduction continues in the silicon-controlled rectifier until the anode terminal becomes more negative than the cathode terminal.
An electronic control module 52 includes means for generating two timing cycles and an enable circuit for enabling the shorter of the two timing cycles to trigger the gate electrode of power-switching device 50 under predetermined conditions. A clock generator 54 produces a clock signal which may be at any convenient substantially constant frequency. The clock frequency is applied to a first divider 56 where it is counted down to a first timer frequency of any convenient value such as, for example, 0.03 Hz (one cycle per 30 seconds). The first timer frequency is connected on a line 58 to an input of a second divider 60 wherein the frequency is divided by a second value to produce a second timer frequency of a second convenient value such as, about one cycle per 10 minutes. An output of second divider 60 is connected on a line 61 to the gate electrode of power-switching device 50.
A motion and angle sensor 62 is connected between ground and reset terminals R of both first divider 56 and second divider 60. Whenever motion and angle sensor 62 is closed, first divider 56 and second divider 60 are reset, whereupon these circuits begin counting toward the end of their timing periods. Motion and angle sensor 62 includes a first quiescent condition in which it is closed when electric iron 10 rests without motion upon its metallic sole plate 12. Motion and angle sensor 62 includes a second quiescent condition in which it opens when electric iron 10 rests without motion upon its heel plate 32 and heel rest 34. Motion and angle sensor 62 may be of any convenient type, but is preferably a conventional mercury switch oriented so that its contacts are closed when electric iron 10 is in a position placing its metallic sole plate 12 in a horizontal position. Motion of electric iron 10 in any angular orientation thereof is effective for periodically opening motion and angle sensor 62, whereby first divider 56 and second divider 60 are continuously reset before the ends of their timing periods.
A short-cycle enable circuit 64 includes a transistor 66 having its base connected to motion and angle sensor 62 through a resistor 68 and a diode 70. The first timer frequency on line 58 is connected on a line 72 to one terminal of a resistor 74. The other terminal of resistor 74 is connected to an emitter terminal of transistor 66. A collector terminal of transistor 66 is connected to the gate terminal of power-switching device 50. A resistor 76 and a capacitor 78 are connected in parallel between the emitter and base terminals of transistor 66.
With motion and angle sensor 62 open, as occurs with electric iron 10 resting stationary on heel plate 32 and heel rest 34, the base of transistor 66 essentially floats. Thus, the emitter-collector path of transistor 66 remains non-conducting. Changes in the condition of the first timing signal applied to the emitter of transistor 66 has no effect on the collector terminal thereof. Thus, the first timing signal is inhibited from triggering power-switching device 50. If electric iron 10 remains stationary in the sole-up condition until the end of the second timing cycle, a resulting positive signal applied from second divider 60 on motion and angle sensor 62 to the gate terminal of power-switching device 50 triggers power-switching device 50 into full conduction on its anode-cathode path. This draws a heavy current through solenoid 48, thereby actuating switch 42 in the opening direction. When switch 42 is thus opened, all power to electric iron 10 is cut off and remains in this condition until power is reapplied by manual actuation of ON pushbutton 36.
Although discrete components may be employed for achieving clock generator 54, first divider 56 and second divider 60, it is contemplated that integrated circuits are preferable. Separate integrated circuits are not required. For example, a conventional integrated-circuit timer may take the place of clock generator 54 and first divider 56. Alternatively, all functions of clock generator 54, first divider 56 and second divider 60 may be performed by a single integrated circuit such as, for example, an integrated circuit type CD4060B, commercially available at the time of filing the present application from the Radio Corporation of America (RCA). Such a single integrated circuit requires only the connection of conventional external passive timing components to control its operation.
A conventional DC power supply 80 provides DC power to all elements in electrical control system 38 requiring it.
Referring now to FIG. 3, ON pushbutton 36 includes an operating surface 82 suitable for actuation by an operator to energize electric iron 10. A shaft 84 includes a dependent boss 86 extending at right angles thereto. Forward pedestal 22 includes a rectangular crevice 88 therein having a forward abutment surface 90 therein effective for limiting forward (leftward) motion of dependent boss 86, and consequently, of ON pushbutton 36. A dependent cam boss 92, at the rear of ON pushbutton 36, includes an inclined cam surface 94 thereon. A slidable latch member 96 is guided for vertical motion under the urging of a coil spring 98. Coil spring 98 is stabilized by a guide post 100. An upper end of latch member 96 includes an inclined cam surface 102 having an angle generally matching an angle of inclined cam surface 94. A hole 104 in latch member 96 includes an inclined cam surface 106.
Solenoid 48 includes an actuator head 108 disposed on an armature shaft (not shown in FIG. 3). An inclined cam surface 110 on actuator head 108, having a cam angle substantially matching the cam angle of inclined cam surface 106, fits within hole 104.
Stationary electrical contact 112 of switch 42 (FIG. 2) is disposed in rectangular crevice 88 at a position remote from forward abutment surface 90. A movable electrical contact 114 of switch 42 is urged against an inner surface 116 of dependent boss 86 by resilient means such as, for example, a spring 118. Although not so illustrated, spring 118 may be replaced with a resilient flat spring supporting movable electrical contact 114.
In order to energize electric iron 10, ON pushbutton 36 is pushed rightward in the FIG. 3. Inclined cam surface 94 slides onto inclined cam surface 102 whereby latch member 96 is moved downward against the urging of spring 118. Sufficient free space is available in hole 104 above inclined cam surface 110 to permit downward motion of latch member 96 until dependent cam boss 92 passes beyond latch member 96, whereupon coil spring 98 urges latch member 96 upward into the locking position as shown in FIG. 4. In this position, stationary electrical contact 112 and movable electrical contact 114 are held in firm electrical contact.
Referring now to FIG. 5, manually actuated, electrically deactuated switch 40 and switch 42 are shown in the process of disconnection. A shaft 120 of solenoid 48 urges actuator head 108 into hole 104, whereby inclined cam surface 110 slides over inclined cam surface 106, driving latch member 96 downward against the urging of coil spring 98. Latch member 96 releases dependent cam boss 92, thereby permitting shaft 84 to move leftward under the urging of spring 118. Stationary electrical contact 112 and movable electrical contact 114 break contact. This de-energizes all items in electric iron 10, including solenoid 48. Shaft 120 and actuator head 108 return to their rightward positions while shaft 84 and movable electrical contact 114 continue to their inoperative positions shown in FIG. 3.
Referring again to FIGS. 2-5, one embodiment of the invention provides for de-activation of electric iron 10 only through the action of manually actuated, electrically deactuated switch 40 and switch 42. That is, once switch 42 is closed, it remains in the condition shown in FIG. 4 until opened by energization of solenoid 48 in the manner described in the foregoing. In a further embodiment of the invention, a mechanical OFF control 122 is provided which may be manually pressed to move actuator head 108 into the unlatching position shown in FIG. 5. Mechanical OFF control 122 may be, for example, the end of the armature of solenoid 48, or an extension thereof.
Having described preferred embodiments of the invention with reference to the accompanying drawings, it is to be understood that the invention is not limited to those precise embodiments, and that various changes and modifications may be effected therein by one skilled in the art without departing from the scope or spirit of the invention as defined in the appended claims.
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An automatic-cutoff electric iron employs two timing cycles for turning off power to the electric iron upon the absence of motion for two different discrete time periods. A motion sensor includes an angle sensor to enable a short timing cycle for cutting off power to the electric iron after the electric iron is motionless with its sole plate in a horizontal orientation. The longer timing cycle is enabled when the electric iron is motionless with its sole plate tilted from the horizontal. The cutoff function is performed by a wedge-shaped actuator driven by a solenoid which releases a spring-urged shaft along with one of the electrical contacts feeding power to the electric iron. The power is turned on by mechanical actuation of the shaft whereby a latch member is engaged behind a cam boss. A manual cutoff is also disclosed.
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CROSS-REFERENCE TO RELATED APPLICATION
This application claims the benefit of, and priority to, previously filed U.S. patent application Ser. No. 12/146,518 entitled “Adding Individual Database Failover/Switchover To An Existing Storage Component With Limited Impact” filed on Jun. 26, 2008, the subject matter of which is hereby incorporated by reference in its entirety.
BACKGROUND
In a distributed application, a desktop application interacts with a server to receive various services. For example, in a messaging application (e.g., an email application), a client desktop receives messaging services. In a small company environment, a single server can be deployed to provide services for clients in a single location. As a company grows, a single server system is no longer sufficient to maintain a working messaging system under all conditions.
In a large scale enterprise-class messaging solution (e.g., a corporate email network), a number of server components are distributed geographically. Typically, a server is required for each geographic location and each server interacts with an associated database. The database can include mailboxes, addresses for all company users, stored email, stored attachments, etc.
Messaging services have become mission critical applications to many enterprises. As a result, failure handling requirements have increased to reduce messaging outages. However, a typical large scale messaging service architecture still exhibits characteristics of a single server solution in that one or more databases are typically associated with a single server. Thus, in the event of a failure of the server, access to its database(s) is also lost.
This system architecture creates difficulties in implementing individual database failover and switchover. If a single database fails, an outage results and a failover recovery operation is performed to recover the database. However, if a number of databases are also associated with the server, the failover operation creates an outage for users of those other databases. As messaging systems continue to evolve, such problems result from attempting to retrofit high availability support into existing “legacy” architecture.
SUMMARY
The following presents a simplified summary in order to provide a basic understanding of some novel embodiments described herein. This summary is not an extensive overview, and it is not intended to identify key/critical elements or to delineate the scope thereof. Its sole purpose is to present some concepts in a simplified form as a prelude to the more detailed description that is presented later.
To that end, the disclosed architecture provides a high availability environment by including a proxy server which facilitates database failover (automatically switching to a redundant or standby server system or data instance) and switchover (manually switching to a redundant or standby server system or data instance) by detecting the failure, activating another instance, and redirecting clients to the active instance.
This is further facilitated by maintaining the state information separately from the configuration information. Both the state information and the configuration information are maintained using semantics that are consistent with the needs of the data. The state information tracks the online/offline state of databases and/or data servers and can change quickly and be easily updated. The configuration information, on the other hand, changes infrequently and is stored in a different repository for interaction by an administrator.
The proxy server receives state information as to which of the data storage instances is a currently active database. The proxy server connects the client(s) to the data server associated with the currently active database, and thereby provides rapid recovery after the failure to facilitate client access to the data. The proxy server leverages protocol indirection capabilities between the data storage layer and the client application to alter the connectivity. Examples of the type of changes include referrals provided by the data component, or initial configuration capabilities that discover the location of a mailbox, for example, using basic client information (e.g., e-mail address). This can aid in hiding the host location of an active database after a failover. The configuration information is altered to ensure that any data description information is not localized to a given data storage instance. This can require adding new objects to maintain the expected semantics of the configuration data.
To the accomplishment of the foregoing and related ends, certain illustrative aspects are described herein in connection with the following description and the annexed drawings. These aspects are indicative of the various ways in which the principles disclosed herein can be practiced, all aspects and equivalents of which are intended to be within the scope of the claimed subject matter. Other advantages and novel features will become apparent from the following detailed description when considered in conjunction with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 illustrates a computer-implemented high availability data system for managing database failure.
FIG. 2 illustrates an alternative embodiment of a high availability data system that is specific to a messaging environment.
FIG. 3 illustrates a system that employs redundancy with database failover and switchover support.
FIG. 4 illustrates an alternative embodiment of the proxy component.
FIG. 5 illustrates a computer-implemented data method.
FIG. 6 illustrates a method of failover and switchover processing.
FIG. 7 illustrates a method of managing instance failover and switchover via information files.
FIG. 8 illustrates a method of using a referral based on attempted connection of an inactive data store instance.
FIG. 9 illustrates a block diagram of a computing system operable to execute high availability failover and switchover in accordance with the disclosed architecture.
FIG. 10 illustrates a schematic block diagram of an exemplary computing environment that facilitates high availability failover and switchover in accordance with the disclosed architecture.
DETAILED DESCRIPTION
The disclosed architecture relates to a computer-implemented high availability data system that accomplishes database failover and switchover in the event of a database failure. For example, the proxy server provides access to backend servers that connect to data storage instances. The architecture uses the proxy server in accordance with active/passive managed redundant databases. Clients connect to the proxy server rather than to the actual data storage component. The proxy server consults current state management functionality of a database (not the configuration information repository) to locate the active database, and connections are established from the proxy server to the database storage component.
This facilitates a much faster move from a failed or inactive data store instances to active data store instances than conventional architectures, which connect clients to such instances through a domain name server (DNS), for example. It can take hours to days to propagate such changes through DNS systems, a situation that is unacceptable for high availability systems; whereas, the proxy implementation described herein facilitates the move to the active data store instance with minimal or no loss in service.
In the context of messaging, for example, messaging clients connect to and are directed by the proxy server (and associated functionality) from a failed database instance to an active instance with imperceptible or no interruption to the clients. This is facilitated by state information and configuration information, which are maintained separately to accommodate potentially fast changing state of the backend servers and data store instances.
Reference is now made to the drawings, wherein like reference numerals are used to refer to like elements throughout. In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding thereof. It may be evident, however, that the novel embodiments can be practiced without these specific details. In other instances, well known structures and devices are shown in block diagram form in order to facilitate a description thereof. The intention is to cover all modifications, equivalents, and alternatives falling within the spirit and scope of the claimed subject matter.
FIG. 1 illustrates a computer-implemented high availability data system 100 for managing database failure. The system 100 not only provides high availability for new designs, but also for existing implementations. The system 100 includes a proxy component 102 for interfacing clients 104 to the correct backend servers 106 , and then to the appropriate and active data store instances 108 in the event of a failover. This is accomplished by way of functionality included with the proxy component 102 , which is described herein below.
The currently active database is one of the data store instances 108 selected based on state information that tracks the state of the data store instances 108 . The data store instances 108 are redundant to each other, and are maintained together (via replication) to provide high availability services in the event that the currently active database (or instance) becomes unavailable. The backend server 106 provide access from the proxy component 102 (and ultimately the clients 104 ) to the desired one of the data store instances 108 .
In support of this capability, the proxy component 102 includes an active manager client (AMC) 110 . The backend servers 106 each include a software component referred to herein as an active manager (AM), and state information (STATE). The AMC 110 communicates with the AMs using any suitable protocol.
The same state information is redundant across the data store instances 108 of the backend servers 106 . The AM (e.g., AM 1 of a first backend server 114 ) manages the state information. The state information provides at least the latest information as to the backend server that is hosting the active copy (or instance) of a database. The state information is stored separately from configuration information 112 . This is because the configuration information changes infrequently and slowly, while the state information changes quickly to track the changing state of the backend servers 106 and associated instances 108 . The configuration information 112 provides a means for identifying where the data store copies reside, and the state information (e.g., STATE 1 of the first backend server 114 ) for the instances 108 then indicates which of the instances 108 is active.
The proxy component 102 can be associated with a middle-tier (“mid-tier”) server that connects the clients 104 to the currently active database (data storage instance). Note that the proxy component 102 does not maintain permanently persisted data.
The introduction of the proxy component 102 into the overall high availability architecture, the separation of the maintenance of the configuration from the maintenance of current state information (that provides the latest information on where the active copy of a database is hosted), the leveraging of any protocol indirection capabilities between the data storage layer and the client application to change the connectivity, and alteration of the configuration information to ensure that data description information is not localized to a given data storage instance, facilitate client connectivity to the proxy component 102 instead of the actual data storage instance. Examples of the type of connectivity changes are referrals provided by the data component or initial configuration capabilities that discover the location of a mailbox using basic client information (e.g., e-mail address). This can aid in hiding the host location of an active database after a failover.
The proxy component 102 consults current state management functionality of a database—not the configuration repository—to locate the active database. Connections are established from the proxy component 102 to the database storage instance. The state management component, the active manager, tracks which database copy is currently mounted, and is also responsible for managing failovers and switchovers of a database. The result is a high availability solution that provides granular recovery and rapid database failover without impact to client access. This is in contrast to past solutions that provided only server level failover and switchover support by manipulating TCP/IP identity information.
FIG. 2 illustrates an alternative embodiment of a high availability data system 200 that is specific to a messaging environment. The system 200 shows how different communications server roles such as a unified messaging (UM) component 202 (for consolidating disparate messaging and communications technologies such as voicemail, email, facsimile, into a single service), a client access server (CAS) component 204 (for accepting connections from many different clients such as software clients that use POP3 and IMAP connections, and hardware clients such as mobile devices that can also connect using POP3 and IMAP), and a hub (HUB) transport component 206 interact with a mailbox server 208 to access a mail database 210 .
The hub transport component 206 can provide routing within an organizational network, and can handle all mail flow, apply transport rules, apply journal rules, and deliver messages to recipient mailboxes. Messages sent to the Internet are relayed by the hub transport component 206 to an edge transport server component 212 that can be deployed on the perimeter network. Messages received from the Internet are processed by the edge transport server component 212 before relayed to the hub transport component 206 .
A personal information manager (PIM) client 214 is shown for accessing the mailbox server 208 and the associated mail database instance 210 . However, rather than interacting directly with the mailbox server 208 to access messaging data, as in conventional topologies, the PIM client 214 indirectly accesses the mailbox server 208 through the client access server component 204 .
In support thereof, the UM component 202 , client access server component 204 , and hub transport component 206 become proxies (e.g., the proxy component 102 ) to connecting entities by the inclusion of the AMCs in each of these roles. For example, the UM component 202 includes a UM AMC 216 , the client access server component 204 includes a CAS AMC 218 , and the hub transport component 206 includes a hub AMC 220 . In other words, each role that accesses the mailbox server 208 now has the active manager client API present in its role. Each AMC interacts with a mailbox server active manager (MBX AM) 222 on the mailbox server 208 to locate the active mail database instance 210 for a given database. To provide the associated database mobility the schema is changed to make a database be a peer object to a server. This incompatibility is masked to clients (e.g., PIM client 214 ) by creating a mailbox server-like object for the proxy functionality hosted on the mailbox server 208 . A given database appears to be hosted on the server (e.g., CAS component 204 ) represented as the proxy. The mailbox server 208 is depicted as also including state information 224 that provides the state of all database instances.
FIG. 3 illustrates a system 300 that employs redundancy with database failover and switchover support. The system 300 shows redundancy (e.g., a cluster) in messaging storage servers 302 and data stores instances 108 associated with the messaging servers 302 . The messaging storage servers 302 are shown as each having an active manager (AM) and are interconnected for heartbeat management. The messaging servers 302 operate as a group via basic clustering services such as quorum management and heartbeat monitoring (checking for offline servers and/or data store instances). The quorum management is a basic clustering service that operates to prevent a “split brain” scenario. In other words, a majority of the servers (or an appropriate alternative quorum strategy, e.g., non-majority) 302 need to be operational in order to start making decisions about activating other (passive) databases. This prevents the inappropriate activation of database copies.
The PIM client 214 interacts with one of the proxy servers (e.g., client access server component 204 using, e.g., messaging application program interface-MAPI) that uses the AMC to interact with the active managers (e.g., AM 1, AM 2, . . . , AM N) on the messaging storage servers 302 . The CAS AMC 218 uses configuration information 112 to identify the correct messaging storage servers 302 to target AM queries. After receiving the configuration information for the current active database copy, the CAS component 204 (a mid-tier proxy) initiates the query to the designated messaging storage server 304 . If the active copy has changed since the query completed and before the CAS component 204 connects, the designated messaging storage server 304 can check its state information 306 and return a referral to a different messaging server (e.g., a messaging storage server 308 ). This architecture provides multiple levels of protection to ensure the system 300 can effectively handle failures during any part of the interaction.
A new client may not have any awareness of where to connect. This can happen when a new system is being configured or when substantial failures have occurred. The system 300 handles this case by providing the client with a discovery mechanism based on the user's email address. This discovery mechanism can also be integrated with the AM to provide the necessary insight into the current state of the system. As previously indicted, the AMs also function as state managers (that reside on the messaging storage servers 302 ) to maintain current state information about which copy of the data storage instances 108 is currently providing service to the PIM client 214 (and other clients and entities).
A state table 310 indicates the state of the system 300 , for example, state S1 (as illustrated) in which a first data storage instance 312 is the currently active database. Each table row can include one of N values, for the number of instances employed.
FIG. 4 illustrates an alternative embodiment of the proxy component 102 . The proxy component 102 can include a referral component 400 for connecting a messaging client 402 to a different backend server 404 (e.g., a messaging server) if a current backend system 406 becomes unavailable. In the event that the currently active database copy changes after a query is completed but before the proxy component 102 is connected, for example, the referral component 400 can detect this condition and, receive and return a referral to connect to the different backend server 404 . Additionally, or alternatively, the referral component 400 can process a referral from the proxy component 102 such that the messaging client 402 is re-routed to the different backend server 404 . This architecture provides multiple levels of protection to ensure effective handling of failures during any part of the interaction. In other words, the current backend system 406 can be contacted to serve a database, but then give back an answer that refers the contact to the different backend system 404 .
Additionally depicted in FIG. 4 , a discovery component 408 can be provided and utilized for designating a backend server for an unassociated messaging client, for example, the messaging client 402 . The messaging client 402 can be unassociated, and therefore, unable to connect. This situation can occur when a new system is being configured or when major failures have occurred. In this scenario, the discovery component 408 can associate the messaging client 402 to its mailbox and the active database with that mailbox using, for example, a user's email address, based on correspondence with a related user group or enterprise branch location. The discovery component 408 can interface to the AMC 110 to obtain information regarding the current state of the backend systems.
Following is a series of flow charts representative of exemplary methodologies for performing novel aspects of the disclosed architecture. While, for purposes of simplicity of explanation, the one or more methodologies shown herein, for example, in the form of a flow chart or flow diagram, are shown and described as a series of acts, it is to be understood and appreciated that the methodologies are not limited by the order of acts, as some acts may, in accordance therewith, occur in a different order and/or concurrently with other acts from that shown and described herein. For example, those skilled in the art will understand and appreciate that a methodology could alternatively be represented as a series of interrelated states or events, such as in a state diagram. Moreover, not all acts illustrated in a methodology may be required for a novel implementation.
FIG. 5 illustrates a computer-implemented data method. At 500 , client communications of a client are received at a mid-tier proxy server. At 502 , configuration information is accessed that defines backend servers of a server cluster for selection and for directing queries. At 504 , the selected backend servers are queried for a currently active data store instance. At 506 , the client communications is routed via the proxy server to an active backend server hosting the currently active data store instance.
FIG. 6 illustrates a method of failover and switchover processing. At 600 , a selected backend server is queried for a currently active data store instance. At 602 , the currently active data store instance is detected as inactive. At 604 , a newly active data store instance is selected. At 606 , client communications are routed via the proxy server to the newly active data store instance.
FIG. 7 illustrates a method of managing instance failover and switchover via information files. At 700 , configuration information is accessed that defines backend servers of a server cluster for selection and for directing queries. At 702 , the selected backend servers are queried for a currently active data store instance. At 704 , state information is accessed and processed that maintains active/inactive state of data store instances and associated backend servers. At 706 , client communications are routed via proxy server to the newly selected active data store instance based in part on state information.
FIG. 8 illustrates a method of using a referral based on attempted connection of an inactive data store instance. At 800 , a client sends a request for data to a proxy server having an active manager client. At 802 , the active manager client accesses and processes configuration information for backend servers to query. At 804 , the active manager client communicates with active managers of backend servers for state information of a currently active data store instance. At 806 , the active manager sends the currently active data store information to the active manager client. At 808 , the proxy server processes the request from the client to the currently active data store instance. At 810 , if the active copy has changed, flow is to 812 where the selected backend server for the currently active data store instance sends a referral to the proxy server for a different backend server hosting the newly active data store instance. At 814 , the proxy server routes the client request to the different backend server. At 810 , of the active copy has not changed, flow is to 816 where the proxy server connects the client to the currently active data store instance.
As used in this application, the terms “component” and “system” are intended to refer to a computer-related entity, either hardware, a combination of hardware and software, software, or software in execution. For example, a component can be, but is not limited to being, a process running on a processor, a processor, a hard disk drive, multiple storage drives (of optical and/or magnetic storage medium), an object, an executable, a thread of execution, a program, and/or a computer. By way of illustration, both an application running on a server and the server can be a component. One or more components can reside within a process and/or thread of execution, and a component can be localized on one computer and/or distributed between two or more computers. The word “exemplary” may be used herein to mean serving as an example, instance, or illustration. Any aspect or design described herein as “exemplary” is not necessarily to be construed as preferred or advantageous over other aspects or designs.
Referring now to FIG. 9 , there is illustrated a block diagram of a computing system 900 operable to execute high availability failover and switchover in accordance with the disclosed architecture. In order to provide additional context for various aspects thereof, FIG. 9 and the following discussion are intended to provide a brief, general description of a suitable computing system 900 in which the various aspects can be implemented. While the description above is in the general context of computer-executable instructions that may run on one or more computers, those skilled in the art will recognize that a novel embodiment also can be implemented in combination with other program modules and/or as a combination of hardware and software.
Generally, program modules include routines, programs, components, data structures, etc., that perform particular tasks or implement particular abstract data types. Moreover, those skilled in the art will appreciate that the inventive methods can be practiced with other computer system configurations, including single-processor or multiprocessor computer systems, minicomputers, mainframe computers, as well as personal computers, hand-held computing devices, microprocessor-based or programmable consumer electronics, and the like, each of which can be operatively coupled to one or more associated devices.
The illustrated aspects can also be practiced in distributed computing environments where certain tasks are performed by remote processing devices that are linked through a communications network. In a distributed computing environment, program modules can be located in both local and remote memory storage devices.
A computer typically includes a variety of computer-readable media. Computer-readable media can be any available media that can be accessed by the computer and includes volatile and non-volatile media, removable and non-removable media. By way of example, and not limitation, computer-readable media can comprise computer storage media and communication media. Computer storage media includes volatile and non-volatile, removable and non-removable media implemented in any method or technology for storage of information such as computer-readable instructions, data structures, program modules or other data. Computer storage media includes, but is not limited to, RAM, ROM, EEPROM, flash memory or other memory technology, CD-ROM, digital video disk (DVD) or other optical disk storage, magnetic cassettes, magnetic tape, magnetic disk storage or other magnetic storage devices, or any other medium which can be used to store the desired information and which can be accessed by the computer.
With reference again to FIG. 9 , the exemplary computing system 900 for implementing various aspects includes a computer 902 having a processing unit 904 , a system memory 906 and a system bus 908 . The system bus 908 provides an interface for system components including, but not limited to, the system memory 906 to the processing unit 904 . The processing unit 904 can be any of various commercially available processors. Dual microprocessors and other multi-processor architectures may also be employed as the processing unit 904 .
The system bus 908 can be any of several types of bus structure that may further interconnect to a memory bus (with or without a memory controller), a peripheral bus, and a local bus using any of a variety of commercially available bus architectures. The system memory 906 can include non-volatile memory (NON-VOL) 910 and/or volatile memory 912 (e.g., random access memory (RAM)). A basic input/output system (BIOS) can be stored in the non-volatile memory 910 (e.g., ROM, EPROM, EEPROM, etc.), which BIOS are the basic routines that help to transfer information between elements within the computer 902 , such as during start-up. The volatile memory 912 can also include a high-speed RAM such as static RAM for caching data.
The computer 902 further includes an internal hard disk drive (HDD) 914 (e.g., EIDE, SATA), which internal HDD 914 may also be configured for external use in a suitable chassis, a magnetic floppy disk drive (FDD) 916 , (e.g., to read from or write to a removable diskette 918 ) and an optical disk drive 920 , (e.g., reading a CD-ROM disk 922 or, to read from or write to other high capacity optical media such as a DVD). The HDD 914 , FDD 916 and optical disk drive 920 can be connected to the system bus 908 by a HDD interface 924 , an FDD interface 926 and an optical drive interface 928 , respectively. The HDD interface 924 for external drive implementations can include at least one or both of Universal Serial Bus (USB) and IEEE 1394 interface technologies.
The drives and associated computer-readable media provide nonvolatile storage of data, data structures, computer-executable instructions, and so forth. For the computer 902 , the drives and media accommodate the storage of any data in a suitable digital format. Although the description of computer-readable media above refers to a HDD, a removable magnetic diskette (e.g., FDD), and a removable optical media such as a CD or DVD, it should be appreciated by those skilled in the art that other types of media which are readable by a computer, such as zip drives, magnetic cassettes, flash memory cards, cartridges, and the like, may also be used in the exemplary operating environment, and further, that any such media may contain computer-executable instructions for performing novel methods of the disclosed architecture.
A number of program modules can be stored in the drives and volatile memory 912 , including an operating system 930 , one or more application programs 932 , other program modules 934 , and program data 936 . All or portions of the operating system, applications, modules, and/or data can also be cached in the volatile memory 912 . It is to be appreciated that the disclosed architecture can be implemented with various commercially available operating systems or combinations of operating systems.
Where the computer 902 is employed as a server machines, the aforementioned application programs 932 , other program modules 934 , and program data 936 can include the proxy component 102 , the AMC 110 , the configuration information 112 , the backend servers 106 , the active managers (AM), the state information, the edge transport server component 212 , the UM component 202 and UM AMC 216 , the client access server component 204 and CAS AMC 218 , the hub transport component 206 and hub AMC 220 , the mailbox server 208 , the mailbox AM 222 , the mailbox server information station 224 , the messaging servers 302 and associated AMs and state, and state table 310 , for example. This further includes the current backend server 406 , the different backend server 404 , referral component 400 , and discover component 408 , for example, and the methods of FIGS. 5-8 .
Where the computer 902 is employed for a client system, application programs 932 , other program modules 934 , and program data 936 can include the clients 104 , the PIM client 214 , and the messaging client 402 , for example.
A user can enter commands and information into the computer 902 through one or more wire/wireless input devices, for example, a keyboard 938 and a pointing device, such as a mouse 940 . Other input devices (not shown) may include a microphone, an IR remote control, a joystick, a game pad, a stylus pen, touch screen, or the like. These and other input devices are often connected to the processing unit 904 through an input device interface 942 that is coupled to the system bus 908 , but can be connected by other interfaces such as a parallel port, IEEE 1394 serial port, a game port, a USB port, an IR interface, etc.
A monitor 944 or other type of display device is also connected to the system bus 908 via an interface, such as a video adaptor 946 . In addition to the monitor 944 , a computer typically includes other peripheral output devices (not shown), such as speakers, printers, etc.
The computer 902 may operate in a networked environment using logical connections via wire and/or wireless communications to one or more remote computers, such as a remote computer(s) 948 . The remote computer(s) 948 can be a workstation, a server computer, a router, a personal computer, portable computer, microprocessor-based entertainment appliance, a peer device or other common network node, and typically includes many or all of the elements described relative to the computer 902 , although, for purposes of brevity, only a memory/storage device 950 is illustrated. The logical connections depicted include wire/wireless connectivity to a local area network (LAN) 952 and/or larger networks, for example, a wide area network (WAN) 954 . Such LAN and WAN networking environments are commonplace in offices and companies, and facilitate enterprise-wide computer networks, such as intranets, all of which may connect to a global communications network, for example, the Internet.
When used in a LAN networking environment, the computer 902 is connected to the LAN 952 through a wire and/or wireless communication network interface or adaptor 956 . The adaptor 956 can facilitate wire and/or wireless communications to the LAN 952 , which may also include a wireless access point disposed thereon for communicating with the wireless functionality of the adaptor 956 .
When used in a WAN networking environment, the computer 902 can include a modem 958 , or is connected to a communications server on the WAN 954 , or has other means for establishing communications over the WAN 954 , such as by way of the Internet. The modem 958 , which can be internal or external and a wire and/or wireless device, is connected to the system bus 908 via the input device interface 942 . In a networked environment, program modules depicted relative to the computer 902 , or portions thereof, can be stored in the remote memory/storage device 950 . It will be appreciated that the network connections shown are exemplary and other means of establishing a communications link between the computers can be used.
The computer 902 is operable to communicate with wire and wireless devices or entities using the IEEE 802 family of standards, such as wireless devices operatively disposed in wireless communication (e.g., IEEE 802.11 over-the-air modulation techniques) with, for example, a printer, scanner, desktop and/or portable computer, personal digital assistant (PDA), communications satellite, any piece of equipment or location associated with a wirelessly detectable tag (e.g., a kiosk, news stand, restroom), and telephone. This includes at least Wi-Fi (or Wireless Fidelity), WiMax, and Bluetooth™ wireless technologies. Thus, the communication can be a predefined structure as with a conventional network or simply an ad hoc communication between at least two devices. Wi-Fi networks use radio technologies called IEEE 802.11x (a, b, g, etc.) to provide secure, reliable, fast wireless connectivity. A Wi-Fi network can be used to connect computers to each other, to the Internet, and to wire networks (which use IEEE 802.3-related media and functions).
Referring now to FIG. 10 , there is illustrated a schematic block diagram of an exemplary computing environment 1000 that facilitates high availability failover and switchover in accordance with the disclosed architecture. The environment 1000 includes one or more client(s) 1002 . The client(s) 1002 can be hardware and/or software (e.g., threads, processes, computing devices). The client(s) 1002 can house cookie(s) and/or associated contextual information, for example.
The environment 1000 also includes one or more server(s) 1004 . The server(s) 1004 can also be hardware and/or software (e.g., threads, processes, computing devices). The servers 1004 can house threads to perform transformations by employing the architecture, for example. One possible communication between a client 1002 and a server 1004 can be in the form of a data packet adapted to be transmitted between two or more computer processes. The data packet may include a cookie and/or associated contextual information, for example. The environment 1000 includes a communication framework 1006 (e.g., a global communication network such as the Internet) that can be employed to facilitate communications between the client(s) 1002 and the server(s) 1004 .
Communications can be facilitated via a wire (including optical fiber) and/or wireless technology. The client(s) 1002 are operatively connected to one or more client data store(s) 1008 that can be employed to store information local to the client(s) 1002 (e.g., cookie(s) and/or associated contextual information). Similarly, the server(s) 1004 are operatively connected to one or more server data store(s) 1010 that can be employed to store information local to the servers 1004 .
What has been described above includes examples of the disclosed architecture. It is, of course, not possible to describe every conceivable combination of components and/or methodologies, but one of ordinary skill in the art may recognize that many further combinations and permutations are possible. Accordingly, the novel architecture is intended to embrace all such alterations, modifications and variations that fall within the spirit and scope of the appended claims. Furthermore, to the extent that the term “includes” is used in either the detailed description or the claims, such term is intended to be inclusive in a manner similar to the term “comprising” as “comprising” is interpreted when employed as a transitional word in a claim.
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High availability architecture that employs a mid-tier proxy server to route client communications to active data store instances in response to failover and switchover. The proxy server includes an active manager client that interfaces to an active manager in each of the backend servers. State information and configuration information are maintained separately and according to semantics consistent with needs of corresponding data, the configuration information changing less frequently and more available, the state information changing more frequently and less available. The active manager indicates to the proxy server which of the data storage instances is the currently the active instance. In the event that the currently active instance is inactive, the proxy server selects a different backend server that currently hosts the active data store instance. Client communications are then routed to the different backend server with minimal or no interruption to the client.
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This is a 371 of PCT/US00/08350 filed Mar. 30, 2000, which is a continuation-in-part of 09/282,855, filed Mar. 31, 1997, now U.S. Pat. No. 6,201,154, the entire disclosure of which is incorporated herein by reference.
FIELD OF THE INVENTION
The invention relates to compositions and methods for the treatment of cancer.
BACKGROUND OF THE INVENTION
Extracellular signals received at transmembrane receptors are relayed into the cells by the signal transduction pathways (Pelech et al., Science 257:1335 (1992)) which have been implicated in a wide array of physiological processes such as induction of cell proliferation, differentiation or apoptosis (Davis et al., J. Biol. Chem . 268:14553 (1993)). The Mitogen Activated Protein Kinase (MAPK) cascade is a major signaling system by which cells transduce extracellular cues into intracellular responses (Nishida et a., Trends Biochem. Sci . 18:128 (1993); Blumer et al., Trends Biochem. Sci . 19:236 (1994)). Many steps of this cascade are conserved, and homologous for MAP kinases have been discovered in different species.
In mammalian cells, the Extracellular-Signal-Regulated Kinases (ERKs), ERK-1 and ERK-2 are the archetypal and best-studied members of the MAPK family, which all have the unique feature of being activated by phosphorylation on threonine and tyrosine residues by an upstream dual specificity kinase (Posada et al., Science 255:212 (1992); Biggs III et al., Proc. Natl. Acad. Sci. USA 89:6295 (1992); Garner et al., Genes Dev. 6:1280 (1992)).
Recent studies have identified an additional subgroup of MAPKs, known as c-Jun NH2-terminal kinases 1 and 2 (JNK-1 and JNK-2), that have different substrate specificities and are regulated by different stimuli (Hibi et al., Genes Dev . 7:2135 (1993)). JNKs are members of the class of stress-activated protein kinases (SPKs). JNKs have been shown to be activated by treatment of cells with UV radiation, pro-inflammatory cytokines and environmental stress (Derijard et al., Cell 1025 (1994)). The activated JNK binds to the amino terminus of the c-Jun protein and increases the protein's transcriptional activity by phosphorylating it at ser63 and ser73 (Adler et al., Proc. Natl. Acad. Sci. USA 89:5341 (1992); Kwok et al., Nature 370:223 (1994)).
Analysis of the deduced primary sequence of the JNKs indicates that they are distantly related to ERKs (Davis, Trends Biochem. Sci . 19:470 (1994)). Both ERKs and JNKs are phosphorylated on Tyr and Thr in response to external stimuli resulting in their activation (Davis, Trends Biochem. Sci . 19:470 (1994)). The phosphorylation (Thr and Tyr) sites, which play a critical role in their activation are conserved between ERKs and JNKs (Davis, Trends Biochem. Sci . 19:470 (1994)). However, these sites of phosphorylation are located within distinct dual phosphorylation motifs: Thr-Pro-Tyr (JNK) and Thr-Glu-Tyr (ERK). Phosphorylation of MAPKs and JNKs by an external signal often involves the activation of protein tyrosine kinases (PTKS) (Gille et al., Nature 358:414 (1992)), which constitute a large family of proteins encompassing several growth factor receptors and other signal transducing molecules.
Protein tyrosine kinases are enzymes which catalyze a well defined chemical reaction: the phosphorylation of a tyrosine residue (Hunter et al., Annu Rev Biochem 54:897 (1985)). Receptor tyrosine kinases in particular are attractive targets for drug design since blockers for the substrate domain of these kinases is likely to yield an effective and selective antiproliferative agent. The potential use of protein tyrosine kinase blockers as antiproliferative agents was recognized as early as 1981, when quercetin was suggested as a PTK blocker (Graziani et al., Eur. J. Biochem . 135:583-589 (1983)).
The best understood MAPK pathway involves extracellular signal-regulated kinases which constitute the Ras/Raf/MEK/ERK kinase cascade (Boudewijn et al., Trends Biochem. Sci . 20, 18 (1995)). Once this pathway is activated by different stimuli, MAPK phosphorylates a variety of proteins including several transcription factors which translocate into the nucleus and activate gene transcription. Negative regulation of this pathway could arrest the cascade of these events.
What are needed are new anticancer chemotherapeutic agents which target receptor tyrosine kinases and which arrest the Ras/Raf/MEK/ERK kinase cascade. Oncoproteins in general, and signal transducing proteins in particular, are likely to be more selective targets for chemotherapy because they represent a subclass of proteins whose activities are essential for cell proliferation, and because their activities are greatly amplified in proliferative diseases.
SUMMARY OF THE INVENTION
It is an object of the invention to provide compounds, compositions and methods for the treatment of cancer and other proliferative diseases. The biologically active compounds are in the form of (Z)-styryl benzylsulfones.
It is a further object of the invention to provide intermediates useful for the preparation of compounds having anticancer activity. The intermediates comprise (Z)-styryl benzylsulfides.
The present invention provides for pharmaceutical compositions comprising a pharmaceutically acceptable carrier and one or more compounds of the formula I
wherein
R 1 is selected from the group consisting of hydrogen, chloro and nitro;
R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo, iodo and fluoro; and
R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo, iodo and fluoro;
provided at least one of R 1 or R 2 is hydrogen.
According to one embodiment of such compositions, R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo and fluoro; and R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo and fluoro. According to another embodiment, at least one of R 2 , R 3 and R 4 is iodo.
According to one preferred embodiment of the invention, pharmaceutical compositions of compounds of formula I are provided wherein R 1 is hydrogen. More preferably, R 1 and R 3 are hydrogen, and R 2 and R 4 are independently selected from the group consisting of chloro, fluoro, iodo and bromo, most preferably selected from chloro, bromo and fluoro.
According to another embodiment of the invention, novel compounds of formula I are provided where R 1 , R 2 , R 3 and R 4 are defined as above, provided:
(a) at least one of R 1 or R 2 is hydrogen;
(b) R 1 and R 2 may not both be hydrogen when:
(i) R 3 and R 4 are both hydrogen,
(ii) R 3 is chloro and R 4 is hydrogen, or
(iii) R 4 is chloro and R 3 is hydrogen; and
(c) when R 1 is hydrogen and R 2 is methyl:
(i) both R 3 and R 4 may not be hydrogen,
(ii) R 3 may not be chloro when R 4 is hydrogen, and
(iii) R 4 may not be chloro when R 3 is hydrogen.
According to one embodiment of novel compounds, R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo and fluoro; and R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo and fluoro. According to another embodiment, at least one of R 2 , R 3 and R 4 is iodo.
Preferably, R 1 is hydrogen in the novel compounds of the invention. More preferably, R 1 and R 3 are hydrogen, and R 2 and R 4 are independently selected from the group consisting of chloro, fluoro, iodo and bromo, most preferably selected from chloro, bromo and fluoro.
According to another embodiment of the invention, novel (Z)-styryl benzylsulfides are provided which are useful as intermediates in the preparation of the biologically active (Z)-styryl benzylsulfones. The (Z)-styryl benzylsulfides have the formula:
wherein:
R 1 is selected from the group consisting of hydrogen, chloro and nitro;
R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo, iodo and fluoro, provided that at least one of R 1 or R 2 is hydrogen;
R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo, iodo and fluoro; provided:
(a) at least one of R 1 or R 2 is hydrogen;
(b) R 1 and R 2 may not both be hydrogen when:
(i) R 3 and R 4 are both hydrogen,
(ii) R 3 is chloro and R 4 is hydrogen, or
(iii) R 4 is chloro and R 3 is hydrogen; and
(c) when R 1 is hydrogen and R 2 is methyl:
(i) both R 3 and R 4 may not be hydrogen,
(ii) R 3 may not be chloro when R 4 is hydrogen, and
(iii) R 4 may not be chloro when R 3 is hydrogen.
According to one embodiment of the aforesaid intermediates, R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo and fluoro; and R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo and fluoro. According to another embodiment, at least one of R 2 , R 3 and R 4 is iodo.
Preferably, R 1 is hydrogen in the aforementioned intermediates. More preferably, R 1 and R 3 are hydrogen, and R 2 and R 4 are independently selected from the group consisting of chloro, fluoro, iodo and bromo, most preferably selected from chloro, bromo and fluoro.
Where R 2 , R 3 and/or R 4 is halogen, the halogen is preferably selected from the group consisting of chloro, bromo and fluoro.
By “lower alkyl” is meant straight or branched chain alkyl containing from one to six carbon atoms. The preferred alkyl group is methyl. By “lower alkoxy” is meant straight or branched chain alkoxy containing from one to six carbon atoms. The preferred alkoxy group is methoxy.
According to another embodiment of the invention, a method of treating an individual for cancer or other proliferative disorder is provided, comprising administering to said individual an effective amount of the aforesaid pharmaceutical composition.
In another embodiment, a method of inhibiting growth of tumor cells in an individual afflicted with cancer is provided, comprising administering to said individual an effective amount of the aforesaid pharmaceutical composition.
In another embodiment, a method of inducing apoptosis-of cancer cells, more preferably tumor cells, in an individual afflicted with cancer is provided, comprising administering to said individual an effective amount of the aforesaid pharmaceutical composition.
DETAILED DESCRIPTION OF THE INVENTION
According to the present invention, certain (Z)-styryl sulfone derivatives selectively kill various tumor cell types without killing normal cells. Without wishing to be bound by any theory, it is believed that the compounds affect the MAPK signal transduction pathway, thereby affecting tumor cell growth and viability. This cell growth inhibition is associated with regulation of the ERK and JNK types of MAPK.
The compounds of the invention have been shown to inhibit the proliferation of various tumor cells by inducing cell death. The compounds are effective against a broad range of tumor types, including but not limited to the following: breast, prostate, ovarian, lung, brain (i.e, glioma) and renal. The compounds are also effective against leukemic cells. The compounds do not kill normal cells in concentrations at which tumor cells are killed.
Treatment of this broad range of tumor cells with the styryl sulfone compounds of the invention leads to inhibition of cell proliferation and induction of apoptotic cell death. In breast tumors, the effect is observed for estrogen receptor (ER) positive as well as estrogen receptor negative cells.
The compounds are also useful in the treatment of non-cancer proliferative disorders, including but not limited to the following: hemangiomatosis in new born, secondary progressive multiple sclerosis, chronic progressive myelodegenerative disease, neurofibromatosis, ganlioneuromatosis, keloid formation, Pagets Disease of the bone, fibrocystic disease of the breast, Peronies and Duputren's fibrosis, restenosis and cirrhosis.
Tumor cells treated with the compounds of the invention accumulate in the G2/M phase of the cell cycle. As the cells exit the G2/M phase, they appear to undergo apoptosis. Treatment of normal cells with the styryl sulfones does not result in apoptosis.
Both cells treated with the styryl sulfone compounds of the invention and untreated cells exhibit similar levels of intracellular ERK-2, but the biochemical activity of ERK-2, as judged by its ability to phosphorylate the substrate myelin basic protein (MBP), is considerably diminished in drug-treated cell compared to untreated cells. Without wishing to be bound by any theory, these results suggest that the styryl sulfones of the present invention block the phosphorylating capacity of ERK-2.
The styryl sulfones of the present invention enhance the ability of JNK to phosphorylate c-Jun protein compared to mock-treated cells. Without wishing to be bound by any theory, this result suggests that the styryl sulfones may be acting like pro-inflammatory cytokines or UV light, activating the JNK pathway, which in turn may switch on genes responsible for cell growth inhibition and apoptosis.
Synthesis of (Z)-Styryl Sulfones
The compounds of the present invention were prepared by synthetic methods yielding pure compounds in the (Z)-isomeric configuration. Thus, the nucleophilic addition of the appropriate thiols to substituted phenylacetylene with subsequent oxidation of the resulting sulfide by hydrogen peroxide yields the Z-styryl sulfone. The procedure is generally described by Reddy et al., Sulfur Letters 13:83 (1991), the entire disclosure of which is incorporated herein as a reference.
The compounds are named according to the Cahn-lngold-Prelog system, the IUPAC 1974 Recommendations, Section E: stereochemistry, in Nomenclature of Organic Chemistry , Pergamon, Elmsford, N.Y., 1979 (the “Blue Book”).
In the first step of the synthesis, the sodium salt of benzyl mercaptan or the appropriate substituted benzyl mercaptan is allowed to react with phenylacetylene or the appropriate substituted phenylacetylene forming the pure Z-isomer of the corresponding styryl benzylsulfide in good yield.
In the second step of the synthesis, the (Z)-styryl benzylsulfide intermediate is oxidized to the corresponding sulfone in the pure Z-isomeric form by treatment with hydrogen peroxide.
General Procedure
A. Synthesis of Intermediate Sulfides
To a refluxing methanolic solution of substituted or unsubstituted sodium benzylthiolate prepared from 460 mg (0.02 g atom) of (i) sodium, (ii) substituted or unsubstituted benzyl mercaptan (0.02 mol) and (iii) 80 ml of absolute methanol, is added freshly distilled substituted or unsubstituted phenylacetylene. The mixture is refluxed for 20 hours, cooled and then poured on crushed ice. The crude product is filtered, dried and recrystalized from methanol or aqueous methanol to yield a pure (Z)-styryl benzylsulfide.
B. Synthesis of Sulfone
An ice cold solution of a (Z)-styryl benzylsulfide (3.0 g) in 30 ml of glacial acetic acid is treated with 7.5 ml of 30% hydrogen peroxide. The reaction mixture is refluxed for 1 hour and then poured on crushed ice. The separated solid is filtered, dried, and recrystalized from 2-propanol to yield the pure (Z)-styryl benzylsulfone. The purity of the compounds is ascertained by thin layer chromatography and geometrical configuration is assigned by analysis of infrared and nuclear magnetic resonance spectral data.
Therapeutic Administration
The styryl sulfones of the invention may be administered in the form of a pharmaceutical composition, in combination with a pharmaceutically acceptable carrier. The active ingredient in such formulations may comprise from 0.1 to 99.99 weight percent. By “pharmaceutically acceptable carrier” is meant any carrier, diluent or excipient which is compatible with the other ingredients of the formulation and to deleterious to the recipient.
The compounds of the invention may be administered to individuals (mammals, including animals and humans) afflicted with breast or prostate cancer. The compounds may be administered by any route, including oral and parenteral administration. Parenteral administration includes, for example, intravenous, intramuscular, intraarterial, intraperitoneal, intranasal, rectal, or subcutaneous administration. The active agent is preferably administered with a pharmaceutically acceptable carrier selected on the basis of the selected route of administration and standard pharmaceutical practice.
The active agent may be formulated into dosage forms according to standard practices in the field of pharmaceutical preparations. See Gennaro Alphonso, ed., Remington's Pharmaceutical Sciences , 18th Ed., (1990) Mack Publishing Co., Easton, Pa. Suitable dosage forms may comprise, for example, tablets, capsules, solutions, parenteral solutions, troches, suppositories, or suspensions.
For parenteral administration, the active agent may be mixed with a suitable carrier or diluent such as water, an oil, saline solution, aqueous dextrose (glucose) and related sugar solutions, or a glycol such as propylene glycol or polyethylene glycol. Solutions for parenteral administration preferably contain a water soluble salt of the active agent. Stabilizing agents, antioxidizing agents and preservatives may also be added. Suitable antioxidizing agents include sulfite, ascorbic acid, citric acid and its salts, and sodium EDTA. Suitable preservatives include benzalkonium chloride, methyl- or propyl-paraben, and chlorbutanol.
For oral administration, the active agent may be combined with one or more solid inactive ingredients for the preparation of tablets, capsules, or other suitable oral dosage forms. For example, the active agent may be combined with carboxymethylcellulose calcium, magnesium stearate, mannitol and starch, and then formed into tablets by conventional tableting methods.
The specific dose of compound according to the invention to obtain therapeutic benefit will, of course, be determined by the particular circumstances of the individual patient including, the size, weight, age and sex of the patient, the nature and stage of the disease, the aggressiveness of the disease, and the route of administration. For example, a daily dosage of from about 0.05 to about 50 mg/kg/day may be utilized. Higher or lower doses are also contemplated.
The practice of the invention is illustrated by the following non-limiting examples.
EXAMPLE 1
Z-styryl Benzylsulfone
A solution of phenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure, part A, to form Z-styryl benzylsulfide. The title compound was obtained in 65% yield by oxidation of the sulfide according to the General Procedure, part B. 1 HNMR (CDC1 3 ) δ4.50 (2H, s), 6.65 (1H, d, J H,H =11.2), 7.18-7.74 (10H aromatic+1H ethylenic).
EXAMPLE 2
Z-styryl 4-Chlorobenzylsulfone
A solution of phenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-styryl 4-chlorobenzylsulfide. The title compound was obtained in 72% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.56 (2H, s), 6.68 (1H, d, J H,H =11.8), 7.20-7.64 (9H aromatic+1H ethylenic).
EXAMPLE 3
Z-styryl 2-Chlorobenzylsulfone
A solution of phenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.029 atom) was subjected to the General Procedure to form Z-styryl 2-chlorobenzylsulfide. The title compound was obtained in 68% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.50 (2H, s), 6.65 (1H, d, J H,H =12.0), 7.18-7.74 (9H aromatic+1H ethylenic).
EXAMPLE 4
Z-styryl 4-Fluorobenzylsulfone
A solution of phenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to from Z-styryl 4-fluorobenzylsulfide. The title compound was obtained in 70% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.58 (2H, s), 6.62 (1H, d, J H,H =11.86), 7.18-7.60 (9H aromatic+1H ethylenic).
EXAMPLE 5
Z-4-Chlorostyryl Benzylsulfone
A solution of 4-chlorophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl benzylsulfide. The title compound was obtained in 74% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.55 (2H, s), 6.66 (1H, d, J H,H =12.12), 7.16-7.65 (9H aromatic+1H ethylenic).
EXAMPLE 6
Z-4-Chlorostyryl 4-Chlorobenzylsulfone
A solution of 4-chlorophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl 4-chlorobenzylsulfide. The title compound was obtained in 76% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.62 (2H, s), 6.68 (1H, d, J H,H =11.92), 7.18-7.60 (8H aromatic+1H ethylenic).
EXAMPLE 7
Z-4-Chlorostyryl 2-Chlorobenzylsulfone
A solution of 4-chlorophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl 2-chlorobenzylsulfide. The title compound was obtained in 73% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.56 (2H, s), 6.70 (1H, d, J H,H =12.05), 7.18-7.64 (8H aromatic+1H ethylenic).
EXAMPLE 8
Z-4-Chlorostyryl 4-Fluorobenzylsulfone
A solution of 4-chlorophenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-chlorostyryl 4-fluorobenzylsulfide. The title compound was obtained in 82% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.60 (2H, s), 6.70 (1H, d, J H,H =11.78), 7.18-7.60 (8H aromatic+1H ethylenic).
EXAMPLE 9
Z-4-Fluorostyryl Benzylsulfone
A solution of 4-fluorophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl benzylsulfide. The title compound was obtained in 76% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.54 (2H, s), 6.68 (1H, d, J H,H =11.94), 7.12-7.58 (9H aromatic+1H ethylenic).
EXAMPLE 10
Z-4-Fluorostyryl 4-Chlorobenzylsulfone
A solution of 4-fluorophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl 4-chlorobenzylsulfide. The title compound was obtained in 82% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.60 (2H, s), 6.68 (1H, d, J H,H =11.84), 7.18-7.60 (8H aromatic+1H ethylenic).
EXAMPLE 11
Z-4-Fluorostyryl 2-Chlorobenzylsulfone
A solution of 4-fluorophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl 2-chlorobenzylsulfide. The title compound was obtained in 74% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.55 (2H, s), 6.66 (1H, d, J H,H =11.94), 7.20-7.65 (8H aromatic+1H ethylenic).
EXAMPLE 12
Z-4-Fluorostyryl 4-Fluorobenzylsulfone
A solution of 4-fluorophenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-fluorostyryl 4-fluorobenzylsulfide. The title compound was obtained in 78% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.60 (2H, s), 6.65 (1H, d, J H,H =11.83), 7.20-7.65 (8H aromatic+1H ethylenic).
EXAMPLE 13
Z-4-Bromostyryl Benzylsulfone
A solution of 4-bromophenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.029 atom) was subjected to the General Procedure to form Z-4-bromostyryl benzylsulfide. The title compound was obtained in 80% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.52 (2H, s), 6.80 (1H, d, J H,H =11.98), 7.18-7.59 (9H aromatic+1H ethylenic).
EXAMPLE 14
Z-4-Bromostyryl 4-Chlorobenzylsulfone
A solution of 4-bromophenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-bromostyryl 4-chlorobenzylsulfide. The title compound was obtained in 87% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.58 (2H, s), 6.72 (1H, d, J H,H =12.08), 7.15-7.68 (8H aromatic+1H ethylenic).
EXAMPLE 15
Z-4-Bromostyryl 2-Chlorobenzylsulfone
A solution of 4-bromophenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-bromostyryl 2-chlorobenzylsulfide. The title compound was obtained in 84% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.57 (2H, s), 6.70 (1H, d, J H,H =11.58), 7.18-7.58 (8H aromatic+1H ethylenic).
EXAMPLE 16
Z-4-Bromostyryl 4-Fluorobenzylsulfone
A solution of 4-bromophenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to from Z-4-bromostyryl 4-fluorobenzylsulfide. The title compound was obtained in 78% yield following oxidation. 1 HNMR (CDC1 3 ) δ4.58 (2H, s), 6.65 (1H, d, J H,H =11.78), 7.22-7.67 (8H aromatic+1H ethylenic).
EXAMPLE 17
Z-4-Methylstyryl Benzylsulfone
A solution of 4-methylphenylacetylene (0.02 mol) and benzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl benzylsulfide. The title compound was obtained in 70% yield following oxidation. 1 HNMR (CDC1 3 ) δ2.48 (3H, s), 4.60 (2H, s), 6.68 (1H, d, J H,H =11.94), 7.20-7.65 (9H aromatic+1H ethylenic).
EXAMPLE 18
Z-4-Methylstyryl 4-Chlorobenzylsulfone
A solution of 4-methylphenylacetylene (0.02 mol) and 4-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl 4-chlorobenzylsulfide. The title compound was obtained in 74% yield following oxidation. 1 HNMR (CDC1 3 ) δ2.46 (3H, s), 4.64 (2H, s), 6.75 (1H, d, J H,H =12.21), 7.18-7.57 (9H aromatic+1H ethylenic).
EXAMPLE 19
Z-4-Methylstyryl 2-Chlorobenzylsulfone
A solution of 4-methylphenylacetylene (0.02 mol) and 2-chlorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl 2-chlorobenzylsulfide. The title compound was obtained in 76% yield following oxidation. 1 HNMR (CDC1 3 ) δ2.50 (3H, s), 4.58 (2H, s), 6.80 (1H, d, J H,H =11.88), 7.20-7.63 (9H aromatic+1H ethylenic).
EXAMPLE 20
Z-4-Methylstyryl 4-Fluorobenzylsulfone
A solution of 4-methylphenylacetylene (0.02 mol) and 4-fluorobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) was subjected to the General Procedure to form Z-4-methylstyryl 4-fluorobenzylsulfide. The title compound was obtained in 69% yield following oxidation. 1 HNMR (CDC1 3 ) δ2.46 (3H, s), 4.62 (2H, s), 6.78 (1H, d, J H,H =11.98), 7.18-7.59 (9H aromatic+1H ethylenic).
EXAMPLE 21
Z-4-Fluorostyryl 4-Iodobenzylsulfone
A solution of 4-fluorophenylacetylene (0.02 mol) and 4-iodobenzyl mercaptan (0.02 mol) and metallic sodium (0.02 g atom) is subjected to the General Procedure to form Z-4-fluorostyryl 4-iodobenzylsulfide. The title compound is obtained following oxidation.
EXAMPLE 22
Effect of Z-Styryl Sulfones on Breast, Prostate and Ovarian Tumor Cell Lines
A. Cells.
The effect of the Z-styryl sulfones on normal fibroblasts and on tumor cells of breast, prostate and ovarian origin was examined utilizing the following cell lines: breast tumor cell lines: MCF-7, BT-20 and 435; prostate tumor cell lines LnCaP and DU-145; and ovarian tumor cell lines OVCAR and SKOV3. NIH/3T3 and HFL cells, which are normal murine and human fibroblasts, respectively, were also tested. LnCap is an androgen-dependent prostate tumor cell line. MCF-7 is an estrogen-responsive breast tumor cell line, while BT-20 and 435 are estrogen-unresponsive breast tumor cell lines. MCF-7, BT-20 and 435 were grown in Dulbecco's modified Eagle's medium (DMEM) containing 10% fetal bovine serum supplemented with penicillin and streptomycin. LnCaP and Du145 were cultured in RPMI with 10% fetal bovine serum containing penicillin and streptomycin. NIH3T3 and HFL cells were grown in DMEM containing 10% calf serum supplemented with penicillin and streptomycin. All cell cultures were maintained at 37° C. in a humidified atmosphere of 5% CO 2 .
B. Treatment with Z-Styryl Sulfones and Viability Assay
Cells were treated with test compound at 2.5 mM concentration and cell viability was determined after 72 hours by the Trypan blue exclusion method. The results are set forth in Table 1.
Activity for each compound is reported as a range of cell induced death (% Death) with the lowest activity in the range of 10-20% and the highest being above 75%. For each compound tested, the activity was found to be in the same range for the three cell types.
Two of the twenty compounds tested (Examples 8 and 14) had kill rates of over 75%; three compounds (Examples 6, 10, and 16) had rates of 60-70%.
The five compounds exhibiting the highest activity contained halogen in the 4-position in Formula I.
Normal cells HFL and NIH 3T3 were treated with the same compounds in Table 1 under the same conditions of concentration and time. The normal cells were not killed.
TABLE 1
Effect of (Z)-styryl benzyl sulfones on tumor cells
Tumor cell type
Ex.
R 1
R 2
R 3
R 4
Breast
Prostate
Ovarian
1
H
H
H
H
−
−
−
2
H
H
H
Cl
+
+
+
3
H
H
Cl
H
+
+
+
4
H
H
H
F
+
+
+
5
H
Cl
H
H
+
+
+
6
H
Cl
H
Cl
+ + +
+ + +
+ + +
7
H
Cl
Cl
Cl
+
+
+
8
H
Cl
H
F
+ + + +
+ + + +
+ + + +
9
H
F
H
H
+
+
+
10
H
F
H
Cl
+ + +
+ + +
+ + +
11
H
F
Cl
Cl
+
+
+
12
H
F
H
F
+ +
+ +
+ +
13
H
Br
H
H
+
+
+
14
H
Br
H
Cl
+ + + +
+ + + +
+ + + +
15
H
Br
Cl
Cl
+
+
+
16
H
Br
H
F
+ + +
+ + +
+ + +
17
H
CH 3
H
H
+
+
+
18
H
CH 3
H
Cl
+
+
+
19
H
CH 3
Cl
Cl
+
+
+
20
H
CH 3
H
F
+
+
+
The activity of the compounds at 2.5 mM after 72 hours.
Breast cell lines: MCF-7, BT-20, 435
Prostate cell lines: LnCaP, DU-145
Ovarian cell lines: OVCAR, SKOV3
10-20% Death = −
20-25% = +
40-50% = + +
60-70% = + + +
above 75% = + + + +
EXAMPLE 23
Effect of Z-Styryl Sulfones on Lung, Renal and Brain Tumor Cell Lines
The procedure of Example 22 was followed for certain of the (Z)-benzylsulfones, substituting the following cancer cell lines: lung, N417 and H157; renal, CAKI-1 and CAKI-2; glioma, U87 and SW1088. The results are set forth in Table 2.
TABLE 2
Effect of (Z)-styryl benzyl sulfones on tumor cells
Tumor cell type
Ex.
R 1
R 2
R 3
R 4
Lung
Renal
Glioma
5
H
Cl
H
H
+
+
+
6
H
Cl
H
Cl
+ + +
+ + +
+ + +
7
H
Cl
Cl
Cl
+
+
+
8
H
Cl
H
F
+ + + +
+ + + +
+ + + +
10
H
F
H
Cl
+ + +
+ + +
+ + +
11
H
F
Cl
Cl
+
+
+
12
H
F
H
F
+ +
+ +
+ +
14
H
Br
H
Cl
+ + + +
+ + + +
+ + + +
15
H
Br
Cl
Cl
+
+
+
16
H
Br
H
F
+ + +
+ + +
+ + +
18
H
CH 3
H
Cl
+
+
+
20
H
CH 3
H
F
+
+
+
The activity of the compounds at 2.5 mM after 72 hours.
Lung cell lines: N417, H157
Renal cell lines: CAKI-1, CAKI-2
Glioma cell lines: U87, SW1088
10-20% Death = −
20-25% = +
40-50% = + +
60-70% = + + +
above 75% = + + + +
All references cited with respect to synthetic, preparative and analytical procedures are incorporated herein by reference.
The present invention may be embodied in other specific forms without departing from the spirit or essential attributes thereof and, accordingly, reference should be made to the appended claims, rather than to the foregoing specification, as indication the scope of the invention.
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(Z)-styryl benzylsulfones of formula I are useful as anticancer agents:
wherein
R 1 is selected from the group consisting of hydrogen, chloro and nitro;
R 2 is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy, chloro, bromo, iodo and fluoro; and
R 3 and R 4 are independently selected from the group consisting of hydrogen, lower alkyl, nitro, chloro, bromo, iodo and fluoro;
provided that at least one of R 1 or R 2 is hydrogen.
The corresponding (Z)-styryl benzylsulfides are useful as intermediates in the preparation of the biologically active (Z)-styryl benzyl sulfones.
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RELATED APPLICATION
This divisional application claims priority to and the benefit of U.S. application Ser. No. 10/403,466, filed on Mar. 31, 2003, which, in turn, claims priority to and the benefit of United Kingdom patent application number 0207643.8, filed on Apr. 2, 2002, which applications are herein incorporated by reference in their entirety.
BACKGROUND
The present invention relates generally to building components and, more particularly, but not exclusively, to building components for roofing, in the form of inflatable cushions.
Inflatable cushions comprise two or more layers of a plastic foil material such as ETFE (ethylene tetra flouro ethylene) inflated with low pressure air. The ETFE foil cushion is restrained in a perimeter frame usually manufactured from extruded aluminium, which in turn is fixed to a support structure. As the ETFE foil cushion is inflated, the ETFE is put under tension and forms a tight drum like skin. ETFE foil cushions are sold under a number of trade names, for example “Texlon.”
ETFE cushions of this kind are fixed to a support structure to form a cladding and are used to enclose atria or other enclosed spaces to provide a transparent or translucent roof or facade to the enclosure, as an alternative to and in a similar way to glass. A number of buildings have been built using this technology most notably the Eden project in Cornwall, England.
Whenever a space is enclosed by a cladding system due consideration needs to be given to the effects of a fire should it break out in the building. In these circumstances, smoke and other products of combustion must be ventilated from the enclosure to prevent injury to the occupants and property. In some specialist buildings, other noxious fumes may also need to be ventilated from the enclosure to prevent injury to the occupants and property. In some specialist buildings, other noxious fumes may also need to be ventilated to atmosphere.
To ventilate noxious fumes to atmosphere, two methods are primarily utilized. Firstly, the smoke, and/or fumes can be extracted by a mechanical extraction system usually consisting of fire-rated duct work and extraction fans. Alternatively, the smoke and/or fumes can be extracted by opening part of the roof or building facade and allowing the smoke to ventilate to atmosphere through the action of convection and/or wind.
ETFE foil cushions can be used to ventilate smoke and/or fumes to the atmosphere in much the same ways as other cladding systems in that they can be fixed to a frame which opens automatically through a mechanical device in the event of fire. In addition, ETFE is a thermo-plastic material and therefore has the innate property of failing if the temperature reaches approximately 200° C., as the material loses its tensile properties as its temperature increases. When the cushion fails, it allows smoke and/or fumes to ventilate naturally to the atmosphere.
The above methods suffer from a number of draw backs. The mechanical extraction approach is expensive and requires fire-rated machinery, regular maintenance and testing. Natural extraction requires expensive opening frames, which are complex to render, weather and watertight. They do not look the same as the adjacent cladding as they require a secondary opening frame, and mechanical operating parts which themselves require regular maintenance and testing. The failure of the ETFE due to high temperature does not occur if the building fire is located some way away from the ETFE, as the ETFE is not sufficiently heated by smoke and/or fumes to fail.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide an economical, visually unobtrusive, method of causing ETFE foil cladding systems to fail on demand in order to allow natural smoke ventilation from a building enclosure.
It is a further object of the invention to allow the system to fail on demand in order to shed high loads such as snow or water ponding.
Thus, according to one aspect, the present invention provides a building component in the form of an inflatable cushion comprising two or more sheets of plastics foil and a relatively rigid frame surrounding and supporting the foil sheets, the building component further incorporating a release mechanism in or adjacent to the frame arranged to release the foil sheets from the frame.
Preferably, the sheets are made from ethylene tetrafluoro ethylene (ETFE). Preferably, the sheets define a space between them which is inflated with air and the frame restrains the sheets about their perimeters, thereby forming the cushion. The release mechanism may extend the entire periphery of the cushion. Alternatively, it may extend only part of the way around, for example, in the case of a polygonal cushion, it may extend around all sides except one. In the case of a rectangular cushion, therefore, it might extend around three sides.
Preferably, the cushion has a bead formed around its periphery, and the bead is located within the frame. The bead may be a rope encapsulated by the sheet material. The bead may be held by a keder edge within the frame.
The frame may be manufactured from extruded aluminium which, in turn, may be fixed to a support structure. The frame preferably incorporates a device which releases the ETFE foil cushion from the frame in the event of fire so allowing the smoke to ventilate to atmosphere.
For releasing the ETFE foil cushion from the frame two exemplary means may be employed, namely, mechanically releasing the cushion or cutting it free.
In the case of mechanical release, this may be achieved by either extracting the rope from the bead which restrains the ETFE foil cushion in the frame, or by hinging a part of the frame so that it releases the keder edge. Preferably, therefore, the release mechanism comprises a device which removes the rope from the bead on demand, releasing the ETFE foil cushion from the frame. Suitable means for removing the rope include, by way of example, a mechanical winch, or ram, block and tackle. This can be done via a turning wheel. Alternatively, the release mechanism may comprise a hinged member engaging the cushion, the hinged member being movable on demand to a position in which it does not engage the cushion, thereby releasing the cushion from the frame.
In the case of cutting the cushion free, preferably, the frame incorporates a cutting device which either physically cuts or melts the ETFE foil along the edge of the cushion. Preferably, therefore, the release mechanism comprises an electrical resistance cable which causes the edge of the cushion to melt on demand, releasing the ETFE foil cushion from the frame. Alternatively, the release mechanism may comprise a cutting blade adjacent to the perimeter frame, and a means for moving the cutting blade so that on demand, the blade moves, cutting the ETFE foil cushion, thereby releasing the ETFE foil cushion from the frame. The cutting blade can be situated either above or below the inflated cushion. Suitable means for moving the blade include a mechanical winch, ram or block and tackle.
Whichever mechanism is used for releasing the ETFE foil cushion from the frame, on release from the frame, the ETFE cushion moves away from the frame so allowing the products of combustion or other noxious fumes to ventilate to atmosphere. On operation of the release mechanism on one or more sides, the ETFE foil cushion may form a cylindrical or spherical shape due to retention of pressurised air in the cushion; flap or fall away from one or more sides of the frame; or flap or fall away from all sides of the frame. In any event, the removal of the cushion from all or part of the frame will allow smoke or noxious fumes to ventilate from the building. It will also allow any excessive water or snow loads to be released.
A better understanding of the objects, advantages, features, properties and relationships of the invention will be obtained from the following detailed description and accompanying drawings which set forth illustrative embodiments which are indicative of the various ways in which the principles of the system and method may be employed.
BRIEF DESCRIPTION OF THE DRAWINGS
For a better understanding of the invention, reference may be had to preferred embodiments shown in the following drawings in which:
FIG. 1 is a plan of an exemplary ETFE cushion constructed in accordance with the present invention;
FIG. 2 is a cross section through the assembly of FIG. 1 ;
FIG. 3 is a detailed cross section of the perimeter cushion frame showing one embodiment of an exemplary release mechanism;
FIG. 4 is a detailed cross section of an alternative perimeter cushion frame showing a variant of the first embodiment of release mechanism;
FIG. 5 is a detailed cross section of the perimeter cushion frame showing a second embodiment of an exemplary release mechanism;
FIG. 6 is a detailed cross section of the perimeter cushion frame showing a third embodiment of an exemplary release mechanism;
FIG. 7 is a detailed cross section of a perimeter cushion frame showing a fourth embodiment of an exemplary release mechanism; and
FIG. 8 is an elevation of FIG. 7 .
DETAILED DESCRIPTION
Turning now to the figures, where like reference numerals refer to like elements, FIGS. 1 and 2 show an exemplary ETFE cushion constructed in accordance with the invention. The cushion 11 comprises three rectangular ETFE foil sheets 12 , 13 , 14 , a support frame 15 and a plenum 16 . The frame 15 is located about the perimeter of the sheets 12 , 13 , 14 and incorporates a release mechanism. The space between the sheets 12 , 13 , 14 is inflated with air via the plenum 16 .
FIG. 3 shows a first embodiment of an exemplary release mechanism. The overall arrangement comprises a cushion 21 , a support frame 22 and a building structure 23 . The cushion 21 has a bead 24 at its perimeter made from a rope 25 encapsulated by an extended portion of the sheets 26 , 27 , 28 . Between the bead 24 and the inflated part of the cushion 21 , there is an edge support 29 . The bead 24 is captured within a keder edge 31 , made from aluminium.
The frame 22 comprises a housing 32 and a cap 33 . The keder edge 31 is clipped into the housing 32 and the cap 33 is bolted into the housing 32 to form a weather-tight seal. The housing 32 is itself bolted to the structure 23 .
The edge support 29 includes a cable 34 , preferably electrically resistant, extending around the perimeter of the cushion 21 , or at least around three sides. When required, current may be passed through the cable 34 for the purpose of raising its temperature to a level where the ETFE foil 26 , 27 , 28 or the support 29 fails and the cushion 21 is freed from the frame 22 .
A further exemplary release mechanism is shown in FIG. 4 which is similar to that of FIG. 3 , but in this case, the bead 44 of the cushion 41 is located in a compressible gasket 42 made, for example, of EPDM which is itself swaged into a retaining channel 43 forming part of the frame 45 . Again, there is a resistance cable 46 in contact with the foil of the cushion 41 which causes the foil to fail when current is passed through the cable 46 .
A still further exemplary release mechanism is shown in FIG. 5 . Again, the cushion 51 is located within the frame 52 by means of a peripheral bead 53 including a rope 54 , the bead being captured by a keder edge 55 which is clipped into the frame housing 56 . However, in this embodiment, there need not be a resistance cable. Instead, the rope 54 may be wound round a pulley 57 and connected to a winch (not shown). Thus, when required, the rope 54 is drawn by a winch, and the bead 53 collapses. As a result, the cushion 51 is released.
Yet another exemplary release mechanism is shown in FIG. 6 . In this case, the cushion 61 is located within the frame 62 by means of a peripheral bead 63 captured by a keder edge 54 clipped into the frame housing 65 . However, in this embodiment, a blade 66 may be provided on a carriage 67 which is arranged to be rotatable and to travel along a track 68 around at least three sides of the periphery of the cushion 61 , when required, cutting through the cushion foils to free the cushion 61 . Although the blade 66 is shown located below the cushion it could equally well be above. In the illustrated example, the blade 66 is shown in its deployed position, cutting through the foils. It is to be understood that in its normal position, the blade 66 would not make contact with the foils. When required, the blade 66 would be swung into the deployed position and moved along the cushion 61 . There may be a separate blade 66 for each side of the cushion 61 .
Still further examples of a release mechanism are illustrated in FIGS. 7 and 8 . In this case the cushion 71 is located within the frame 72 by means of a peripheral bead 73 captured by a keder edge 74 clipped into the frame housing 75 . However, in this embodiment, the foils, between the bead 73 and the inflated part of the cushion 71 are supported on and held along each edge by a hinged member 76 forming part of the housing 75 . Each hinged member 76 is pivoted about an axle 77 . Each hinged member 76 is held in its normal position, engaging the foils, by a series of levers 78 which are pivotally connected to the frame 72 by pins 79 . The levers 78 are connected together by connecting rods 81 and one lever is connected to a pneumatic or hydraulic ram 82 . When it is desired to release the cushion 71 , the ram 82 associated with each side is operated. This draws the levers 78 towards the ram 82 , rotating them clockwise about the pins 79 to the positions shown in broken lines. This in turn allows the hinged member 79 to pivot downwards about the axle 77 to the positions shown in broken lines, so releasing the cushion 71 from the housing 75 .
From the foregoing, it will be understood, when the cushion is released, smoke can be ventilated and/or any accumulated excess snow or water loads can be released.
While various embodiments of the invention have been described in detail, it will be appreciated by those skilled in the art that various modifications and alternatives to those details could be developed in light of the overall teachings of the disclosure. For example, it is to be appreciated that the arrangements shown in FIGS. 6 and 7 could be combined, to allow the cushion to be released downwards to the blade. It will also be appreciated that, as with the earlier embodiments, the release mechanism illustrated in FIGS. 7 and 8 can act on three sides or all four sides of the cushion. Accordingly, it will be understood that the particular arrangements and procedures disclosed are meant to be illustrative only and not limiting as to the scope of the invention which is to be given the full breadth of the appended claims and any equivalents thereof.
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A building component for forming a roof. The component includes an ETFE foil cushion comprising sheets of ETFE foil which are held in a frame about their periphery, and which are inflated. The frame includes a release mechanism for releasing the cushion from the frame, for example, in the event of a fire.
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[0001] This application claims priority under 35 USC §120 to application Ser. No. 10/036,793, which was filed on Nov. 8, 2001, the entire contents of which are hereby expressly incorporated by reference. This application also claims priority, under 35 USC §119(e), to provisional application 60/282,428, which was filed on Apr. 9, 2001, the entire contents of which are hereby expressly incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to fibrous substrates useful in the manufacture of carbon fiber/carbon matrix composites, and to carbon fiber/carbon matrix composites manufactured therefrom. Representative of such composites are aircraft and high performance automotive brake discs made by depositing carbon matrices on carbon fiber substrates of this invention and subsequently carbonizing the combinations to provide carbon matrices that are reinforced with carbon fibers.
[0004] 2. Related Art
[0005] Many advances have been made over the years in the art relating to brake discs.
[0006] U.S. Pat. No. 5,388,320 describes the manufacture of carbonizable needle-punched filamentary structures (typically, annular performs) made up of layers of unidirectional filaments and staple fibers. These structures can be used to make shaped articles (typically, brake discs) of carbon reinforced with carbon fibers. As taught in column 7 of the patent, some of the arc segments used to make up the structures are cut in such a way that the majority of the filaments extend substantially radially of the eventual annulus, while others are cut so that the majority of the filaments extend substantially chordally of the annulus. The former segments have greater dimensional stability in the radial direction and the latter segments have greater dimensional stability in the chordal direction.
[0007] U.S. Pat. No. 5,546,880 describes fibrous substrates for the product of carbon fiber reinforced composites comprising multilayered annular shaped fibrous structures, suitable for use in the manufacture of friction discs, made from multidirectional fabric, that is, fabric having filaments or fibers extending in at least two directions.
[0008] The present invention involves the recognition that, in carbon fiber composite friction linings, the orientation of the fiber at the friction surface plays a major role in the wear characteristics of the material. When fibers of opposing direction on the friction surfaces slide against each other, mechanical wear takes place and the fiber bundles are torn form the friction surface. This fiber pull-out leads to breakdown of the surrounding matrix of carbon. As more areas of fiber pull-out occur on the friction surface, the matrix surrounding these fibers also breaks down to fill the voids created. This results in a reduction in the overall thickness of the frictional material.
SUMMARY OF THE INVENTION
[0009] This invention addresses the need of both brake manufacturers and their customers, by increasing the field life (via reduction of the wear rate) of carbon fiber friction materials and thereby reducing the cost of ownership.
[0010] Methods for manufacturing annular preforms made from tows of oxidized polyacrylonitrile continuous filaments are described in U.S. Pat. No. 5,388,320, the entire contents of which are hereby expressly incorporated by reference. In the new preform technology of the present invention, fiber orientation in the preform is in the radial direction. This means that the continuous fibers run mainly from the inner diameter to the outer diameter of the annular disc. By orienting the fibers in this fashion, fiber pull-out is minimized, thereby reducing mechanical wear. Testing has shown that by using this preform fiber architecture, wear rates can be reduced up to 40 percent while maintaining disc strength and integrity.
[0011] One embodiment of this invention is a carbon fiber brake preform comprising an annular disc built up of fabric arc segments composed of from 90 to 70 weight-% continuous fibers and from 10 to 30 weight-% staple fibers. A typical annular disc of this invention may, for instance, be composed of 85 weight-% continuous fibers and 15 weight-% staple fibers. Preferably, both the continuous fibers and the staple fiber are oxidized polyacrylonitrile fibers. In this preform, at least 80% of the continuous fibers in the fabric segments are arranged to be located within 60° of radially from th e inner diameter to the outer diameter of the annular disc. Thus, for instance, the fabric arc segments may be arranged with substantially all of their continuous fibers oriented in the radial direction and parallel to the segment arc bisector, or the fabric arc segments may be arranged in alternating layers in which, respectively, approximately half of their continuous fibers are oriented at a +45 degree angle with respect to the segment arc bisector and approximately half of their continuous fibers are oriented at a −45 degree angle with respect to the segment arc bisector.
[0012] Another embodiment of this invention is a method for making a preform composite. The method includes the steps of: a.) providing a needle-punched nonwoven fabric comprising a major portion of unidirectional continuous fiber and a minor portion of staple fiber; b.) making from this fabric a plurality of segments having the outside diameter and the inside diameter of the preform to be manufactured from the fabric; c.) arranging the segments in a multilayered intermediate to a weight and dimension calculated to provide a desired preform density for the application; d.) heating the multilayered intermediate to a temperature above 1500° C. in an inert atmospher e for an amount of time sufficient to convert the fibers to carbon; and e.) densifying the carbonized product by carbon deposition to the desired preform density. The segments may b arranged in step c.) with their continuous fibers oriented in the radial direction and parallel to the segment arc bisector or in alternating layers in which their continuous fibers are oriented alternatively at a +45 degree angle with respect to the segment arc bisector and at a −45 degree angle with respect to the segment arc bisector. The carbonized product may be densified in step e.) using Chemical Vapor Infiltration/Chemical Vapor Deposition. A typical density for a finished disc produced by this method is in the range 1.70-1.80 g/cc.
[0013] Still another embodiment of this invention is a method of reducing wear in an annular brake disc which comprises manufacturing said disc from preforms reinforced with a plurality of continuous fibers in which at least about 80% of the continuous fibers are aligned in a generally radial manner, for instance within 60° of the r adii of the annular brake disc. In two specific cases, the continuous fibers are located on the radii of the annular brake disc or the continuous fibers are located at angles of 45° from the r adii of said annular brake disc. Using this method, wear of the brake disc may be reduced, for example, by 25% or more compared to wear of an otherwise comparable brake disc made from preforms in which half of the continuous fibers are located outside of the 120° arcs bis ected by the radii of each of the preform segments.
[0014] This invention also provides a carbon fiber brake preform comprising an annular disc built up of a plurality of annular fabric arc segments composed of unidirectional continuous fibers and staple fibers, wherein each of said annular segments has radial directions oriented from the center of the annulus to points on its outer diameter and wherein the radial direction that passes through the center of the segment outer diameter constitutes a segment arc bisector. In this aspect of the present invention, the improvement comprises arranging said fabric segments with the continuous fibers in said fabric segments oriented in the radial direction and parallel to the segment arc bisectors. In other words, this invention provides a shaped fibrous (e.g., OPAN) fabric structure having an annular disc configuration and being formed of multiple, successively-stacked layers of abutting fabric arc segments composed of continuous fibers and staple fibers, said fabric arc segment layers being interconnected by at least a portion of said staple fibers, wherein each of said annular segments has radial directions oriented from the center of the annulus to points on its outer diameter and wherein the radial direction that passes through the center of the segment outer diameter constitutes a segment arc bisector, and wherein the continuous fibers in said fabric segments are oriented in the radial direction and parallel to the segment arc bisectors. These preform composites may be made by: a.) providing a needle-punched nonwoven fabric comprising a major portion of unidirectional continuous fiber tow and a minor portion of staple fiber web, b.) making from said fabric a plurality of segments having the continuous fibers oriented in said fabric segments in the radial direction and parallel to segment arc bisectors of said fabric segments, c.) arranging said segments to provide a multilayered intermediate having a weight and dimension calculated to provide a desired preform density for the application, d.) heating said multilayered intermediate to a temperature above 1500° C. in an inert atmospher e to convert the fibers to carbon, and e.) densifying the carbonized product by carbon deposition to the desired preform density.
[0015] Wear in an annular brake disc may be reduced by manufacturing said disc from a preform made by the method described above. This aspect of the invention provides a reduction in wear of the brake disc by 40% while maintaining disc strength and integrity.
[0016] Finally, this invention provides a shaped fibrous fabric structure having an annular disc configuration and being formed of multiple, successively-stacked layers of abutting fabric arc segments composed of from 90 to 70 weight-% continuous fibers and from 10 to 30 weight-% staple fibers, the fabric arc segment layers being interconnected by at least a portion of the staple fibers, wherein at least 80% of the continuous fibers in the fabric arc segments are located within 60° of radially from the inn er diameter to the outer diameter of the annular disc. The fabric arc segments may be arranged with their continuous fibers oriented in the radial direction and parallel to the segment arc bisector, or they may be arranged in alternating layers in which their continuous fibers are oriented alternatively at a +45 degree angle with respect to the segment arc bisector and at a −45 degree angle with respect to the segment arc bisector.
[0017] Implementation of these new fiber preform architectures (radial and ±45°) en ables the brake manufacturer to produce fewer friction linings to meet existing airline requirements. In addition, the brake manufacturer will be able to meet increasing demand without further capital investment by utilizing the excess production capacity created by this technology.
[0018] Additional advantages of the present invention will become more apparent from the detailed description given hereinafter. However, it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the invention, are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The drawings that accompany this application are presented by way of illustration only, and do not limit the scope of the present invention.
[0020] [0020]FIGS. 1A and 1B are top plan views of two different fabric segment orientations that may be used in accordance with the present invention. FIG. 1C is a top plan view of prior art fabric segment orientations.
[0021] [0021]FIG. 2 illustrates, in a schematic perspective view, a preform of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0022] [0022]FIGS. 1A and 1B illustrate preform fabric segments that may be used according to the present invention, while FIG. 1C illustrates prior art preform segments such as those shown in FIG. 5 of U.S. Pat. No. 5,388,320. In all of these Figures, the fields of horizontal lines represent continuous fibers. FIG. 1A depicts a fabric segment in which a continuous fiber is situated in the radius of a segment, while FIG. 1B depicts fabric segments oriented such that their radii describe an angle of 45° with respect to the dir ection of the continuous fibers in the fabric. FIG. 1C, which is illustrative of the prior art, includes a fabric segment having its continuous fibers oriented in the radial direction and parallel to the segment arc bisector as well as a fabric segment oriented such that its radius describes an angle of 900 with respe ct to the direction of the continuous fibers in the fabric. Conventionally, performs are made up with both types of fabric segments, as shown in FIG. 6 of U.S. Pat. No. 5,388,320. Such constructions result in composites which are subject to greater frictional wear than are similar composites manufactured in accordance with the present invention.
The Fabric
[0023] The following process may be used to manufacture fabric segments in accordance with the present invention. A carded web is crosslapped to achieve a desired areal weight, and then needle punched to form a staple fiber web fabric. The staple fiber web could alternatively be formed by airlaying the staple fibers. Separately, large continuous tows are spread, using a creel, to form a sheet of the desired areal weight. The sheet is processed through a needle loom to impart integrity to the continuous fiber fabric. This fabric is known as a continuous tow fabric. Then the staple fiber web is needle punched into the continuous tow fabric to form what is called a duplex fabric. The +45°, −45°, and radial segments used in accordance with the present invention are cut from the duplex fabric.
[0024] One aspect of this invention is manufacturing the preform from segments that have been cut from nonwoven fabric composed mainly of unidirectional continuous fiber. The nonwoven fabric will also contain a minor but significant percentage (typically, from 10 to 30 weight-%) of staple fiber, which provides structural integrity upon needle-punching. Excellent results may be obtained with a fabric made up, for example, of 85 weight-% unidirectional continuous fiber and 15 weight-% staple fiber. Generally, the fabric is composed of a carded needled punched staple web which has been needled to a layer of needle punched continuous tow. The resulting fabric is known as a duplex fabric.
[0025] The fiber used to produce this nonwoven fabric must be of a carbonaceous nature. Oxidized polyacrylonitrile (OPAN) fiber is particularly preferred, although other conventional fibers including thermoset pitch fibers, unoxidized polyacrylontrile fibers, carbon fibers, graphite fibers, ceramic fibers, and mixtures thereof, may be used. In accordance with the present invention, the fiber is used as a strand of continuous filaments, generally referred to as a “tow”. The staple fiber used in this invention may be selected from the same types of fibers as the continuous fiber. It need not necessarily be the same as the continuous fiber. However, OPAN fiber is preferred for the staple fiber too.
[0026] In implementing the present invention, segments having a segment arc of, for example, 68 degrees are cut from the fabric sheet, with the segment having the outside diameter and the inside diameter of the preform to be manufactured. Sixty-eight degree arcs are preferred, since this arc dimension minimizes butt joint overlap within the parts being manufactured. However, other arc dimensions may be used if desired.
[0027] The inside and outside diameters of the arc segments are chosen based upon the preform to be manufactured. For instance, rotor preforms can be manufactured from segments having an inside radius of 5.5 inches and an outside radius of 10.5 inches. Stator preforms can be manufactured from segments having an inside radius of 4.875 inches and an outside radius of 9.75 inches. Those skilled in the art will have no difficulty in setting the appropriate inside and outside diameters for the specific preform type to be manufactured.
[0028] These segments are then needled together following a helical lay-up pattern to a specified weight and dimension, based upon the desired preform density for the application. The fabric layers are interlocked by the staple fibers, which are transported by the needles into the z-direction.
Needling
[0029] Needling may be carried out with an annular needling machine such as that described in U.S. Pat. No. 5,388,320, the entire disclosure of which is hereby expressly incorporated by reference. Annular needling is the process of continuously placing individual fabric segments (one at a time) onto a rotating closed cell polymeric foam ring having the inside diameter and outside diameter of the desired annular shape to which the segments are needled. One example of such a ring has an inside diameter of 10 inches and an outside diameter of 20 inches. However, those skilled in the art will appreciate that such dimensions can be varied widely, depending upon the shape to be manufactured. The segments are laid end to end and are needled together following a helical lay-up pattern to a desired weight and dimension.
[0030] The foam ring base provides the rigid structure on which the first few layers of segments are needled. The needles penetrate through the layers of fabric and into the foam ring. These segments layers are mechanically bonded to the foam ring as z-direction fibers (mainly the staple fibers) are transported through the fabric layers into the foam. This provides the integrity needed to assemble the subsequent layers of segments as the structure is manufactured. As the layers of segments are built, the segments are no longer needled into the foam ring but into the previous layers of segments by mechanically interlocking fiber bundles between the fabric layers.
Preforms
[0031] This layer needling process forms a thick annular ring called a preform. As the preform grows in thickness, it is lowered to maintain the same needle penetration depth from layer to layer. The resultant preform is composed of many layers of segments that are mechanically bonded together during the needling process. Typical preforms are made up of from 15 to 35 layers. However, those skilled in the art will appreciate that fewer or many more layers may be used, depending upon the shape to be manufactured. The foam ring is removed at the end of the preforming process. A resulting preform ( 20 ) is depicted in FIG. 2, made up of multiple segments ( 21 ) each having a thickness ( 28 ). In FIG. 2, the segments are characterized by radial tow ( 25 ). They are joined to segment layers above and below by staple fibers ( 26 ) that have been needled into the z-direction (that is, perpendicular to the planes of the segments).
[0032] Two preform architectures using this new concept of radially oriented fibers at the friction surface have been manufactured in accordance with the present invention. One preform architecture of this invention provides segments in which the continuous fibers are oriented parallel to the segment arc bisectors. These segments are referred to as radial segments, and are depicted in FIG. 1A. The other preform architecture of this invention provides preforms manufactured from alternating layers of fabric segments that are angled—within a spe cified range—with resp ect to the continuous fibers derived from the unidirectional tow. FIG. 1B illustrates +45 degree fiber oriented segments and −45 degree fiber oriented segments. The “−45” degree fiber oriented segments used in accordance with this invention can be made by changing the die cut angle, as shown in FIG. 1B, or simply by inverting “+45” degree segments.
[0033] The first preform architecture is manufactured from segments with all of the continuous fibers oriented in the radial direction. This means that the unidirectional tow fibers run parallel to the segment arc bisector. In combination with the, e.g., 68 degree arc of the segment, the bias from layer to layer of the preform is set to inhibit linear faults forming along the fiber length in the radial direction.
[0034] The second preform architecture is manufactured using two different segment types. In the first segment type, the unidirectional tow fibers run at a +45 degree angle to the segment arc bisector and in the second segment type, the unidirectional tow fibers run at a −45 degree angle to the segment arc bisector. The segment lay-up for this preform follows a ±45 degree orientation. This lay-up pattern is repeated throughout the layering of the preform. This preform architecture provides a more desirable bias from layer to layer to improve overall mechanical properties of the composite disc.
[0035] The preforms manufactured from these architectures are heat-treated to a very high temperature, for instance to above 1500° C., in an inert atmosphere to convert the fibers to carbon. The precise temperature and length of time can be varied widely, so long as it provides carbonization of the fibers in the preform. The preforms are then densified using conventional processes to deposit carbon matrices in the fibrous preform substrates.
Densification
[0036] Deposition of carbon on the substrate is effected by in situ cracking of a carbon bearing gas. This process is referred to as Carbon Vapor Deposition (CVD) or Carbon Vapor Infiltration (CVI)—these terms are interchangeable for purposes of the present invention. Alternatively, the substrate can be repeatedly impregnated with liquid pitch or carbon bearing resin and thereafter charring the resin.
[0037] Carbon vapor infiltration and deposition (CVI/CVD) is a well known process for depositing a binding matrix within a porous structure. The terminology “carbon vapor deposition” (CVD) generally implies deposition of a surface coating, but the term is also used to refer to infiltration and deposition of a matrix within a porous structure. As used herein, the terminology CVI/CVD is intended to refer to infiltration and deposition of a matrix within a porous structure. The technique is particularly suitable for fabricating high temperature structural composites by depositing a carbonaceous or ceramic matrix within a carbonaceous or ceramic porous structure. These composites are particularly useful in structures such as carbon/carbon aircraft brake discs, and ceramic combustor or turbine components. The generally known CVI/CVD processes may be classified into four general categories: isothermal, thermal gradient, pressure gradient, and pulsed flow.
[0038] In an isothermal CVI/CVD process, a reactant gas passes around a heated porous structure at absolute pressures as low as a few millitorr. The gas diffuses into the porous structure driven by concentration gradients and cracks to deposit a binding matrix. This process is also known as “conventional” CVI/CVD. The porous structure is heated to a more or less uniform temperature, hence the term “isothermal,” but this is actually a misnomer. Some variations in temperature within the porous structure are inevitable due to uneven heating (essentially unavoidable in most furnaces), cooling of some portions due to reactant gas flow, and heating or cooling of other portions due to heat of reaction effects. In essence, “isothermal” means that there is no attempt to induce a thermal gradient that preferentially affects deposition of a binding matrix. This process is well suited for simultaneously densifying large quantities of porous articles and is particularly suited for making carbon/carbon brake discs.
[0039] In a thermal gradient CVI/CVD process, a porous structure is heated in a manner that generates steep thermal gradients which induce deposition in a portion of the porous structure. The thermal gradients may be induced by heating only one surface of a porous structure, for example by placing a porous structure surface against a susceptor wall, and may be enhanced by cooling an opposing surface, for example by placing the opposing surface of the porous structure against a liquid cooled wall. Deposition of the binding matrix progresses from the hot surface to the cold surface.
[0040] In a pressure gradient CVI/CVD process, the reactant gas is forced to flow through the porous structure by inducing a pressure gradient from one surface of the porous structure to an opposing surface of the porous structure. Flow rate of the reactant gas is greatly increased relative to the isothermal and thermal gradient processes, which results in increased deposition rate of the binding matrix. This process is also known as “forced-flow” CVI/CVD. An annular porous wall may be formed, using this process, from a multitude of stacked annular discs (for making brake discs) or as a unitary tubular structure.
[0041] Finally, pulsed flow CVI/CVD involves rapidly and cyclically filling and evacuating a chamber containing the heated porous structure with the reactant gas. The cyclical action forces the reactant gas to infiltrate the porous structure and also forces removal of the cracked reactant gas by-products from the porous structure.
[0042] In all of these variants of the CVI/CVD process, carbon deposition is continued until a preset density is achieved for the friction material application. Following the densification process, a final heat treatment may be performed to set the thermal, mechanical, and frictional properties desired for the composite.
EXAMPLES
Example 1
[0043] A preform is manufactured totally from segments in which the continuous fibers are oriented parallel to the segment arc bisector. These segments are referred to as radial segments, and are depicted in FIG. 1. Needling is carried out with a conventional annular needling machine. Individual fabric segments are placed one at a time onto a rotating closed cell polymeric foam ring having the inside diameter and outside diameter of the annular shape of the preform being manufactured. The segments are laid end to end and needled together following a helical lay-up pattern to a desired weight and dimension. As the preform grows in thickness, it is lowered to maintain the same needle penetration depth from layer to layer. The resultant preform is composed of many layers of segments that are mechanically bonded together during the needling process. The foam ring is removed at the end of the performing process. The resulting preform is depicted schematically in FIG. 2.
Example 2
[0044] A preform was manufactured from alternating layers of +45 degree fiber oriented segments and −45 degree fiber oriented segments. An oxidized polyacrylonitrile fiber sold under the trade name Panox by SGL was used for both the continuous fiber and the staple fiber. The fabric was a duplex fabric composed of a carded needle punched staple web which had been needled to a layer of needle punched continuous tow. Segment thickness in the free stage form before the preform assembly needling process was 3-4 mm. Two different size segments were used in the manufacture of the preforms of this Example. Rotor preforms were manufactured from segments having an inside radius of 5.5 inches and on outside radius of 10.5 inches. Stator preforms were manufactured from segments having an inside radius of 4.875 inches and an outside radius of 975 inches. Both segments types were manufactured using the 68 degree arc. The number of segment layers in the preforms used in this Example ranged form 26 to 32. These segments were derived from +45 degree and −45 degree s egments like those depicted in FIG. 1B. In this embodiment of the invention, the continuous fibers were at a +45 degree fiber angle to the segment arc bisector in half of the layers of the preform, and each of the +45 degree segment layers was separated from other +45 degree segment layers by a −45 degree segment layer. The −45 orientation was achieved by inverting +45 degree segments.
[0045] Needling was carried out with a conventional annular needling machine. Individual fabric segments were placed one at a time onto a rotating closed cell polymeric foam ring having the inside diameter and outside diameter of the annular shape of the preform being manufactured. The segments were laid end to end and needled together following a helical lay-up pattern to a desired weight and dimension. As the preform grew in thickness, it was lowered to maintain the same needle penetration depth from layer to layer. The resultant preform was composed of many layers of segments that are mechanically bonded together during the needling process. The foam ring was removed at the end of the preforming process. The resulting preform is depicted schematically in FIG. 2.
[0046] The preforms manufactured from these architectures were heat-treated to a approximately 1500° C., in an in ert atmosphere, to convert the fibers to carbon. The performs were then densified with a mixed hydrocarbon gas, using a forced flow CVI/CVD process to deposit carbon matrices in the fibrous preform substrates. Finally, the densified preforms were heated again to above 1500° C. to set desired therm al, mechanical, and frictional properties for the composite.
Example 3
[0047] Full size aircraft brake discs were made following the ±45 degree architecture procedure of Example 2. The discs were configured in standard B767-300 geometry. The full scale brake was of a four rotor configuration. That is, the brake was composed of 4 rotors, 3 stators, 1 pressure plate, and 1 backing plate. The approximate dimensions of the components were as follows:
Outside Diameter Inside Diameter Thickness Brake part (inches) (inches) (inches) Rotor 18.13 11.00 1.06 Stator 16.75 10.00 1.06 Pressure plate 16.75 10.00 0.97 Backing plate 16.75 11.00 0.80
[0048] These discs were subjected to a Wear test designed to mimic a standard commercial aircraft usage spectrum, including cold taxi stops (representing pre-takeoff taxi stops), a landing stop, and a series of hot taxi stops (representing post-landing taxi stops as the aircraft approaches the gate). Wear test landing energies are distributed between various energy levels representing the variations in aircraft loadings which occur in actual commercial service.
[0049] The Wear test was run as follows:
[0050] Sequence #1—nine c old taxis, 50% service energy (1.463 Mft-lbs) landing stop, eight hot taxis. (Sequence repeated 120 times.)
[0051] Sequence #2—nine c old taxis, 75% service energy (2.194 Mft-lbs) landing stop, seven hot taxis. (Sequence repeated 60 times.)
[0052] Sequence #3—nine c old taxis, 100% service energy (2.925 Mft-lbs) landing stop, seven hot taxis. (Sequence repeated 20 times.)
[0053] Each test was run once in a Single Rotor Brake configuration and once in a Full Brake configuration. For the Single Rotor Brake test, the resulting wear was only 84 micro-inches/surface/sequence, and for the Full Brake test, the resulting wear was only 92 micro-inches/surface/sequence. In comparison, conventional B767 brake discs show a wear in these tests of 154 micro-inches/surface/sequence.
[0054] It is to be understood that the foregoing description and specific embodiments are merely illustrative of the principles of the invention. Modifications and additions to the invention may easily be made by those skilled in the art without departing from the spirit and scope of the invention as it is recapitulated in the appended claims.
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Carbon fiber brake preforms ( 20 ), specifically, annular discs built up of fabric arc segments ( 21 ) composed of continuous fibers ( 25 ) and staple fibers ( 26 ). Most of the continuous fibers ( 25 ) in the fabric segments ( 21 ) are arranged to be located within 60° of radially from th e inner diameter to the outer diameter of the annular disc ( 20 ). The fabric arc segments have substantially all of their continuous fibers oriented in the radial direction and parallel to the segment arc bisector, or the segments are arranged in alternating layers in which, respectively, half the continuous fibers are oriented at a +45 degree angle with respect to the segment arc bisector and half the continuous fibers are oriented at a −45 degree angle with respect thereto. Methods for making preform composites comprise providing needle-punched nonwoven fabric of unidirectional continuous fibers and staple fibers, making a plurality of fabric segments, arranging the segments in a multilayered intermediate, heating the multilayered intermediate to convert the fibers to carbon, and densifying the carbonized product. In brake discs made as described, fiber pull-out is minimized, reducing mechanical wear. The disclosed preform fiber architecture reduces wear rates while maintaining brake disc strength.
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REFERENCE TO PROVISIONAL APPLICATION
This application claims benefit of the filing date of U.S. Provisional Application No. 60/374,731 filed Apr. 23, 2002.
BACKGROUND OF THE INVENTION
The present invention relates to a fitting for use with air tanks and, more particularly, to a fitting including a twist end bushing for interfacing with an opening in an air tank.
Air tanks are typically provided with fittings for connection to tubing or other passageways leading to the air tank. In the past, such fittings have been attached to the air tank by means of a bushing welded to an aperture formed through the wall of the tank. Accordingly, production of the tank requires attention to proper formation of the weld connection and a corresponding labor and manufacturing time cost associated with this operation.
Accordingly, there is a need for a fitting structure for use with air tanks wherein the fitting structure is easily assembled to the tank. In addition, there is a need for such a fitting structure wherein the fitting structure provides a reliable seal with the tank.
SUMMARY OF THE INVENTION
A fitting connection is provided for use with a pressure vessel wherein the fitting connection includes a bushing having a cylindrical bushing body and a head portion located at an upper end of the bushing body. The bushing body is inserted through an aperture in a pressure vessel wall to form an interface between the pressure vessel wall and a fitting, such as a fitting for an air tube leading from the pressure vessel.
In one embodiment, a pair of diametrically opposed locking members are located on the bushing body in spaced relation to the head portion to define a groove between a lower surface of the head portion and an upper surface of the locking members for receiving edge portions of the vessel wall defining the aperture. In addition, an upper surface of each locking member is contoured to increase frictional engagement and provide a resistance to turning of the bushing body when it is mounted to the pressure vessel in order to insure that a predetermined torque force is required to remove or loosen the bushing from the pressure vessel. The contoured surface includes a recess for receiving a detent formed on an interior surface of the pressure vessel wall.
The locking members are further formed with catch elements extending parallel to a longitudinal axis of the bushing body and located in spaced relation to the bushing body. The catch elements include a tang element at a distal end thereof for preventing withdrawal of the bushing body from the aperture.
In a second embodiment, the bushing body has four equally spaced locking members, which have contoured surfaces with recesses to receive the four equally spaced detents on the interior surface of the pressure vessel wall.
Other objects and advantages of the invention will be apparent from the following description, the accompanying drawings and the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a bottom perspective view of the bushing for the fitting connector of the present invention;
FIG. 2 is a side elevational view of the bushing of FIG. 1 ;
FIG. 3 is a cross-sectional view taken along the line 3 — 3 of FIG. 2 through the center of the bushing and passing through the locking members;
FIG. 4 is a top perspective view of an end wall for a pressure vessel configured for use with the bushing of the present invention;
FIG. 5 is an interior plan view thereof;
FIG. 6 is a cross-sectional view taken along line 6 — 6 in FIG. 5 ;
FIG. 7 is a cross-sectional view taken through the assembled bushing and pressure vessel wall;
FIG. 8 is a bottom perspective view of a second embodiment of the bushing for the fitting connector of the present invention;
FIG. 9 is a side elevational view of the bushing of FIG. 8 ;
FIG. 10 is a bottom plan view of the bushing of FIG. 8 ; and
FIG. 11 is an interior plan view of an embodiment of an end wall for a pressure vessel configured for use with the bushing of FIG. 8 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to FIGS. 1-3 , the fitting structure of the present invention includes a bushing 10 for mounting to the wall of a tank and for supporting a fitting, illustrated diagrammatically as 12 . The bushing includes a cylindrical body 14 defined by a cylindrical outer surface 16 and a cylindrical inner surface 18 wherein the cylindrical inner surface 18 defines a cylindrical aperture through the bushing 10 .
A head portion 20 is formed integrally with and extends radially outwardly from the cylindrical body 14 . The head portion 20 defines a tool-engaging portion of the bushing 10 and in the illustrated embodiment is provided with a hexagonal shape for engagement with a wrench.
A pair of locking members 22 , 24 are located on diametrically opposite sides of the cylindrical body 14 . Each locking member 22 , 24 includes a base portion 25 extending radially from the outer surface 16 of the cylindrical body 14 and includes an upper surface 26 facing toward a lower surface 28 of the head portion 20 .
Each locking member 22 , 24 further includes a catch element 30 extending downwardly from the base portion 25 parallel to a longitudinal axis 13 of the body 14 and in spaced relation to the outer surface 16 of the cylindrical body 14 . The catch elements 30 each include a pair of tangs 32 , which are separated by a notch or groove 130 .
The upper surface 26 of the base portion 25 includes an end wall 34 at one end thereof, and the surface 26 at an opposite end 36 is inclined or ramped slightly upwardly in a direction toward the end wall 34 (see FIG. 2 ). Further, the upper surface 26 includes a recessed portion 38 intermediate the ends of the upper surface 26 .
Referring to FIGS. 4-6 , an end wall 40 for an air tank is illustrated and includes an aperture 42 having a diameter closely matching the diameter of the outer surface 16 of the cylindrical body 14 . A pair of slots 44 , 46 are defined on diametrically opposite sides of the aperture 42 and are formed with a length in a circumferential direction, which corresponds to the circumferential length of the catch elements 30 .
In addition, a protruding detent element 48 , 50 is located adjacent to each of the slots 44 , 46 on an interior surface 52 of the end wall 40 , as may be best seen in FIGS. 5 and 6 .
It should be noted that the end wall 40 is generally formed with a dome shape. However, the area directly surrounding the aperture 42 is formed as a circular flattened area to define a generally flat annulus area 54 .
Referring further to FIG. 7 , the bushing 10 is assembled to the end wall 40 by inserting the bushing 10 with the locking elements 22 , 24 passing through the slots 44 , 46 . It should be noted that as the locking members 22 , 24 pass through the slots 44 , 46 , the tangs 32 will cause the catch elements 30 to flex inwardly, and further will prevent removal of the bushing 10 from the aperture 42 without application of an inward force on the catch elements 30 .
With the bushing 10 fully inserted through the aperture 42 , a groove area 56 (see FIG. 3 ) defined between the upper surface 26 of the locking members 22 , 24 and the lower surface 28 of the head portion 20 will be aligned with an edge of the end wall 40 . Rotation of the bushing 10 in a clockwise direction will cause the edge of the end wall 40 to pass into the grooves 56 . Further, during rotation, the detents 48 , 50 will ride along the inclined portions 36 until they engage within the recesses 38 in a stop position. The end walls 34 are located to engage edges of the slots 44 , 46 to prevent over-rotation of the bushing 10 .
It should be noted that rotation of the bushing 10 results in the detents 48 , 50 progressively biasing the head portion 20 into engagement with the upper surface of the end wall 40 , and that engagement of the detents 48 , 50 within respective recesses 38 provides a predetermined frictional engagement between the bushing 10 and the end wall 40 which requires a predetermined torque force to remove the bushing 10 through counterclockwise rotation. Further, the downward force applied against the head portion 20 results in a sealing force applied against an O-ring 58 located within a groove 60 in the lower surface 28 of the head portion 20 . Also, to further facilitate sealing of the head portion 20 against the upper surface of the end wall 40 , the upper surface of the end wall 40 is provided with a powder coating to insure a very smooth sealing surface between the O-ring 58 and the end wall 40 .
When air pressure is present interiorly of the end wall 40 , such as air pressure present within an air tank, the bushing 10 will be biased outwardly, thus increasing the frictional pressure at the engagement between the upper surfaces 26 of the locking members 22 , 24 and the detents 48 , 50 . This additional pressure and frictional force insures that the bushing 10 is prevented from being rotated out of engagement with the end wall 40 when an air pressure is present within the tank.
FIGS. 8-11 show a second embodiment of the bushing generally indicated at 10 ′ for insertion in an end wall 40 ′, which has slots 44 and 46 and additional slots 144 and 146 . The four slots 44 , 46 , 144 and 146 are equally spaced around the opening or aperture 42 ′. The end wall 40 ′ has the two detents 48 and 50 along with additional detents 148 and 150 , so that the four detents are equally spaced around the aperture 42 ′. The bushing 10 ′ has four equally spaced locking members 22 ′, 122 , 24 ′ and 124 , whose structure is the same as members 22 and 24 , except the catch element 30 ′ of each member does not have the ramped or inclined surface 36 and does not have the groove or notch 130 of the embodiment of FIGS. 1-3 and, thus, each locking member 22 ′, 122 , 24 ′ and 124 has a continuous tang 32 ′. However, each of the elements 30 ′ could be further modified to have an inclined or ramped surface at the open end of the groove 56 ′.
The bushing 10 ′ is assembled in the end wall 40 ′ in the same manner as the bushing 10 in the end wall 40 . The only difference is that the bushing 10 ′ has four locking members 22 ′, 122 , 24 ′ and 124 , each with a depression or recessed portion 38 instead of just two locking members 22 and 24 .
While the form of apparatus herein described constitutes a preferred embodiments of this invention, it is to be understood that the invention is not limited to this precise form of apparatus, and that changes may be made therein without departing from the scope of the invention which is defined in the appended claims.
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A fitting connector for a pressure vessel including a bushing for mounting within an aperture defined in a pressure vessel wall. The bushing includes a cylindrical bushing body having a head portion at one end thereof and including at least a pair of locking members for engaging along an interior surface of the pressure vessel wall. The locking members are provided with a contoured surface for engaging with detent members formed on the interior of the pressure vessel wall whereby the bushing is positively locked in a predetermined rotational orientation on the pressure vessel wall and is retained in place until a predetermined torque force is applied.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The present invention relates to background signal processing technologies, and, more specifically, to a background signal processing method and a background signal processing system used in a touch panel.
[0003] 2. Description of Related Art
[0004] It is necessary to filter out the background noise in order to accurately detect the signal with a touch panel, particularly when used in capacitance type of touch panel, so as to prevent signal distortion. However, the background noise of the sensor is not constant. As a result, it is required to frequently detect the background noise and also update the background noise value, to ensure the quality of signals that are to be captured.
[0005] However, with the increasing size of the touch panel, the high precision requirement and so on, the numbers of sensors used in a touch panel must increase, such that the workloads for regularly detecting the background noise and updating information increase. Further, high frequently performing tasks for updating background noise in a system that is overloaded can adversely lower the reading frequency, leading to low performance for the torch panel, such as an interruption of signal when a continuous touch signal is being detected.
[0006] On the contrary, signal distortion may be resulted when the frequency of updating background noise is too low, and unaffordable workload for processing and updating background noise can adversely affect the reading frequency. Thus, there is an urgent need for developing a solution for reducing the workload of updating background noise as well as increasing the updating speed, so as to increase the reading frequency of signals.
SUMMARY OF THE INVENTION
[0007] In view of the foregoing prior art problems, the present invention provides a background signal processing method and a background signal processing system to reduce the burden of updating background noise so as to increase the speed with the quality assured signals being captured, for increasing the reading frequency of the touch penal frequency.
[0008] The present invention provides a background signal processing method, which is used in a sensor device having a plurality of conductive wires and a plurality of predetermined background signal thresholds and background base signal values, the background signal processing method comprising the following steps of: detecting a first background signal measurement value of a first conductive wire group in the conductive wires according to a first conductive wire number interval, beginning from an n th conductive wire, wherein n is a positive integer; determining whether the first background signal measurement value complies with the predetermined first background signal threshold, if yes, stopping in this step, otherwise, determining whether the first background signal measurement value complies with the predetermined second background signal threshold, if yes, updating the background signal, otherwise, detecting a second background signal measurement value of a second conductive wire group in the conductive wires according to the first conductive wire number interval, beginning from an (n+m) th conductive wire, wherein m is a positive integer; and calculating a background signal speculating value of a third conductive wire group in the conductive wires according to the first background signal measurement value and the second background signal measurement value, wherein the third conductive wire group is derived by excluding the first conductive wire group and the second conductive wire group.
[0009] The present invention provides a background signal processing system, which is used in a sensor device having a plurality of conductive wires and a plurality of predetermined background signal thresholds and background base signal values, the background signal processing system comprising: a storage unit that stores the background signal threshold; a measurement unit that detects a background signal measurement value of the conductive wires; and a determination module that determines whether the background signal measurement value complies with the background signal threshold.
[0010] Compared with the conventional technology, which measures the background signals of all the conductive wires, the present invention provides a background signal processing method and a background signal processing system, which measure some of the conductive wires: the first conductive wire group to obtain the first background signal measurement value, then determine whether a subsequent action is required according to the first background signal measurement value. If the first background signal measurement value complies with the first background signal threshold, the difference between the current background signal and the background base signal can be ignored. Therefore, remaining detection steps can be omitted. This greatly simplifies the updating steps for background signals and reduces the workload.
[0011] If subsequent actions are required, the background signal is updated according to the first background signal measurement value or a subsequent measurement is performed. If the first background signal measurement value complies with the second background signal threshold, the background signal is directly updated, or the second conductive wire group among all the conductive wires is measured to obtain a more accurate value. According to the second background signal measurement value obtained and first background signal measurement value obtained prior to that, a background signal speculating value of a third conductive wire group, other than the first conductive wire group and the second conductive wire group, in the conductive wires is calculated. Through setting the threshold to select an appropriate conductive wire number to be measured to calculate the signal speculating values of the remaining unmeasured conductive wires. This provides a complete accurate background signal to ensure reduced total workload as well as quality signal being captured.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is a schematic view showing the arrangement of conductive wires applied in a background signal processing method and a background signal processing system according to the present invention;
[0013] FIG. 2 is a flow chart of a background signal processing method according to the present invention;
[0014] FIG. 3 is a flow chart of a background signal processing method of another embodiment according to the present invention; and
[0015] FIG. 4 is a functional block diagram of a background signal processing system according to the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0016] The present invention is described in the following with specific embodiments, so that one skilled in the pertinent art can easily understand other advantages and effects of the present invention from the disclosure of the present invention.
[0017] FIG. 1 is a schematic view showing the arrangement of conductive wires applied in a background signal processing method and a background signal processing system according to the present invention.
[0018] The background signal processing method according to the present invention can be applied in a sensor device having a plurality of conductive wires, such as a sensor device used in a touch panel. In an embodiment, the arrangement of a plurality of conductive wires can be used in a touch panel with capacitance type of sensor technology. As shown in FIG. 1 , two conductive wire groups each comprise nine conductive wires are arranged in an orthogonal manner. The conductive wires arranged in rows are A 1 -A 9 , and the conductive wires arranged in columns are B 1 -B 9 . Each of the conductive wires can have both driving and sensing functions.
[0019] In an embodiment, the capacitive sensing technology is used to determine the location of the touch control signal. The method of capacitive sensing can be measuring the self capacitance and mutual capacitance from the conductive wires. Take the conductive wires arrangement in FIG. 1 , when the self capacitance of the conductive wires A 1 -A 9 are measured, conductive wires B 1 -B 9 are not driven, the sensor function of A 1 -A 9 are respectively used to sensing the self capacitance. On the other hand, when measuring the mutual capacitance, firstly conductive wire A 1 , then conductive wires B 1 -B 9 are driven, as well as using the senor function of A l to sense the mutual capacitance with respect to the conductive wires B 1 -B 9 , after that, repeat the same steps for conductive wires A 2 -A 9 , respectively to obtain the mutual capacitance of the conductive wire A 1 -A 9 with respect to the conductive wires B 1 -B 9 , and so on. Moreover, the background signal processing method and system proposed by the present invention can be simultaneously used for the measuring method for self capacitance and mutual capacitance.
[0020] The sensor device may be configured to have a plurality of predetermined background signal thresholds. In an embodiment, after the sensor device has performed a plurality of (e.g., 10 to 30 times) complete set of background signal measurement in an isolated electromagnetic compatibility (EMC) environment, a set of base signal, including the average value and standard deviation of the background signal, is obtained using a static method, which is used as the basis for updating the background signal, and according to the background base signal to determine the background signal thresholds. For instance, the background signal thresholds can be the absolute value of the difference of the two (or more than two) standard values of the background base signals.
[0021] FIG. 2 is a flow chart of a background signal processing method according to the present invention. The background signal processing method comprises the following steps of:
[0022] (S 1 ) detecting a first background signal measurement value of a first conductive wire group in the conductive wires according to a first conductive wire number interval, beginning from an n th n conductive wire, wherein n is a positive integer;
[0023] (S 2 ) determining whether the first background signal measurement value complies with the predetermined first background signal threshold, if yes, stopping in this step, otherwise proceeding to step ( 3 );
[0024] (S 3 ) determining whether the first background signal measurement value complies with the predetermined second background signal threshold, if yes, preceding to step ( 4 ), otherwise, proceeding to step ( 5 );
[0025] (S 4 ) updating the background signal;
[0026] (S 5 ) detecting a second background signal measurement value of a second conductive wire group in the conductive wires according to the first conductive wire number interval, beginning from an (n+m) th conductive wire, wherein m is a positive integer; and
[0027] (S 6 ) calculating a background signal speculating value of a third conductive wire group in the conductive wires according to the first background signal measurement value and the second background signal measurement value, wherein the third conductive wire group is derived by excluding the first conductive wire group and the second conductive wire group.
[0028] In step (S 1 ), n is a positive integer. Referring to FIGS. 1 and 2 , take the configuration that two groups each having 9 conductive wires as an example. As shown in FIG. 1 , when the conductive wires A 1 -A 9 are measured, n can be made equal to 1, that is from conductive wire A 1 , the first conductive wire number interval (for example 4) is used to detect conductive wires A 1 -A 9 , i.e., conductive wires A 1 , A 5 and A 9 , which are in the first conductive wire group, so as to obtain the first background signal measurement value.
[0029] In step (S 2 ), the first background signal measurement value is to be determined whether it complies with the predetermined background signal threshold, so as to determine the current first background signal measurement value and whether the difference between the background base signals exceeds the predetermined permissible range. In an embodiment, the background signal threshold can be, but is not limited to, the absolute value of two standard value of the base signal. When the first background signal measurement value complies with the background signal threshold, it is indicated that the absolute value of the first background signal measurement value is smaller than the background signal threshold. If this condition is met, which means the difference of the base signals is still within the predetermined permissible range, updating or other actions are not required, and the method ends and enters a touch signal detecting mode. If the condition is not met, which means the difference between the base signals exceeds the predetermined permissible range, step (S 3 ) follows.
[0030] In step (S 3 ), whether the first background signal measurement value complies with the predetermined second background signal threshold is determined, so as to determine the next move to be updating or measuring more wires. In an embodiment, the second background signal threshold can be the absolute value of three (or more than three) standard difference values of the background base value. The background signal can be directly updated, when the first background signal measurement value complies with the second background signal threshold, meaning that the absolute value of the first background signal measurement value is smaller than the second background signal threshold, proceeding to step (S 4 ). If the above condition is not met, meaning that the difference value between the background signal and the base signal exceeds the permissible range, proceeding to step (S 5 ).
[0031] In step (S 4 ), the first background base signal is modified according to the first background signal measurement value, in order to update all of the background signals of the sensor device. Then, the touch signal detecting mode can be entered.
[0032] In step (S 5 ), m is a positive integer, for example 2 . As shown in FIG. 1 , in the embodiment of n=1, beginning from the (n+m) th conductive wire, i.e., from conductive wire A 3 , the first conductive wire number interval (for instance 4 ) is used to detect conductive wires A 1 -A 9 , i.e., conductive wires A 3 and A 7 , which are in the second conductive wire group, so as to obtain the second background signal measurement value.
[0033] In step (S 6 ), according to the first background signal measurement value measured from conductive wires A 1 , A 5 and A 9 , and the second background signal measurement value measured from conductive wires A 3 and A 7 , the background signal speculating value of the conductive wires A 2 , A 4 , A 6 and A 8 in the third conductive wire group outside of the A 1 , A 5 and A 9 in the first conductive wire group and the A 3 and A 7 in the second conductive wire group can be obtained.
[0034] In the background signal processing method according to the present invention, through setting a plurality of background signal thresholds to select appropriate wire numbers, fewer wires are to be measured when the measured background signals comply with a predetermined permissible range, so as to reduce the system workload and increase the processing speed.
[0035] When the measured background signal is beyond the predetermined permissible range, more wires shall be measured to obtain a more detailed information for the background signal, through obtaining the background signals of all wires A 1 -A 9 or the speculating values, for serving as the reference, in order to filter out the noise during the subsequent process of capturing the touch signals, thereby ensuring high accuracy and quality of the touch signals being captured. For instance, only conductive wires A 1 , A 3 , A 5 , A 7 and A 9 are measured, as compared to all conductive wires in the prior art. In other words, only 5/9 of the conductive wires are measured, thereby greatly reducing the workload for updating the background noise, as well as increasing the updating speed.
[0036] In an embodiment, the background signal processing method according to the present invention further comprises step (S 7 ) updating all of the background signals of the sensor device according to the first background signal measurement value, the second background signal measurement value and the background signal speculating value of a third conductive wire group as the new basis. Then, the touch signal detecting mode can be entered.
[0037] Referring to FIG. 3 , in another embodiment the background signal processing method further comprises the step of (S 7 ′) updating all of the background signals of the sensor device according to a ratio of the first background signal measurement value, the second background signal measurement value and the background signal speculating value of the third conductive wire group to the background base signal, that is multiplying the background base signal with the ratio, to calculate the background signals of all the conductive wires for updating. Then, the touch signal detecting mode can be entered.
[0038] In an embodiment, the aforesaid step (S 4 ) comprises the following steps of:
[0039] ( 4 - 1 ) calculating a ratio between first background signal measurement value and background signal base value; and
[0040] ( 4 - 2 ) updating all of the background signals of the sensor device according to the ratio, and then entering the touch signal detecting mode. Through the ratio between the first background signal measurement value and the background signal base value, that is multiplying the background base value by the ratio, the background signal for all wires can be calculated for the updating.
[0041] In the aforesaid step (S 6 ) of one embodiment, the background speculating value of the third wire group is calculated by interpolation method, such as lagrange interpolation, spline interpolation or other interpolation method. Take the aforementioned embodiment of measuring of the wires A 1 -A 9 as an example, the background signal measurement value of the wires A 1 and A 3 are used to calculate the background signal speculating value of wire A 2 using linear interpolation method; or use the background signal measurement value of wire A 3 and A 5 , to calculate the background signal speculating value of wire A 4 using linear interpolation method, and so on.
[0042] FIG. 4 is a functional block diagram of a background signal processing system 1 according to the present invention. The background signal processing system 1 can be applied in a sensor device having a plurality of conductive wires. The sensor device comprises a plurality of predetermined background signal thresholds and background base signal values. The background signal processing system 1 comprises a storage unit 10 , a measurement unit 11 and a determination module 12 , and a processing unit 13 or a calculation module 14 , optionally.
[0043] The storage unit 10 is used to store the background signal threshold, which is determined by the base signal.
[0044] The measurement unit 11 is used to detect the background signal measurement value of the conductive wires.
[0045] The determination module 12 is used to determine whether the background signal measurement value complies with the background signal threshold. In an embodiment, the background signal threshold can be the absolute value of two standard difference value of the base signal. When the background signal measurement value complies with the threshold, it is indicated that the absolute value of the background signal measurement value is smaller than the threshold.
[0046] In an embodiment, the sensor device comprises a first background threshold and a second background signal threshold that is higher than the first background threshold. For instance, the first background threshold is the absolute value of the two standard difference values of the background base signal, and the second background signal threshold is the absolute value of the absolute values of the three standard difference values of the background base signal. In an embodiment, the determination module 12 further generates a background signal updating signal when the background signal measurement value does not comply with the first background signal threshold, but complies with the second background signal threshold, which indicates that the absolute value of the background signal measurement value is greater than the first background signal threshold, but less than the second background signal threshold. The background signal processing system 1 can optionally includes a processing unit 13 that updates the background signals after receiving the first background signal updating information.
[0047] In an embodiment, the processing unit 13 further calculates the ratio between the background signal measurement value and the background base signal value. The ratio is used to update the background signal value.
[0048] In an embodiment, the sensor device comprises a first background signal threshold and a second background threshold that is higher than the first background signal threshold. The determination module 12 further used sends the second background signal updating instructions when the background signal measurement value does not comply with the second background base signal value. The background signal processing system 1 can optionally comprise a processing unit 13 for updating the background signals after receiving the second background signal updating information
[0049] In an embodiment, the background signal processing system 1 can be applied in a sensor device having a plurality of conductive wires arranged in an orthogonal manner, as shown in FIG. 1 .
[0050] In an embodiment, the measurement unit 11 can be used to detect the first background signal measurement value of the first conductive wire group in the conductive wires, beginning from the n th conductive wire, according to the first conductive wire number interval. The determination module 12 is used to determine whether the first background signal measurement value complies with the predetermined background signal threshold, wherein n is a positive integer. The determination module 12 determines whether the first background signal measurement value complies with the predetermined first background signal threshold. The determination module 12 , when determining that the first background signal measurement value does not comply with the first background signal threshold, further determines whether the first background signal measurement complies with the predetermined second background signal threshold.
[0051] When the determination module 12 determines that the first background signal measurement value does not comply with the second background threshold, the measurement unit 11 can be used to, when the first background signal measurement value does not comply with the predetermined background signal threshold, detect the second background signal measurement value of the second conductive wire group in the plurality of conductive wires according to the first conductive wire number interval, beginning from the (n+m) th conductive wire, wherein m is a positive integer.
[0052] In an embodiment, the background signal processing system 1 can optionally includes a calculation module 14 , which is used to calculate the background signal speculating value of the third conductive wire group, other than the first conductive wire group and the second conductive wire group, in the conductive wires according to the first background signal measurement value and the second background signal measurement value. Since the background signal measurement value or the background signal speculating value are obtained for all the conductive wires, the noise can be filtered out during the process of capturing the touch signals, for ensuring that the signals to be captured have high precision and high quality.
[0053] In an embodiment, the calculation module 14 is used to calculate the background signal of the third conductive wire group by an interpolation method, such as Lagrange interpolation, Spline interpolation or other interpolation method, so as to obtain the background signal speculating value.
[0054] In summary, the background signal processing method and the background signal processing system according to the present invention measure some of the conductive wires: the first conductive wire group to obtain the first background signal measurement value, then determine whether a subsequent action is required according to the first background signal measurement value, if the measurement value complies with the first background signal threshold, the difference between the current background signal and the background base signal can be omitted, such that the remaining other detection steps are omitted. This greatly simplifies the updating steps for background signal and reduces the workload.
[0055] If subsequent actions are required, updating or further measuring is determined according to the first background signal measurement value. If the first background signal measurement value complies with the second background signal threshold, the background signal is updated directly, or the second conductive wire group of all the conductive wires is measured, and the second background signal measurement value obtained and the first background signal measurement value obtained prior to that are used to calculate the background signal speculating value of the third conductive wire group, other than the first conductive wire group and the second conductive wire group, in the conductive wires. Through setting the threshold to select an appropriate conductive wire number to be measured to calculate the signal speculating values of the remaining unmeasured conductive wires, complete background signals can be provided. Therefore, the quality of the captured signals is ensured, and the workload of the background signals is reduced.
[0056] The present invention has been described using exemplary preferred embodiments. However, it is to be understood that the scope of the present invention is not limited to the disclosed embodiments. On the contrary, it is intended to cover various modifications and similar arrangements. The scope of the claims, therefore, should be accorded the broadest interpretation so as to encompass all such modifications and similar arrangements.
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A background signal processing method and a background signal processing system are provided. The background signal processing method includes measuring a first conductive wire group, comparing a first background signal measurement value with a predetermined background signal threshold value to determine their difference, and executing the following steps according to the amount of the difference: (1) performing no updating; updating the background signal according to the first background signal measurement value; and further measuring a second conductive wire group and calculating a background signal speculating value of a third conductive wire group, other than the first and second conductive wire groups, based on the second background signal measurement value and the first background signal measurement value, to provide the complete background signals and ensure the quality of the captured signals.
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BACKGROUND OF THE INVENTION
This invention relates to the generation of charged particles, and more particularly, to the control of electrostatic latent images formed from this charged particle source.
A wide variety of techniques are commonly employed to generate ions in various applications. Conventional techniques include air gap breakdown, corona discharges, spark discharges, and others. The use of air gap breakdown requires close control of gap spacing, and typically results in non-uniform latent charge images. Corona discharges, widely favored in electrostatic copiers, provide limited currents and entail considerable maintenance efforts. Electrical spark discharge methods are unsuitable for applications requiring uniform ion currents. Other methods suffer comparable difficulties.
Apparatus and method for generating ions representing a considerable advance over the above techniques are disclosed in copending application Ser. No. 824,252, filed Aug. 12, 1977. The ion generator of this invention, shown in one embodiment at 10 in FIG. 1, involves the use of two conducting electrodes 12 and 13 separated by a solid insulator 11. When a high frequency electric field is applied between these electrodes by source 14, a pool of negative and positive ions is generated in the areas of proximity of the electrode edges and the dielectric surface. Thus in FIG. 1, an air gap breakdown occurs relative to a region 11-r of dielectric 11, creating an ion pool in hole 13-h, which is formed in electrode 13.
These ions may be used, for example, to create an electrostatic latent image on a dielectric member 15 with a conducting backing layer 16. When a switch 18 is switched to position X and is grounded as shown, the electrode 16 is also at ground potential and little or no electric field is present in the region between the ion generator 10 and the dielectric member 15. However, when switch 18 is switched to position Y, the potential of the source 17 is applied to the electrode 13. This provides an electric field between the ion reservoir 11-r and the backing of dielectric member 15. Ions of a given polarity (in the generator of FIG. 1, negative ions) are extracted from the air gap breakdown region and charge the surface of the dielectric member 15.
One advantageous use of this invention, disclosed in the above application, is the formation of characters and symbols in high speed electrographic printing. Apparatus for the formation of dot matrix characters and symbols on dielectric paper or intermediate dielectric members is shown in FIG. 2. A matrix ion generator 20 includes a dielectric sheet 21 with a set of apertured air gap breakdown electrodes 22-1 through 22-4 on one side and a set of selector bars 23-1 through 23-4 on the other side. A separate selector 23 is provided for each different aperture 24 in each finger electrode 22. Ions can only be extracted from an aperture when both its selector bar is energized with a high voltage alternating potential and its finger electrode is energized with a direct current potential applied between the finger electrode and the counterelectrode of the dielectric surface to be charged. Dot matrix characters may be formed using this apparatus by stringing together a series of electrostatic dot images. This is done by moving the dielectric surface to be charged at a prescribed rate past the matrix ion generator 20, and applying direct current pulses to the finger electrodes 22 at a suitable frequency to create a series of overlapping dots.
It has been discovered, however, that this invention suffers a serious disadvantage when utilized in such a dot matrix embodiment, which is illustrated in FIGS. 2 and 3. At an initial time t 1 , a given aperture 24 23 on matrix ion generator 20 is energized by a direct current pulse which creates a negative potential on a finger electrode 22-2, while a high frequency potential is applied to selector bar 23-3. This causes the formation of an electrostatic dot image which is negative in polarity, occupying regions 32 and 33 on dielectric surface 30 with backing electrode 31. At a later time t 2 , aperture 24 23 is over regions 33 and 34, selector bar 23-3 is still energized, but as charging is not desired, no negative pulse is applied to finger electrode 22-2. The presence of negative electrostatic image in region 33, however, attracts positive ions from the aperture 24 23 , erasing the previously created image in this region.
Accordingly it is a principal object of the invention to provide improved apparatus of the type described above for generating ions. A related object of the invention is the achievement of better control over the charging of dielectric members using such ion generating apparatus.
It is another object of the invention to provide a superior matrix printing apparatus using this ion generating principle. A related object is the avoidance of undesired erasures of electrostatic images.
SUMMARY OF THE INVENTION
In accomplishing the foregoing and related objects, the invention provides for applying a potential between electrodes separated by a solid dielectric member, with a third electrode used to control the discharge of ions thus generated. A high frequency alternating potential is applied between a first, "driver" electrode and a second, "control" electrode, causing an electrical air gap breakdown in fringing field regions. A third, "screen" electrode is separated from the control electrode by a second layer of dielectric. Ions produced by the air gap breakdown can be extracted subject to the influence of the screen electrode and applied to a further member.
In accordance with one aspect of the invention, the applied alternating potential stimulates the generation of a pool of ions of both polarities in a discharge aperture at a junction of the first dielectric member and the control electrode. Ions of one polarity are attracted from this pool to a remote dielectric member if a direct current potential of the same polarity is applied between the control electrode and a conducting layer underlying the remote dielectric member. The screen electrode may be given a lesser constant potential of the same polarity to counteract the tendency of an electrostatic image of this polarity to attract oppositely charged ions from the discharge aperture when the direct current potential is removed between the control electrode and the conducting sublayer.
In accordance with another aspect of the invention, the screen electrode is advantageously included in an ion generator which is intended for applications involving matrix electrographic printing of overlapping images. In a preferred embodiment of the invention, a dot matrix electrographic printer incorporates the screen electrode for the controlled creation of electrostatic images.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic and sectional view of a prior art ion generator and extractor.
FIG. 2 is a plan view of a prior art matrix ion generator.
FIG. 3 is a perspective view of a toned electrographic image on a conductor-backed dielectric member, as produced by the matrix ion generator of FIG. 3.
Various aspects of the invention will become apparent after considering several illustrative embodiments, taken in conjunction with the following:
FIG. 4 is a schematic and sectional view of an ion generator in accordance with the invention.
FIG. 5 is a schematic and sectional view of an ion generator and extractor in accordance with the invention.
FIG. 6 is a schematic view of an alternative circuit to be employed in the ion generator and extractor of FIG. 5.
DETAILED DESCRIPTION
Reference should be had to FIGS. 4-6 for a detailed description of the invention. An ion generator 40 in accordance with the invention is shown in the sectional view of FIG. 4. The ion generator 40 includes a driver electrode 41 and a control electrode 45, separated by a solid dielectric layer 43. A source 42 of alternating potential is used to provide an air gap breakdown in aperture 44.
A third, screen electrode 49 is separated from the control electrode by a second dielectric layer 47. The second dielectric layer 47 has an aperture 46 which advantageously is substantially larger than the aperture 44 in the control electrode. This is necessary to avoid wall charging effects. The screen electrode 49 contains an aperture 48 which is at least partially positioned under the aperture 44. In an electrographic matrix printer, for example, the driver and control electrodes may be the selector bars and finger electrodes of FIG. 2, and the screen electrodes may consist of either additional finger electrodes with apertures matching the pattern of the control electrodes or a continuous apertured metal plate or other member, with its openings adjacent to all printing apertures. The latter embodiment of the screen electrodes may take the form, for example, of an open mesh screen.
The application of the above ion generator in electrographic matrix printing is illustrated in FIG. 5. FIG. 5 shows the ion generator 40 of FIG. 4 used in conjunction with dielectric paper 50 consisting of a conducting base 53 coated with a dielectric layer 51, and backed by a grounded auxiliary electrode 55. When switch 52 is closed at position Y, there is simultaneously an alternating potential across dielectric layer 43, a negative potential V C on control electrode 45, and a negative potential V S on screen electrode 49. Negative ions in aperture 44 are subjected to an accelerating field which causes them to form an electrostatic latent image on dielectric surface 51, as in Ser. No. 824,252. The presence of negative potential V S on screen electrode 49, which is chosen so that V S is smaller than V C in absolute value, does not prevent the formation of the image, which will have a negative potential V I (smaller than V C in absolute value).
With switch 52 at X, and a previously created electrostatic image of negative potential V I partially under aperture 44, a partial erasure of the image would occur in the absence of screen electrode 49. Screen potential V S , however, is chosen so that V S is greater than V I in absolute value, and the presence of electrode 49 therefore prevents the passage of positive ions from aperture 44 to dielectric surface 41. See Example 1.
The inclusion of screen electrode 49 in the ion generator of the invention confers advantages beyond the prevention of image discharge under the conditions discussed above. The screen electrode may be used alone or in connection with the control electrode to control matrix image formation. With V S = 0, no latent image is produced due to the above discharge phenomenon. Thus, three level matrix image control is possible in an electrographic matrix printer in accordance with the invention.
Screen electrode 49 provides unexpected control over image size. Using the dot matrix print configuration shown in FIG. 2 with finger screen electrodes overlaid in accordance with the invention, image size may be controlled by varying the size of screen apertures 48. See Example 2, infra. Furthermore, using such a configuration, with all variables constant except the screen potential 56, a larger screen potential has been found to produce a smaller dot diameter. See Example 3. This technique may be used for the formation of fine or bold images. It has also been found that proper choices of V S and V C will allow an increase in the distance between ion generator 40 and dielectric surface 51 while retaining a constant dot image diameter. This is accomplished by increasing the absolute value of V S while keeping the potential difference between V S and V C constant. See Example 4.
Image shape may be controlled by using a given screen electrode overlay in a matrix electrographic printer. See Example 5. Screen apertures 48 may, for example, assume the shape of fully formed characters which are no larger than the corresponding round or square control apertures 44.
The electronic configuration used to control the electrographic printer of FIG. 5 may be modified to allow the possibility of biasing the system, as shown in the circuit schematic of FIG. 6. Element 61 is a pulse generator. The magnitude of the control pulse may be varied to produce a desired V C and V S by choosing an appropriate bias potential. For example, the following combinations will all produce V S =- 700 volts, V C =- 800 volts:
1. V Bias =-600 volts; ΔV S =-100 volts; ΔV C =-200 volts
2. V Bias =-500 volts; ΔV S =-200 volts; ΔV C =-300 volts
3. V Bias =-400 volts; ΔV S =-300 volts; ΔV C =-400 volts
4. V Bias =-300 volts; ΔV S =-400 volts; ΔV C =-500 volts
5. V Bias =-200 volts; ΔV S =-500 volts; ΔV C =-600 volts
The above advantages are further illustrated with reference to the following non-limiting examples:
EXAMPLE 1
A 1 mil. stainless steel foil is laminated to both sides of a sheet of 0.001 inch thick Kapton® polyimide film. The foil is coated with Resist and photoetched with a pattern similar to that shown in FIG. 2, with holes or apertures approximately 0.006 inches in diameter. A second Kapton® film, 0.006 inch in thickness is bonded to the foil in accordance with FIG. 4. A screen electrode with apertures of 0.015 inch diameter in the same pattern as those of the fingers is photo-etched from 1 mil. stainless steel, and bonded to the second Kapton® film with the finger and screen apertures being concentric. This construction provides a charging head which is used to provide a latent electrostatic image on dielectric paper, as illustrated in FIG. 5, with V C =-500 volts, V S =-400 volts, and an alternating potential 42 of 1 kilovolt peak at a frequency of 500 kilohertz. A spacing of 0.006 inch is maintained between the print head assembly and the dielectric surface 51. V C takes the form of a print pulse 20 microseconds in duration. Under these conditions, a latent image in the form of a dot of approximately -300 volts is produced on the dielectric sheet. This image is subsequently toned and fused to provide a dense dot matrix character image. The ion current extracted from discharge head as collected by an electrode 0.006 inch away from the head is found to be 0.5 milliampere per square centimeter. With the screen electrode 49 omitted, however, any electrostatic image under the control aperture will be erased when no print pulse is applied.
EXAMPLE 2
The electrographic printer of Example 1 was tested with a variety of diameters for screen aperture 48, and the size of the resulting electrostatic dot image measured. The following results are representative:
______________________________________ScreenAperture Diameter (inches) Dot Image Diameter (inches)______________________________________.015 .015.010 .012.008 .010______________________________________
It was found, in general, that a reduction in the size of the screen apertures caused a corresponding reduction of latent image size, without any compromise in image charge.
EXAMPLE 3
The electrographic printer of Example 1 was tested with a variety of screen potentials, V S , and the size of the resulting electrostatic dot measured. The following results are representative.
______________________________________Screen Potential (Volts) Dot Image Diameter (Inches)______________________________________-300 .022-400 .017-500 .012-600 .008______________________________________
It was found, in general, that by increasing the potential on the screen, the latent image size was reduced without any compromise in image charge.
EXAMPLE 4
The electrographic printer of Example 1 was tested using a variety of spacings between the print head assembly and the dialectric surface 51. By varying the screen potential, V S , and holding the potential difference between V S and V C constant, the size of the resulting electrostatic dot image was held constant. The following results are representative:
______________________________________Separation Dot Image Diameter(inches) V.sub.S (Volts) VC (Volts) (Inches)______________________________________.006 -400 -500 .015.010 -500 -600 .015.013 -600 -700 .015______________________________________
It was found in general, that with increasing print head assembly to dielectric surface spacing, an increase in screen potential, V S , provides constant dot image diameter without any compromise in image charge.
EXAMPLE 5
The electrographic printer of Example 1 was modified so that the screen had apertures 48 in the form of slots instead of holes. The resulting toned latent electrostatic images were oval in shape.
While various aspects of the invention have been set forth by the drawings and the specification, it is to be understood that the foregoing detailed description is for illustration only and that various changes in parts, as well as the substitution of equivalent constituents for those shown and described, may be made without departing from the spirit and scope of the invention as set forth in the appended claims.
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Generation of charged particles by extracting them from a high density source provided by an electrical gas breakdown in an electrical field between two conducting electrodes separated by a solid insulator, subject to the influence of a third electrode. The ions are generated by a high frequency alternating potential between a "driver" electrode and a "control" electrode. The ions are employed in charging a dielectric member to form a latent electrostatic charge image. A "screen" electrode between the control electrode and dielectric member isolates the potential on the dielectric member from the ion generating means, and provides an electrostatic lensing action.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent application Ser. No. 12/055,428, filed on Mar. 26, 2008.
BACKGROUND OF THE DISCLOSURE
[0002] 1. Field of the Disclosure
[0003] The present disclosure relates to methods for removing drill collars from well bores.
[0004] 2. Description of the Related Art
[0005] In oil and gas wells, a drill string that is used to drill a well bore into the earth. The drill string is typically a length of drill pipe extending from the surface into the well bore. The bottom end of the drill string has a drill bit.
[0006] In order to increase the effectiveness of drilling, weight in the form of one or more drill collars is included in the drill string. A string of drill collars is typically located just above the drill bit and its sub. The string of drill collars contains a number of drill collars. A drill collar is similar to drill pipe in that it has a passage extending from one end to the other for the flow of drilling mud. The drill collar has a wall thickness around the passage; the wall of a drill collar is typically much thicker than the wall of comparable drill pipe. This increased wall thickness enables the drill collar to have a higher weight per foot of length than comparable drill pipe.
[0007] During drilling operations, the drill string may become stuck in the hole. If the string cannot be removed, then the drill string is cut. Cutting involves lowering a torch into the drill string and physically severing the drill string in two, wherein the upper part can be removed for reuse in another well bore. The part of the drill string located below the cut is left in the well bore and typically cannot be retrieved or reused. Cutting is a salvage operation. A particularly effective cutting tool may be a radial cutting torch as disclosed by U.S. Pat. No. 6,598,679.
[0008] The radial cutting torch produces combustion fluids that are directed radially out to the pipe. The combustion fluids are directed out in a complete circumference so as to cut the pipe all around the pipe circumference.
[0009] It is desired to cut the drill string as close as possible to the stuck point, in order to salvage as much of the drill string as possible. Cutting the drill string far above the stuck point leaves a section of retrievable pipe in the hole.
[0010] If, for example, the drill bit or its sub is stuck, then in theory one of the drill collars can be cut to retrieve at least part of the drill collar string. Unfortunately, cutting a drill collar, with its thick wall, is difficult. It is much easier to cut the thinner wall drill pipe located above the drill collars. Consequently, the drill collar string may be left in the hole, as the drill string is cut above the drill collar.
[0011] It is desired to cut a drill collar for retrieval purposes.
SUMMARY OF THE DISCLOSURE
[0012] Embodiments of the present disclosure provide a method of severing a drill string or other tubular string that may include the steps of lowering a torch into the drill string, positioning the torch at a joint in the drill string, such that the joint may have a pin component engaged with a box component, igniting the torch to produce cutting fluids, and directing the cutting fluids into the joint in a direction that is along a length of the drill string to cut the joint.
[0013] The present disclosure provides a method of severing a drill collar string, which drill collar string forms part of a stuck drill string in a borehole. A torch is lowered into the drill string. The torch is positioned at a joint in the drill collar string. The torch is ignited so as to produce cutting fluids. The cutting fluids are directed into the joint in a direction that is along the length of the drill collar string so as to cut the joint and allow the joint to unwind.
[0014] In accordance with one aspect of the present disclosure, the step of positioning the torch at a joint in the drill collar string further comprises the step of positioning cutting fluid openings of the torch at the joint.
[0015] In accordance with still another aspect of the present disclosure, the step of directing the cutting fluids into the joint further comprises producing a pattern of cutting fluids, the pattern having a length at least as long as the joint.
[0016] In accordance with still another aspect of the present disclosure, the joint further comprises a pin component on an inside diameter and a box component on an outside diameter. The pin component is severed while leaving the box component unsevered.
[0017] In accordance with still another aspect of the present disclosure, the portion of the drill collar string that is above the cut joint is removed from the borehole.
[0018] In accordance with still another aspect of the present disclosure, the cut end of the drill collar with the cut joint is redressed so as to make a new, uncut joint.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] FIG. 1 is a cross-sectional view of a borehole with an uncut drill collar and a torch, in accordance with an embodiment of the present disclosure.
[0020] FIG. 2 is the same as FIG. 1 , but the torch has been ignited, in accordance with an embodiment of the present disclosure.
[0021] FIG. 3 shows the drill collar of FIG. 1 , having been cut and separated, in accordance with an embodiment of the present disclosure.
[0022] FIG. 4 is a cross-sectional view of FIG. 1 , taken along lines IV-IV, in accordance with an embodiment of the present disclosure.
[0023] FIG. 5 is a cross-sectional view of FIG. 3 , taken along lines V-V, in accordance with an embodiment of the present disclosure.
[0024] FIG. 6 is a longitudinal cross-sectional view of the torch, in accordance with an embodiment of the present disclosure.
[0025] FIG. 7 is a side elevational view of the nozzle pattern of the torch, taken along lines VII-VII of FIG. 6 , in accordance with an embodiment of the present disclosure.
[0026] FIGS. 8A-8C show the dressing of a cut end of a drill collar to form a new pin joint, in accordance with an embodiment of the present disclosure.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0027] The present disclosure cuts a drill collar 11 (see FIGS. 1 and 4 ) in a well 12 , thereby enabling the retrieval and future reuse of some or most of the drill collar string. The present disclosure utilizes a cutting torch 15 lowered down inside of the drill string 17 . A torch is positioned at one of the joints 21 of one of the drill collars. The joints are high torque couplings.
[0028] When the torch 15 is ignited (see FIG. 2 ), it produces combustion fluids 81 . The combustion fluids form a longitudinal slice or cut 23 through the coupling 21 . This is different than conventional cutting techniques that cut a pipe all around its circumference. The longitudinal cut effectively splits the coupling (see FIGS. 3 and 5 ). Because the coupling is under high torque before being cut, after being cut it unwinds and decouples. Thus, a relatively small amount of cutting energy can effectively cut a thick walled drill collar 11 . The portion of the drill collar string that is decoupled is retrieved.
[0029] The present disclosure will be discussed now in more detail. First, a drill collar 11 will be discussed, followed by a description of the torch 15 and then the cutting operation will be discussed.
[0030] Referring to FIG. 1 , the drill collar 11 is part of a drill string 13 that is located in a well 12 or borehole. The drill string 13 typically has a bottom hole assembly made up of a drill bit 25 and its sub and one or more drill collars 11 . There may be other components such as logging while drilling (LWD) tools, measuring while drilling (MWD) tools and mud motors. Drill pipe 27 extends from the bottom hole assembly up to the surface. The drill string may have transition pipe, in the form of heavy weight drill pipe between the drill collars and the drill pipe. The drill string forms a long pipe, through which fluids, such as drilling mud, can flow.
[0031] The various components of the drill string are coupled together by joints. Each component or length of pipe has a coupling or joint at each end. Typically, a pin joint is provided at the bottom end, which has a male component, while a box joint is provided at the upper end, which has a female component. For example, as shown in FIG. 1 , the lower joint of a drill collar 11 is a pin joint 21 A, while the upper joint 21 B is a box joint.
[0032] As illustrated in FIG. 1 , the drill collar 11 is a heavy or thick walled pipe. The thickness of the drill collar wall 31 is greater than the thickness of the drill pipe wall 33 . A passage 35 extends along the length of the drill collar, between the two ends.
[0033] The wall thickness of the pin joint 21 A is less than the thickness of the wall 31 of the drill collar portion that is located between the two ends. Typical dimensions of the pin joint are 4 inches in length and ½ to 1 inch in wall thickness. The pin joint is tapered to fit into the similarly tapered box joint 21 B.
[0034] The joints or couplings in the drill string and particularly in the drill collars are tight due to drilling. During drilling, the drill string 13 is rotated. This rotation serves to tighten any loose couplings. Consequently, the joints are under high torque.
[0035] The cutting torch 15 is shown in FIG. 6 . The torch 15 has an elongated tubular body 41 which body has an ignition section 43 , a nozzle section 45 and a fuel section 47 intermediate the ignition and fuel sections. In the preferred embodiment, the tubular body is made of three components coupled together by threads. Thus, the fuel section 47 is made from an elongated tube or body member, the ignition section 43 is made from a shorter extension member and the nozzle section 45 is made from a shorter head member.
[0036] The ignition section 43 contains an ignition source 49 . In the preferred embodiment, the ignition source 49 is a thermal generator, which may resemble the thermal generator disclosed by U.S. Pat. No. 6,925,937. The thermal generator 49 is a self-contained unit that can be inserted into the extension member. The thermal generator 49 has a body 51 , flammable material 53 and a resistor 55 . The ends of the tubular body 51 are closed with an upper end plug 57 , and a lower end plug 59 . The flammable material 53 is located in the body between the end plugs. The upper end plug 57 has an electrical plug 61 or contact that connects to an electrical cable (not shown). The upper plug 57 is electrically insulated from the body 51 . The resistor 55 is connected between the contact 61 and the body 51 .
[0037] The flammable material 53 is a thermite, or modified thermite, mixture. The mixture includes a powered (or finely divided) metal and a powdered metal oxide. The powdered metal includes aluminum, magnesium, etc. The metal oxide includes cupric oxide, iron oxide, etc. In the preferred embodiment, the thermite mixture is cupric oxide and aluminum. When ignited, the flammable material produces an exothermic reaction. The flammable material has a high ignition point and is thermally conductive. The ignition point of cupric oxide and aluminum is about 1200 degrees Fahrenheit. Thus, to ignite the flammable material, the temperature must be brought up to at least the ignition point and preferably higher. It is believed that the ignition point of some thermite mixtures is as low as 900 degrees Fahrenheit.
[0038] The fuel section 47 contains the fuel. In the preferred embodiment, the fuel is made up of a stack of pellets 63 which are donut or toroidal shaped. The pellets are made of a combustible pyrotechnic material. When stacked, the holes in the center of the pellets are aligned together; these holes are filled with loose combustible material 65 , which may be of the same material as the pellets. When the combustible material combusts, it generates hot combustion fluids that are sufficient to cut through a pipe wall, if properly directed. The combustion fluids comprise gasses and liquids and form cutting fluids.
[0039] The pellets 65 are adjacent to and abut a piston 67 at the lower end of the fuel section 47 . The piston 67 can move into the nozzle section 45 .
[0040] The nozzle section 45 has a hollow interior cavity 69 . An end plug 71 is located opposite of the piston 67 . The end plug 71 has a passage 73 therethrough to the exterior of the tool. The sidewall in the nozzle section 45 has one or more openings 77 that allow communication between the interior and exterior of the nozzle section. The nozzle section 45 has a carbon sleeve liner 79 , which protects the tubular metal body. The liner 75 is perforated at the openings 77 .
[0041] The openings are arranged so as to direct the combustion fluids in a longitudinal manner. In the embodiment shown in FIG. 7 , the openings 77 are arranged in a vertical alignment. The openings 77 can be rectangular in shape, having a height greater than a width. Alternatively, the openings can be square or circular (as shown). In another embodiment, the nozzle section 45 can have a single, elongated, vertical, slot-type opening.
[0042] The piston 67 initially is located so as to isolate the fuel 63 from the openings 77 . However, under the pressure of combustion fluids generated by the ignited fuel 63 , the piston 67 moves into the nozzle section 45 and exposes the openings 77 to the combustion fluids. This allows the hot combustion fluids to exit the tool through the openings 77 .
[0043] The method will now be described. Referring to FIG. 1 , the torch 15 is lowered into the drill string 13 , which drill string is stuck. Before the torch is lowered, the decision has been made to cut the drill string and salvage as much of the drill string as possible. Also, the drill string is stuck at a point along the drill collar string or below the drill collar string.
[0044] The torch 15 can be lowered on a wireline, such as an electric wireline. The torch is positioned inside of the drill collar 11 which is to be cut. Specifically, the openings 77 are located at the same depth of the pin coupling 21 A which is to be cut. The length of the arrangement of openings is longer than the pin joint. The longer the arrangement of openings, the less precision is required when positioning the torch relative to the pin joint 2 1 A. Then, the torch is ignited. An electrical signal is provided to the igniter 49 (see FIG. 6 ), which ignites the fuel 65 , 63 . The ignited fuel produces hot combustion fluids. The combustion fluids 81 produced by the fuel force the piston 67 down and expose the openings 77 . The combustion fluids 81 are directed out of the openings 77 and into the pin coupling 21 A (see FIG. 2 ). The combustion fluids are directed in a pattern that is longitudinal, rather than circumferential. The combustion fluid pattern is at least as long as the pin joint, and in practice extends both above and below the pin joint.
[0045] The torch creates a cut 23 along the longitudinal axis in the pin joint 21 A (see FIGS. 3 and 5 ). The pin 21 A is severed. The portions of drill collar above and below the pin joint have longitudinal cuts therein, but due to the wall thickness, these cuts do not extend all the way to the outside. FIG. 5 shows the cut extending part way into the corresponding box joint. Thus, the box joint and the portions of the drill collar above and below the pin joint are not cut completely through and are unsevered. Nevertheless, when the pin joint is cut, it unwinds or springs open. The joint decouples and the drill string becomes severed at the joint. Thus, only the pin joint need be cut to sever the drill collar. That portion of the drill string that is unstuck, the upper portion, is retrieved to the surface.
[0046] The drill collar 11 that was cut at its pin joint can be reused. Referring to FIG. 8A , the pin joint 21 A has a longitudinal cut 23 therein. The pin joint 21 A is cut off of the drill collar, as well as any damaged portions of the collar to form a clean end 83 (see FIG. 8B ). The end 83 is remachined to form a new pin joint (see FIG. 8C ). The drill collar can now be reused.
[0047] Each of the torches can be provided with ancillary equipment such as an isolation sub and a pressure balance anchor. The isolation sub typically is located on the upper end of the torch and protects tools located above the torch from the cutting fluids. Certain well conditions can cause the cutting fluids, which can be molten plasma, to move upward in the tubing and damage subs, sinker bars, collar locators and other tools attached to the torch. The isolation sub serves as a check valve to prevent the cutting fluids from entering the tool string above the torch.
[0048] The pressure balance anchor is typically located below the torch and serves to stabilize the torch during cutting operations. The torch has a tendency to move uphole due to the forces of the cutting fluids. The pressure balance anchor prevents such uphole movement and centralizes the torch within the tubing. The pressure balance anchor has either mechanical bow spring type centralizers or rubber finger type centralizers.
[0049] The foregoing disclosure and showings made in the drawings are merely illustrative of the principles of this disclosure and are not to be interpreted in a limiting sense.
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A method of severing a drill string or other tubular string that includes lowering a torch into the drill string, positioning the torch at a joint in the drill string, such that the joint may have a pin component engaged with a box component, igniting the torch to produce cutting fluids, and directing the cutting fluids into the joint in a direction that is along a length of the drill string to cut the joint.
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RELATED APPLICATION
[0001] This application claims the benefit of U.S. Provisional Application No. 62/162,221 filed May 15, 2015 and entitled, Ceiling Ladder.
FIELD OF THE INVENTION
[0002] The present invention pertains generally to ladders, and more particularly to those adapted for mounting in a ceiling opening for the purpose of providing access to the area there above.
BACKGROUND OF THE INVENTION
[0003] A ceiling ladder, also known as an “attic ladder” or “loft ladder” is a retractable ladder that is installed into an opening in the floor of an attic and ceiling of the floor below the attic to facilitate passage from one floor to the other. They are used as an inexpensive and compact alternative to having a permanent staircase that ascends to the attic of the home or building in which they are installed.
[0004] Ceiling ladders of the prior art are typically of two general types, namely the folding type and telescopic type. Folding ceiling ladders include a ladder component which is normally in a contracted stowed configuration and may be extended in length to a deployed configuration by unfolding of two or more ladder sections which are hingedly attached to one another. As may be readily appreciated, ceiling ladders of the telescopic variety also include a ladder component normally in a contracted stowed configuration and extendable in length to a deployed configuration through telescopic extension of its subparts. In both varieties, extension and contraction of the ladder component may be carried out automatically or manually. In both varieties, the ladder component, when in its contracted stowed configuration, is typically stowed horizontally above the floor opening and concealed from view by a pivotable door or concealment panel component to which a portion of the ladder is fixedly attached. In common embodiments, the door is hinged to a side of the framing defining the opening and the door is attached directly to a portion of the ladder rails or indirectly but still in close proximity thereto. The door is sized and shaped to fill the opening and to lay flush with the surrounding ceiling when closed, and is typically opened by pulling on a depending drawstring Pulling on the drawstring to open the door automatically causes pivoting of the ladder to initiate its deployment, and pivoting of the ladder to its stowed configuration automatically initiates closing of the door.
[0005] For ceiling ladders of the folding type, because the door is fixedly attached either directly or in close proximity to the back of at least the upper portion of the ladder, the door interferes with proper foot placement on the adjacent ladder rungs creating a significant safety issue. More specifically, the door limits the depth of foot penetration across these rungs permitting only the toes of the foot to contact the rungs rather than a deeper penetration that would include the ball and arch of the foot which affords more stable foot placement. Although it is typically recommended that users always face the ladder while ascending and descending the ladder, it is common practice to descend ceiling ladders facing away from the ladder such as to permit carrying of items stored in the attic or other space being accessed. In such cases, only the heel portion of the user's feet can make contact with the rungs further adding to the risk of a fall.
[0006] It would, therefore, be ideal to have known in the art ceding ladder assembly that affords safer foot placement on the ladder rungs.
SUMMARY OF THE INVENTION
[0007] According to one aspect of the present invention, there is provided A foldable ceiling ladder for installation within a ceiling opening defined by framing members, the ceiling ladder comprising a ladder comprising a first ladder section hingedly attached to a second ladder section; each said first ladder section and said second ladder section comprising a pair of parallel rails connected to one another by a plurality of incrementally spaced rungs; said ladder having a deployed configuration wherein said first and ladder section and said second ladder section are aligned to form a continuous ladder, and a stowed configuration wherein said first ladder section and said second ladder section are foldable upon themselves above the ceiling opening when said ceiling ladder is not in use; mounting means for pivotally mounting said first ladder section to a framing member along a first axis of rotation; and a concealment panel sized and shaped to substantially cover the ceiling opening, said concealment panel having a first portion fixedly attached to said first ladder section in co-planar fashion, and a second portion in coplanar alignment with said first portion and parallel to said rails of said first ladder section when said ladder is in said stowed configuration, and out-of-plane with said fixed portion and non-parallel to said rails of said first ladder section when said ladder is in said deployed configuration, whereby pivoting of the second portion of said concealment panel away from said ladder permits uninhibited foot access to said ladder rungs by a user.
[0008] In certain embodiments, the fixed portion and door portion of the concealment panel share the same axis of rotation. In certain embodiments, the fixed portion and door portion of the concealment panel have a different but parallel axis of rotation. In certain embodiments of the invention, the concealment panel is not divided into a fixed portion and a door portion; the entire concealment panel is hinged to the framing of the ceiling opening, is removably attached to the first ladder section for concealing the ceiling opening when the ladder is in its stowed configuration, and is capable of pivoting away from the ladder rungs when the ladder is in its deployed configuration to permit the desired increased foot access to the ladder rungs.
[0009] Certain embodiments further include at least one stowage latch configured to retain the door portion in its closed position (i.e., in coplanar alignment with the fixed portion of the concealment panel) until the stowage latch is released. In those embodiments where the entire concealment panel is adapted for pivotal rotation (i.e., where there is no door portion) one or more stowage latches are included to retain the concealment panel in proximity to the ladder for the purpose of ladder stowage and opening concealment.
[0010] There has thus been outlined, rather broadly, the more important components and features of the invention in order that the detailed description thereof that follows may be better understood, and in order that the present contribution to the art may be better appreciated. There are, of course, additional features of the invention that will be described hereinafter and which will form the subject matter of the claims appended hereto. In this respect, before explaining at least one embodiment of the invention in detail, it is to be understood that the invention is not limited in its application to the details of construction and to the arrangements of the components set forth in the following description or illustrated in the drawings. The invention is capable of other embodiments and of being practiced and carried out in various ways. Also, it is to be understood that the phraseology and terminology employed herein are for the purpose of description and should not be regarded as limiting. As such, those skilled in the art will appreciate that the conception, upon which this disclosure is based, may readily be utilized as a basis for the designing of other structures, methods and systems for carrying out the several purposes of the present invention. It is important, therefore, that the claims be regarded as including such equivalent constructions insofar as they do not depart from the spirit and scope of the present invention.
[0011] Further, the purpose of the included abstract is to enable the U.S. Patent and Trademark Office and the public generally, and especially the scientists, engineers and practitioners in the art who are not familiar with patent or legal terms or phraseology, to determine quickly from a cursory inspection the nature and essence of the technical disclosure of the application. The abstract is neither intended to define the invention of the application, which is measured by the claims, nor is it intended to be limiting as to the scope of the invention in any way.
[0012] It is therefore a primary object of the subject invention to provide a ceiling ladder that not only provides concealment of the ladder and ceiling opening when the ladder is in its stowed configuration, but also permits uninhibited foot access on all ladder rungs by the user thereby enhancing safety when ascending and descending the ladder.
[0013] It is also a primary object of the subject invention to provide a ceiling ladder designed for rapid installation within a framed ceiling opening.
[0014] It is also an object of the subject invention to provide a ceiling ladder that is simple in design and therefore capable of rapid construction and assembly at a relatively low cost. These together with other objects of the invention along with the various features of novelty which characterize the invention, are pointed out with particularity in the claims annexed to and forming a part of this disclosure. For a better understanding of the invention, its advantages and the specific objects attained by its uses, reference should be had to the accompanying drawings and descriptive matter in which there is illustrated a preferred embodiment of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] The invention will be better understood and objects other than those set forth above will become apparent when consideration is given to the following detailed description thereof. Such description makes reference to the annexed drawings herein:
[0016] FIG. 1 is a perspective view of foldable ceiling ladder of the prior art, shown in its deployed configuration;
[0017] FIG. 2 is a left side elevation view of the foldable ceiling ladder of FIG. 1 shown in its stowed configuration;
[0018] FIG. 3 is a left side elevation view of the ceiling ladder of FIG. 1 illustrating how the concealment panel impedes proper foot placement on the ladder rungs;
[0019] FIG. 4 is a perspective view of a foldable ceiling ladder of the subject invention, shown in its deployed configuration;
[0020] FIG. 5 is a left side elevation view of the foldable ceiling ladder of FIG. 4 shown in its stowed configuration;
[0021] FIG. 6 is a left side elevation view the ceiling ladder of FIG. 4 illustrating the door portion of the concealment panel;
[0022] FIG. 7 is a bottom view of the ceiling ladder of FIG. 4 illustrating how the concealment panel and door portion thereof share a common axis of rotation;
[0023] FIG. 8 is a perspective view of one embodiment of a shared hinge arrangement for the concealment panel and door portion thereof of a ceiling ladder of the subject invention;
[0024] FIG. 9 is a bottom view of a ceiling ladder of the subject invention illustrating how the concealment panel and door portion thereof share different but parallel axes of rotation; and
[0025] FIG. 10 is a perspective view of one embodiment of a parallel hinge arrangement for the concealment panel and door portion thereof of a ceiling ladder of the subject invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
[0026] It should be clearly understood at the outset like reference numerals are intended to identify the same structural elements, portions or surfaces consistently throughout the several drawings herein, as such elements, portions or surfaces may be further described or explained by the entire written specification, of which this detailed description is an integral part. Unless otherwise indicated, the drawings are intended to be read (e.g., cross-hatching, arrangement of parts, proportion, degree, etc.) together with the specification, and are to be considered a portion of the entire written description of this invention. As used in the following description, any reference to the terms “horizontal”, “vertical”, “left”, “right”, “up” and “down”, as well as adjectival and adverbial derivatives thereof (e.g., “horizontally”, “rightwardly”, “upwardly”, etc.), simply refer to the orientation of the illustrated structure as the particular drawing figure faces the reader. Similarly, the terms “inwardly” and “outwardly” generally refer to the orientation of a surface relative to its axis of elongation, or axis of rotation, as appropriate. The terms “rung” or “rungs” of a ladder shall also include ladder “steps” or “treads” between ladder rails. Except where the context requires otherwise, the term “attic” as used herein means any space having a floor or surface with an opening through which a person can pass and an accessible lower level area or floor below the attic floor into which a ladder can be extended and from which a person can ascend the ladder through the opening. Similarly, the area below the attic is referred to generically herein as the “bottom floor”, and the floor of the attic is sometimes referred to as the “ceiling” of the bottom floor.
[0027] Before describing the construction and operation of the subject folding ceiling ladder, it is helpful to understand the construction of conventional ceiling ladders and their shortcomings. Accordingly, reference is first made to FIGS. 1-3 depicting a folding ceiling ladder 200 of the prior art. Folding ceiling ladder 200 includes a ladder component 202 which is normally in a contracted stowed configuration ( FIG. 2 ) and which may be extended in length to a deployed configuration ( FIGS. 1 and 3 ) by unfolding of two or more ladder sections 202 a,b,c which are hingedly attached to one another. The ladder component, when in its contracted stowed configuration, is typically stowed horizontally above the floor opening and concealed from view by a pivotably mounted door 204 (also known as a “concealment panel”) to which ladder 200 is fixedly attached. In common embodiments, the door 204 is hinged to a side of the framing 102 defining an opening 100 in the ceiling. Door 204 is typically attached to the back of the ladder rails 206 in abutting coplanar relationship. The door is sized and shaped to fill the opening and to lay flush with the surrounding ceiling when closed, and is typically opened by pulling on a depending drawstring (not shown). Pulling on the drawstring to open the door automatically causes pivoting of the attached ladder to initiate its deployment, and pivoting of the ladder to its stowed configuration automatically initiates closing of the attached door. Because the door 204 is fixedly attached to the back of the ladder 200 , spanning across its rails 206 , it interferes with, proper foot placement on the adjacent ladder rungs creating a significant safety issue as described supra. The improved ceiling ladder of the subject invention obviates this problem by allowing a portion of the concealment panel, namely the portion between the ladder rails, to pivot away from the ladder to provide improved foot access to the ladder rungs.
[0028] Accordingly, reference is now made to FIGS. 4-6 in which there is illustrated a preferred embodiment of a ceiling ladder of the subject invention designated generally by reference numeral 10 and of the folding ladder variety. Ceiling ladder 10 is designed for installation within a ceiling opening 100 defined by framing members 102 and is comprised of two primary components, namely a folding ladder assembly 12 , and a concealment panel 14 sized and shaped to cover the ceiling opening 100 . As is well known in the art, when ceiling ladder 10 is mounted within opening 100 , the ladder assembly 12 is normally in a contracted stowed configuration ( FIG. 2 ) and may be extended in length to a deployed configuration ( FIGS. 1 and 3 ) by unfolding of its at least two ladder sections 12 a,b,c which are hingedly attached to one another in series via hinges 13 . Conversely, when ladder assembly 12 is in its contracted towed configuration with its ladder sections 12 a,b,c folded one on top of the other, it is stowed horizontally above the floor opening 100 and concealed from view by concealment panel 14 to which ladder assembly 12 is fixedly attached.
[0029] In the embodiment illustrated, ladder assembly 12 is comprised of a first ladder section 12 a hingedly attached via a hinge 13 to a second ladder section 12 b which in turn is hingedly attached via another hinge 13 to a third ladder section 12 c. In other embodiments a fewer or greater number of ladder sections may be employed. Ladder sections 12 a,b,c comprise a pair of parallel rails 6 a,b,c , respectively, each rail being connected to its neighboring rail by a plurality of incrementally spaced rungs 18 . Mounting means are included for pivotally mounting the first ladder section 12 a to a framing member 102 . In a preferred embodiment, the mounting means comprises at least one hinge 20 pivotally connecting first ladder section 12 to framing member 102 along a first axis of rotation 22 such that ladder section 12 a and the other ladder sections attached to it are capable of downward rotation from a horizontal stowed position to an angular deployed position. A pair of articulating mounting brackets 24 connect each side rail 16 a of ladder section 12 a to opposing framing members 102 in order to provide support and stability to ladder assembly 12 . A pair of springs 26 operably connected between each mounting bracket 24 and the framing member 102 to which it is connected controls the rate of decent of the ladder assembly 12 and limits the amount of force required to return the ladder assembly 12 to its stowed position above the ceiling C in a manner well known in the art. As may be readily appreciated, different bracket and spring arrangements may be employed for these purposes, the example described above being only for illustrative purposes.
[0030] Concealment panel 14 includes a first portion 14 a fixedly attached to the back of side rails 16 a of first ladder section 12 a in co-planar relationship. The attachment may be a direct attachment or, as illustrated in the instant embodiment, concealment panel 14 may be fixedly attached to one or more cross members 30 transversely mounted to the back of side rails 16 a connecting one rail with the other. First portion 14 a of concealment panel 14 is pivotally attached to a frame member 102 via panel hinge 20 having an axis of rotation 22 parallel to ladder rungs 18 .
[0031] Concealment panel 14 further includes a second portion 14 b (also referred to herein as “door portion 14 b ”) in the form of a pivotable door sized and shaped to substantially conform to the area between side rails 16 a of first ladder section 12 a. With additional reference now being made to FIGS. 7 and 8 , in one embodiment door portion 14 b is pivotably mounted to frame member 102 via panel hinge 20 thereby sharing a common axis of rotation 22 with first portion 14 a. In this embodiment, first portion 14 a is more accurately comprised of two parallel panel's separated by door portion 14 b. With reference now being made to FIGS. 9 and 10 , in another embodiment door portion 14 b of concealment panel 14 is pivotably mounted to first portion 14 via door hinge 40 having second axis of rotation 42 which is parallel to axis of rotation 22 of hinge 20 . In both of the above described embodiments, door portion 14 b is in coplanar alignment with the first portion of concealment panel 14 and parallel to rails 16 a of first ladder section 12 a when the ladder assembly 12 is in its stowed configuration, and out of plane with the first portion of concealment panel 14 and non-parallel to rails 16 a of the first ladder section 12 a when the ladder assembly 12 is in its deployed configuration. Door portion 14 b may further include longitudinal flanges 15 depending from its side edges. Flanges 15 overlap the side edges of first portion 14 a of concealment panel 14 when door portion 14 b is in its closed position, thus bridging the gaps between first portion 14 a and door portion 14 b for insulation and aesthetic purposes.
[0032] With specific reference to FIG. 6 , as should be appreciated, when ladder assembly 12 is lowered from its horizontal stowed configuration to its deployed configuration by downward rotation of concealment panel 14 about its axis of rotation 22 , door portion 14 b may then be rotated downwardly about its axis of rotation 22 or 42 to swing away from the normally adjacent ladder rungs 18 thereby permitting deeper foot penetration across the rungs than would be possible if concealment panel 14 remained in abutting relationship with said rungs as is the case with ceiling ladders of the prior art.
[0033] Certain embodiments further include at least one stowage latch 36 configured to retain the door portion 14 b in its closed position (i.e., in coplanar alignment with the first portion 14 a of concealment panel 14 ) until the stowage latch is released allowing door portion 14 b to rotate downwardly by virtue of gravity. In the embodiment illustrated, each latch 36 is rotated about its axis of rotation as illustrated by directional arrow 38 ( FIG. 4 ) until it depends from an adjacent cross member 30 . As will be readily appreciated by those skilled in the art, a myriad of other latching mechanisms may be employed to releasably retain door portion 14 b in coplanar relationship with first portion 14 a of concealment panel 14 .
[0034] For those embodiments of the subject ceiling ladder 10 that require manual operation to raise and lower the apparatus from its stowed position above the ceiling to its operable or deployed position, a drawstring 32 is disposed through a cross member 30 of ladder assembly 12 and through concealment panel 14 and terminates in at least one end in handle 34 . Pulling on the handle when door portion 14 b is latched in coplanar alignment with first portion 14 a of concealment panel 14 causes pivoting of the ladder assembly 12 to initiate its deployment. Pulling on the opposite end of the drawstring, which may also be adapted with a handle, causes pivoting of door portion 14 b upwardly for latching to its counterpart first portion 14 a. Pivoting of the concealment panel 14 upwardly initiates its closing and stowage of ladder assembly 12 above the ceiling.
[0035] Although the present invention has been described with reference to the particular embodiments herein set forth, it is understood that the present disclosure has been made only by way of example and that numerous changes in details of construction may be resorted to without departing from the spirit and scope of the invention. Thus, the scope of the invention should not be limited by the foregoing specifications, but rather only by the scope of the claims appended hereto.
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A foldable ceiling ladder assembly for installation within a ceiling opening includes a concealment panel sized and shaped to substantially cover the ceiling opening when the ladder is in a stowed configuration; the concealment panel including a swingout door portion capable of pivotal rotation away from the ladder when in a deployed configuration to permit uninhibited foot access on the ladder rungs by the user for improved safety and for facilitating ease of ascending and descending the ladder.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a National State Entry of International Application No. PCT/FR2007/002116, filed on Dec. 19, 2007, which claims priority to French Patent Application No. 0611493, filed on Dec. 29, 2006, both of which are incorporated by reference herein.
BACKGROUND AND SUMMARY
[0002] The present invention relates to the free circulation of any audiovisual and multimedia file and content and provides a method and a system for the free circulation, the control and the follow-up of each utilisation or consumption of audiovisual and multimedia files and contents on any telecommunication network.
[0003] The general issue is to provide a device capable of circulating freely and of having a controlled consumption, by authorised users, of compressed digital audiovisual and multimedia files, for example of the MPEG type for video, of the JPEG type for still images or MP3 type for audio, on any type of telecommunication or computer network, without this list being limitative. With the present solutions, it is possible to transmit multimedia contents in a digital form via any type of network. To avoid the hacking of the thus diffused streams, two techniques for transmitting these contents exist. According to a first technique, they are either encrypted by various means which are well known to the persons skilled in the art. According to a second technique, they are transmitted in the form of streams in client/server mode. However, these two transmission techniques have advantages and drawbacks which are not simultaneous.
[0004] As regards the first technique, solutions based on an encryption are provided, such as the one described in the application for the US patent 2002/108035 aiming at limiting the duration and useless repetition of the encryption of a whole file having a different decryption key. Therefore, it provides a method for partially encrypting a data file including a step of dividing a data file into a first file and a second file, with the second file containing a part of the content of the original data file to prevent the reconstruction of the original data file from the first file only and a step for encrypting the second file. The main drawback of such encryption solutions is that not only the encrypted contents must be transmitted to the users but also the decryption keys and the utilisation licenses to a terminal identified and authentified by the user, so as to enable the execution of said contents. Thus, the necessity exists to implement rights management systems DRM based on the issuing of licenses.
[0005] In the state of the art is more particularly known the “Windows Media DRM” system which enables the digital management of the multimedia content rights on a network. This system further implements authorisation, authentication and encryption techniques for enabling a user to consult a protected content from a terminal via a network. Customised licenses are then implemented via encryption keys and certifications of the reading device.
[0006] Solutions complying with this system are extremely efficient but they are also extremely constraining for the user and the owner. In the absence of very efficient license and/or encryption, the contents are generally thus decrypted. In addition, the utilisation of the file and the content thereof depends on the licensed terminal and the authentication thereof. The licensed management such as performed in the conventional DRM and which induces an important complexity for the owner and the user is not required in the method according to the present invention.
[0007] A second technique based on the transmission of streams partly remedies the drawback of the first technique described hereabove, but has several drawbacks, among which the requirement for the transfer of the whole digital file upon each utilisation, and a connection by the user to the server via a generally high bandwidth connection. If said digital file is heavy, for example a very high quality digitalised audiovisual file, the owner will reach only the users which are well serviced by large bandwidth connections. The result is that the servers and the transport networks systematically and quickly reach their saturation level. If said connection rate is too low, the file and the content thereof lose all their market values for the owner without, however, eliminating the same drawbacks related to the bandwidth. More particularly, each utilisation requires the total transfer of the file and the content thereof. In addition, the utilisation thereof depends on the site where it is broadcast from.
[0008] Finally, these two techniques have other major drawbacks. The first one is that they are not able to authorise the transfer of the file without control. The second is that the utilisation of said file, broadcast or transferred from one user to another user, is not controlled.
[0009] In order to correct these various defects, the invention, in its broadest sense, relates to a method for controlling the distribution and the use of digital multimedia files composed of binary data blocks according to an original format, and separated into at least two parts, characterised in that it includes a step of transmission, from a server of the utilisation conditions, of the preferred parameters for the reconstruction of the whole or a part of said original file on a terminal. In a particular embodiment, said two parts are composed of a first modified file having the format of the original file and a complementary file having any format including information on the modifications brought to said original file.
[0010] Advantageously, said preferred embodiment can be modified at any time by the owner. Advantageously, said step of transmitting the preferred parameters is carried out through an authorisation server and through a telecommunication network. Advantageously, said step of transmission of the preferred parameters is carried out upon said reconstruction. Advantageously, said preferred parameters are defined by utilisation parameters. Advantageously, said preferred parameters relate to one part only of said original file. Advantageously, said preferred parameters relate to a limited period.
[0011] Advantageously, said preferred parameters are valid for only one part of said terminals. Advantageously, said preferred parameters are linked to a transaction. Advantageously, said preferred parameters can be modified at will. Advantageously, said preferred parameters can be deleted at any time.
[0012] In another particular embodiment, said complementary file is transmitted to said terminal after the authorisation by said authorisation server. In another embodiment, said complementary file is transmitted to said terminal through a channel encrypted with a temporary key.
[0013] Advantageously, said temporary key is calculated by an application in said authorisation server. Advantageously, said temporary key is transmitted to the server of the complementary files. Advantageously, said temporary key is transmitted to said terminal. Advantageously, said temporary key is transmitted through the server of the complementary files. Advantageously, the existence of said temporary key lasts for only the time of said transfer.
[0014] Finally, the invention also relates to a device for the controlled distribution and use of digital multimedia files separated into at least two parts with a view to implementing the method and including at least a server of the preferred parameters and a server for the reconstruction, and characterised in that it includes a device for transmitting said preferred parameters and reconstruction parameters for the whole or part of said original file on any terminal. The invention enables a total control of all the utilisations and the utilisation conditions of the copies of the files and the audiovisual and multimedia contents thus circulated or broadcast. Said conditions are given by the owner of the rights on the original content. The invention also makes it possible for said owner of the rights to modify the conditions of utilisation at any time, including of the contents and files already broadcast. The owner can also definitely delete any utilisation of a content, including the utilisation of contents and files already broadcast or saved.
BRIEF DESCRIPTION OF DRAWINGS
[0015] The present invention will be best understood when reading the description of a non limitative exemplary embodiment, and referring to the appended drawings, wherein:
[0016] FIG. 1 describes the assembly architecture of a system for implementing the method according to the invention;
[0017] FIG. 2 describes the architecture of the portal and the servers of data according to the invention; and
[0018] FIG. 3 shows a particular embodiment of a receiving terminal according to the invention.
DETAILED DESCRIPTION
[0019] In FIG. 1 , when the user of a terminal 1 : 1 i , 1 j , 1 k , etc. wishes to view an audiovisual content available on a physical medium 7 or a server 8 or on a storage 10 of its terminal of FIG. 3 , it makes a request to the portal 3 through said telecommunication network 2 a . Said portal then decides, as a function of the operational parameters supplied by the owner 9 of the rights to broadcast the content and stored in the server 5 of the utilisation conditions, to send or not to send the complementary elements stored in the server 4 and corresponding to this audiovisual and multimedia content, through the networks 2 b . Information on the follow-up of the utilisations requested by said owner 9 for editing purposes is stored on the follow-up server 6 .
[0020] Prior to this phase, the original audiovisual and multimedia content 31 supplied by an owner 9 in the downloading 2 b or on a physical medium 7 will be prepared by the portal 3 as shown in FIG. 2 . Each audiovisual file 31 is shown in a compressed digital form and is composed of binary data blocks, resulting from digital transformations applied to an audiovisual and multimedia content according to an original file format. The original format of an original content 31 , for example a file having an original MPEG-2, MPEG-4 or H264 format for video, or an original MP3 or AAC format in the case of audio files, or an original JPEG format in the case of still images or photographic files.
[0021] In a first step, the original content 31 is separated into at least two parts, among which a first modified file 32 having the format of the nominal original file and into a complementary file 33 having any format including information on the modification brought to said original file 31 . The reconstruction of the original file 31 cannot be carried out but from both files 32 and 33 but not from one of them only.
[0022] During a second step and through a portal 3 and through a telecommunication network 2 b , said owner 9 supplies the parameters management system 35 its preferences as regards the economic and marketing conditions of the reconstitution of said original file on any terminal 1 : 1 i , 1 j , 1 k , etc. by any user who wishes to read, listen to or see the content of the original file. Said preferences are defined by the utilisation parameters which can be of any kind and more particularly:
[0023] free to be used during a limited period or an unlimited period by any user or only by dedicated users (for example, countries, member of an intranet or an extranet, etc.),
[0024] payment upon each utilisation,
[0025] subscription to a certain number of utilisation for a limited or unlimited period,
[0026] subscription for a determined period with or without limit on the number of utilisation,
[0027] free but linked to a transaction as for example against information on the user: name, email, company, function, utilisation condition etc.,
[0028] free authorisation for one or several extract or extracts (for example, teasing, etc.),
[0029] free authorisation for the first reading or starting from the nth reading, etc.,
[0030] free authorisation or reduced price authorisation against the playing of advertising contents,
[0031] with “url pointer” on the original site of the content where the contexts and/or the explanations are given on this content or for any other reasons,
[0032] with or without the display of a copyright and/or a sub-title,
[0033] with the integration of keywords for the marking, or “tagging” system by third parties,
[0034] etc.
[0035] Such operational parameters are stored on a server 5 of the utilisation conditions by the portal 3 management system 35 . The owner also provides its preferences for editing purposes during this same step. These follow-up parameters can be of any kind and more particularly:
[0036] user's country or region,
[0037] rate noted during the utilisation,
[0038] dates and times of the beginning and the end of the utilisation,
[0039] the mistakes made during the utilisation or during the authorisation mechanism,
[0040] the utilisation of the video recorder keys during the utilisation,
[0041] the reasons for the refusal of a request for authorisation,
[0042] the abandon of a user during the authorisation mechanism,
[0043] the confirmation of a correct utilisation,
[0044] the progressive mode playing,
[0045] etc.
[0000] These so-called follow-up parameters are stored on said follow-up servers 6 by the portal 3 management system 35 .
[0046] During a third step, the servers for 4, 5 and 6 references where are respectively stored the complementary file 33 of the original content and all the associated parameters are integrated into the meta-data of the modified file 32 for obtaining a mobile modified file 34 . Upon completion of these steps of processing the audiovisual and multimedia contents, said mobile modified files 34 are freely transmitted and broadcast to the terminals 1 through said telecommunication network 2 a via the interface 36 .
[0047] In a particular exemplary embodiment, said mobile modified files 34 are freely transmitted and broadcast by any exchange network like, for example, a community network, a blog network, a social network or a P2P network. In another example, said mobile modified files 34 are freely transmitted and broadcast by physical media 7 like for example DVDs, CD-ROMs or any other storage of the USB or hard disk types, etc. Advantageously, said mobile modified files 34 are freely transmitted and broadcast on one or several conventional audiovisual and multimedia servers 8 . The multimedia content are now available for the users 1 : 1 i , 1 j , 1 k , etc. through said mobile modified files 34 , and controlled by the owner's parameters stored in the servers 5 of the utilisation conditions as shown in FIG. 3 .
[0048] A mobile modified file is then available for the user 1 : 1 i , 1 j , 1 k on a mass storage 10 of his or her terminal or on an external medium 7 like a DVD, a CD-ROM, a USB key, etc., or through the downloading from the server 8 or from another terminal 1 though the transfer on the Internet or provided with a client/server software, or P2P, etc. When the user 1 wants to use the mobile modified file 34 , the latter is either played on the hard disk 10 , the DVD or a CD 7 on his or her terminal, or downloaded onto his or her terminal through his or her interface 13 . Whatever the user's connection rate, specific software 11 for the player adapted to the format of the original file is downloaded automatically or upon the user's request, or is already available on his or her terminal or integrated in an html window or as an autonomous application on the terminal. Said specific software 11 :
[0049] reads the meta-data of the mobile modified file 34 , more particularly the identification of the content and the owner and the reference of the servers 4 , 5 and 6 , which are managed by the system provided,
[0050] sets up a client/server connection with the server of the complementary files 4 managed by the system provided, the references of which are noted in said meta-data,
[0051] and transmits the owner's identifications and the content of the mobile modified file 34 to said server.
[0052] Said server of the complementary files 4 interrogates the server 5 of the utilisation conditions and implements the owner's utilisation conditions for this mobile modified file. The following steps are then executed:
[0053] transmission of the “url” address of the server 14 to the software 11 . Said server 14 is for example an LD for requesting marketing information, online payment, subscription management, etc. Advantageously, said server 14 is that of the provided system or that of the owner or of a third party. Advantageously, said server 14 is also used as an authorisation server. Advantageously, said server 14 is also used as an identification server.
[0054] said identification server 14 transmits the authorisation or the absence of authorization for the operation of the mobile modified file by the user,
[0055] said server 5 of the utilisation conditions transmits to the software 11 the authorisation to operate the mobile modified file 34 through said complementary files server 4 ,
[0056] if the authorisation is denied, the software 11 plays the downloaded file without the information of the complementary file, thus in a way which is indiscernible by the user,
[0057] if the authorisation is granted, the software 11 plays the downloaded file and simultaneously receives from the complementary files server 4 the complementary file for reconstructing the original file on the user's terminal,
[0058] the events such as listed in the above-mentioned follow-up parameters are transmitted by the software 11 to said follow-up server 6 by said complementary files server 4 .
[0059] More particularly, the user of the terminal 1 consults a menu or a server 8 via his or her interface 12 . Said user selects the contents he or she wishes to consume and the mobile modified file 34 corresponding to this content is transmitted by the server 8 to the terminal 1 . Said interface 12 is for example connected to a screen, to loudspeakers, to a keyboard, to a mouse, etc. Said mobile modified file 34 is recorded via the interface 13 of FIG. 3 in the storage 10 composed for a hard disk or any other type of mass storage.
[0060] As from the beginning of the connection between said terminal 1 and said server 8 , the player 11 plays the meta-data of said mobile modified file 34 , more particularly the reference of said complementary file 33 of said complementary file server 4 . Said terminal 1 then connects to said complementary files server 4 in client/server mode. Said complementary files server 4 converses with said utilisation conditions server 5 and then checks that said user 1 has been granted the authorisations to consume said modified multimedia file 34 and takes all necessary measures so that the utilisation conditions supplied by said owner 9 are complied with. Said complementary files server 4 then transmits in a synchronised way the elements of the complementary file 33 to the player 11 of the terminal of said user 1 which reconstructs a synthesis of the original audiovisual file, from the calculation of the receiving terminal 1 , as a function of said mobile modified file 34 and the elements of said complementary file 33 . Said synthesis of the original audiovisual content is then displayed on the screen via the interface 12 .
[0061] Advantageously, said synthesis of the reconstructed contents is carried out as soon as the first information on said modified multimedia file 34 and the first elements of said complementary file 33 are received. Advantageously, said synthesis of the reconstructed content is recorded under the control of said complementary file server 4 , in the storage 10 of the terminal 1 . Advantageously, said synthesis of the reconstructed contents is marked with a tattooing system.
[0062] Advantageously, said synthesis of the reconstructed contents is recorded under the control of said complementary file server 4 on a physical medium 7 like a DVD, a CD-ROM, a USB storage, etc. Advantageously, the user of the terminal 1 i transmits a copy of said mobile modified file 10 or 7 to another terminal 1 : 1 i , 1 j , 1 k , etc. Advantageously, the events connected to the follow-up of the utilisation of the mobile modified file 34 by the user 1 are transmitted through said complementary files server 4 to said follow-up server 6 referenced in the meta-data of the mobile modified file 34 .
[0063] Each utilisation of a mobile modified file, whether authorised or not, is thus recorded in said follow-up server 6 according to the condition parameters requested by the owner thereof and managed by the servers 5 and 6 . The owner can consult the tracks of the utilisation managed by said follow-up server 6 at any time through the management system 35 of the portal 3 and make statistics he requires for his editorial chart system. It can more particularly change the operational parameters stored in said utilisation conditions servers 5 can be changed at any time, of any mobile modified file 34 inclusive of those already broadcast mobile modified files.
[0064] Advantageously, the transfer of the complementary file 33 to the terminal of a user 1 and when the utilisation of the contents 34 is authorised for said user 1 , is carried out for a channel encrypted with a temporary key. Advantageously, said temporary key is calculated by an application 5 a executed by said server 5 of the utilisation conditions. Said temporary key is then transmitted by said server 5 of the utilisation conditions to the player 11 and to said complementary files server 4 in a synchronised manner. Advantageously, the validity of said temporary key lasts only for the time required for said transfer.
[0065] In another particular embodiment, whatever the reasons, said original file which must no longer be operated in the way mentioned hereabove, is deleted by simply deleting the corresponding complementary file 33 in said complementary files server 4 , even though the corresponding mobile modified file has already been broadly broadcast via the networks.
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The present invention relates to a method for controlling the distribution and use of digital multimedia files composed of binary data blocks according to an original format, and separated into at least two parts, characterised in that it includes a step of transmission, from a server of utilisation conditions, of the preferred parameters for the reconstruction of the whole or a part of said original file on a terminal.
The invention also relates to a device for the controlled distribution and use of digital multimedia files separated into at least two parts with a view to implementing the method according to any one of claims 1 to 19 , including at least one server for the preferred parameters and one server for the reconstruction and characterised in that it includes a device for transmitting said preferred parameters and for the reconstruction of the whole or a part of said original file on any terminal.
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RELATED APPLICATIONS
[0001] The present application claims the benefit of U.S. Provisional Patent Application, Serial No. 60/462,787, filed Apr. 14, 2003. The entire disclosure of the above-mentioned application is hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] This invention relates to an apparatus useful in medical and non-medical applications to introduce accessory devices into collapsible and non-collapsible, body cavities or canals, pipes, lumens and other generally tubular spaces or environments. More particularly, the invention relates to a propulsion system for endoscopic systems.
BACKGROUND OF THE INVENTION
[0003] An endoscope is any instrument used to obtain a view of the interior of a patient's body using a variety of means to capture and transmit the view to an observer. Endoscopes can also be used to perform a variety of diagnostic and interventional procedures such as biopsies and other small surgical procedures. Examples of endoscopes include: a colonoscope used within the colon, a gastroscope used inside the stomach, and a bronchoscope used within the trachea and bronchi. Endoscopes are often inserted into body cavities or lumens via natural orifices but can also be inserted into incisions to gain access to areas of the body where no natural entrance exists.
[0004] Traditional endoscopes consist of a rigid or flexible rod or shaft with a means of collecting and transmitting an image from inside the patient's body. The rod or shaft is inserted and pushed to the location of interest. The rod or shaft typically surrounds a number of pathways used to house fiber optic cables and route instruments, catheters, devices, gasses, liquids and other substances in and out of the area of interest.
[0005] Traditional endoscopes require a minimal rigidity for successful insertion and work well when the body cavity or canal, or other lumens having curves and turns. However, when it is constricted, convoluted and consists of many curves, as is the case with the colon, it can be difficult or impossible to push the endoscope to its desired location. Steerable articulating endoscopes are often used to make navigation of turns easier; however, the increased friction associated with each additional turn limits the number of turns that can be navigated successfully and ultimately limits the distance an endoscope can be introduced into the patient's body. In addition, the increased force required to complete more turns and corners raises the risk of complications such as bowel perforation as well as the discomfort and pain experienced by the patient. It would be useful to have an apparatus for endoscopic medical procedures that can navigate in such environments and can overcome the physical and procedural limitation of traditional endoscopes. It would further be useful if such an apparatus were self-propelled.
[0006] Endoscopic devices may also be utilized in non-medical or commercial and industrial applications to obtain views from or introduce instruments or devices into generally tubular spaces or environments such as lumens, sections of pipe or other structures, which may have a number of curves and turns. Such tubular spaces or environments may be partially occluded or have buildup on their interior surfaces and thus present a irregular internal shape or diameter. To navigate through such spaces and environments, it would be useful to have a device or apparatus that can adapt to the internal shape or diameter of the space or environment into which it is introduced and of further use if the apparatus were self-propelled.
SUMMARY OF THE INVENTION
[0007] The invention in it various embodiments is a propulsion apparatus that can be used to transport accessory devices within body cavities or canals, sections of pipe, lumens, and other generally tubular spaces and environments and is generally comprised of a toroid and a powered or motorized frame. The motion of the toroid can be powered or unpowered and the direction and speed may be controlled.
[0008] In an embodiment of the invention, the apparatus is comprised of a toroid and a frame. The toroid is a fluid-filled, enclosed ring formed of a flexible material. The enclosed ring defines a central cavity, having an interior volume and presenting an exterior surface and an interior surface which move continuously in opposite directions when the apparatus is in motion.
[0009] In one embodiment, the frame is formed of a support structure, a housing structure and a series of at least two sets of interlocking rollers or skids located on the support and housing structures. The support structure is located within the interior volume of the enclosed ring. The housing structure is concentrically and coaxially located relative to the support structure and disposed in the central cavity of the enclosed ring. The rollers or skids are located so as to maintain the two structures in a fixed spatial relationship with the flexible material of the enclosed ring being positioned between the two structures and the rollers or skids located thereon.
[0010] In another embodiment, the frame is formed of a support structure located within the interior volume of the enclosed ring and a series of at least two sets of interlocking rollers or skids located on the support structure. The rollers or skids are located so as to maintain the flexible material of the enclosed ring between them.
[0011] In other embodiments of the invention, the apparatus is a propulsion apparatus for transport of accessory devices. The apparatus is comprised of a toroid and a powered frame. The toroid is a fluid-filled, enclosed ring formed of a flexible material. The enclosed ring defines a central cavity and has an interior volume. The powered frame is formed of a support structure and housing structure or a support structure alone. A series of at least two sets of interlocking rollers or skids located on the support and housing structures or on the support structure in the case there is no housing structure. The support structure is located within the interior volume of the enclosed ring. The housing structure is concentrically and coaxially located relative to the support structure and disposed within the central cavity of the enclosed ring. The rollers or skids are located so as to maintain the two structures in a fixed spatial relationship with the flexible material of the enclosed ring being positioned between the two structures and the rollers or skids located thereon. The rollers may be connected to a power source and when powered provides a motive, directional force to the flexible material.
[0012] In its various embodiments, the apparatus of the invention may further comprise at least one accessory device. Depending upon whether the apparatus is to be used for medical or non-medical applications, the at least one accessory device may be selected from the group consisting of endoscopes, cameras, video processing circuitry, fiber optic cables, electronic communication cables, lasers, surgical instruments, medical instruments, diagnostic instruments, instrumentation, sensors, stent catheters, fluid delivery devices, drug delivery devices, electronic devices, tools, sampling devices, assay devices, articulating segments, cables to articulate the articulating segments, other accessory devices, and combinations thereof.
[0013] The apparatus of the invention may further comprise a power source connected to the rollers which when powered provide a motive force to the flexible material of the enclosed ring. The power source may be an external power source or an internal power source and may be transmitted through the shaft by various means.
[0014] In its various embodiments, the apparatus of the invention may further comprise an accessory tube. The accessory tube has at least one pathway through which accessory devices can be inserted into the patient or connected to external supporting devices.
[0015] The apparatus of the invention may be utilized to perform medical or non-medical procedures. In an embodiment of a procedure according to the invention, the apparatus is utilized for medical procedures. The procedure of this embodiment comprising the steps of: introducing a self-propellable, endoscopic apparatus according to the invention into the rectum and anal canal of a patient, the apparatus being equipped with at least one accessory device and connected to at least one external support device; powering the apparatus to propel the apparatus forward through the anal canal and into the colon up to a location in the colon at which at least one medical procedure is to be performed; performing the at least one medical procedure with the at least one accessory device; optionally, serially propelling the apparatus to another location in the colon at which the at least one medical procedure is to be performed and performing said at least one medical procedure; propelling the apparatus backward through the colon and into the anal canal; and removing the apparatus from the patient.
[0016] In another embodiment of the invention, an endoscopic procedure is provided. The endoscopic procedure comprises the steps of: introducing a self-propellable, endoscopic apparatus into the generally tubular space or environment, the apparatus being equipped with at least one accessory device and connected to at least one external support device; powering the apparatus to propel and navigate the apparatus forward in the tubular space to a location at which at least one endoscopic procedure is to be performed; performing the at least one endoscopic procedure with the at least one accessory device; optionally, serially propelling the apparatus to another location in the tubular space at which the at least one endoscopic procedure is to be performed and performing said at least one endoscopic procedure; propelling the apparatus backward through tubular space; and removing the apparatus from the tubular space.
BRIEF DESCRIPTION OF THE DRAWINGS
[0017] [0017]FIG. 1 is a sectional view of an apparatus in accordance with an exemplary embodiment of the invention.
[0018] [0018]FIG. 2 is a sectional view of an apparatus in accordance with an additional exemplary embodiment of the invention.
[0019] [0019]FIG. 3 is an axial cross-sectional view of an apparatus in accordance with an exemplary embodiment of the present invention.
[0020] [0020]FIG. 4 is an axial cross-sectional view of an apparatus in accordance with an additional exemplary embodiment of the present invention.
[0021] [0021]FIG. 5 is an enlarged, partial, cross-sectional view of an apparatus in accordance with an exemplary embodiment of the invention.
[0022] [0022]FIG. 6 is an enlarged, partial, cross-sectional view of an apparatus in accordance with an exemplary embodiment of the invention.
[0023] [0023]FIG. 7 is an enlarged, partial, cross-sectional view of an apparatus in accordance with an additional exemplary embodiment of the invention.
[0024] [0024]FIG. 8 is an enlarged, partial, cross-sectional view of an apparatus in accordance with an exemplary embodiment of the invention.
[0025] [0025]FIG. 9 is an enlarged, partial cross-sectional view of an apparatus in accordance with an additional exemplary embodiment of the invention.
[0026] [0026]FIG. 10 is an additional enlarged, partial cross-sectional view of the apparatus shown in the previous figure.
[0027] [0027]FIG. 11 is an enlarged, partial, cross-sectional view of an apparatus in accordance with an exemplary embodiment of the invention.
[0028] [0028]FIG. 12 is an additional enlarged, partial cross-sectional view of the apparatus shown in the previous figure.
[0029] [0029]FIG. 13 is an enlarged, partial cross-sectional view of an apparatus in accordance with an additional exemplary embodiment of the present invention.
[0030] [0030]FIG. 14 is a cross-sectional view of a bladder in accordance with an exemplary embodiment of the present invention.
[0031] [0031]FIG. 15 is an additional cross-sectional view of bladder shown in the previous figure.
DETAILED DESCRIPTION OF THE INVENTION
[0032] The self-propellable or self-propelled endoscopic system or apparatus of the invention can be utilized to transport a variety of accessory devices to desired locations within a number of generally tubular spaces and environments, both collapsible and non-collapsible, for medical, industrial and commercial applications. With the system of the invention, an operator, such as a doctor, medical or other technician, can navigate and traverse within generally tubular spaces and/or environments whether of standard or non-standard dimensions and/or of uniform or non-uniform quality that cause difficulty when navigated by pushing a rod or “snake” through it. Examples of such spaces or environments would include, but are not limited to a circular, square, rectangular, or other shaped tube or a tube presenting one or more such shapes along its length that is partially occluded or interior surface of which is irregular, possibly due to material buildup on the surface. And may further include a route with varying diameters, constrictions and curves.
[0033] [0033]FIG. 1 is a sectional view of an apparatus 100 in accordance with an exemplary embodiment of the invention. With reference to FIG. I it will be appreciated that the system or apparatus 100 of the invention employs a toroid 102 . In the embodiment of FIG. 1, the toroid 102 comprises a bladder 104 of a flexible material 106 . The flexible material 106 of bladder 104 has an interior surface 120 and an exterior surface 122 . Interior surface 120 of flexible material 106 defines an interior volume 124 of bladder 104 . In some embodiments of the present invention, interior volume 124 of bladder 104 contains or is filled with a fluid, a gas, liquid or combination thereof. Exterior surface 122 of flexible material 106 defines a central cavity 126 .
[0034] The apparatus 100 shown in FIG. 1 also includes a frame 108 . Frame 108 both supports and interacts with flexible material 106 of bladder 104 . Frame 108 is formed of a support structure 128 and a housing structure 130 . With reference to FIG. 1, it will be appreciated that housing structure 130 is disposed in central cavity 126 defined by exterior surface 122 of flexible material 106 of bladder 104 . Also with reference to FIG. 1, it will be appreciated that support structure 128 is disposed within interior volume 124 defined by interior surface 120 of flexible material 106 of bladder 104 .
[0035] Support structure 128 and housing structure 130 each rotatably support a plurality of rollers. In FIG. 1, a pair of motive rollers 134 are shown contacting flexible material 106 of bladder 104 . In the embodiment of FIG. 1, rotation of motive rollers 134 will cause flexible material 106 to move relative to the rotational axis of each motive roller 134 . In the embodiment of FIG. 1, each motive roller 134 comprises a plurality of teeth 140 . With reference to FIG. 1, it will be appreciated that the teeth 140 of each motive roller 134 mate with a first thread 142 of a worm gear 144 . Accordingly, in the embodiment of FIG. 1, rotation of worm gear 144 will cause motive rollers 134 to rotate.
[0036] The power for rotating motive rollers 134 can be any of a variety of internal or external power sources known to those skilled in the art to be suitable for the given application. In the case of electrical power, the power source may be stored inside the apparatus, or the power may be transmitted via wires from outside the patient or space through an accessory tube (not shown) connected to the apparatus or to one or more electrical motors located inside the housing structure or otherwise operatively connected to motive rollers 134 and/or worm gear 144 . The electrical motors, in turn, power the motive rollers 134 and/or worm gear 144 . In the case of mechanical power, rollers 134 and/or worm gear 144 may be powered by a thin, flexible, spinning rod or wire powered from a remote motor located outside the patient or space. The motion of the rod or wire is transmitted to the rollers located on the housing structure. Mechanical power may also be transmitted by a spinning spiral or spring component located inside or outside of the apparatus. This power may be manually generated.
[0037] In the embodiment of FIG. 1, housing structure 130 rotatably supports a plurality of stabilizing rollers 136 . With reference to FIG. 1, it will be appreciated that each stabilizing roller 136 contacts exterior surface 122 of flexible material 106 of bladder 104 . In the embodiment of FIG. 1, a suspended stabilizing roller 138 is located proximate each stabilizing roller 136 . Each suspended stabilizing roller 138 contacts interior surface 120 of flexible material 106 of bladder 104 . In the embodiment of FIG. 1, each suspended stabilizing roller 138 defines a groove 146 that is dimensioned to receive a portion of flexible material 106 and a portion of a stabilizing roller 136 .
[0038] In the embodiment of FIG. 1, each suspended stabilizing roller 138 is pivotally coupled to an arm 148 . In some useful embodiments of the present invention, each arm 148 and suspended stabilizing roller 138 act to bias exterior surface 122 of flexible material 106 against a stabilizing roller 136 . Also in FIG. 1, a plurality of suspended motive rollers 132 are disposed proximate each motive roller 134 . Each suspended motive roller 132 is pivotally supported by support structure 128 . In some useful embodiments of the present invention, support structure 128 and suspended motive rollers 132 act to bias exterior surface 122 of flexible material 106 against motive rollers 134 .
[0039] For some applications, bladder 104 may be generally longer than it is wide. However, for other applications or depending upon the size or dimension of the space or environment into which the toroid 102 is to be introduced, the bladder 104 may be of substantially equal length and width or may be wider than it is long.
[0040] [0040]FIG. 2 is a sectional view of an apparatus 200 in accordance with an additional exemplary embodiment of the invention. With reference to FIG. 2 it will be appreciated that apparatus 200 comprises a bladder 204 that is generally toroidal or ring shaped. Bladder 204 comprises a flexible material 206 . Flexible material 206 of bladder 204 has an interior surface 220 and an exterior surface 222 . Interior surface 220 of flexible material 206 defines an interior volume 224 of bladder 204 . In some embodiments of the present invention, interior volume 224 of bladder 204 contains or is filled with a fluid, a gas, liquid or combination thereof. Exterior surface 222 of flexible material 206 defines a central cavity 226 .
[0041] The apparatus 200 shown in FIG. 2 also includes a frame 208 . Frame 208 both supports and interacts with the flexible material 206 of the bladder 204 . Frame 208 comprises a support structure 228 and a housing structure 230 . With reference to FIG. 2, it will be appreciated that housing structure 230 is disposed in central cavity 226 defined by exterior surface 222 of flexible material 206 of bladder 204 . Also with reference to FIG. 2, it will be appreciated that support structure 228 is disposed within interior volume 224 defined by interior surface 220 of flexible material 206 of bladder 204 .
[0042] Support structure 228 and housing structure 230 each rotatably support a plurality of rollers. In FIG. 2, a plurality motive rollers 234 are shown contacting flexible material 206 of bladder 204 . In the embodiment of FIG. 2, rotation of motive rollers 234 is capable of causing flexible material 206 to move relative to the rotational axis of each motive roller 234 . In the embodiment of FIG. 2, each motive roller 234 comprises a plurality of teeth 240 . Each motive roller 234 is capable of mating with a worm gear 244 .
[0043] With reference to FIG. 2, it will be appreciated that worm gear 244 comprises a first thread 242 and a second thread 243 . In FIG. 2, the teeth 240 of a first set of motive roller 234 are shown mating with first thread 242 of worm gear 244 . Accordingly, in the embodiment of FIG. 2, rotation of worm gear 244 will cause the first set of motive rollers 234 to rotate.
[0044] In some embodiments of an apparatus in accordance with an exemplary embodiment of the present invention, a one or more motive rollers are powered by a worm gear. A housing structure of the apparatus may contain a hollow cavity to hold the worm gear in place as illustrated, for example, in FIG. 2. This hollow cavity allows the worm gear 244 to rotate relative to housing structure 230 . Worm gear 244 may also move forwards and backward along the central axis of the apparatus in the embodiment of FIG. 2. This movement allows second thread 243 of worm gear 244 to selectively engage a second set of motive rollers while first thread 242 disengages from first set of motive rollers 234 . This selective engagement may facilitate forwards and backwards movement of the apparatus. In a variation of this embodiment, the apparatus may be configured so that the first and the second set of motive rollers 234 respectively engage first and second threads 242 , 243 .
[0045] In the embodiment of FIG. 2, housing structure 230 rotatably supports a plurality of stabilizing rollers 236 . With reference to FIG. 2, it will be appreciated that each stabilizing roller 236 contacts the exterior surface 222 of flexible material 206 of bladder 204 . In the embodiment of FIG. 2, a plurality of suspended stabilizing rollers 238 are located proximate each stabilizing roller 236 . Each suspended stabilizing roller 238 contacts interior surface 220 of flexible material 206 of bladder 204 . In some useful embodiments of the present invention, each suspended stabilizing roller 238 acts to bias exterior surface 222 of flexible material 206 against a stabilizing roller 236 .
[0046] With continuing reference to FIG. 2, a suspended motive roller 232 is disposed proximate each motive roller 234 . Each suspended motive roller 232 is pivotally supported by support structure 228 . In some useful embodiments of the present invention, support structure 228 and suspended motive rollers 232 act to bias exterior surface 222 of flexible material 206 against motive rollers 234 .
[0047] Various embodiments of housing structure 230 and support structure 228 are possible without deviating from the spirit and scope of the present invention. One exemplary embodiment may be viewed as two tubes positioned with one inside the other. The outer tube being the support structure which is located within the interior volume of the enclosed ring or bladder. The inner tube being the housing structure which is located within the central cavity. In another embodiment exemplary embodiment, either the support structure, the housing structure or both may be comprised of a series of one or more beams that may or may not form the general shape of a cylinder.
[0048] The housing and support structures may be, for example, cylindrical with a circular cross section or they may have a cross section in the shape of a square, rectangle, triangle, hexagon or any other shape with straight or curved surfaces or any combination thereof. The frame structures may also be comprised of multiple cross sectional shapes throughout its length. The flexible material 206 of the bladder 204 surface runs between the two tubes which are spaced in fixed relationship relative to each other. The distance between the two tubes is sufficient to accommodate the interlocking rollers or skids and to allow the flexible material 206 for bladder 204 to pass between the support and housing structures even if the material folds over itself or is bunched up.
[0049] [0049]FIG. 3 is an axial cross-sectional view of an apparatus 300 in accordance with an exemplary embodiment of the present invention. Apparatus 300 includes a bladder 304 comprising a flexible material 306 . The flexible material 306 of bladder 304 has an interior surface 320 and an exterior surface 322 . Interior surface 320 of flexible material 306 defines an interior volume 324 of bladder 304 . In some embodiments of the present invention, interior volume 324 of bladder 304 contains or is filled with a fluid, a gas, liquid or combination thereof. Exterior surface 322 of flexible material 306 defines a central cavity 326 .
[0050] In the embodiment of FIG. 3, a housing structure 330 is disposed in central cavity 326 defined by exterior surface 322 of flexible material 306 of bladder 304 . The housing structure 330 rotatably supports a plurality of motive rollers 334 . In FIG. 3, motive rollers 334 are shown contacting exterior surface 322 of flexible material 306 . In the embodiment of FIG. 3, each motive roller 334 comprises a plurality of teeth 340 . The teeth 340 of each motive roller 334 mate with a thread 342 of a worm gear 344 . Thus, in the embodiment of FIG. 3, rotation of worm gear 344 will cause motive rollers 334 to rotate. Also in the embodiment of FIG. 3, rotation of the motive rollers 334 will cause flexible material 306 to move relative to the rotational axis of each motive roller 334 .
[0051] With continuing reference to FIG. 3, it will be appreciated that a support structure 328 is disposed within an interior volume 324 defined by the interior surface 320 of flexible material 306 . In the embodiment of FIG. 3, support structure 328 rotatably supports a plurality of suspended motive rollers 332 . In FIG. 3, one suspended motive roller 332 is shown disposed proximate each motive roller 334 . Also in FIG. 3, each suspended motive roller 332 can be seen contacting interior surface 320 of flexible material 306 of bladder 304 . In some useful embodiments of the present invention, support structure 328 and suspended motive rollers 332 act to bias exterior surface 322 of flexible material 306 against motive rollers 334 .
[0052] In the exemplary embodiment of FIG. 3, housing structure 330 and support structure 328 each have a generally tubular shape. Thus, housing structure 330 and support structure 328 may be viewed as two tubes positioned with one inside the other. The outer tube being support structure 328 which is located within interior volume 324 defined by interior surface 320 of bladder 304 . The inner tube being housing structure 330 which is located within central cavity 326 defined by exterior surface 322 of bladder 304 .
[0053] It will be appreciated that various embodiments of housing structure 330 and support structure 328 are possible without deviating from the spirit and scope of the present invention. The housing and support structures may be, for example, cylindrical with a circular cross section or they may have a cross section in the shape of a square, rectangle, triangle, hexagon or any other shape with straight or curved surfaces or any combination thereof. The frame structures may also be comprised of multiple cross sectional shapes throughout their length. The flexible material 306 of the bladder 304 surface runs between the two structures which are spaced in fixed relationship relative to each other. The distance between the two structures is sufficient to accommodate the interlocking rollers or skids and to allow the flexible material 306 for bladder 304 to pass between the support and housing structures even if the material folds over itself or is bunched Up.
[0054] [0054]FIG. 4 is an axial cross-sectional view of an apparatus 400 in accordance with an additional exemplary embodiment of the present invention. Apparatus 400 comprises a bladder 404 of a flexible material 406 . In FIG. 4 a support structure 428 is shown disposed within an interior volume 424 defined by the interior surface 420 of flexible material 406 . In the embodiment of FIG. 4, support structure 428 rotatably supports a plurality of suspended stabilizing rollers 438 . With reference to FIG. 4, it will be appreciated that each suspended stabilizing roller 438 contacts the interior surface 420 of flexible material 406 of bladder 404 . In some useful embodiments of the present invention, support structure 428 and suspended stabilizing roller 438 act to bias exterior surface 422 of flexible material 406 against a stabilizing roller 436 .
[0055] In the embodiment of FIG. 4, a housing structure 430 is disposed in a central cavity 426 defined by an exterior surface 422 of flexible material 406 of bladder 404 . Housing structure 430 rotatably supports a plurality of stabilizing rollers 436 . With reference to FIG. 4, it will be appreciated that each stabilizing roller 436 contacts the interior surface 420 of flexible material 406 of bladder 404 . In the embodiment of FIG. 4, each suspended stabilizing roller 438 defines a groove 446 that is dimensioned to receive a portion of flexible material 406 and a portion of a stabilizing roller 436 .
[0056] [0056]FIG. 5 is an enlarged, partial, cross-sectional view of an apparatus in accordance with an exemplary embodiment of the invention. Apparatus 500 comprises a housing structure 530 and a support structure 528 . Housing structure 530 rotatably supports a motive roller 534 and support structure 528 rotatably supports a plurality of suspended motive rollers 532 . A flexible material 506 is disposed between motive roller 534 and suspended motive rollers 532 . Flexible material 506 may form, for example, a portion of a bladder in accordance with the present invention. Suspended motive rollers 532 are rotatably supported by a support structure 528 . In the embodiment of FIG. 5, housing structure 530 rotatably supports a worm gear 544 . A first thread 542 of worm gear 544 engages teeth 540 of motive roller 534 . In the embodiment of FIG. 5, rotation of worm gear 544 will cause motive roller 534 to rotate. Rotation of motive roller 534 , in turn, causes flexible material 506 to move relative to housing structure 530 . With reference to FIG. 5, it will be appreciated that flexible material 506 has an interior surface 520 and an exterior surface 522 .
[0057] [0057]FIG. 6 is an enlarged, partial, cross-sectional view of an apparatus 600 in accordance with an exemplary embodiment of the invention. Apparatus 600 comprises a housing structure 630 that rotatably supports a worm gear 644 . A first thread 642 of worm gear 644 engages the teeth 640 of a motive roller 634 . Motive roller 634 is rotatably supported by housing structure 630 . A flexible material 606 is disposed between motive roller 634 and a skid 650 . Flexible material 606 may form, for example, a portion of a bladder in accordance with the present invention.
[0058] In the embodiment of FIG. 6, rotation of worm gear 644 causes rotation of motive roller 634 . Rotation of motive roller 634 , in turn, causes flexible material 606 to move relative to housing structure 630 . With reference to FIG. 6, it will be appreciated that skid 650 contacts an interior surface 620 of flexible material 606 . In some useful embodiments of the present invention, skid 650 acts to bias an exterior surface 622 of flexible material 606 against motive roller 634 .
[0059] [0059]FIG. 7 is an enlarged, partial, cross-sectional view of an apparatus 603 in accordance with an additional exemplary embodiment of the invention. Apparatus 603 comprises a housing structure 630 that rotatably supports a motive roller 634 . A flexible material 606 is disposed between motive roller 634 and a skid 650 . In the embodiment of FIG. 7, a pair of springs 652 act to bias skid 650 against an interior surface 620 of flexible material 606 . Springs 652 are diagrammatically illustrated in FIG. 7. Springs 652 may comprise, for example, sheet metal arms. A compression motion and an extension motion of springs 652 and skid 650 are illustrated with arrows in FIG. 7.
[0060] In some useful embodiments of the present invention, skid 650 and springs 652 act to bias an exterior surface 622 of flexible material 606 against motive roller 634 . Teeth 640 of motive roller 634 engage a first thread 642 of a worm gear 644 that is rotatably supported by housing structure 630 . In the embodiment of FIG. 7, rotation of worm gear 644 causes rotation of motive roller 634 . Rotation of motive roller 634 , in turn, causes flexible material 606 to move relative to housing structure 630 .
[0061] [0061]FIG. 8 is an enlarged, partial, cross-sectional view of an apparatus in accordance with an exemplary embodiment of the invention. Apparatus 700 includes a frame 708 comprising a housing structure 730 and a support structure 728 . Housing structure 730 rotatably supports a motive roller 734 and support structure 728 rotatably supports a plurality of suspended motive rollers 732 . A flexible material 706 is disposed between motive roller 734 and suspended motive rollers 732 .
[0062] Suspended motive rollers 732 are rotatably supported by a support structure 728 . A pair of springs 752 of support structure 728 are diagrammatically illustrated in FIG. 8. In the embodiment of FIG. 8, springs 752 act to bias suspended motive rollers 732 against an interior surface 720 of flexible material 706 . Springs 752 may comprise, for example, sheet metal arms. A compression motion and an extension motion of springs 752 and suspended motive rollers 732 are illustrated with arrows in FIG. 8.
[0063] In the embodiment of FIG. 8, housing structure 730 rotatably supports a worm gear 744 . A first thread 742 of worm gear 744 engages teeth 740 of motive roller 734 . In the embodiment of FIG. 8, rotation of worm gear 744 will cause motive roller 734 to rotate. Rotation of motive roller 734 , in turn, causes flexible material 706 to move relative to housing structure 730 .
[0064] [0064]FIG. 9 is an enlarged, partial cross-sectional view of an apparatus 800 in accordance with an additional exemplary embodiment of the invention. With reference to FIG. 9 it will be appreciated that apparatus 800 comprises a bladder 804 . In some embodiments of the present invention, bladder has a generally toroidal or ring shape. Bladder 804 comprises a flexible material 806 . Flexible material 806 of bladder 804 has an interior surface 820 and an exterior surface 822 . Interior surface 820 of flexible material 806 defines an interior volume 824 of bladder 804 . In some embodiments of the present invention, interior volume 824 of bladder 804 contains or is filled with a fluid, a gas, liquid or combination thereof. Exterior surface 822 of flexible material 806 defines a central cavity 826 .
[0065] The apparatus 800 shown in FIG. 9 also includes a frame 808 . Frame 808 both supports and interacts with the flexible material 806 of the bladder 804 . Frame 808 comprises a support structure 828 and a housing structure 830 . In the embodiment of FIG. 9, housing structure 830 rotatably supports a stabilizing roller 836 and support structure rotatably supports a suspended stabilizing roller 838 . With reference to FIG. 9, it will be appreciated that suspended stabilizing roller 838 contacts the interior surface 820 of flexible material 806 of bladder 804 . Stabilizing roller 836 is shown contacting an exterior surface 822 of flexible material 806 of bladder 804 . The rotation of the rollers and the movement of flexible material 806 are illustrated with arrows in FIG. 9.
[0066] [0066]FIG. 10 is an additional enlarged, partial cross-sectional view of apparatus 800 shown in the previous figure. In some useful embodiments of the present invention, suspended stabilizing roller 838 acts to bias exterior surface 822 of flexible material 806 against stabilizing roller 836 . In the embodiment of FIG. 10, an arm 848 of Support structure 828 acts to bias suspended stabilizing roller 838 against interior surface 820 of flexible material 806 . A flexing motion of arm 848 is illustrated using arrows in FIG. 10.
[0067] [0067]FIG. 11 is an enlarged, partial, cross-sectional view of an apparatus 900 in accordance with an exemplary embodiment of the invention. Apparatus 900 comprises a housing structure 930 that rotatably supports a worm gear 944 . A stabilizing roller 936 is rotatably supported by housing structure 930 . A flexible material 906 is disposed between stabilizing roller 936 and a skid 950 . Flexible material 906 may form, for example, a portion of a bladder in accordance with the present invention. With reference to FIG. 11, it will be appreciated that skid 950 contacts an interior surface 920 of flexible material 906 . In some useful embodiments of the present invention, skid 950 acts to bias an exterior surface 922 of flexible material 906 against stabilizing roller 936 .
[0068] [0068]FIG. 12 is an additional enlarged, partial cross-sectional view of apparatus 900 shown in the previous figure. Skid 950 of apparatus 900 is shown in cross section in FIG. 12. With reference to FIG. 12, it will be appreciated that skid 950 defines a depression 956 . In the embodiment of FIG. 12, depression 956 is dimensioned to receive a portion of flexible material 906 and a portion of stabilizing roller 936 . The rotation of stabilizing roller 936 and the motion of flexible material 906 are illustrated with arrows in FIG. 12.
[0069] [0069]FIG. 13 is an enlarged, partial cross-sectional view of apparatus 900 in accordance with an additional exemplary embodiment of the present invention. Apparatus 900 includes a frame 908 comprising a housing structure 930 and a support structure 928 . A stabilizing roller 936 is rotatably supported by housing structure 930 . A flexible material 906 is disposed between stabilizing roller 936 and a skid 950 . With reference to FIG. 13, it will be appreciated that skid 950 contacts an interior surface 920 of flexible material 906 . In some useful embodiments of the present invention, skid 950 acts to bias exterior surface 922 of flexible material 906 against stabilizing roller 936 . In the embodiment of FIG. 13, an arm 948 of support structure 928 acts to bias skid 950 against interior surface of flexible material 906 . A flexing motion of arm 948 is illustrated using an arrow in FIG. 13.
[0070] [0070]FIG. 14 is a cross-sectional view of a bladder 104 in accordance with an exemplary embodiment of the present invention. Bladder 104 comprises a flexible material 106 . The movement of flexible material 106 is illustrated with arrows in FIG. 14. With reference to FIG. 14, an exterior portion of bladder 104 can be viewed as moving in one direction while an interior portion of bladder 104 is moving in the opposite direction. The result is that the entire shape can move along its central axis while the external material rolls around itself. Thus, the flexible material may be described as circulating around and through the frame in a continuous motion from inside the central cavity long is central axis to the outside where the exterior surface of the flexible material travels along in contact with the interior surface of a generally tubular space or environment or other lumen. A travel direction of bladder 104 is labeled TD in FIG. 14. This motion is well adapted to travel within a generally cylindrical or tubular space, even a collapsible one, such as exists with the colon or rectal canal. The entire object moves with minimal to no slipping because its exterior surface remains in relatively constant or continuous contact with the interior of the space while the interior surface of the flexible materials moves forward in the direction of travel as shown.
[0071] [0071]FIG. 15 is an additional cross-sectional view of bladder 104 shown in the previous figure. In the embodiment of FIG. 15, bladder 104 is traveling a in second travel direction TD that is generally opposite the travel direction shown in the previous figure. The movement of flexible material 106 of bladder 104 is illustrated with arrows in FIG. 15. With reference to FIG. 15, an exterior portion of bladder 104 can be viewed as moving in one direction while an interior portion of bladder 104 is moving in the opposite direction.
[0072] In some exemplary embodiments of an apparatus in accordance with the present invention, a frame is formed of a support structure and a series of at least two sets of interlocking rollers or skids located on the support structure. The support structure is located within the interior volume of the enclosed ring. The rollers or skids are located so as to maintain the flexible material of the enclosed ring between them. To further accommodate folds and wrinkles in the flexible material the rollers or skids may be suspended and may apply force to the flexible material and the matching rollers or skids. Embodiments of possible suspension mechanisms are illustrated in the figures.
[0073] The ends of support and housing structures may be tapered for some applications. Embodiments of the invention having tapered ends are well-suited, but not necessary for medical applications and procedures, e.g., colonoscopy or rectal examination. However, such tapering is not necessary for all applications, particularly those involving spaces or environments of large dimension. The tapered ends of the support and housing structures may serve a number of functions, including, but not limited to allowing the two structures to fit and work together without sliding apart; presenting a smooth and gradual surface to over which the flexible material travels, and easing the apparatus' through constrictions and its passage around curves and comers.
[0074] The series of at least two sets of interlocking rollers or skids are located on the support and housing structures or in the case where only a support structure is utilized, the rollers or skids are located on the support structure. A set of rollers or skids may be comprised of one or more roller, one or more skid or combination thereof located on one or more of the structures. A set may be formed of a single roller or skid, a pair of adjacent rollers or skid, a single roller or skid on one structure and a pair comprised of two or more rollers, two or more skids or a combination of both on the other, and other variations and combinations of rollers and skids located in corresponding aligned position on each structure. The rollers or skids are interlocked in two directions, along and across the apparatus' central axis. The interlocking is done in such a way as to maintain a generally constant or fixed distance between the support and housing structures, so that they are in a generally fixed spatial relationship. As shown in the figures, the flexible material of the enclosed ring passes between the rollers or skids. This helps to prevent the toroid's flexible material from being compressed between the two structures except where it interacts with the rollers or skids. When powered, the rollers engage the flexible material and provide a motive, directional force to the flexible material which allows the apparatus to move in a forward or backward direction. With the exterior surface of the enclosed ring contacting and conforming to the interior surface or surfaces of a generally tubular space or environment, the powering of the rollers moves the flexible material as illustrated in the figures. This movement of the flexible material provides the self-propulsion for the apparatus.
[0075] If unpowered, the rollers or skids provide a means of facilitating the motion of the flexible material between the support and housing structures, for example when the apparatus is initially being introduced. When propelled, preferably, only the rollers on the advancing side of the apparatus are powered. This will tend to keep the flexible material from wrinkling, kinking and bunching-up by pulling the flexible material through the toroid's central cavity instead of pushing it. However, the apparatus can be operated with the rearward roller (rearward relative the direction of motion) being powered or both forward and rearward rollers being powered.
[0076] The fluid-filled toroid is also well adapted to the numerous curves, comers and constrictions found in body cavities and lumens. As one part of the shape is squeezed or pushed the liquid or gas is displaced and accommodated by the flexibility of the bladder.
[0077] The apparatus may include an accessory tube, such as a flexible tube, connected to the apparatus and leading outside the patient or other space into which it is introduced. For example, as the apparatus enters and travels within the patient, the tube remains connected and is pulled by the device. It can also be pushed or pulled as a means of moving the inside a patient or other space. The accessory tube can be a single pathway or conduit or may contain multiple pathways or conduits which can be used to insert a variety of accessory devices into the patient or to connect such devices to external support devices know to those skilled in the art, including but not limited to computers, analytical or diagnostic equipment or other electronic equipment appropriate to the given application.
[0078] Various types of accessory devices can be utilized with or mounted to the apparatus. Such accessory devices include, but are not limited to, endoscopes, cameras, fiber optic cables, electronic communication cables, lasers, surgical instruments, medical instruments, diagnostic instruments, instrumentation, sensors, stent catheters, fluid delivery devices, drug delivery devices, electronic devices, tools, sampling devices, assay devices, other accessory devices, and combinations thereof.
[0079] The material requirements for the various components of the invention can be fulfilled by a number of substances. For medical applications, all materials must possess a high degree of biocompatibility and be capable of withstanding sterilization methods know to those skilled in the art, such as radiation, steam or chemical vapor.
[0080] The fluid located inside the enclosed ring or bladder may be a liquid, such as a light oil, water, saline solution, lubricant; a gas, such as air, nitrogen, or carbon dioxide; or a combination thereof. Preferably, for medical or veterinary application or use, the fluid will be non-toxic. For the enclosed ring or bladder the flexible material should be a material with puncture, rupture and abrasion resistance characteristic as appropriate to the conditions of the interior surface of the space or environment into which the apparatus will be introduced. The flexible material may also posses a textured surface that would assist its motion against the surface of the lumen it traverses. Other characteristics to be considered in the selection of suitable materials, for example, softness, flexibility and conformability. The toroid's material must also be capable of being sealed into an enclosed ring or closed bladder by some means such as heat sealing, an adhesive or a chemical bond. A variety of polymeric or plastic materials can be used as the flexible material.
[0081] The support and housing structures may be formed of either a semi-flexible or semi- rigid material such as a polymer or a rigid material, such as stainless steel, a composite material or combinations thereof. The rollers or skids will require a material or group of materials that is high in strength and capable of being formed into very small parts. The roller material must also provide a sufficiently high degree of friction (not slip) against the flexible material without damaging it while the skids must provide a sufficiently low degree of friction (slip) against the flexible material without damaging it. The surfaces of the support and housing structures may be comprised of one or more materials that reduce or eliminate friction caused by the motion of the flexible material across the surfaces of the support and housing structures.
[0082] For applications of a non-medical nature, the materials required must retain most properties described above but do not necessarily require biocompatibility or sterilization tolerance. The materials used for the invention in non-medical applications will require sufficient durability and compatibility to suit the environment in which they are to be used.
[0083] Though a number of applications and uses of the apparatus of the invention have been identified herein above, additional applications and uses include, but are not limited to, inspection of difficult to reach pipes, tubes and caverns by carrying a camera or other optical, electrical or mechanical inspection device; transporting remotely controlled tools for use in difficult to reach locations; routing or pulling cable, wires rope, etc. through long narrow passages; pushing or pulling material through a pipe by taking advantage of the invention's ability to conform to the shape of its environment allowing it to provide a seal between the spaces on either side, i.e. the invention could facilitate emptying a pipe of material without mixing it with air or other material on the other side of the invention. Many of these applications would work equally well if the device was self-propelled or simply pushed or pulled from the outside.
[0084] While exemplary embodiments of this invention and methods of practicing the same have been illustrated and described, it should be understood that various changes, adaptations, and modifications might be made therein without departing from the spirit of the invention and the scope of the appended claims.
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A self propelled, endoscopic apparatus formed of a flexible, fluid-filled toroid and a motorized or powerable frame The apparatus may be used to advance a variety of accessory devices into generally tubular spaces and environments for medical and non-medical applications. The apparatus when inserted into a tubular space or environment, such as the colon of a patient undergoing a colonoscopy, is advanced by the motion of the toroid. The toroid's surface circulates around itself in a continuous motion from inside its central cavity along its central axis to the outside where its surface travels in the opposite direction until it again rotates into its central cavity. As the device advances within the varying sizes, shapes and contours of body lumens, the toroid compresses and expands to accommodate and navigate the environment. The motion of the toroid can be powered or unpowered and the direction and speed may be controlled. The apparatus may be used to transport a variety of accessory devices to desired locations within tubular spaces and environments where medical and non-medical procedures may be performed.
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BACKGROUND OF THE INVENTION
Not all harmful impurities in potable waters are detectable by taste and/or odor. Nitrates, for example, are undetectable by the senses yet them may be physiologically harmful. In humans, especially in infants, consumed nitrates may be reduced to nitrites in the gastrointestinal tract. Upon absorption into the bloodsteam, nitrites react with hemoglobin to produce methemoglobin, which impairs oxygen transport.
The presence of nitrate in municipal water supplies is becoming an urgent problem in some locations at its level increases due to the use of nitrogen fertilizers and to pollution.
Investigators of nitrate ion exchange phenomena are familiar with the interference other ions exert on nitrate removal by anion resins. All major anions found in groundwater consume resin capacity although not to the same degree. This reduces nitrate removal efficiency of the resin and increases the quantity of regenerant chemicals. It is understandable that various investigators have sought some ideal "nitrate-selective resin" as a remedy for the observed process inefficiencies and complexities. Such a resin could remove nitrate ions only and allow other anions to pass; thus preserving some original qualities of the untreated water. At the end of the run, the resin would be nitrate loaded making the regeneration of resin more efficient. However, in practice with available resins, interfering ions cannot only alter the quality of product water but also present the possibility of producing a higher nitrate level if the nitrate breakthrough is exceeded. This latter effect is called "reverse adsorption" or "autoregeneration" and can occur if sulfate ion is present. The product water differs from treated water by having bicarbonate, nitrate, and sulfate partially or completely replaced by chloride. In some cases, this can result in a water exceeding secondary chloride standards and a water low in bicarbonate and high in pH and corrosivity. The higher the affinity of the resin for nitrate compared to other ions, the fewer product water quality problems will be encountered.
The presence of significant amounts of dissolved sulfate ion (about 50 ppm or more), in particular, has been an impediment to nitrate removal. A review of work on nitrate removal by strongbase ion exchangers is given by Gauntlet. (Gauntlet, R. B., "Nitrate Removal From Water By Ion Exchange, Water Treatment and Examination", Water Treatment and Examination, Vol. 24, Part 3 (1975), pp. 172f.) The early work reported by Gauntlet shows that irrespective of the resin used sulfate ions were adsorbed more strongly by the resins. Using various resins and waters of varying nitrate and sulfate composition in column tests, it was demonstrated that resin capacity for nitrate decreased with increasing feedwater sulfate content. Gauntlet compared the chemical efficiency of complete column regeneration with partial regeneration and found much better efficiency for partial regeneration for high sulfate waters and moderate improvement for low sulfate waters. He believed that complete regeneration of a single bed to have the disadvantage of producing a corrosive high chloride to alkalinity ratioed product.
An ion exchange plant for nitrate removal was put into operation in 1969 in Garden City Park, N.Y. (Sheinker, M., and J. Codoluto, "Making Water Supply Nitrate Removal Practicable", Public Works, June, 1977, pp. 71f.) The plant uses a strong-base anion exchange resin in a continuous flow loop system (Higgins, I. R., "Continuious Ion Exchange Equipment", Ind. and Eng. Chem., 53, 1961, p. 336.) The influent water has a 14.9 mg/nitrate nitrogen content. No sulfates are reported but are believed to be quite low.
Midkiff, W. S., and W. J. Weber, "Operating Characteristics of Strong Base Anion Exchange Reactors", Engineering Bulletin, Prudue University Extension Service, 1970, 37, 593-604, reported significant work on nitrate removal with DOWEX 21K strong-base anion resin. Column operation was examined for a water containing both nitrate and sulfate.
Korngold, E., "Removal of Nitrates from Potable Water by Ion Exchange", Wat. Air Soil Pollution, 1973, 2, 15-22, reports experiments with Amberlite-400 and high chloride, low sulfate nitrate laden waters. His results show typical breakthrough curves for the four major anions. Of major interest is his brief study on the use of seawater as a regenerant.
Buelow, R. W. et al, "Nitrate Removal by Anion-Exchange Resins", Journal AWWA, September 1975, pp. 528f, investigated a reported nitrate selective resin and how specific anions interfere with anion resins in nitrate removal service. The DOWEX 21K which was reported as "nitrate selective" by Chemical Separations Corporation did not show nitrate selectivity in waters of TDS (total dissolved solids) concentrations of about 500 ppm. At high TDS levels, the resin did show nitrate selectivity. This was pointed out to be expected because of the monovalent ion preference in feedwaters of high ionic concentrations. Sulfate, iron, and silica were pointed out to be the most problematical.
Dalton, G. L., "The Removal by Ion Exchange of Nitrates From Borehole Water at Aroab SWA", report of the National Institute for Water Research, Pretoria, 1978, studied the application of nitrate removal by ion exchange to waters in the Republic of South Africa and southwest Africa. Amberlite IRA 904 resin was selected from 32 resins as having the highest nitrate-to-sulfate selectivity and was used in pilot plant tests. The waters tested were of high TDS allowing electroselectivity effects to give high nitrate-to-sulfate selectivity.
Grinstead, R. R., and K. C. Jones, "Nitrate Removal from Wastewaters by Ion Exchange", EPA report 17010FSJ01/71, January 1971, reported studies on porous polymer beads carrying alkyl substituted amidines. Typical K Cl N values ranged from 15 through 40 and log K S N values were 5 to 6 (NSS=1.69 to 2.69). Their object was to increase K Cl N of an ion exchanger for removal of nitrate from wastewaters of high chloride content and thereby obtain better efficiency. Loss of extractant from the polymer beads to the product stream and the low ion exchange capacity of the resin of below 0.2 eq/l were the observed disadvantages of the process. The high K Cl N of the resin precluded the possibility of obtaining high nitrate concentrations in the waste regenerant.
U.S. Pat. No. 4,134,861 issued to Roubinek (Diamond Shamrock) adopted the amidine approach of Grinstead and Jones. The patent describes a method of resin preparation by introduction of the amidine groups into a preformed polymer which is preferably a vinyl polymeric matrix cross-linked by divinylbenzene, resulting in the recurring structure --CH 2 --CHX--, wherein X is the amidine group. It was found that the best balance between nitrate selectivity and ease of regeneration is obtained when the total number of carbon atoms on the amidine was 5 to 7. Butyl and ethyl groups were generally preferred. K Cl N values were reported to be 7 to 10. No K S N values were reported nor were any column tests or regeneration efficiencies reported.
Clifford, D. A., and W. J. Weber, "Nitrate Removal From Water Supplies by Ion Exchange", EPA-600/2-78-052, June 1978, reported an exhaustive study comparing the ionic selectivities of 19 strong-base and 13 weak-base commercial resins. They found that for groundwaters having TDS concentrations up to at least 3,000 ppm all resins preferred sulfate to nitrate. Clifford et al found that nitrate-to-sulfate selectivity among strong-base resins increased to some degree, dependent on the degree of cross-linking, but was unaffected by the number of carbon atoms surrounding the ammonium nitrogen atom. Clifford et al found the reverse to be true in the case of weak-base resins, i.e., that nitrate-to-sulfate selectivity increases with increasing R group size but that the degree of cross-linking in the substrate resin has no significant effect. The Clifford et al report also concluded (at page 6) that "Sulfate/nitrate selectivity was nearly irrelevant in determining the average equivalent fraction of nitrate on the resin at the end of a run" and that higher sulfate selectivity increases rather than decreases the amount of nitrate at the end of a column run. Thus, the findings of Clifford et al seem to lead to the conclusion that increases in nitrate/sulfate selectivity would not improve the column performance of resins for nitrate removal in the presence of sulfate. In any event, the commercial resins studied by Clifford et al did not show enough nitrate selectivity to be of significant value and should not be regarded as nitrate-to-sulfate selective (NSS) resins.
In summary, a need for anion exchange resin having significantly higher nitrate-to-sulfate selectivity remains a long-standing need in the art. If higher nitrate selectivity could be translated into a higher capacity for adsorbed nitrate, a NSS resin might offer significant regenerant savings because, in general, the more nitrate on a resin at the end of the run, the more nitrate will be removed per pound of regenerant. Whether or not a given resin is fully loaded with nitrate, 4 to 6 bed volumes of a 6 percent saline solution are required to effect regeneration. However, any increase in capacity which might be afforded by higher nitrate-to-sulfate selectivity might be partially or wholly offset by an increase in nitrate-to-chloride selectivity which would render the resin more difficult to regenerate. Such an offset was seen in the work of Walitt and Jones who incorporated nitrate analytical reagents into polystyrene to make an anion exchange resin selective for nitrate. They concluded "It appears that we have chosen to examine in depth a specific example of the proposed concept which was far too successful; that is, the affinity of the 1-naphthylmethylamine group (in the polystyrene resin) for nitrate ion is so great that regeneration to the free base by ordinary methods is unsuccessful." Walitt, A. L., and H. L. Jones "Basic Salinogen Ion-Exchange Resins for Selective Nitrate Removal from Potable and Effluent Waters", U.S. EPA, Cincinnati, Advanced Waste Treatment Laboratory, 1970, U.S. GPO, Washington, D.C. Thus, "nitrate selective" is terminology which can imply both advantages and disadvantages.
SUMMARY OF THE INVENTION
It has now been discovered that certain tributyl amine resins have a nitrate to sulfate selectivity which is sufficiently high that the removal of nitrate ions from municipal water supplies containing significant amounts of sulfate ions becomes economically feasible. These strongly basic quaternary ammonium anion resins may be represented by the following formula: ##STR1## Experimental work has demonstrated that the tri-n-butyl derivative of the styrene-divinyl benezene copolymer, used as the resin intermediate in the commercial manufacture of DUOLITE A-104, (trademark of Duolite International) has a threshold value K S N for nitrate to sulfate selectivity of about 10,000 and has demonstrated effective nitrate removal for flow rates over 45 gpm per square foot of bed area (2.75 BV per minute). These properties are significantly superior to those found for the trimethyl (K S N =100), trimethyl (K S N =1000) and tripropyl (K S N =1100) amine derivatives of the same copolymer.
Several ancilliary benefits deriving from the use of the tributyl amine resin have also been found. The tributyl amine resin has been found to remove less bicarbonate ions from the water and, accordingly, the effluent is less acidic and therefore less corrosive. Also, surprisingly, the tributyl species, unlike its lower alkyl homologues, has been found to have signifcant algicidal activity.
Contrary to any inference from the above-noted work of Clifford et al, the higher nitrate-to-sulfate selectivity afforded by the tri-butyl amine resin translates into a much higher capacity for the adsorption of nitrate and better column performance in the presence of sulfate. Unlike the commercial resins investigated by Clifford et al which exhibit nitrate breakthrough before sulfate breakthrough, the tributyl species used here gives sulfate breakthrough before significant nitrate leakage occurs.
The tri-butyl amine resin used in the present invention is a "nitrate-selective resin" which term as used herein means a resin which in a column operation with common groundwaters retains nitrate as the last ion to break through when exchanging ions at anionic strengths of 10 meq/l. The latter concentration is chosen as a convenient and practical concentration. At very low anion concentrations (especially sulfate), the term "nitrate-selective resin" loses practical significance or fades in importance because relatively large volumes of water can be treated with a given resin bed. At high concentrations, electroselectivity will produce the selectivity reversal; consequently, the column operation should be assessed at anion concentrations more typical of groundwaters, i.e., total dissolved solids (TDS) levels of 500-700 ppm or less. It is pointed out that the definition follows the normally observed breakthrough order when only monovalent ions are present.
The high nitrate absorption capacity (meq of nitrate retained on column at nitrate breakthrough) affords important advantages in terms of savings on capital investment for equipment and in savings from a reduced requirement for regenerant. The higher K S N value reflects yet another advantage in that the column can be used through the sulfate breakthrough point, up to the nitrate breakthrough point, so that little or no regenerant is spent in removing the sulfate from the column.
Accordingly, the method of the present invention provides for removal of nitrate from waters containing a signifcant amount of sulfate ion, on the order of 50 ppm or more, and a TDS of about 1000 ppm or less (at such TDS levels electroselectivity is not a significant influence on nitrate-to-sulfate selectivity), by passing the water through a bed of a tributyl amine derivative of a copolymer of a monovinyl aryl compound and a polyolefinic cross-linking agent. The purified water is collected as the effluent from the resin bed. The resin bed is periodically washed with an aqueous salt solution for regeneration. Most preferably, in each cycle the nitrate removal is continued through the sulfate breakthrough point and then washed with the regenerant prior to the nitrate breakthrough point. Most preferably, each periodic wash is discontinued at a point where a substantial amount, i.e., about 10 percent or more, of the adsorbed nitrate is left on the resin when the resin column is returned to service.
Accordingly an object of the present invention is to provide for nitrate removal from potable water containing about 200 ppm or more nitrate, about 50 ppm or more sulfate and about 1000 TDS or less.
It is another object of the present invention to reduce nitrate levels in potable water to below about 10 mg per liter.
Yet another object of the present invention is to provide for higher nitrate-to-sulfate selectivity and nitrate adsorption capacity than previously realized without impairing regeneration.
Other objects and further scope of applicability of the present invention will become apparent from the detailed description to follow.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The Resins
The backbone resins used as substrates to produce the tributyl anion exchange resins employed in the method of the present invention are copolymers of a (A) vinyl aryl compound and (B) a polyolefinic cross-lining agent. The monovinyl aromatic compounds are suitably vinyl aromatic hydrocarbons, such as styrene, ortho-, meta- and para-methyl and ethyl styrenes, vinyl naphthalene, vinyl anthracene and the homologues of these compounds. Styrene is preferred. Also, the monovinyl aryl moiety of the copolymer may consist of nuclear substituted chlorine or bromine substituted vinyl aryl compounds, such as the ortho-, meta- and para-chloro and bromo styrenes copolymerized with other diluting monovinyl aryl compounds. The preferred polyolefinic cross-linking agents are polyvinyl aromatic compounds, also selected from the benzene and naphthalene series. Examples of polyvinyl-aromatic compounds are divinylbenzene, divinyltoluene, divinylxylene, divinyl-naphthalene and divinylethylbenzene.
The backbone resin used in applicant's studies to data is the styrene-divinyl benzene copolymer used as the resin intermediate in the commercial manufacture of DUOLITE A-104 (trademark of Duolite International) which may be characterized as a strong-base quaternary amine and as a type II hydroxyl-containing resin which is represented by the formula: ##STR2## DUOLITE A-104 shows a preference for sulfate over nitrate (K S N =50). In the context of the present useage of the term, DUOLITE A-104 is not considered a nitrate-to-sulfate selective (NSS) resin.
Studies conducted by Clifford et al and by the present applicant indicate that higher amounts of divinylbenzene in the copolymer (15-20 wt %) provide increased porosity and cross-linking, which factor, in turn, favors nitrate-to-sulfate selectivity. These factors are believed to explain the higher nitrate-to-sulfate selectivity of AMBERLITE IRA-900, as compared with DUOLITE A-101D and A-104.
The anion exchange resins employed in the present invention may be formed by first reacting one of the aforementioned copolymers with a halogen in the presence of a halogenating catalyst to produce halomethyl radicals attached to aromatic nuclei in the resin in the manner more fully described in U.S. Pat. No. 2,614,099 issued Oct. 14, 1952 to W. C. Bauman et al, the teachings of which are incorporated herein by reference. The halogenated resin is then reacted with tributylamine, in the manner also taught by Bauman et al.
Nitrate Removal
The tributyl resin is utilized in a conventional manner for treatment of waters containing both nitrate and sulfate ions. Standard commercial water softening equipment may be used; however, some modification may be desirable to improve distribution of the influent flow and brine regenerant. Further, the resin column should be declassified by thorough mixing of the resin subsequent to downflow regeneration and prior to reuse.
Continuous nitrate removal may be achieved in the conventional manner by using a number of resin columns in parallel and switching the influent flow from one column to another as each column is, in turn, regenerated.
Suitable flow rates for influent and for regenerant are those conventionally used for other strong-base anion exchange resins.
Regeneration
The resins used in the method of the present invention, upon reaching the first nitrate breakthrough point, may be completely regenerated by washing with about 4 bed volumes (BV) of a 6 wt % NaCl Brine. The regenerant is preferably passed through the resin column in the same direction as the water undergoing treatment. While NaCl is an attractive regenerant from the viewpoint of material cost, this apparent economic advantage may be offset by the cost of disposal of the spent brine solution. In contrast, the use of calcium chloride as a regenerant produces a waste brine containing calcium nitrate and sulfate, both of which are disposable to agricultural lands. Ammonium chloride is also an attractive regenerant that gives an ammonium nitrate and sulfate-containing waste brine a significant agricultural value.
Because anion exchange resins are quite selective for sulfate ion, the presence of sulfate in raw water decreases the efficiency of the conventional resins to absorb nitrate. With the resin used in accordance with this invention, however, sulfate is easily removed from the spent resin by the sodium chloride regenerant in nearly stoichiometric proportions whereas excess regenerant is required for nitrate removal (5-10 moles of NaCl per mole of nitrate). Sulfate, by preventing a large build up of nitrate on the resin, promotes low nitrate leakage from a partially regenerated column. The overall effect of sulfate, however, is to increase the salt required to remove a unit quantity of nitrate per unit quantity of water treated. Applicant's studies have confirmed that large quantities of regenerant (20 pounds per cubic foot of resin) are required to remove most of the nitrate from the spent resin. Not all nitrate need be removed, however, to reduce nitrate levels in treated water to below 45 ppm.
Partial regeneration is highly desirable because more nitrate is removed per equivalent of salt regenerant than if complete regeneration is used. In a plot for mole fraction of nitrate remaining on the column during regeneration (vertical axis) vs. bed volumes of a given regenerant (horizontal axis) is examined, it will be seen that the amount of nitrate on the column drops off quite sharply for the initial quantities of regenerant used and then levels off drastically as the mole fraction of nitrate approaches zero. Accordingly, economies in the cost of the regenerant and in the disposal of the waste, nitrate-containing wash water can be realized by only partially regenerating, for example, to the point where about 10 percent or more of the adsorbed nitrate remains on the column. Further, by operating the column through the sulfate breakthrough point, which is possible because sulfate breaks through first using the tributyl species, the amount of regenerant expended in removing sulfate from the column can be substantially reduced.
The advantage of partial regeneration afforded by the present invention can be illustrated by assuming a feed water by having the following composition:
______________________________________Nitrate = 1.5 MEQ/L (93 PPM)Sulfate = 7.0 (336 PPM)Cl + HCO.sub.3 = 3.5______________________________________
Assuming that the nitrate level must be reduced to 35 ppm (0.56 meq/liter) the nitrate on the column must be reduced to a mole fraction of 0.35. A further reduction is not economical and therefore partial regeneration is preferred. At sulfate breakthrough, the nitrate level is determined by the K S N value of the resins. With the tributyl resin of the present invention, at sulfate breakthrough, the nitrate in the effluent from the treatment of the above-described water, will be 35 ppm. Using the triethyl resin homologue having a K S N of 1,000 to treat the same influent, the nitrate leakage after sulfate breakthrough would be about 75 ppm which is well in excess of the 35 ppm objective. Accordingly, using the triethyl species the nitrate removal cycle must be terminated prior to sulfate breakthrough. Thus, in the case of the triethyl species, the full nitrate absorbing capacity of the resin is not used and the process cannot take advantage of the nitrate selectivity of the resin. To take advantage of the nitrate selectivity of the triethyl resin complete regeneration is required which is substantially less economical.
Nitrate-to-Sulfate Selectivity--Experimental
Samples of resins were put in the nitrate form by passing one normal sodium nitrate solution through a column of each resin. The resins were supplied to us in the chloride form. A measured 5-ml sample of wet resin was placed in a bottle with meansured 150 ml of a sodium sulfate solution of about 50 meq/l. The tightly stoppered bottle was periodically shaken and allowed to stand overnight before sulfate and nitrate analyses were performed for both the resin phase and the aqueous phase. On the basis of these analytical results the values given in Table I below were calculated.
TABLE I______________________________________Properties of Resins.sup.1 as Determined Experimentally Moisture.sup.2 Vol. Content Capacity.sup.2 K.sub.S.sup.NNo. & Designation (%) (eq/L) (Approx.) NNS.sup.4______________________________________ 1 R--TM 51.0 1.41 100 -0.14 2 R--TE 47.9 1.19 1,000 +0.92 3 R--MDEOH 41.1 1.41 10 -1.15 4 R--EDEOH 38.9 1.30 50 -0.41 5 R--TEOH 33.1 1.23 10 -1.09 6 R--DEMEOH.sup.3 45.7 1.42 50 -0.45 7 R--DEEOH 43.5 1.29 100 -0.11 8 R--N--MM 44.6 1.35 200 +0.17 9 (Duolite A-101D) (48 to 55) (1.3) (25) -0.7110 R--TP 30.4 0.84 1,100 +1.1211 R--TB 33.0 0.66 11,100 +2.22______________________________________ .sup.1 All resins synthesized from the resin intermediate used in commercial manufacture of Duolite A104 .sup.2 Data supplied by Duolite International .sup.3 Same as Duolite A104 .sup.4 NSS = log K.sub.S.sup.N - log --C+ 1 R represents the styrenedivinylbenzene copolymer used as the resin intermediate for DUOLITE A104 TM trimethyl TE triethyl MDEOH methyldiethoxy EDEOH ethyldiethoxy TEOH triethoxy DMEOH dimethylethoxy DEEOH diethylethoxy NMM TP tripropyl TB tributyl
Column Performance--Experimental
The following conditions were chosen for the experimental column work:
______________________________________Column Size 2-inch-ID by 4-foot lengthBed Depth 24 inchesCross-Sectional Area of 3.14 in.sup.2 ; 20.26 cm.sup.2 ; 0.022 ft.sup.2ColumnBed Volume of Ion Exchange 1.245 ml; 0.044 ft.sup.3Resin______________________________________
Ion exchange experiments were conducted with the five strong base anion exchange resins listed below in the 2-inch-diameter columns. Flow rates were held near 1/2 BV per minute. Water directly from a well near McFarland, Calif. was used either diluted with deionized water or undiluted to give the influent water compositions seen in Table II below.
An automatic sampler was constructed to obtain effluent samples at least once every 60 minutes. A flowmetering device was also constructed to record the flow rate through the column. This was necessary because it was observed that flow rate changes varied slightly over long periods of operation and required either frequent readjustment or automatic recording.
The resins, feed water compositions, and meq of sulfate passed and meq of nitrate retained (nitrate capacity) at nitrate breakthrough are given in Table II.
TABLE II__________________________________________________________________________ Meq of Sulfate passedResin Influent Water* by column (1 liter) Meq of Nitrate remaining on(see Table I meq/l Mole Fraction before nitrate break- 1 liter of resin atfor definition) Sulfate Nitrate Sulfate Nitrate through** breakthrough**__________________________________________________________________________DUOLITE 7.29 1.21 0.56 .093 0 211A-101DR-TE 7.29 1.21 0.56 .093 1050 321R-TP 7.81 1.78 0.55 0.126 900 294R-TB 7.5 1.77 0.54 .128 2833 531R-TEOH 6.67 1.21 0.54 .098 meq of nitrate passed by 1 meq sulfate retained by liter column before sulfate 1 liter of resin at breakthrough sulfate breakthrough 107 1134__________________________________________________________________________ *Meq chloride + Meq bicarbonate in each composition is approximately 4.5 **Calculated at breakthrough point for last ion to breakthrough Breakthrough defined as point where concentration of breaking ion = 1/2 its influent concentration
The invention may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are therefore to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.
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The invention relates to a method for separating nitrate from waters containing a significant amount of sulfate ion. Nitrate removal is accomplished by passing the water to be treated through a bed of a strong-base anion exchange resin which is a tributyl amine derivative of a copolymer exemplified by styrene-divinyl benzene. The tributyl species has been found to have an unusually high selectivity for nitrate over sulfate and provides not only a high capacity for nitrate removal but also economies in regeneration due to the ability to operate with only a partially regenerated resin bed.
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TECHNICAL FIELD OF THE INVENTION
[0001] The present invention is directed, in general, to the use of reinforced ice for road surfaces over water.
BACKGROUND OF THE INVENTION
[0002] In cold climates roads are made out of ice over naturally frozen lakes and other bodies of water to permit the transport of goods and materials to outlying areas by trucks, automobiles and other vehicles. The current method making roads out of ice, or ice roads, is to allow a body of water to freeze and thereafter use the frozen surface as a roadbed without any type of reinforcement. In these same climates ice is also used to re-surface roads that are in poor driving condition.
[0003] The use of natural ice for the road surface and support is subject to weather conditions and the inherent strength of the ice created from only frozen water. These ice roads are unreliable and of unknown strength. Further they require the truck and other means of transport to proceed at slow speeds, because the natural ice will bend forming a wave in front of the truck. As the trucks speed increase this wave grows and eventually caused the ice to crack. Also the trucks weight must be restricted to prevent the ice from cracking.
[0004] The use of natural ice results in the natural ice melting at temperatures above freezing.
[0005] Therefore, improvements in the strength of the ice roads and making the ice roads more resistant to thawing would be beneficial and to the businesses that require their products, materials and supplies to be shipped over the ice roads, and in addition will improve the safety of the vehicle drivers
SUMMARY OF THE INVENTION
[0006] The present invention provides a method of fabricating ice roads using wood pulp mixed with water or re-surfacing roads in cold climates. Additional features of the invention will be described hereinafter that form the subject of the claims of the invention. Those skilled in the art should appreciate that they can readily use the disclosed conception and specific embodiment as a basis for designing or modifying other structures for carrying out the same purposes of the present invention. Those skilled in the art should also realize that such equivalent constructions do not depart from the spirit and scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] For a more complete understanding of the present invention, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:
[0008] FIG. 1 illustrates a diagram of an embodiment of ice road constructed according to the principles of the present invention; and
[0009] FIG. 2 illustrates a flow diagram of an embodiment of a method of fabricating an ice road carried out according to the principles of the present invention.
DETAILED DESCRIPTION
[0010] The present invention provides a roadway that utilizes wood pulp embedded in frozen water or ice to form a composite structure. Wood pulp is used in the composite structure of the ice to assist in creating a surface with a higher compressive and tensile strength and to assist in dispersing the weight of the vehicles over a greater area. The wood pulp is in suspension in the ice to form the composite structure. The composite ice is a much stronger structure than natural ice. Research has shown that natural ice has a modulus of around 22.5 kg/cm 2 but since natural ice is very inconsistent its modulus could be as low as 5 kg/cm 2 . Where as the composite ice has a modulus that is much more consistent, that is much less variability in its strength. Its modulus is 25% higher than natural ice. Typical composites will have a modulus of 77 kg/cm 2 . Thus, the composite structure is more capable of carrying greater weight before failure.
[0011] The composite structure is also much more ductile them natural ice and has been shown to be able to withstand high velocity rifle shots without shattering. The composite ice is also 4 to 5 times stronger than natural ice in tension.
[0012] Additionally, the addition of the wood pulp to the ice makes the ice more resistant to thawing because of it insulating properties.
[0013] The composite structure possesses properties that would allow you to build a roadway that for a given thickness could support a heavier load, withstand vehicles being driven at a higher speeds and would last longer than the natural ice as the temperature rose above freezing.
[0014] Also, given the fact that the composite is more consistent than natural ice, the thickness of the composite ice does not need to be as thick as natural ice to ensure the safe transport of materials across the roadway. The consistence of the composite ice reduces the cost of maintaining the roadway, since less testing and analysis has to be done to maintain the roadway.
[0015] All of the advantages describe above for making roads over frozen lakes also apply to using the composite ice approach to re-surface roads in poor condition located in cold climates.
[0016] Turning now to FIG. 1 , illustrated is a diagram of an embodiment of the ice road surface, constructed according to the principles of the present invention.
[0017] Once the lake 100 has frozen to the point that the natural ice 110 will support light construction equipment the construction of the composite roadway can begin. First barriers 120 must be built on each side of the roadway that will be filled with the materials used to create the composite ice road. These barriers 120 can be built using naturally available materials such as snow, or manmade materials such as plastic tubes that can be filled with water.
[0018] Once the barriers 120 are in place, the mixture of water and wood pulp 130 is put between the barriers and allowed to freeze. The mixture is 14 percent wood pulp to water based upon volume. The mixture can either be pumped or sprayed in place. If additional strength members 140 are needed to support the roadway load then only part of the water and wood pulp mixture 130 is added and allowed to freeze and then the strength members 140 are added to the roadway. The additional strength members can consist of cables laid along the direction of traffic on the roadway or netting added to the road way. These cables or netting can be made of metal, synthetic or natural fibers. The choice of material will depend upon the strength needed and the cost of the materials. The remaining mixture of water and wood pulp 130 is then added to the roadway.
[0019] Once the roadway freezes, water based, colored dye 150 is placed over the roadway and allowed to freeze. Then another layer of composite ice mixture 130 is place on the roadway. This represents the wear surface for the roadway. Any time the colored dye is exposed, the road maintenance crews will know that another layer of composite ice needs to be added to the roadway to ensure that the roadway is safe.
[0020] On top of this top road surface, a traction layer 160 can be added to the roadway to improve the vehicles traction. This traction surface 160 can consist of a mixture of water and gravel. The percent of gravel that is added is a function of how much traction is required and what size gravel is used.
[0021] FIG. 2 illustrates a flow diagram of a method of fabricating an ice road carried out according to the principles of the present invention. This block diagram lays out the step by step procedures for building a composite ice roadway.
[0022] The procedure begins in step 210 . After the lake has frozen 220 enough to support light construction equipment, construction of the road can begin. The composite road surface is built over this natural ice base.
[0023] The roadway is then laid out 230 and the barriers that will hold the composite ice are constructed. Once the barriers are in place the mixture of water and wood pulp is added between the barriers 240 .lf the design of the roadway requires the inclusion of additional strength members 250 , they are added at this time. Then another layer of composite ice 260 is added to the roadway.
[0024] At this point the roadway would be ready for traffic, but additional feature such as a safety warning layer and a traction layer can be added.
[0025] After the basic roadway is formed a safety color layer is placed on the roadway. Then a wear layer of composite ice 280 is added to the roadway. Once this layer has frozen, a traction layer 290 can be added to the roadway.
[0026] Although the present invention has been described in detail, those skilled in the art should understand that they can make various changes, substitutions and alterations herein without departing from the spirit and scope of the invention in its broadest form.
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The present invention provides a method of fabricating road surfaces in cold climates for ice roads. In one embodiment the road surface includes: a combination of water and sawdust that is placed on the road surface and frozen.
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BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] The invention relates in general to shipping containers, and more particularly, to a shipping container for flowable material which comprises a large outer container (i.e., a common twenty foot shipping container, or the like) and an inner flexible tank. Furthermore, the invention is directed to a flexible tank used within the shipping container.
[0003] 2. Background Art
[0004] Shipment of flowable material in large quantity over relatively long distances has increased over the last few decades. Whereas dry cargo has been essentially revolutionized in the last 40 years, with the introduction of the standard shipping container, the ISO tank has remained the common mode of transporting flowable materials.
[0005] In the past several years, however, there has been a move toward the use of flexible tanks positioned and retained within standard shipping containers for transporting relatively large shipments of flowable materials. Among other reasons, such a system allows for the use of conventional shipping containers, where a tank, after use can be folded and stored. As containers are quite standard, the folded flexible tanks can be shipped to a location, whereas the bulky rigid standard containers can be obtained locally.
[0006] Great logistical advantages can be achieved through the use of flexible tanks within standard containers. Furthermore, a great cost savings is realized inasmuch as the construction costs of ISO tanks are typically quite expensive when compared to a standard shipping container and a flexible tank.
[0007] While such advantages are leading a revolution in the shipment of flowable materials, there have been drawbacks. Generally, to insure safe travel of the flowable material, the flexible tanks are relatively thick and heavy duty. Whereas dispensing bag films may be on the order of 2-8 mils, the flexible tanks associated with the present invention are substantially thicker (i.e., at least approximately 15 mils and often approximately 40 mils or greater). While thick films are required, these films must have also possess qualities of flexibility, resistance to shock, the resistance to flex cracking and the ability to be sealed so as to form a substantially fluid-tight cavity.
[0008] Typically, to achieve the desired strength and flexibility characteristics, the predominantly used material has been LDPE and LLDPE. Such a material exhibits relatively large oxygen transmission rates (OTR). For example, the OTR for such films is approximately on the order of twelve cubic centimeters per one hundred square inches per day.
[0009] Such an OTR is quite high and can adversely affect the quality of oxygen sensitive materials when shipped any appreciable distances. For example, such an OTR makes the otherwise desirable transport system less suitable for the satisfactory shipment of wine from Australia to North America, or from Argentina to Europe.
[0010] To avoid the degradation of the flowable material, one solution is to use conventional ISO tanks, or, to first package the wine into bottles or small dispensing bags (i.e., 3 to 10 liter). There is a great increase in cost with either system. One particular downside with the packaging of wine into smaller dispensing bags prior to long-haul shipment is that the bags are generally placed into small rigid paperboard boxes. In turn, if one of the thousands of bags is compromised, generally a number of rigid paperboard container of adjoining bags in the same shipment are destroyed. Thus, even a small breach in one bag can ruin a number of different bags in a single shipment.
[0011] It is an object of the present invention to provide a flexible tank which has an oxygen transmission rate suitable for long haul shipment of oxygen sensitive materials.
[0012] It is another object of the present invention to provide a flexible tank which is suitable for long haul shipment of wine and other oxygen sensitive materials.
[0013] It is another object of the invention to provide a flexible tank film which has a relatively low oxygen transmission rate (OTR) for a relatively thick film.
[0014] These objects as well as other objects of the present invention will become apparent in light of the present specification, claims, and drawings.
SUMMARY OF THE INVENTION
[0015] The invention is directed to a shipping container for flowable material, in a first aspect. In particular, the shipping container includes a large rigid shipping container, such as a conventional twenty foot shipping container, and a flexible tank. The flexible tank is positionable within the rigid shipping container. The flexible tank includes a film having a plurality of seals to define a cavity, and a dispensing means for dispensing a flowable material positioned within the cavity. The film includes a layer comprising a co-extruded blend of HDPE and TPE, to, in turn minimize oxygen transmission within the film.
[0016] In a preferred embodiment of the invention, the film comprises a thickness of at least 15 mils, and more preferably at least 30 mils.
[0017] In another preferred embodiment, the cavity of the flexible tank is between 10,000 and 30,000 liters, and preferably at least 20,000 liters.
[0018] In yet another preferred embodiment, the film comprises a co-extrusion with the layer comprising the product contact layer.
[0019] In certain embodiments, the layer of the film further comprises at least one of EVOH, Nylon, PET, an oxygen scavenger and anhydride-modified PE.
[0020] In other embodiments, the film may include a second layer comprising at least one of an LLDPE and an LDPE material. The second layer is positioned about the first layer.
[0021] In another aspect of the invention, the film further includes a third layer comprising at least one of an LLDPE and an LDPE material. The third layer positioned about the first layer opposite the second layer.
[0022] Preferably, the layer, the second layer and the third layer are co-extruded.
[0023] Most desirably, the film has an OTR, the OTR of the film being less than six cubic centimeters per one hundred square inches per day, and wherein the film is at least 30 mils in thickness.
[0024] In another aspect of the invention, the invention comprises a flexible tank for use in association with a rigid shipping container for the transport of flowable material. The flexible tank comprises an oxygen sensitive flowable material. The flexible tank is positionable within the rigid shipping container. The flexible tank includes a film having a plurality of seals to define a cavity, and a dispensing means for dispensing a flowable material positioned within the cavity. The film comprises a layer having a co-extruded blend of HDPE and TPE, to, in turn minimize oxygen transmission within the film.
[0025] In another aspect of the invention, the invention comprises a shipping container for flowable material which includes a large rigid shipping container and a flexible tank positioned within the rigid shipping container. The shipping container has a substantially rectangular cubic configuration with common attachment regions. The flexible tank is positionable within the rigid shipping container. The flexible tank includes a generally rectangular cubic configuration. At least certain dimensions of the flexible tank corresponds to dimensions of the large rigid shipping container so that the flexible tank has a generally form fit retention within the large rigid shipping container. The flexible tank further comprises a film which together with a plurality of seals defines a substantially rectangular cubic cavity. A dispensing means is provided which extends through the film for selectively placing the cavity in fluid communication with an outside dispenser. The film comprises a layer comprising a co-extruded blend of HDPE and TPE, to, in turn minimize oxygen transmission within the film.
[0026] In a preferred embodiment, the film comprises a thickness of at least 30 mils and has an OTR of less than six cubic centimeters per one hundred square inches per day.
[0027] In another preferred embodiment, the film includes a second layer extending about the first layer and a third layer extending about the second layer. The second and third layers comprising at least one of an LLDPE and an LDPE material.
[0028] In another preferred embodiment, the large rigid shipping container comprises a standard twenty foot container.
BRIEF DESCRIPTION OF THE DRAWINGS
[0029] The invention will now be described with reference to the drawings wherein:
[0030] FIG. 1 of the drawings is a perspective view of a shipping container having the flexible tank of the present invention;
[0031] FIG. 2 of the drawings is a perspective view of a flexible tank in the articulated configuration; and
[0032] FIG. 3 of the drawings is a partial enlarged cross-sectional view of one embodiment of a film which is suitable for use in association with the flexible tank of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0033] While this invention is susceptible of embodiment in many different forms, there is shown in the drawings and described herein in detail a specific embodiment with the understanding that the present disclosure is to be considered as an exemplification of the principles of the invention and is not intended to limit the invention to the embodiment illustrated.
[0034] It will be understood that like or analogous elements and/or components, referred to herein, may be identified throughout the drawings by like reference characters. In addition, it will be understood that the drawings are merely schematic representations of the invention, and some of the components may have been distorted from actual scale for purposes of pictorial clarity.
[0035] Referring now to the drawings and in particular to FIG. 1 , a shipping container for flowable material is shown generally at 10 . The shipping container includes a large rigid outer container 20 and inner flexible tank 30 . The large rigid outer container preferably comprises a standard twenty foot container. Typically, such a container has a twenty foot length an eight foot width and an eight foot, six inch height. This is commonly referred to as a TEU, or twenty four equivalent unit. These types of containers have a maximum payload of approximately 21,600 kg and a gross weight of 24,000 kg (with a volume of approximately 38,500 liters).
[0036] Such containers are popular and available virtually everywhere in the world. Furthermore, other containers, such as forty foot containers, forty-five foot containers, forty-eight foot containers and fifty-three foot containers are likewise contemplated, however, with most flowable material, a container larger than the twenty foot container is typically heavier than the permissible gross weight of the filled container. However, the invention is not limited to any particular sized container, but is quite suitable for conventional shipping containers.
[0037] Such containers include a rectangular cubic configuration having a top surface 70 , a bottom surface 72 , opposing side surfaces 74 , 76 , front surface 78 and back surface 80 , all of which cooperate to define inner space 85 . The top surface 70 opposes the bottom surface 72 . One of the front surface 78 and the back surface 80 comprise a pair of doors 82 , 84 which provide ingress to inner space 85 . Typically the doors are hinged about the edges of the opposing side surfaces 74 , 76 and include clasps and locking mechanisms (not shown) to retain the doors in the closed configuration.
[0038] The flexible tank 30 is shown in FIG. 2 as comprising a plurality of panels of film 40 which are sealed to each other by way of seals 42 to form a substantially rectangular cubic configuration. Specifically, the flexible tank comprises top surface 90 , bottom surface 92 , opposing side surfaces 94 , 95 , front surface 96 and back surface 98 . Seals and/or folds define the demarcation of the various panels of the flexible tank. Typically the volume of the rigid outside container is on the order of approximately 38,500 liters, and the flexible tank may have a volume which is as large as inner space 85 (minus any volume taken by the flexible tank film and other structures, and any other necessary equipment. More typically, the volume of the flexible tank is between 10,000 and 30,000 liters per TEU of the outer rigid container, and more preferably at least 20,000 liters.
[0039] A dispensing means 46 is provided on one of the front and back surfaces or on one of the top or bottom surfaces. The dispensing means may comprise a spout having a fitment integrated therewith or separately positioned thereon. The dispensing means may comprise a plurality of spouts which are positioned in a spaced-apart relationship along any one or more of the panels. Indeed, it is contemplated that multiple spouts may be provided so that one spout can be used for filling and another for removing the flowable material. In other embodiments, multiple filling spouts and dispensing spouts may be provided. Furthermore a vent (not shown) is typically provided on the top of the flexible tank so as to release any air captured within the cavity.
[0040] The dispensing means is positioned such that access can be gained thereto when the flexible tank is positioned within the rigid outer container. In many instances, a bottom discharge means comprising a valve is utilized, while top discharge locations are likewise contemplated. Of course, in other embodiments, where is desirable to limit the access to the dispensing means, the dispensing means can be moved away from the region proximate the doors of the outer rigid container.
[0041] With reference to FIG. 3 , the flexible tank film 40 most preferably comprises a three layer co-extrusion having an outer layer 54 comprising a low density polyethylene (LDPE) and/or a linear low density polyethylene (LLDPE) material, an inner layer 52 likewise comprising a LDPE and/or LLDPE material and a layer 50 comprising a blended high density polyethylene material (HDPE) and a thermoplastic elastomer (TPE). Due to the rugged environment and vast distances covered by such containers, the film comprises a thickness of at least 15 mils, and more preferably at least 30 mils or greater. In a preferred embodiment, the thickness is approximately 40 mils wherein the outer layer 54 has a thickness of approximately 7 mils, the inner layer 52 has a thickness of approximately 7 mils, and the layer 50 has a thickness of approximately 26 mils. As far as ratios, the different layers may have relative thicknesses of 20/60/20, 5/90/5 as well as a number of different ratios as well. Furthermore, carbon black may be included in certain layers to provide an opaqueness to the flexible tank.
[0042] Whereas HDPE, while a vastly improved oxygen barrier over LDPE or LLDPE, lacks the necessary characteristics (strength, ductility, flex cracking resistance, etc.) to be useful for such a container, it has been found that, surprisingly, HDPE along with TPE, in a blended co-extrusion yields a final layer which has a vastly improved oxygen transmission as compared to LDPE or LLDPE, while having strength, ductility, and flex cracking characteristics which are substantially similar to LDPE/LLDPE. Additionally, and again quite surprisingly, the combination of the blended HDPE and TPE can be co-extruded with layers of LDPE and/or LLDEP. The performance of the HDPE and TPE blend, especially for relatively thick films has been rather unexpected. It will be understood that in certain embodiments, it may be desirable to utilize a single layer co-extrusion of the blended HDPE and TPE where it forms the product contact layer. It is also contemplated that a two layer co-extrusion can be provided wherein the second layer comprises an LDPE or LLDPE layer.
[0043] In a preferred embodiment, the HDPE and TPE blend comprises a 60% HDPE to 40% TPE blend, while other combinations are likewise contemplated. It will be understood that in certain formulations, EVOH, Nylon, PET, oxygen scavengers and/or anhydride-modified Polyethylene (PE) may be included in the blended HDPE and TPE. Furthermore, additional layers may be present which include PE, EVOH, Nylon, oxygen scavengers, PET and/or anhydride-modified PE. It will be understood that certain of the layers may be laminated onto the blended HDPE and TPE layer.
[0044] Whereas such large flexible tanks are formed from ˜0.918 g/cc density butene, hexene and/or octene LLDPE, such materials include a oxygen transmission rate (OTR) or approximately twelve cubic centimeters per one hundred square inches per day. By replacing the layer 50 with a HDPE and TPE blend of the present invention, the OTR can be reduced to approximately five cubic centimeters per one hundred square inches per day. Thus the OTR can be reduced by a factor of two and a half. Indeed, a HDPE/TPE blend has an OTR that is three to six times lower than LLDPE, while having the same stiffness, as well as similar strength, flex crack resistance and shock absorption.
[0045] In use, typically, the flexible tank is provided in a collapsed condition. It is subsequently installed into a rigid outer container. The two are sized such that the flexible tank fits within the rigid outer container substantially snugly (while there may be open space between the top of the flexible tank and the top panel of the outer container.
[0046] Once fitted, structures may be provided to attach portions of the flexible tank to the outer rigid container, to, in turn, support the flexible tank in an articulated position when empty. The flexible tank can then be filled through the dispensing means. Once filled as desired, the flexible tank can be sealed and the rigid outer container can be closed so as to preclude ingress into the container.
[0047] The container can then be shipped to a destination as desired. Once at a destination, the flexible tank can be emptied. It may be emptied at once or in stages. Inasmuch as air is typically not directed into the flexible tank, the flexible tank collapses as it empties. Once emptied, the user can, if necessary, disconnect the flexible tank from the outer container. Next, the user can remove and discard the flexible tank.
[0048] Advantageously, a number of the flexible tanks can be collapsed and placed into a single container. Subsequently, they can be shipped in that container to a filling destination. Once at the destination, containers can be obtained locally, and each flexible tank can be articulated in a separate container. As such, great advantages in shipping can be achieved over ISO tanks inasmuch as the flexible tanks can be collapsed when not in use, and the ubiquitous shipping containers can be sourced at the filling location.
[0049] The foregoing description merely explains and illustrates the invention and the invention is not limited thereto except insofar as the appended claims are so limited, as those skilled in the art who have the disclosure before them will be able to make modifications without departing from the scope of the invention.
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A shipping container for flowable material including a large rigid shipping container and a flexible tank. The shipping container has a substantially rectangular cubic configuration with common attachment regions. The flexible tank is positionable within the rigid shipping container. The flexible tank includes a generally rectangular cubic configuration. At least certain dimensions of the flexible tank corresponding to dimensions of the large rigid shipping container so that the flexible tank has a generally form fit retention within the large rigid shipping container. The flexible tank further comprises a film which together with a plurality of seals defines a substantially rectangular cubic cavity. A dispensing means is provided which extends through the film for selectively placing the cavity in fluid communication with an outside dispenser. The film comprises a layer comprising a co-extruded blend of HDPE and TPE, to, in turn minimize oxygen transmission within the film.
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This application is a continuation of application Ser. No. 08/185,074 filed Jan. 18, 1994 now abandoned.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to accelerometers including a silicon capacitive acceleration detector, and to a method for measuring the capacitive unbalance of the detector, providing an electric signal representative of an acceleration.
2. Discussion of the Related Art
A schematic exemplary silicon capacitive acceleration detector is illustrated in the cross-sectional view of FIG. 1. Detector 1 includes a central silicon plate 2 sandwiched between two external silicon plates 3 and 4. The central silicon plate 2 is etched prior to being assembled so as to include a frame 5 and a central plate, or pendulous mass 6, that is fastened to frame 5 by one or more holding arms 7. The insulation of the frame 5 of the central plate from the external plates 3 and 4 is provided by insulating strips 8 and 9, generally of silicon oxide. The external plates 3 and 4 delineate with frame 5 a space within which is suspended the pendulous mass 6. The upper and lower surfaces of the pendulous mass 6, as well as the surfaces of plates 3 and 4 facing the pendulous mass 6, include conductive surface areas, or electrodes 10, 11, 12, 13, forming a system including two capacitors Cs, Ci that are symmetrically disposed with respect to the median plane of detector 1. Electrodes 10-13 are accessed through contact pads and internal connections (not shown in FIG. 1). Usually, the mobile electrodes 10 and 11 are not insulated from the pendulous mass 6 (they are then doped silicon areas) and are at the same potential; so, a single contact pad is provided for electrodes 10 and 11.
When the device is at rest, capacitors Cs and Ci have substantially an equal value, as follows:
cs=ci=εS/do
where ε is the dielectric constant of the gas present in detector 1, S is the surface area of electrodes 10-13, and do is the distance separating, at rest, the pendulous mass 6 from each external silicon plate 3 and 4.
When the device withstands an acceleration, the pendulus mass 6 moves, with respect to its null position, by a quantity z proportional to the acceleration. In this case, capacitors Cs and Ci vary and have the following values:
Cs=εS/(do+z) (1)
Ci=εS/(do-z) (2)
where z is an algebraic length, whose sign is conventionally determined.
To measure acceleration, a system for measuring the unbalance of capacitors Cs and Ci is combined with the above described detector.
FIG. 2 represents the electric diagram of a conventional accelerometer 20 including the above-described detector 1 and such a measurement system. Detector 1 is represented by the two capacitors Cs and Ci that are formed by electrodes 10, 12 and 11, 13; the pad common to electrodes 10 and 11 being represented by a node 14. The measurement system includes an excitation unit 21 for exciting capacitors Cs and Ci, that is fed by a reference a.c. voltage v, a unit 30 for processing the signal from the detector, providing a measuring voltage vs, and a feedback loop 26 connecting voltage vs at the input of the excitation unit
The excitation unit 21 drives the fixed electrode of capacitor Cs through a differential amplifier 22, and the fixed electrode 3 of capacitor Ci through a summing amplifier 23. The negative input of amplifier 22 and a first input of amplifier 23 are connected to an amplifier 24 having a gain b, receiving the reference voltage v. The positive input of amplifier 22 and the second input of amplifier 23 are connected to the output of an amplifier 25 having a gain a, receiving the voltage vs provided by the processing unit 30 through the feedback loop 26.
The processing unit 30 mainly includes a current/voltage converter 3 having its input connected to node 14, followed by an amplifier 33 having a very high gain G, providing the measuring voltage vs. In FIG. 2, converter 31 is schematically represented by an operational amplifier 32 having its output connected to its input through a capacitor having a capacitance Cr.
Voltage vs is used as the output voltage of the measurement system. Voltage vs is rectified in a demodulator 40 that is connected to the output of the feedback loop 26 and synchronized with voltage v, and that provides a voltage Us constituting the output signal of the accelerometer.
The above description shows that the excitation unit 21 applies to the fixed electrodes 12 and 13 of capacitors Cs and Ci excitation voltages, avs-bv and avs+bv, respectively. The input of the current/voltage converter 31 collects a differential current from node 4 resulting from the excitation of capacitors Cs and Ci. At the output of the processing unit 30, voltage vs is:
vs=K(Cs-Ci)/(Cs+Ci), (3)
where K is a constant.
The theoretical advantage of such a measurement system is that the amplitude of voltage vs is proportional to displacement z of the pendulous mass 6 of the detector and, hence, to the acceleration. In combining equations (1), (2) and (3), it can be appreciated that vs=K z/do.
However, in this prior art accelerometer, the measurement of the displacements of the pendulous mass is actually significantly affected by the presence of high stray capacitances present in the detector, to such an extent that the output signal Us obtained by demodulation of voltage vs is erroneous. Thus, it is noted that the output signal does not linearly increase as acceleration increases, in contrast to what is expected from the above theoretical equation (3). Such stray capacitances (labeled as C1 and C2 in FIG. 2) are predominantly formed in the region of the insulation layers 8 and 9 between frame 5 of the central silicon plate 2 and the corresponding surfaces of the external plates 3 and 4.
To avoid this drawback, various technological approaches, aiming at modifying the detector structure in order to reduce stray capacitances, have been proposed. However, these technological approaches involve an increase in the cost and/or the complexity of the detector.
The applicant proposes a fully different approach, consisting in reducing the influence of the stray capacitances in the measurement system instead of modifying the structure of the conventional detectors.
SUMMARY OF THE INVENTION
Thus an object of the present invention is to provide an accelerometer in which the impairing effect of the stray capacitances on the linearity of the output signal is compensated for.
To achieve this object, the present invention provides an accelerometer including a silicon capacitive detector forming a system including two variable capacitors whose capacitive unbalance is dependent upon acceleration, the capacitors being impaired by parallel stray capacitances; and an electronic device for measuring the capacitive unbalance of the detector, providing an output voltage representative of the acceleration. The electronic device includes an excitation unit to apply to the capacitors excitation voltages generated by the weighted combination of a reference voltage with the output voltage; a current/voltage converter unit to collect currents from each capacitor, providing a measuring voltage; a feedback loop to connect back the measuring voltage to the excitation unit, the output voltage being drawn from the output of the feedback loop. The accelerometer includes a compensation unit for compensating the impairing effect of the stray capacitances, for injecting into the measurement system a correcting electric signal generated from the reference and measuring voltage, and chosen so that the output voltage is substantially proportional to the ratio between the difference and the sum of the capacitors' capacitances.
According to an embodiment of the invention, the compensation unit injects into the feedback loop a correction voltage that is selected so that the output voltage is equal to the weighted sum of the measuring voltage and reference voltage, the weighting coefficients of the weighted sum being adjustment parameters of the compensation unit.
Advantageously, the compensation unit includes an operational amplifier disposed in series in the feedback loop and connected as an adder, the amplifier output being connected to its input through a first resistor, the measuring voltage and reference voltage being applied to the same input through a second and a third resistor, respectively, the ratio between the first and second resistor and the ratio between the first and third resistors constituting the adjustment parameters of the compensation unit.
The reference voltage, measuring voltage and output voltage can be a.c. voltages or d.c. voltages. In the latter case, the excitation unit includes switches for chopping the excitation voltages applied to the capacitors, the converter unit includes a current/voltage converter followed by a demodulator.
According to another embodiment of the invention, the converter unit injects at the input of the compensation unit a correcting current that is added to the currents drawn from the capacitors, and is selected to cancel the current generated by the excitation of the stray capacitances.
Advantageously, the correcting current is drawn from two compensation capacitors that are excited by voltages respectively equal to the difference and to the sum of a voltage proportional to the reference voltage plus or minus a voltage proportional to the measuring voltage, the excitation voltages of the compensation capacitors constituting the adjustment parameters of the compensation unit.
Advantageously, the reference voltage, the output voltage and the measuring voltage are d.c. voltages, the excitation voltages of the detection capacitors and of the compensation capacitors being chopped by switches operating in phase opposition, the converter unit including a current/voltage converter followed by a demodulator having a very high static gain.
Preferably, the compensation capacitors include a sandwich formed by a silicon oxide layer and two silicon plates.
The foregoing and other objects, features, aspects and advantages of the invention will become apparent from the following detailed description of the present invention when taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF DRAWINGS
FIGS. 1 and 2, above described, respectively represent a schematic cross-sectional view of a silicon capacitive detector and the electric diagram of a prior art accelerometer;
FIG. 3a is an electric block diagram of an accelerometer according to the invention;
FIG. 3b illustrates in more detail a block of FIG. 3a;
FIG. 3c is an equivalent diagram of the block of FIG. 3b;
FIG. 4 represents an alternative embodiment of the accelerometer of FIG. 3a; and
FIG. 5 is an electric diagram of an alternative embodiment of an accelerometer according to the invention.
DETAILED DESCRIPTION
The invention is based on a study of the perturbations generated by stray capacitances in a prior art accelerometer. The accelerometer 20 illustrated in FIG. 2 will serve as an example. As seen in FIG. 2, the stray capacitances can be represented by a capacitor C1 disposed in parallel with capacitor Cs, and a capacitor C2 disposed in parallel with capacitor Ci, so that the excitation voltages (avs-bv, avs+bv) applied to capacitors Cs and Ci also act on capacitors C1 and C2. Under these conditions, the "true" equation giving the output voltage vs is:
(Cr/G)vs=avs(Cs+Ci)-bv(Cs-Ci)+avs(C1+C2) -bv(C1-C2). (4)
Neglecting the perturbation introduced by the stray capacitances (that is, considering that CI=C2=0), and selecting an amplifier 25 with a very high gain G, equation (4) is simplified and equation (3) of the prior art is again true:
vs=K(Cs-Ci)/Cs+Ci) (3)
where K=(b/a)v.
As explained above, equation (3) is representative of the linearity of the output voltage vs or, in other words, of the proportionality between the amplitude of the output voltage vs and the displacements z of the pendulous mass 6. Equation (3) also indicates that the measurement capacitors are excited at a constant charge, and that no parasitic electrostatic force, liable to draw the pendulous mass 6 near the fixed electrodes and to impair the linearity of the output voltage vs, is generated.
Thus, the present invention predominantly aims at re-establishing equation (3) in the system defined by equation (4), in which the stray capacitances C1 and C2 are taken into account.
To achieve this purpose, the invention provides for adding to the prior art accelerometer a compensation unit injecting into the measurement system an electric signal for correcting the perturbations caused by the stray capacitances. Hereinafter, two embodiments of the present invention will be described. According to the first embodiment, the correcting signal is a voltage, introduced upstream of the detection capacitors Cs, Ci, and added to the excitation voltages thereof. In the second embodiment, the correcting signal is a current, introduced downstream of capacitors Cs and Ci, at the input of the processing unit 30.
FIRST EMBODIMENT: adding a voltage compensation unit to the measurement system.
FIG. 3a represents the electric diagram of an accelerometer 50, according to the invention that differs from the conventional accelerometer of FIG. 2 only by the provision of a compensation unit 45. For the sake of simplicity, the components that are common to FIG. 2 are labeled with the same reference characters and will not be described again.
The compensation unit 45 is introduced into the feedback loop 26 applying to the excitation unit 21 the measuring voltage (now labeled vd) provided by the processing unit 30, the output voltage vs being drawn at the output of the feedback loop 26, after the compensation unit 45, and is conventionally applied to amplifier 25 and to demodulator 40. Thus, the compensation unit 45 implements the following function f:
vs=f(vd).
Under these conditions, the above equation (4) applies to voltage vd and is:
(Cr/G)vd=avs(Cs+Ci)-bv(Cs-Ci)+avs(C1+C2) -bv(C1-C2). (5)
To compensate for the impairing effect of the stray capacitances, the invention provides that the compensation unit 45 implements following equation (6):
(Cr/G)vd=avs(C1+C2)-bv(C1-C2). (6)
In this case, by combining equation (5) with equation (6), equation (5) can be simplified and becomes:
avs(Cs+Ci)-bv(Cs-Ci=)0, (5)
that is,
vs=(bv/a) (CS-Ci)/(Cs+Ci). (5)
Equation (5) becomes equivalent to equation (3), and the linearity of the output voltage vs is re-established despite the presence of stray capacitances, vs being proportional to the displacements z of the pendulous mass 6 and, therefore, to the acceleration.
Thus, it is appreciated that the perturbations caused by the stray capacitances in the measurement system are compensated for when equation (6) is achieved. Equation (6) is arranged to let appear the function vs=f(vd) of the compensation unit 45: ##EQU1## or, in a simplified form:
vs=Avd+Bv, (6)
where ##EQU2##
An exemplary embodiment of the compensation unit 45 is schematically illustrated in FIG. 3b. Unit 45 includes an operational amplifier 46 having its output connected back to its negative input through a resistor 47. Voltages vd and v are applied at the input of amplifier 46 through resistors 48 and 49, respectively. Resistors 47, 48 and 49 are adjusted so that:
R47/R48=A
and
R47/R49=B.
In practice, unit 45 can be adjusted through calibration on a testing stand or during construction, once the stray capacitances have been theoretically or experimentally determined.
By examining the equations providing gains A and B of the compensation unit 45, those skilled in the art will appreciate that amplifier 33 need not, in the present case, have a very high gain G. Indeed, equation (3) giving the linearity of the output voltage vs no longer depends on term G. Finally, gain G, gain a of amplifier 25, and gain b of amplifier 24 are adjustment parameters of the accelerometer. A particularly simple embodiment consists in considering that a, b, and G are equal to 1.
Additionally, voltage avs must be strictly in phase with voltages bv and -by so that accelerometer 50 adequately operates. Those skilled in the art will be able to take steps so that the sum of the phase shifting introduced by the various elements of accelerometer 50 satisfy this requirement.
FIG. 4 shows an accelerometer 60 that is an alternative embodiment of the accelerometer of FIG. 3a, with the further advantage of being insensitive to possible phase shift problems. In accelerometer 60, the various voltages vs, v, avs, by, and vd are d.c. voltages. The various elements forming the excitation unit of the system of FIG. 3a are maintained, and are labeled with the same reference characters. Amplifiers 22 and 23 of the excitation unit 21 provide d.c. voltages avs-bv, avs+bv, respectively. These voltages are chopped by switches 27, 28 (for example, MOS transistors) that are controlled by a clock signal H, prior to being applied in the form of square waves to capacitors Cs and Ci. The processing unit 30 receiving the current from capacitors Cs and Ci includes the above current/voltage converter 31, amplifier 33 being replaced by a demodulator 34 having a static gain G, synchronized with the clock signal H. Voltage vd from demodulator 34 is applied to the compensation unit 45 according to the invention (above described with reference to FIG. 3b), operating in the present example in a d.c. mode. The output voltage vs from the compensation unit 45 is directly usable as an output signal Us.
The accelerometer 60 operates in the same manner as the accelerometer 50 of FIG. 3a; the above equations (5) and (6) being still valid.
It should be noted that the function vs=f(vd) achieved by the compensation unit 45 corresponds to adding to the measurement signal vd provided by the processing unit 30 a correction signal vc=(A-1)vd+Bv, which, combined with voltage vd, provides voltage vs. Thus, the compensation unit 45 can be represented by the general diagram of FIG. 3c, in which unit 45 includes a first amplifier 452 having a gain A-1 and receiving vd, a second amplifier 453 having a gain B and receiving v, and a summing amplifier 454 receiving the outputs of amplifiers 452 and 453 and providing the correction signal vc, vc being injected into the feedback loop 26 through an adder 451 receiving vc and yd.
SECOND EMBODIMENT: adding a current compensation unit to the measurement system.
It is reminded that the above-described equation (4) defines the "true" equation of the output voltage of a conventional measurement system, in the presence of stray capacitances C1 and C2.
In this embodiment of the invention, a current I is injected at the input of the processing unit so that equation (4) is modified and becomes:
(Cr/G)vs=avs(Cs+Ci)-bv(Cs-Ci)+avs(C1+C2)-bv(C1-C2)-I. (7)
To compensate for the perturbations caused by the stray capacitances, I is made equal to:
I=avs(C1+C2)-bv(C1-C2). (8)
(For the sake of simplicity, in equations (7) and (8). A conventional term expressing the periodicity of signals, if the signals are sine-wave signals, is eliminated. Thus, term I has the dimension of a current divided by a periodicity term, and represents an electric charge).
Advantageously, it is also devised that current I is provided by two compensation capacitors Cn1 and Cn2, that are excited by voltages cvs-dv and cvs+dv, respectively, c and b being adjustment coefficients. So, I is:
I=cvs(Cn1+Cn2)-dv(Cn1-Cn2). (9)
The adjustment coefficients c and d, and also possibly a and b, are chosen so that equation (8) is true. In this case, in equation (7), the terms C1 and C2 are eliminated by the compensation current I. If G is chosen very high, equation (7) becomes:
avs(Cs+Ci)-bv(Cs-Ci)=0. (10)
It can be seen that equation (10)=equation (3) and that the linearity of the output voltage vs is reached.
FIG. 5 represents the electric diagram of an accelerometer 80 including a current compensation unit 70. Accelerometer 80 includes the above-described excitation unit 21 and the processing unit 30, that operate in the present example by chopping d.c. voltages. Thus, amplifiers 22 and 23 connect capacitors Cs and Ci through two switches 27 and 28 synchronized with the clock signal H; the processing unit 30 includes the demodulator 34 that has, in the present case, a very high static gain G. The reference voltage v of the excitation unit 21 that is applied to amplifier 24 is a d.c. voltage, and voltage vs provided by the demodulator 34 acts as an output signal Us of the accelerometer 80.
The compensation unit 70 according to the invention is mounted in parallel with the excitation unit 21 and detector 1. Unit 70 receives voltage vs from the feedback loop 26, and the reference voltage v. The output o unit 70 is connected to node 14, that is, to the input of the processing unit 30, and provides a current I for correcting the impairing effect of the stray capacitances. unit 70 includes, at its input, an amplifier 71 having a gain c, receiving voltage vs, and an amplifier having a gain d, receiving voltage v. The output of amplifier 71 is connected to the positive input of a differential amplifier 73 and to an input of a summing amplifier 74. The output of amplifier 72 is connected to the negative input of amplifier 73 and to the second input of amplifier 74. The output of amplifier 73 drives a first compensation capacitor Cn1 through a chopping switch 75, and the output of amplifier 74 drives a second compensation capacitor Cn1 Cn2 through a chopping switch 76. Switches 75 and 76 are synchronized with the clock signal H and operate in phase opposition with switches 27 and 28 of the excitation unit 21. Common terminals of capacitors Cn1 and Cn2 are connected to a node 77 that constitutes the output of the compensation unit 70, node 77 being connected to node 14.
The observation of the electric diagram of the compensation unit 70 shows that it substantially constitutes a duplication of the excitation unit 21 and of detector 1, and similarly operates. Indeed, amplifiers 73 and 74 of the compensation unit provide d.c. voltages cvs-dv and cvs+dv that are chopped by switches 75 and 76 prior to being applied to capacitors Cn1 and Cn2 and, similarly, amplifiers 22 and 23 of the excitation unit provide d.c. voltages avs-bv and avs+bv that are chopped by switches 27 and 28 prior to being applied to capacitors Cs and Ci. Therefore, node 14 provides the sum of a current generated by the excitation of Cs and Ci and of a spurious current generated by the excitation of C1 and C2, decreased by the value of the compensation current I (in phase opposition) provided by unit 70 and generated by capacitors Cn1 and Cn2 (current I is defined by equation (9)).
The expression of the output voltage vs provided by accelerometer 80 is given by equation (7) and also depends upon the sum of currents at node 14. As explained above, the effect of the stray capacitances is compensated for in accelerometer 80 by selecting parameters a, b, c, d, so that the equality of equation (8) is reached. Like the voltage compensation unit described with reference to FIGS. 3a and 4, the current compensation unit of FIG. 5 can be adjusted through calibration on a testing plant, or during construction, once the stray capacitances have been theoretically or experimentally determined.
A particularly advantageous embodiment of the compensation unit 70 consists in providing compensation capacitors Cn1 and Cn2 of the same technology as the detector, and preferably having capacitances close to C1 and C2 in order to have the same thermal variations. Thus, the system is adequately compensated for, whatever be its operation temperature.
Those skilled in the art will note that the accelerometer 80 also operates with a.c. voltages v and vs. In this case, chopping switches 27, 28, 75, and 76 are eliminated, and demodulator 34 is replaced with an amplifier having a very high gain G. Also, current I must be phase-shifted by 180° and the output voltage vs must be demodulated to obtain signal Us.
In practice, the various systems according to the invention provide very satisfactory results. Experiments carried out by the applicant have evidenced that the voltage compensation systems allow for the correction of about 90% of the non linearity of the accelerometer output signals in a range of temperature from -55° C. to 125° C., the current compensation systems allowing to reach a correction of approximately 95% with the use of compensation capacitors Cn1 and Cn2 fabricated in the same technology as detector 1. The second type of system is slightly more expensive to fabricate, while remaining more advantageous than the prior art systems which consist in modifying the structure of the detector to decrease C1 and C2.
Various modifications can be made to the above described embodiments of the invention, more particularly for the practical implementation of the electric diagrams.
In the above, it has been considered that the output signal Us of the accelerometer is an electric signal. In practice, it is possible to add to the accelerometer means for transforming the output signal into a signal of a different nature, for example optical, or for encoding the output signal.
The invention can also apply to detectors including several pairs of measurement capacitors that are disposed in parallel, this type of detectors being electrically equivalent to a two-capacitor detector.
Last, it will be apparent to those skilled in the art that the two compensation (voltage or current) modes provided by the present invention are equivalent both for the result they provide and for the function they achieve. Indeed, the analysis of the compensation mechanisms involved shows that each case of injection of a correction signal into the measurement system in fact corresponds to an injection of weighted electric charges compensating for the effect of electric charges produced by the stray capacitances.
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An accelerometer includes a silicon capacitive detector and an electronic device for measuring the capacitive unbalance of the detector, providing an output voltage representative of the acceleration. To avoid the perturbations caused by the stray capacitances present in the detector, there is provided a compensation system for injecting into the measurement system a predetermined correcting electric signal so that the output voltage of the accelerometer is substantially proportional to the ratio between the difference and the sum of the capacitances of the detector's capacitors.
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FIELD OF THE INVENTION
This invention relates to apparatus for airless atomization for electrostatic deposition of a coating material upon a substrate.
BACKGROUND OF THE INVENTION
Commercial equipment for atomizing and electrostatically depositing coating material, such as paint, commonly utilizes either airless or air atomization of the coating material. In coating certain types of articles, as where a high coating delivery rate is desired, or where there is a need to penetrate into a recess, for example, it is desirable to atomize the coating material without the presence of air. This is done by projecting the coating material through a small nozzle orifice under high pressure. The interaction of the pressurized stream of coating material with air as it passes through the small nozzle orifice causes a break-up, or atomization, of the coating material into small particles, which then may be electrostatically charged.
The electrostatic charge has the effect of improving the efficiency of deposition of the coating material onto the substrate being coated. An electrode, also sometimes called an antenna, is commonly located near the spray nozzle, and is connected to a source of high voltage to establish an electrostatic field in the vicinity of the region of atomization. The electrostatic field imparts a charge to the spray particles which causes the particles to be attracted to a grounded substrate. The charged atomized coating material is in effect drawn to the substrate, resulting in increased and more efficient deposition of coating material.
An airless spray gun and spray gun system such as that described is disclosed in U.S. Pat. No. 4,355,764. Spray guns of this type are characterized by an elongated electrode for charging the atomized spray from the gun nozzle. The electrode of such guns is characteristically connected to a high voltage power supply through electrical circuitry contained in the the spray gun body. Such circuitry includes a high ohmage resistor in the gun barrel to reduce the current flow to the electrode and to avoid inadvertent discharge of electricity or arcing if the gun is moved too close to a grounded workpiece or too close to a grounded wall of the spray booth within which the gun is operating.
In order to further reduce the current to the electrode and the capacity of the gun, such guns also characteristically include a "tip" resistor in the electrical circuit between the barrel resistor and the electrode. A typical tip resistor has a bent thin wire lead extending from its forward end to electrically connect the tip resistor to the electrode. Generally this electrical connection includes a conductive washer positioned so that the base of the electrode contacts one face of the washer and the bent wire lead the other face. The bent lead end gives the connection some resiliency to accommodate spacing differences between the electrode and tip resistor due to tolerance variations in the nozzle assembly parts. The rearward end of the tip resistor characteristically has another thin wire lead which connects the tip resistor to the barrel resistor.
It has been found that when the nozzle assembly is removed and then replaced in electrostatic spray guns of the type described hereinabove, such as for changing nozzles or for cleaning of the nozzle assembly, the lead at the front of the tip resistor is bent and flexed. Repeated bending and flexing can result in the lead snapping, thereby breaking contact between the tip resistor and the electrode, and interrupting power to the electrode. The tip resistor then has to be removed from its bore and replaced with a new tip resistor having a good lead.
Replacement of the tip resistor in this type of gun has been complicated by the fact that the rearward lead of the tip resistor has to be connected to the barrel resistor. The rearward lead has to be inserted in the front of the bore in which the barrel resistor is received where it can contact the conductive end of the barrel resistor. In order to ensure good electrical contact however, the barrel resistor has to be removed for proper positioning of the tip resistor lead, with the barrel resistor than replaced in position. This procedure entails further disassembly of the gun in order to access the barrel resistor. A good solid electrical connection between the elements making up the electrical circuitry, and between those elements and the electrode, is of course of critical importance in the operation of the spray gun.
The nozzle assemblies of spray guns of the type described typically have a number of small internal parts. Some of these parts are loose when the assembly is not attached to the gun.
As is often the case when cleaning the nozzle assembly, it will be taken off of the gun over a vat of cleaning solvent. The loose parts can easily fall out of the nozzle assembly and into the solvent vat, where they can be difficult to locate and retrieve. The loose parts can likewise be dropped and become lost when the nozzle assembly is being changed. Replacement of the lost parts is of course costly, and consumes time when the spray gun could otherwise be productively used.
SUMMARY OF THE INVENTION
One objective of this invention is to provide a better and more dependable tip resistor to electrode connection which is not affected by repeated nozzle assembly adjustments. It is in accordance with this invention to further provide a direct tip resistor to electrode connection in a manner which readily accommodates spacing variations which may exist between the tip resistor and electrode elements, such as may be caused by tolerance differences in the nozzle assembly parts, and which ensures continuous electrical contact for charging the electrode.
Yet another object of the invention is to provide a tip resistor which can be easily replaced without requiring manipulation of the barrel resistor to electrically connect the tip resistor thereto, and to provide an assured electrical connection between the barrel resistor and the tip resistor simply from insertion of the tip resistor in its bore. Still a further object is to better seal the bores within which the tip resistor and barrel resistor are located against solvent leaking therein.
It is another objective of the invention to provide a mechanism to associate the loose pieces making up the nozzle assembly to prevent them from becoming lost when the nozzle assembly is removed from the spray gun.
These objectives, as well as others, have been accomplished by this invention in an improved airless spray gun which includes a novel electrode element having a spring loop portion. The preferred electrode element has two electrodes, one long and one short, which both extend through throughbores in the nozzle assembly. The electrodes are the respective end portions of a single electrode wire which has its major portion between the electrodes formed into a spiral spring. The two electrodes form the forward portions of the electrode element, with the spring forming the rearward portion and having a forward loop and a rearward loop.
A direct electrical connection between the tip resistor and the electrode is made in this invention through the use of a conductive fitting fixed to the forward lead of the tip resistor which presents a relatively broad and sturdy bearing surface that abuts against the rearward loop of the electrode spring. A number of significant advantages are immediately realized by this arrangement. First, a circuit part in the form of the conductive washer formerly used is eliminated, being replaced by the electrode spring. Second, good direct electrical contact between the tip resistor and the electrode is assured, since the electrode spring portion is resilient and therefore accommodates differences in the distance between the tip resistor bearing surface and the electrode, such as may be caused by tolerance variations between the nozzle parts. Continuous electrical contact is likewise maintained by the circular shaped rear spiral loop which always engages the tip resistor bearing surface regardless of the rotational position of the nozzle assembly relative to the tip resistor. Thirdly, the flimsy bent electrical lead contact formerly commonly used with the tip resistor is eliminated, being replaced by a sturdy and broad bearing surface. The broad bearing surface is of course not subject to breakage problems from the nozzle assembly being repeatedly removed from and reattached to the gun.
Another significant advantage of this invention is also accomplished through the use of the electrode spring. As noted, the nozzle assembly has small parts, two of which are a nozzle adapter within which the nozzle is mounted and which is itself mounted within a nozzle support ring, and a sealing plug which connects the nozzle mount with a liquid passage in the gun body so that liquid will flow from the passage through the plug and adapter and then to the nozzle. The forward loop of the electrode spring portion is received in a recess on the sealing plug and holds the sealing plug within the loop. The two electrodes are carried by the nozzle support ring, and the sealing plug is consequently held in place within the nozzle assembly. The sealing plug in turn holds the nozzle adapter in place within the support ring, since the forward end of the sealing plug seats in the adapter mount. There is thus no longer any problem of losing these nozzle assembly pieces when the nozzle assembly is removed from the spray gun. Further, the two electrodes are simply pulled out of their channels to disassociate the nozzle assembly parts, when desired.
Another aspect of this invention is in an improved electrical connection between the tip resistor and the barrel resistor. To this end, the tip resistor is provided with a spring lead at its rearward end which engages a conductive cap surrounding the forward end of the barrel resistor. The conductive cap extends for a small distance rearwardly of the forward portion of the barrel resistor, thus enabling an electrical connection with the barrel resistor rearwardly of the front end. That is, the rearward lead from the tip resistor no longer has to engage the front of the barrel resistor for electrical contact, but rather need only make electrical contact with a rearward portion of the conductive cap. Replacement of the tip resistor thus no longer requires that the barrel resistor be disturbed, since the rearward lead from the tip resistor need now merely engage the conductive cap to make electrical connection. The use of a spring lead further assures that a good electrical connection between the cap and the tip resistor will be made. Replacement of the tip resistor, when necessary, is thus readily accomplished by withdrawing the tip resistor needing replacement from its bore, and simply sliding a new unit into place.
Both the fitting for the tip resistor and the conductive cap for the barrel resistor are also provided with O-ring seals which are concentric with the resistors and which serve to seal their respective resistor bores against solvent or other liquid leaking therein. Extra protection against damage to the resistor from leaking solvent is thus provided by this invention.
These and other objects and advantages of this invention will be made more readily apparent from the following detailed description of the invention taken in conjunction with the following drawings, in which:
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a partially diagrammatic illustration of an electrostatic airless spray system incorporating the invention;
FIG. 2 is an enlarged cross-sectional view of the forward portion of the spray gun within the circled area 2--2 of FIG. 1;
FIGS. 3a and 3b illustrate a side view and a bottom view, respectively, of the dual electrode spring;
FIG. 4 is an enlarged view of the dual electrode spring and sealing plug as assembled;
FIG. 5 is a view similar to that of FIG. 2, but illustrating a modified form of the invention;
FIG. 6 is an enlarged view of the dual electrode spring, sealing plug and adapter as assembled in the modified embodiment of FIG. 5.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 illustrates an airless spray system which includes the invention of this application. The system includes a gun 10 which would ordinarily be held in the hand of an operator. The gun need not be handheld, however, but may be mounted on a robot, platform, etc., and either fixed or movable. In use, articles (not shown), are conveyed past the nozzle of the gun 10 to be coated or sprayed.
The gun 10 has a body portion 11, a handle 12, and a trigger 13. A hose 14 connects the gun with a source 15 of coating material under high pressure, typically on the order of 300 to 1000 p.s.i. An exemplary coating material would be an enamel paint to be applied to automobile framework, furniture, etc. It will be noted that most of the coating materials sprayed will contain a solvent, which can be highly corrosive to the resistive elements in the spray gun circuitry. Solvents are also used for cleaning purposes, such as in a changeover from one color paint to another.
An electrical power supply 18 is connected to the gun 10 through a cable 19. Power carried by the cable 19 passes through electrical circuitry, to be described in more detail hereafter, to an electrode element 20, which generates an electrostatic field to charge particles atomized through passage through a nozzle insert 26. The electrode element 20 has a dual electrode, i.e. it has two electrodes, one electrode 20a which extends forwardly of the nozzle insert 26 and generates the electrostatic field in the atomization region adajcent the nozzle insert 26, and a shorter electrode 20b. The shorter electrode 20b is used to bleed off charge which may build up on the conductive nozzle insert 26 to reduce the chance of arcing upon an inadvertent approach to a grounded object with the nozzle insert 26.
The invention of this application resides the forward end portion of the gun which is generally indicated within the circled area in FIG. 1. The remainder of the gun rearwardly from this portion has not been illustrated in detail in this application because it is conventional, and has previously been described in U.S. Pat. No. 3,731,145, which is assigned to the assignee of this application. The disclosure of the foregoing patent is incorporated by reference herein for purposes of more completely describing the details of the gun 10.
With reference now to FIG. 2, the nozzle assembly is generally indicated at 25, and includes the nozzle insert 26 which is mounted within a nozzle adapter 27, a nozzle support ring 28, and a sealing plug 29. The sealing plug 29 is located between the nozzle adapter 27 and a gun body extension 30 for sealing a liquid flow passage which extends through the gun and to the nozzle insert 26. A nozzle retaining nut 31 is threaded on the gun body extension 30, and secures the nozzle support ring 28 in place on the gun body extension.
It will be noted that the elements of the nozzle assembly 25, the gun body extension 30 and the nozzle retaining nut 31 are all described in specific detail in U.S. Pat. No. 4,355,764, which is also assigned to the assignee of this application. The disclosure of that patent is incorporated by reference for additional detail on the structure and arrangement of these elements.
A central bore 32 extends axially through the extension 30 and gun body 11 into communication with the hose 14 through which liquid under high pressure is supplied to the gun. A conventional valving mechanism 24 is mounted within the central bore 32 and is operated by the trigger 13 to control the flow of liquid through the central bore 32. The other end of the central bore 32 communicates with a stepped axial bore 33 which extends through the sealing plug 29, and which is collinearly aligned with the central bore 32. The plug bore 33 is in turn collinearly aligned with a bore 34 which extends axially through the adapter 27, and within which is received the nozzle insert 26. The nozzle insert 26 has an axial passageway 35 terminating in atomizing orifice 36.
A fluid flow restrictor 37 is press-fit into the bore 33 of the sealing plug 29, and engages a shoulder 38 (FIG. 4) of the bore at its forward end. The purpose of the restrictor 37 is to break up any laminar flow of liquid to the nozzle to cause a turbulent flow, which in turn eliminates undesirable "tails" which would otherwise be on the edges of the fan-shaped pattern of liquid which emerges from the nozzle orifice 36. More specific detail concerning the restrictor and its location within the plug bore can be obtained by reference to the aforementioned U.S. Pat. No. 4,355,764.
Both the nozzle adapter ring 27, nozzle insert 26, and sealing plug 29 are mounted within a stepped axial bore 39 within the nozzle support ring 28. The adapter 27 has a flange portion 40 which extends radially outwardly from its rearward end, and which abuts a shoulder 41 formed in the support ring bore 39. This abutment is maintained by engagement of a tapered forward end section 42 of the sealing plug 29 which seats within a tapered seat 43 formed in the adapter bore 34. The sealing plug 29 has a second tapered section 45 located at its rearward end which is received in a tapered seat 46 formed in the central bore 32.
Engagement between the tapered end sections of the sealing plug and their respective tapered seats is accomplished through securing the nozzle support ring 28 and nozzle assembly 25 in place with the nozzle retaining nut 31. That is, the nozzle support ring 28 has a radially outwardly extending flange 47 which is engaged by a shoulder 48 of the nozzle retaining nut 31 such that, when the nut is threaded onto the threaded portion of the gun body extension 30, the nut engages the flange 47 of the nozzle support ring and moves the ring 28 toward the gun body extension 30. This action in turn seats the two ends of the sealing plug 29 in place, and presses the nozzle adapter 27 against the support ring 28 and the support ring against the shoulder 48 of the nut 31.
It will be noted that the length of the sealing plug is such that the plug will be tightly wedge in the tapered seat 43 of the adapter bore and the tapered seat 46 of the central bore. A gap or open space 49 is left between the rearward end of the nozzle support ring 28 and the forward end of the gun body extension 30. A pressure relief channel 50 extends from this open space to a vent to relieve any pressure buildup which might occur, as by a plugged nozzle.
The two electrodes 20a, 20b, extend through respective throughbores 52a and 52b formed in the nozzle support ring 28. As previously indicated, the longer electrode 20a forms the high voltage field in the vicinity of the atomization region around the nozzle orifice 36 to electrostatically charge the atomized particles for deposition on a substrate.
With specific reference to FIGS. 3a and 3b, the dual electrode element is formed from a single piece of wire, such as 20/1000 inch (25 guage) stainless steel wire. The ends of the wire form the electrodes 20a, 20b, which extend roughly parallel to each other. Intermediate these electrode portions is formed an electrode spring portion 54 which is a spring spiral having a first or forward loop 55 and a second or rearward loop 56. The forward loop 55 is a continuation of the longer electrode 20a while the rearward loop 56 turns into the shorter electrode portion 20b. A single piece dual electrode having a rearward spring portion 54 is thus provided.
With reference to FIG. 4, the forward loop 55 of the electrode is snap-fit around the circumference of the sealing plug 29, being received in an annular recess 57 formed slightly rearward of the center of the sealing plug. It will be noted that the sealing plug has a reduced diameter section 58 rearwardly of the annular recess 57, with the rearward tapered portion 45 next after the reduced diameter section 58. The rearward loop 56 of the electrode spring is of a slightly greater diameter than that of forward loop 55 and, moreover, is of a greater diameter than the portion of the sealing plug which it overlies. The rearward spring portion 56 is thus free to move axially, as by compression of the spring portion 54.
It will be seen that the relatively loosefitting parts of the nozzle assembly 25 will no longer drop out of the nozzle support ring 28 and become lost, due to the fact that the sealing plug 29 is now retained in its seat within the nozzle adapter ring 27 by the dual electrode element 20. That is, the electrodes 20a and 20b extending through the nozzle supporting ring hold the sealing plug 29 in place via the electrode spring portion 54. To this end, the longer electrodes 20a has a radially inwardly bent portion 60 which further secures the electrode element 20 in place (FIG. 2). Because the dual electrode element 20 is fairly resilient, it and the sealing plug 29 can be easily pulled out of the nozzle support ring when desired without damage to the electrodes 20a, 20b. The electrode element 20 is also easily removed from and applied to the sealing plug 29.
Referring again to FIG. 2, a second passage or bore 62 extends longitudinally through the gun body 11 and is offset from the liquid flow passage of the central bore 32. A high ohmage resistor 63, commonly referred to as a barrel resister herein, is housed within the longitudinal bore 62. This barrel resistor 63 is a 75M ohm hollow fiberglass resistor having a carbon spiral pattern formed along its outside. As previously indicated, the barrel resistor serves to reduce the current flowing through the circuitry to the electrode 20a, and also reduce the capacitance of the system to avoid arcing.
Another bore 65 communicates with the lower front of the barrel resistor bore 62, and angles radially downwardly therefrom to open into the open area 49. A second resistor 66, commonly referred to as a tip resistor herein, is housed within this bore 65. A typical tip resistor would be a metal oxide 12M ohm resistor, which, as previously indicated, provides additional resistance in the electrical circuit to further reduce current flow, as well as the overall system capacitance.
Electrical contact between the tip resistor 66 and the electrode 20 is accomplished through the use of a brass fitting 67 fixed to the forward end of the tip resistor 66. The fitting 67 has a broad bearing surface 70 which contacts the rearward spring loop 56 of the electrode 20. The brass fitting 67 is of course electrically conductive, and is fixed to a lead 68 extending from the forward end of the tip resistor by soldering at the bearing surface 70.
The fitting 67, and the associated tip resistor 66, are slip-fit into the tip resistor bore 65, with the bearing surface 70 extending into the open space 49 to contact and slightly compress the rearward loop 56 of the electrode spring portion 54. The broad bearing surface 70 presents a good contact surface, and continuous and direct electrical connection between the electrode element 20 and tip resistor 66 is maintained regardless of how the nozzle support ring 28, which carries electrode element 20, is attached to the gun. That is, the electrical contact between the rearward spring loop 56 and the conductive bearing surface 70 is maintained regardless of the rotational position of the nozzle assembly 25 on the gun body extension 30.
It will be noted that the use of a spring portion 54 as part of the electrode element has the additional advantage of accommodating any variations in distance between the sealing plug 29 and tip resistor 66 which might occur through tolerance variations in the nozzle parts. An annular recess 71 is also provided surrounding the forward opening of the tip resistor bore 65 to permit ready access to the fitting 67 with a pry tool for removal of the fitting and tip resistor from the bore.
The electrical connection between the tip resistor 66 and the barrel resistor 63 is made with a spring lead 72 which extends from the rearward end of the tip resistor and which contacts a conductive end cap 73 surrounding the forward end of the barrel resistor 63. The spring load 72 is secured at one end by soldering to the rearward end of the tip resistor 66, and is left free to abut against an angled shoulder 74 formed around the conductive cap 73.
The conductive cap 73 is made of a conductive Teflon, such as Teflon containing 15-25% graphite or carbon. The cap 73 is mounted in the forward end of the bore 62, with the barrel resistor forward end abutting the front 75 of the cap. An insulative tube 76, such as are made of polyethylene, is located within the bore 62 rearwardly of the cap 73.
Use of the conductive cap 73 herein permits the electrical connection with the barrel resistor 63 to be made at a point rearwardly of the forward end of the barrel resistor. That is, the lead 72 from the tip resistor no longer has to be connected at the very front of the barrel resistor, but can now be easily connected at a more rearward point on the barrel resistor, thus simplifying replacement of the tip resistor. Use of a spring lead 72 also assures that the gap between the tip resistor 66 and the cap 73 will be spanned and a good electrical contact will be made, thus further simplifying the replacement of the tip resistor.
Both the tip resistor fitting 67 and the conductive cap 73 of the barrel resistor 63 are provided with O-ring seals to seal the respective bores against solvent leaking therein which could degrade the resistors, particularly the barrel resistor 63. Fitting 67 is provided with an O-ring seal 78 which is received in a circumferential recess 79. The conductive cap 73 is likewise provided with an O-ring seal 80 received in a circumferential recess 81 formed in the cap. The two bores 65 and 62 are thus sealed against solvent leaking into the bores and damaging the two resistors.
Reference is now made to FIGS. 5 and 6 which show a modified version of the invention. The spray gun assembly illustrated in these figures is substantially similar to that previously described, except that the sealing plug 29 does not have its rearward portion 45 seated in a tapered seat formed in the central bore 32. Instead, the rearward tapered portion 45 of the sealing plug seats within a ringshaped adapter 85 which is provided with an internally tapered seat portion 86. The adapter 85 is made of stainless steel, and is engaged in an interference fit on the reduced diameter portion 58 of the sealing plug 29 (FIG. 6). The rearward loop 56 of the electrode spring portion 54 engages the exterior of the adapter 85. The adapter is provided with a slight exterior taper which is at an angle to lightly compress the spring portion 54 of the electrode assembly to make good electrical contact between the conductive stainless steel adapter 85 and the rearward loop 56.
Referring again to FIG. 5, the adapter 85 has an annular shaped skirt portion 88 which engages the surface of a conductive washer 89 which is mounted in a recess 90 formed in the front end of the gun body extension 30 concentric with the axial bore 32. Continuous electrical contact between the flat edge of the adapter skirt edge and the conductive washer 89 is maintained by this arrangement, since the skirt 88 will always be engaged with the washer surface, regardless of the rotational position of the nozzle assembly. The conductive washer 89 is in turn electrically connected to a barrel resistor (not shown in this embodiment) through the use of a lead in the form of a conductive pin 92 mounted in the gun body extension 30. No tip resistor is used in this embodiment, which illustrates an earlier version of the gun previously described. It will also be noted that the surface contact between the adapter skirt 88 and the conductive washer 89 serves to seal this area against the leakage of fluid or solvent from the axial bore 32.
As in the previous embodiment, this embodiment has the advantage of keeping all of the pieces of the nozzle assembly 25 together when the nozzle assembly is removed by virtue of the electrode element 20 which holds the sealing plug 33 in place against the nozzle adapter ring 27. The adapter 85 is of course tightly fit to the sealing plug, and will therefore not fall off.
Thus, while the invention has been described in connection with certain presently preferred embodiments, those skilled in the art will recognize modifications of structure, arrangement, portions, elements, materials, and components which can be used in the practice of the invention without departing from the principals of this invention.
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A spray gun for airless atomization for electrostatic deposition of a coating material upon a substrate includes a novel dual electrode element having a spring loop portion. The two electrodes are the respective end portions of a single electrode wire, which has its major portion between the electrodes formed into a spiral spring. A tip resistor is provided with a conductive fitting that presents a broad and sturdy bearing surface which abuts the electrode spring portion to thereby directly connect the electrode with a high voltage charging circuit. The electrode spring accommodates spacing variations between the electrode and tip resistor, and provides a continuous electrical connection regardless of the rotational position of the electrode relative to the tip resistor. The dual electrode spring further serves to secure a number of otherwise loose parts of the gun nozzle assembly together, and prevents the parts from falling out and getting lost when the nozzle assembly is removed from the spray gun. An improved electrical circuit is also achieved through the use of a conductive cap which surrounds one end of a high voltage barrel resistor used in the gun. The conductive cap has a portion which extends along the barrel resistor body which is electrically connected to the tip resistor by a spring lead from the tip resistor.
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BACKGROUND OF THE INVENTION
1. Field Of the Invention
This invention relates to the field of preparing floral arrangements, and in particular to preparing individual flowers for such floral arrangements by inserting on the stem of a flower a stem pick. The invention also relates to the field of cutting flower stems, and more particularly to cutting flower stems in an airless environment. Finally, the invention relates to methods and apparatuses combining these concepts in various ways.
2. Brief Description of the Prior Art
Floral stem picks have been in use for many years for the purposes of strengthening and supporting the stems of individual botanical items, such as flowers, so that they can be easily handled and placed in position, for example in floral foam, without crushing the stems of the flowers. Such prior art stem picks may be made of steel and may have a number of fingers which wrap around and grasp the stem of the flower. In this manner, the stem pick acts as a rigid prolongation of the flower stem.
Prior to application of the stem pick to the flower stem, it is usually necessary to cut the stem of the flower to a length such that the finished combination of flower, flower stem and stem pick is of the proper length for the floral arrangement. In the past, the cutting of the flower stem to an appropriate length has been done manually or with an automatic cutter as a separate step in the preparation of the flower prior to attachment of the stem pick.
Processing flowers by cutting underwater is becoming popular by wholesalers and florists. Many wholesalers are cutting all of their flowers underwater, particularly roses, imports, and more expensive flowers. The benefit in cutting flower stems underwater is that it prevents the formation of an air gap or air bubbles in the vascular tissue of the plant, thereby interrupting the transpiration stream of water within the xylem. This procedure also avoids the skinning effect, i.e., it prevents sealing of the tubules of the stem with sap that oozes from the end of the flower stem after the stem is cut. The water thus, in addition to displacing air from the raw cut flower stem, prevents or retards skinning over the tubules which occurs in the natural healing process for the damaged (cut) plant.
In spite of the benefits of underwater cutting, many wholesalers and florists, especially during the holiday seasons, find that the time constraints and the volume of flowers necessary to process makes it impractical to cut all of the flowers under water. In such a case, the lesser quality flowers are cut without submergence in water. Additionally, a water source may not be handy or the extra time taken to manipulate the flower stems to both cut the stem underwater and, in a subsequent step, attach a stem pick, simply requires too much time and is not cost effective.
Pick stemming machines have been developed and manufactured in both a table top model and a portable model in which a stack of stem picks is inserted in the machine, and by moving a handle, an operator can cause the stem pick to attach to the flower stem, and the assembled flower and stem pick arrangement is then manually removed from the machine. Such machines have been made by B & K Tool, Die and Stamping Co., Inc. located in Ridgewood, New York. While such machines are effective to attach a stem pick to a flower stem, the problems of interrupting the transpiration stream in the flower stem and skinning over of the tubules are not solved, and the life of the floral arrangement containing flowers with picks applied by the machines of the prior art is foreshortened.
SUMMARY OF THE INVENTION
In the following description, the term "botanical item" is used to mean a natural or artificial herbaceous or woody plant, taken singly or in combination. The term "botanical item" also means any portion or portions of natural or artificial herbaceous or woody plants including stems, leaves, flowers, blossoms, buds, blooms, cones, or roots, taken singly or in combination, or in groupings of such portions such as bouquet or floral grouping. For convenience only, the term "flower" will be used generically as a substitute for the term "botanical item" such that when the term "flower" is used, what is meant is the term "botanical item".
As used herein the term "growing medium" means any liquid, solid or gaseous material used for plant growth or for the cultivation of propagules, including organic and inorganic materials such as soil, humus, perlite, vermiculite, sand, water, and including the nutrients, fertilizers or hormones or combinations thereof required by the plants or propagules for growth. Such life enhancing additives are readily available and are made and sold under various trade names.
The term "water bath" as used herein, includes, but is not limited to, containers or chambers of water, a flower or stream of water, steam, water spray, or water mist.
The phrase "substantially simultaneous" as used herein to describe the temporal relationship between severing a flower stem and attaching a stem pick to the flower stem, is to be understood to include: severing the flower stem prior to the initiation of or the completion of the attachment of a stem pick to the flower stem; attaching a stem pick to the flower stem prior to the initiation of or the completion of the severing of the flower stem; and initiating or completing the severing of the flower stem at the same time as initiating or completing the attaching of a stem pick to the flower stem.
The present invention overcomes the disadvantages associated with prior art methods and apparatuses as discussed above by providing a method and apparatus for stemming a flower in which the flower stem is cut substantially simultaneously with attaching a floral pick to the flower stem. This eliminates the separate steps of cutting the flower stem and subsequently attaching a stem pick, by combining these two operations essentially into one operation.
In another aspect of the invention, the flower stem is cut in an environment which displaces air from the region of the severed plant stem by submerging the portion of the plant stem in the region of severance underwater or by subjecting it to a flow of water or a spray of water or other growing medium which would prevent formation of an air gap in the vascular tissue of the plant and/or skinning over of the tubules. If desired, the water or growing medium used for displacing air in the region of severance may contain a floral preservative or nutrient or bacteria stat or other material to help prolong the shelf life of the flower.
Other features of the invention will be become evident by reference to the following description having reference to the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a floral steaming machine incorporating the pick attachment assembly and stem cutting combination according to the present invention;
FIG. 2 shows a prior art steel stem pick;
FIG. 3 is a schematic partial plan view of the pick attachment assembly and the flower stem cutting arrangement, with the cutting knife operating to cut the flower stem perpendicular to its axis;
FIG. 4 is a schematic partial plan view of the pick attachment assembly and the flower stem cutting arrangement, with the cutting knife operating to cut the flower stem at an angle with respect to the axis of the flower stem;
FIG. 5 is a partial front view of the stemming machine of FIG. 1 showing an arrangement of the stem pick attachment jaws and cutting knife assembly with the flower stem offset from the axis of the stem pick;
FIG. 6 illustrates a flower with its stem cut off and with a stem pick attached to the extremity of the flower stem;
FIG. 7 is a perspective view of a stemming machine, similar to that of FIG. 1, showing the embodiment of the invention wherein the flower stem cutting and stem pick attachment procedures are conducted under water;
FIG. 8 shows the cutting region of a stemming machine being doused by a flow of fluid from a nozzle;
FIG. 9 shows the cutting region of a stemming machine being doused by a water spray issuing from a nozzle;
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to FIG. 1, a flower stemming machine is illustrated, and all illustrated parts of the machine in FIG. 1 are known from the prior art with the exception of the addition of a cutter assembly, and the addition of an adjustable stem stop.
Stemming machine 1 includes a base 2 upon which is mounted a stem pick stacker 3 carrying a number of stem picks 5, a stem pick attachment assembly 7, a cutting assembly 21, and an adjustable stem stop 11. One stem pick 5 is shown in a position ready for attachment to the extremity of a flower stem, the stem pick 5 having a plurality of fingers 6 extending horizontally within the attachment assembly 7 and between movable jaws 9. A flower stem precut or selected to a length approximately 1/8 inch to 1/2 inch longer than its length after cutting, is inserted in the attachment assembly 7 between jaws 9 and moved forward such that the face end of the flower stem abuts the front face of adjustable stem stop 11.
While the flower stem is in the position ready to receive an attached stem pick, handle 13 is moved in a downward direction which draws jaws 9 on each side of attachment assembly 7 toward one another. At the same time, knife 23 and backup knife 25 move toward one another to sever the flower stem 31 by the scissors action between the plane surfaces of knife 23 and backup knife 25, thereby effecting a shear action to sever the end of the flower stem from the rest of the flower. Desirably, cutting assembly 21 can be attached to the end jaws 9 in attachment assembly 7, so that the cutting of the flower stem occurs simultaneously with the bringing together of jaws 9 to crimp the fingers 6 of stem pick 5 without substantial redesign of the stemming machine mechanism.
In order to accommodate stems of different lengths, stem stop 11 is made adjustable by means of a thumb screw 22 fitting through a slot 26 in adjustment bar 24. The end of stop 11 opposite that of thumb screw 22 can be a free end or may have a downward protrusion extending into a slot (not shown) in base 2 or other known means for giving stability to the end of stop 11 opposite thumb screw 22. To adjust the length of the cutoff portion of the flower stem, thumb screw 22 is loosened, stop 11 is slid left or right (in FIG. 1) to the desired position, and then thumb screw 22 is screwed tight to lock stop 11 in place.
FIG. 2 shows the outline of a prior art thin steel stem pick 5 having fingers 6, a V-groove channel 8 (better seen in FIG. 5), barbs or spikes 10, and a pointed tip 12.
FIG. 3 shows a schematic plan view of part of the stemming machine of FIG. 1 with a stem pick 5 in position between jaws 9 and partially bent in a direction to eventually embrace the stem 31 of a flower. The fingers 6 are shown to be partially curled (out of the paper in FIG. 3) by the action of the curved surfaces of jaws 9 but not yet clamped or cinched about the flower stem 31. At this point in the process of attaching the stem pick 5, knife 23 has already severed the end of flower stem 31, and the cutoff portion 35 of stem 31 is discharged from the machine.
As illustrated, movable knife 23 is fixed to the upper right jaw 9 by means of screws 28 or other fastening means, and the opposing jaw 9 is machined to have a cutting surface cooperating with knife blade 23 such that the upper left jaw 9 in FIG. 3 functions as the backup knife 25. It will be understood that both knife 23 and backup knife 25 can be operated by a mechanism not directly connected to jaws 9, or an additional pair of specially designed jaws 9 can be attached to the attachment assembly 7 and act as the knife and backup knife. Finally, instead of using the upper left jaw 9 as backup knife 25, a separate, removable, backup knife 25 can be attached to upper jaw 9 by screws or other fasteners. Removability permits ease of sharpening and replacement of the knife parts.
In FIG. 3, the knife 23 and backup knife 25 are shown attached to the upper right and upper left jaws 9 so as to reciprocate along a path perpendicular to the axes of stem pick 5 and flower stem 31.
In FIG. 4, the same cutting action as that described in connection with FIG. 3 is shown to take place by the cutter knife 23 and backup knife 25, with the exception that the knife components are aligned so that the cutting action is at an angle with respect to the axes of the stem pick 5 and flower stem 31. In this embodiment of the invention, the knife components 23 and 25 cannot be attached to the jaws 9 for obvious reasons. Cutting the flower stem 31 at an angle has the benefit of creating a greater cross-sectional area of the cut stem thereby enhancing the transpiration of water and/or nutrients through the xylem of the flower stem.
In FIG. 5, a pair of opposing jaws 9 are shown to be pivotable about corresponding pins 14, and the jaws, as shown, are in their fully open position. In this position, and noting that knife 23 and backup knife 25 are mechanically connected to the tops of opposing jaws 9, a gap 18 is defined within which the flower stem 31 is inserted and comes to rest on the top of stem pick 5. The top corners of knife parts 23, 25 are beveled so as to assist the operator in easily locating flower stem 31 in gap 18.
Normally, the flower stem 31 would fall naturally in the center of stem pick 5 and lie in the V-groove 8. However, as can be appreciated by observing the limitations on space that the knife parts 23, 25 have for shearing the stem 31, if the stem 31 was fully seated in groove 8, the knives would only shear the top, although major, portion of stem 31 and perhaps leave some strands of connected fiber such that the cut end of flower stem 31 would not be completely severed. To solve this problem, knife block 25 is shown offset over the center of V-groove 8, and this limits the location of flower stem 31 forcing it to ride on the raised portion of stem pick 5 such that the blades 23, 25 can fully sever the stem.
As a further aid to insure that no fragment of the flower stem 31 is trapped between the bottoms of the sliding knife parts 23, 25 and the V-groove 8, a protuberance 43 is formed at the bottom of the backup knife 25 and extends a distance into V-groove 8.
The knife parts 23 and 25 are shown in FIG. 5 to extend below the tops of finger tips 44, which is possible because there are no fingers 6 at the cutting location.
In operation, as the jaws 9 are drawn toward one another, the finger tips 44 are cammed upwardly by the curved surfaces 41 of jaws 9 at about the same time that the knife 23 engages the flower stem 31. Accordingly, by the time the fingers 6 are formed about the flower stem 31, knife 23 has already severed the stem 31, and the cut free end of flower stem 31 is then free to move laterally and seek a centered position in V-groove 8, i.e. vertically axially aligned with the axis of the stem pick 5. Thus, the offset axes of flower stem 31 and stem pick 5 as shown in FIG. 5 is a temporary situation, since jaws 9 are symmetrically arranged about the ultimate common axis of the pick 5 and flower stem 31 and force the desired alignment upon completion of the step of attaching the pick.
FIG. 6 shows a stem pick 5 attached to the extremity of flower stem 31 with fingers 6 wrapped thereabout and a fresh cut end 33 of stem 31.
FIG. 7 illustrates a simplistic way of cutting the flower stem underwater. In this case, the entire assembly of FIG. 1 is disposed within a container 51 filled with water 53 to a level to exceed the level of cutting of the stem 31 of the flower. A notch 54 in container 51 is provided for relatively unrestricted insertion of the flower stem into attachment assembly 7, although the level of water 53 would be close to the bottom of notch 54. In this embodiment, an operating lever 55 is bent so as to be fully operable by the operator without interference from the sides of the container 51.
All parts of the machine shown in FIG. 7 should be made of stainless steel, plastic, or other components that are not susceptible to rust or corrosion by the water bath environment. The embodiment of FIG. 7 is shown for the sake of simplicity in setting forth this particular feature of the invention, and it will be understood that various forms of this embodiment would be within the spirit and scope of the invention. That is, a small container (not shown) can hold the cutter assembly 21, or the attachment assembly 7 and cutter assembly 21 combination, separate from the other parts of the stemming machine, taking into consideration water seals, an entrance notch for the flower stem 31, and like considerations.
FIG. 8 is an alternate embodiment of the arrangement of FIG. 7 in which, rather than filling container 51 completely full of water above the level of the cutter knives 23, 25, a stream or flow of water is provided by a nozzle 61 fed by a water line 63, and the assembly is fixed to body 2 by any convenient mounting means 65. In this embodiment, a drain 68 with an attached run-off tube 70 carries the water to a filter and recycling pump, if desired for minimizing the environmental impact. In this embodiment, container 51 is simply a collector vessel and may be quite shallow.
FIG. 9 is similar to that of FIG. 8 with the exception that, rather than a flow nozzle 61 as in FIG. 8, a spray nozzle 71 is provided to create a highly saturated water environment for the end of the flower stem being cut.
As discussed earlier in this description, instead of water, other materials could be used for displacing the air about the end of the flower stem being cut, including materials or additives that incorporate a floral preservative, nutrient, or bacteria stat, or any other growing medium.
It will be apparent to those skilled in the art that changes may be made in the construction and in the operation of the various components, elements and assemblies described herein, or in the steps or the sequence of steps of the methods described herein, without departing from the spirit and scope of the invention. For example, the timing of the cutting relative to the attachment of the stem pick is not critical. The stem can be cut before, during, or after attachment of the stem pick to the flower stem. The arrangement described herein is merely one example of a preferred embodiment of the invention in these respects. Accordingly, the invention is to be interpreted only as to the scope of the appended claims.
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A method and apparatus for stemming a flower in which the flower stem is cut substantially simultaneously with attaching a flower pick to the flower stem, thereby eliminating the separate steps of cutting the flower stem and subsequently attaching a stem pick by combining these two operations. In another aspect of the invention, the flower stem is cut in an environment which displaces air from the region of the severed plant stem by submerging the portion of the plant stem in the region of severance underwater or by subjecting it to a flow of water or a spray of water or other material which would prevent formation of an air gap in the vascular tissue of the plant and/or skinning over of the tubules. The water or other material used for displacing air in the region of severance may contain a floral preservative or nutrient or bacteria stat or other material to help prolong the shelf life of the flower.
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The present invention starts from known methods for the production of structures of electrically conducting material using printing methods. The invention relates to a method by means of which it is possible to deposit nanofibres in a targeted manner with a high spatial precision onto any desired surface. This is made possible by a specially adapted process of so-called electrospinning in conjunction with a material suitable for this purpose, from which the electrically conducting structures are formed, wherein the structures consist of electrically conducting particles or are subjected to a post-treatment in order to impart conductivity.
BACKGROUND OF THE INVENTION
Many structural parts (e.g. many internal fittings of automobiles; discs) and objects of daily use (e.g. beverage bottles) consist substantially of electrically insulating materials. This includes known polymers, such as polyvinyl chloride, polypropylene etc., but also ceramics, glass and other mineral materials. In many cases the insulating effect of the structural part is desired (e.g. in the case of housings of portable computers). However, there is often also a need to apply an electrically conducting surface or structure to such structural parts or objects, in order for example to integrate electronic functions directly into the structural part or the object.
Further requirements placed on the surface of articles of daily use and their material include as great an artistic freedom as possible in the design and configuration, positive mechanical properties (e.g. high impact strength), as well as specific optical properties (e.g. transparency, gloss, etc.), which are achieved in different degrees particularly by the materials listed above by way of example.
There is therefore the need to obtain the positive properties of the material and, specifically, to produce an electrically conducting surface. In particular the optical transparency and gloss are in this connection technically demanding. These can be achieved only in three ways. Either the substrate material itself is specifically made electrically conducting, without thereby adversely affecting its mechanical and optical properties, or a material is used that is conducting but is not visually recognisable by the human eye and can easily be applied in a targeted manner to the surface of the substrate, or a conducting material is used, which although itself is not transparent, can however be applied by means of a suitable process to the surface in such a way that the resulting structure is in general not perceivable by the human eye without the assistance of optical aids. In this way the properties of gloss and transparency of the substrate are not affected.
In general any structure which, when applied to a two-dimensional surface does not exceed a characteristic length of 20 μm in one of its two dimensions on the substrate plane, is regarded as visually non-recognisable. In order reliably to exclude any influencing of the surface recognition, structures in the submicron range (i.e. with a line width of ≦1 μm) are particularly desirable.
A large number of methods exist for applying in particular conducting material to surfaces. In particular conventional printing methods, such as screen printing or ink jet printing, are suitable for this purpose. Corresponding formulations for conducting materials—also termed inks—already exist particularly for these printing techniques, which in conjunction with the methods enable conducting structures to be formed on the surface.
Whereas screen printing methods on account of the very small available mesh width of the printing screen are in principle not able to produce structures with an optical resolution of less than 1 μm, ink jet printing methods for example would theoretically be suitable for this purpose, since the dimensions of the resulting structure on the substrate in the case of ink jet printing methods directly correlate to the nozzle diameter of the printing head that is used. However, in this connection the characteristic length of the minimal dimension of the resulting structure is as a rule larger than the diameter of the employed nozzle head [J. Mater. Sci 2006, 41, 4153; Adv. Mater 2006, 18, 2101]. Nevertheless, in principle structures with a line width of less than 1 μm could be produced if printers with nozzle openings of significantly less than 1 μm can be used. However, this is not feasible in practice since with increasing reduction of the nozzle diameter the requirements on the inks that can be used become much more stringent. Should the employed ink contain particles, then their mean diameter would have to match the reduction in the nozzle diameter, which in principle already excludes all inks with particles of size ≧1 μm. Furthermore, the requirements placed on the rheological properties of the ink (e.g. viscosity, surface tension, etc.) so that it can still be used for the printing head increase. In many cases these parameters cannot however be adjusted separately from the behaviour (e.g. spreading and adherence) of the ink on the respective substrate, which means that the ink and printing method combination cannot be used to produce conducting structures in this size range.
One method with which alternatively structures of size less than 1 μm can be produced on polymer surfaces is the so-called hot stamping method. By means of this method circular surface structures with a diameter of ca. 25 nm have already been produced [Appl Phys Lett 1995, 67, 3114; Adv Mater 2000, 12, 189]. The disadvantage of hot stamping however is that the structural shape is restricted to the shape of the stamping punch or stamping roller that is used in each case. A free choice in the configuration of the structure is not possible with this method. Particularly thin fibres, which potentially could also be applied to the surface of a suitable substrate, can be produced by means of a method that has become established under the name “electrospinning”. In this way it is possible by using a spinnable material to produce fibres of a few nanometres in diameter [Angew Chem 2007, 119, 5770-5805].
Electrospun fibres are however obtained only in the form of large, disordered fibre mats. Up to now ordered fibres can however be obtained only by spinning on a rotating roller [Biomacromolecules, 2002, 3, 232]. It is also known that in principle electrically conducting fibres can be spun by means of “electrospinning”. A corresponding conducting material for such an application utilising the conductivity of carbon nanotubes is also known [Langmuir, 2004, 20(22), 9852].
In US2001-0045547 methods and materials are disclosed, with which conducting fibre mats can be obtained.
A targeted deposition of non-conducting fibres on planar surfaces has also been achieved by reducing the distance between the spinning head and the substrate [Nano Letters, 2006, 6, 839].
Up to now no electrically conducting structures with a specific arrangement on a substrate surface have been produced by means of electrospinning.
In US2005-0287366 a method and a material are disclosed, by means of which conducting fibres can be produced. The method includes electrospinning at an interspacing of about 200 mm, with the result that disordered fibre mats are likewise obtained. The material is a polymer that is made electrically conducting by further post-treatment steps, including a thermal treatment. A targeted orientation and application of the resultant fibres to a substrate is not disclosed.
The object of the present invention is accordingly to develop a process with which, by using the electrospinning technique, conducting structures that are visually not directly recognisable by the human eye can be specifically produced on a surface.
SUMMARY OF THE INVENTION
This object is achieved by the use of an arrangement for the production of electrically conducting linear structures with a line width of at most 5 μm on an, in particular, non-electrically conducting substrate, which is the subject-matter of the invention, comprising at least one substrate holder, a spinning capillary, which is connected to a reservoir for a spinning liquid and to an electrical voltage supply, an adjustable movement unit for moving the spinning capillary and/or the substrate holder relative to one another, an optical measuring instrument, in particular a camera, for following the spinning process at the outlet of the spinning capillary, and a computing unit for regulating the distance of the spinning capillary relative to the substrate holder depending on the spinning process.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a diagrammatic illustration of the spinning arrangement according to the invention.
DETAILED DESCRIPTION
Preferably the spinning capillary has an opening width of at most 1 mm, preferably 0.25-0.75 mm, particular preferably 0.3-0.5 mm. Particularly preferred is an arrangement in which the spinning capillary has a circular opening with an internal diameter of 0.01 to 1 mm, preferably 0.01 to 0.5 mm and particularly preferably 0.01 to 0.1 mm.
In a preferred implementation of the new arrangement the voltage supply source delivers an output voltage of up to 10 kV, preferably 0.1 to 10 kV, particularly preferably 1 to 10 kV and most particularly preferably 2 to 6 kV.
In a further preferred implementation the adjustable movement unit serves to move the substrate holder.
Also preferred is an arrangement which is characterised in that the spinning capillary can be adjusted to a distance of 0.1 to 10 mm, preferably 1 to 5 mm and particularly preferably 2 to 4 mm from the substrate surface.
In a particularly preferred variant of the arrangement, the reservoir for the spinning liquid is provided with a conveying device that conveys the spinning liquid to the spinning capillary. A plunger-type syringe which is provided with a motor spindle as the plunger drive is for example suitable for this purpose.
The invention also provides a method for producing electrically conducting linear structures with a line width of at most 5 μm on an, in particular, non-electrically conducting substrate by electrospinning and post treatment, characterised in that a spinning liquid containing an electrically conducting material or a precursor compound for an electrically conducting material is spun onto the substrate surface from a spinning capillary with an opening width of at most 1 mm under the application of an electrical voltage between the substrate or substrate holder and spinning capillary or spinning capillary holder of at least 100 V at an interspacing of at most 10 mm between the outlet of the spinning capillary and the surface of the substrate, and the substrate surface is moved relative to the outlet of the spinning capillary, wherein the relative movement is controlled depending on the spinning flow, followed by removal of the solvent of the spinning liquid and optionally post-treatment of the precursor compound to form an electrically conducting material.
Suitable substrates are electrically non-conducting or poorly conducting materials such as plastics, glass or ceramics, or semi-conducting substances such as silicon, germanium, gallium arsenide and zinc sulfide. In a preferred method the distance between the outlet of the spinning capillary and the substrate surface is adjusted to 0.1 to 10 mm, preferably 1 to 5 mm and particularly preferably 2 to 4 mm.
The viscosity of the spinning liquid is preferably at most 15 Pa·s, particularly preferably 0.5 to 15 Pa·s, more particularly preferably 1 to 10 Pa·s and most particularly preferably 1 to 5 Pa·s.
The spinning liquid consists preferably of at least one solvent, in particular at least one solvent selected from the group consisting of: water, C 1 -C 6 alcohols, acetone, dimethylformamide, dimethyl acetamide, dimethyl sulfoxide and meta-cresol, a polymeric additive, preferably polyethylene oxide, polyacrylonitrile, polyvinylpyrrolidone, carboxymethylcellulose or polyamide, and a conducting material.
Particularly preferred is a method in which the spinning liquid contains as conducting material at least one member of the group consisting of: conducting polymer, a metal powder, a metal oxide powder, carbon nanotubes, graphite and carbon black.
Particularly preferably the conducting polymer is selected from the group consisting of: polypyrrole, polyaniline, polythiophene, polyphenylenevinylene, polyparaphenylene, polyethylenedioxythiophene, polyfluorene, polyacetylene, and mixtures thereof, particularly preferably polyethylenedioxythiophene/polystyrenesulfonic acid.
In the case where the spinning liquid preferably comprises a conducting material at least one metal powder of the metals silver, gold and copper, preferably silver, then water containing a dispersant and optionally in addition C 1 -C 6 alcohol is used as solvent, in which connection the metal powder is present in dispersed form and has a particle diameter of at most 150 nm.
Preferably the dispersant includes at least one agent selected from the following list: alkoxylates, alkylolamides, esters, amine oxides, alkylpolyglucosides, alkylphenols, arylalkylphenols, water-soluble homopolymers, water-soluble random copolymers, water-soluble block copolymers, water-soluble graft polymers, in particular polyvinyl alcohols, copolymers of polyvinyl alcohols and polyvinyl acetates, polyvinyl pyrrolidones, cellulose, starch, gelatins, gelatin derivatives, amino acid polymers, polylysine, polyaspartic acid, polyacrylates, polyethylene sulfonates, polystyrene sulfonates, polymethacrylates, condensation products of aromatic sulfonic acids with formaldehyde, naphthalene sulfonates, lignin sulfonates, copolymers of acrylic monomers, polyethyleneimines, polyvinylamines, polyallylamines, poly(2-vinylpyridines), block copolyethers, block copolyethers with polystyrene blocks and/or polydiallyldimethyl ammonium chloride.
A particularly preferred spinning liquid is characterised in that the silver particles a) have an effective particle diameter of 10 to 150 nm, preferably 40 to 80 nm, measured by laser correlation spectroscopy.
The silver particles a) are preferably contained in the formulation in an amount of 1 to 35 wt. %, particularly preferably 15 to 25 wt. %.
The content of dispersant in the spinning liquid is preferably 0.02 to 5 wt. %, particularly preferably 0.04 to 2 wt. %.
The size determination by means of laser correlation spectroscopy is known in the literature and is described for example in: T. Allen, Particle Size Masurements, Vol. 1, Kluver Academic Publishers, 1999.
In another variant of the new method a spinning liquid is used which comprises a precursor compound for an electrically conducting material that is selected from the group consisting of: polyacrylonitrile, polypyrrole, polyaniline, poly-ethylenedioxythiophene and which additionally contains a metal salt, in particular an iron(III) salt, particularly preferably iron(III) nitrate. Suitable solvents are for example acetone, dimethyl acetemide, dimethylformamide, dimethyl sulfoxide, meta-cresol and water.
The method is most particularly preferably carried out in such a way that the new arrangement described above or a preferred variant thereof is used to spin the spinning liquid.
The desired fine electrically conducting structures are produced by electrospinning by means of the above arrangement. Depending on the spinning solution that is used the structures have to be post-treated in order to achieve or increase the desired conductivity.
When a voltage is applied between the capillary or capillary holder and the substrate holder, a droplet from which the spinning thread emerges is formed at the opening of the capillary.
In addition receptacles for the capillary and substrate are configured so that a relative positioning of the capillary opening with respect to the substrate surface is possible. In a preferred embodiment the capillary can be positioned above the substrate by means of adjustment motors, while in another embodiment it is possible with adjustment motors to position the substrate underneath the capillary during the spinning. Preferably the substrate is moved underneath the capillary.
In order to produce the desired conducting structures from the spinning liquid, it should be ensured that the spinning process is stabilised in such a way that the resulting structure does not exhibit any breaks/discontinuities on the surface. Preferably this is achieved by regulating the capillary distance relative to the substrate surface, in which the forward movement of the line is interrupted by means of a regulating loop depending on a camera image, if the spinning thread obviously breaks. Particularly preferably the procedure is stabilised by arranging for a computer to analyse the camera image and interrupt the relative feed movement of the capillary with respect to the substrate if the analysis shows a break in the continuous fibre.
The minimum voltage to be applied in the method varies linearly with the adjusted interspacing and also depends on the nature of the spinning liquid. Preferably an operating voltage of 0.1 to 10 kV should be employed for the spinning process so as to obtain a structured deposition of the fibres, as described above.
Particularly good results are achieved with distances between the head of the capillary and substrate surface in the range of from about 0.1 to about 10 mm. It was also found that for the implementation of the method, the material to be spun should have a viscosity of in particular at most 15 Pa·s, in order reliably to produce conducting structures with the spinning material.
After the steps described above have been carried out the specified material is present in the desired form on the substrate, and can if necessary be post-treated in order to increase the conductivity.
This post-treatment includes for example supplying energy to the produced structures. In the case of conducting polymers (in particular polyethylene dioxythiophene) the polymer particles present in suspension in the solvent are fused with one another on the substrate by for example heating the suspension, the solvent being at least partially evaporated. Preferably the post-treatment step is carried out at least at the melting point of the electrically conducting polymer, and particularly preferably above its melting point. In this way continuous conducting paths are formed. Also preferred is a post-treatment of the structures/fibres on the substrate by means of microwave radiation.
In the case of a spinning material containing carbon nanotubes, the solvent between the particles present in dispersed form is evaporated by the post-treatment of the lines that are formed, so as to obtain continuous strips of carbon nanotubes capable of percolation. The treatment step is in this connection carried out in the region of the evaporation temperature or thereabove of the solvent contained in the material, and preferably above the evaporation temperature of the solvent. When the percolation boundary is reached, the desired conducting paths are formed.
Alternatively conducting structures can also be produced by depositing a precursor material for an electrically conducting material, for example polyacrylonitrile (PAN), on the substrate and then heat treating the substrate under alternating gaseous media so as to produce carbon in the form of a conducting substance, as described hereinafter.
In this case a solution of a polymer (e.g. PAN or carboxymethylcellulose) and a metal salt (e.g. an iron(III) salt such as iron nitrate) is prepared in a solvent (e.g. dimethylformamide (DMF)) that is suitable for both components. The polymer should be able to be converted into a material which is stable and conducting at such temperatures. Particularly preferred polymers are those that can be converted to carbon by high temperature treatment. Particularly preferred are graphitisable polymers (such as for example polyacrylonitrile at 700°-1000° C.). In the case of the metal salts those are preferred whose disintegration temperature or decomposition temperature under a reductive atmosphere lie below the decomposition temperature of the respective polymer (e.g. iron(III) nitrate nonahydrate at 150° C. to 350° C.). After the conversion of the metal salts into metal particles, preferably by purely thermal disintegration or using gaseous reducing agents, particularly preferably by hydrogen, the polymer is converted into carbon in the presence of the metal particles. Finally, carbon is optionally in addition deposited from the gaseous phase onto the structures, preferably by chemical gaseous phase deposition from hydrocarbons. For this purpose volatile carbon precursors are led at high temperatures over the structures. It is preferred to use short-chain aliphatic compounds in this case, particularly preferably for example methane, ethane, propane, butane, pentane or hexane, especially preferably the aliphatic hydrocarbons n-pentane and x-hexane that are liquid at room temperature. In this case the temperatures should be chosen so that the metal particles promote the growth of tubular carbon filaments and an additional graphite layer along the fibres. In the case of iron particles this temperature range is for example between 700° and 1000° C., preferably between 800° and 850°. The duration of the gaseous phase deposition in the above case is between 5 minutes and 60 minutes, preferably between 10 minutes and 30 minutes.
If according to the preferred procedure the aforedescribed suspensions of noble metal nanoparticles in solvents are used as spinning liquid to produce conducting structures, then the post-treatment can be carried out by heating the whole structural part or specifically the conducting paths to a temperature at which the metal particles sinter together and the solvent at least partially evaporates. In this connection particle diameters as small as possible are advantageous, since in the case of nanoscale particles the sintering temperature is proportional to the particle size, with the result that with small particles a lower sintering temperature is necessary. In this connection the boiling point of the solvent is as close as possible to the sintering temperature of the particles and is as low as possible, in order thermally to protect the substrate. Preferably the solvent of the spinning liquid boils at a temperature <250° C., particularly preferably at a temperature <200° C. and most preferably at a temperature <100° C. All the temperatures specified here refer to boiling points at a pressure of 1013 hPa. The sintering step is carried out at the specified temperatures until a continuous conducting path has been formed. The duration of the sintering step is preferably 1 minute to 24 hours, particularly preferably 5 minutes to 8 hours and most particularly preferably 2 to 8 hours.
The new method can be used in particular for the production of substrates that comprise conducting structures on their surface, that in one dimension have a length of not more than 1 μm, preferably 1 μm to 50 nm, and particularly preferably 500 nm to 50 nm, in which the conducting material is preferably a suspension of conducting particles, as described above, and the substrate is preferably transparent, for example of glass, ceramics, semiconductor material or a transparent polymer as described above.
The invention is described in more detail hereinafter by way of example and with reference to FIG. 1 , which shows diagrammatically the spinning arrangement according to the invention.
EXAMPLES
Example 1
Conducting Nanostructures with Carbon Nanotubes
The following apparatus (see FIG. 1 ) was used for spinning the spinning solution:
The holder 1 for the substrate 9 , which is a silicon disc, and the metallic holder 13 for the spinning capillary 2 , which is provided with a liquid reservoir 3 for the spinning solution 4 and is connected to an electrical voltage supply 5 . The voltage source 5 supplies D.C. voltage up to 10 kV. The spinning capillary 2 is a glass capillary with an internal diameter of 100 Mm. The controllable adjustment motor 6 serves to move the spinning capillary 2 and the adjustment motor 6 ′ serves to move the substrate holder 1 relative to one another so as to adjust the distance between them. The camera 7 is trained on the outlet of the spinning capillary 2 so as to follow the spinning procedure and is connected to a computer 8 with image processing software for evaluating the image data provided by the camera. The drive of the motor 6 ′ of the substrate holder 1 is adjusted by the computer 8 depending on the outflow of the spinning solution 4 from the spinning capillary 2 . A spinning solution 4 was prepared from 10 wt. % of polyacrylonitrile (PAN: mean molecular weight 210 000 g/mol) and 5 wt. % of iron(III) nitrate nonahydrate in dimethylformamide. The viscosity of the resultant solution was about 4.1 Pa·s. The spinning process was initiated at an interspacing of 0.6 mm between the capillary opening and surface of the substrate 9 at a voltage of 1.9 kV between the spinning capillary 2 and substrate 9 . After the establishment of a stable fibre flow the voltage was set to 0.47 kV and the interspacing was increased to 2.2 mm. At this setting the spinning solution 4 was spun onto the surface of the substrate 9 and the substrate was moved sideways so as to form lines.
The substrate 9 together with the contained PAN fibres was next heated from 20° to 200° C. within 90 minutes, and then treated for 60 minutes at 200° C. Following this the air of the drying oven in which the sample 9 was contained was replaced by argon and the temperature was raised to 250° C. within 30 minutes. Argon was then replaced by hydrogen. The temperature was again held for 60 minutes at 250° C. under this hydrogen atmosphere. This atmosphere was then replaced once again by argon as gas for the drying oven, and the sample 9 was heated to a temperature of 800° C. within 2 hours. Finally, hexane was metered into the argon for 7 minutes and following this the sample 9 was cooled once more under argon again to room temperature. The cooling process was not regulated in this case, but was monitored until the interior of the oven had again fallen to a temperature of 20° C.
A conducting line based substantially on carbon was formed. On contacting two points on the line spaced apart by 190 μm, a resistance of 1.3 kOhm was measured. The line had a line width of ca. 130 nm.
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Apparatus and method for producing electrically conducting nanostructures by means of electrospinning, the apparatus having at least a substrate holder ( 1 ), a spinning capillary ( 2 ), connected to a reservoir ( 3 ) for a spinning liquid ( 4 ) and to an electrical voltage supply ( 5 ), an adjustable movement unit ( 6, 6′ ) for moving the spinning capillary ( 2 ) and/or the substrate holder ( 1 ) relative to one another, an optical measuring device ( 7 ) for monitoring the spinning procedure at the outlet of the spinning capillary ( 2 ), and a computer unit ( 8 ) for controlling the drive of the spinning capillary ( 2 ) relative to the substrate holder ( 1 ) in accordance with the spinning procedure.
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TECHNICAL FIELD
[0001] The present invention relates to a lightning protection of a wind turbine.
BACKGROUND ART
[0002] Generally, countermeasures against lightning are implemented for blades of a wind turbine. FIG. 9 is a side view showing an example of a wind turbine. A tower 102 of the wind turbine 101 is built on the basement 106 . A nacelle 103 is mounted on the tower 102 via a yaw bearing 109 . The nacelle 103 can rotate around the yaw axis being an approximately vertical rotation axis by the yaw bearing 109 . A rotor head 104 is mounted on an end of the nacelle 103 via a main bearing 108 . The rotor head can rotate to the nacelle 103 around the main axis being an approximately horizontal rotation axis by the main bearing 108 . A plurality of blades 105 which are arranged in the circumferential direction of the main axis are mounted on the rotor head 104 via the blade bearing 107 . The blade 105 can rotate around a pitch axis being a rotation axis of the blade bearing 107 to be directed to a controlled pitch angle.
[0003] By the wind force received by the blades 105 , the rotor head 104 rotates, and then the main axis supported by the main bearing 108 is rotated. The rotation of the main axis is accelerated by a step-up gear arranged inside the nacelle 103 and drives a generator to generate an electric power.
[0004] For the lightning protection, a plurality of receptors (metallic lightning receiving parts) for receiving the lightning discharge are mounted on the surface of each blade 105 . The receptor 110 is connected to the down conductor 111 (pull-down wire) which is arranged through the inside of the blade. The lightning current conducted to the root of the blade by the down conductor 111 is electrically connected to the earth line. The earth line is grounded through a route of the lightning current provided in the rotor head 104 , the nacelle 103 , and the tower 102 .
[0005] In such a lightning protection structure of the wind turbine 101 , the route of the lightning current is required to be grounded through rotatable parts such as the blade bearing 107 , the main bearing 108 , the yaw bearing 109 or the like by some kind of means. By utilizing these bearings as a part of the conducting line of the lightning current, it is possible for the down conductor 111 to be grounded and to let the lightning current from the receptor 110 of the blade 105 off.
[0006] For further enhancing the safety or the durability, a structure of conducting the lightning current by bypassing the bearing parts may be considered. Specifically, by utilizing the earth brash or the sliding contact as the bypassing means, it is possible for a part of the lightning current flowing through bearings to bypass the bearings.
CITATION LIST
Patent Literature
[0000]
Patent Literature 1: U.S. Pat. No. 7,390,169
SUMMARY OF THE INVENTION
[0008] In the above-mentioned bypassing means, since consumable supplies which are subjected to the sliding or abrasion by the rotation of the bearings are used, it is required to maintenance them periodically. Then, a lightning protection technique which can ease the maintenance is desired.
[0009] A means of utilizing a spark gap can also be adopted. In the spark gap, a current route between a bearing is formed via a gap, and the current flows via the gap by a spark. However, in this means, some countermeasures for overcoming the following problems are required.
(1) There may be a case where the bypassing is not enough and a current flows through the bearing or other unexpected parts. (2) The electromagnetic wave generated by the spark may cause undesired influences on the control devices and the like. (3) The members of the gap structure itself and the members around it may suffer physical damages by the spark. (4) The gap length varies by the aging so that the spark characteristics change.
[0014] Considering the above problems, a lightning protection technique using a current route which does not require the spark gap and being able to ease the maintenance is desired.
[0015] According to an aspect of the present invention, the lightning current received by a receptor of a blade is conducted to an earth line in the blade. The earth line is conducted to the internal space of the rotor head via the internal side space of the bearing for changing the pitch angle of the blade. It is possible to conduct the lightning current to the rotor head side without using the bearing as the current route and without using a sliding or wearing member such as a brash or the like.
[0016] According to an aspect of the present invention, a wind turbine includes: a rotor head; a blade on which a receptor for receiving a lightning discharge is mounted; a bearing configured to connect the blade to the rotor head such that a pitch angle of the blade is variable; and an earth line configured to conduct the lightning discharge to a side of the rotor head via the blade and a space of an internal side of the bearing.
[0017] According to another aspect of the present invention, the wind turbine further includes: a blade attachment plate fixed to at least one of: an edge surface of a blade root of the blade; an inner surface of the blade root; and a step formed in the inner surface of the blade root, by a connecting means; and the blade attachment plate has a through hole through which the earth line passes.
[0018] According to further another aspect of the present invention, the wind turbine further includes: an electrically insulating member formed on an inner side of the through hole.
[0019] According to further another aspect of the present invention, the wind turbine further includes: a plate member attached on the bearing in an opposite side of the blade attachment plate. The earth line which is drawn via the through hole into an opposite side of the blade is routed along a surface of the blade attachment plate in a side of the bearing, and further routed along a surface of the plate member in an opposite side of the blade.
[0020] According to further another aspect of the present invention, the wind turbine further includes: a plate member attached on the bearing in an opposite side of the blade attachment plate. A first part of the earth line is attached to the blade attachment plate on a surface of a side of the blade, and a second part of the earth line is attached to the plate member in an opposite side of the blade, and an angle between an extending direction of the first part of the earth line and an extending direction of the second part of the earth line is 90 degree or less.
[0021] According to further another aspect of the present invention, the angle between the extending direction of the first part of the earth line and the extending direction of the second part of the earth line is 30 degree or less when the blade is a feather position.
[0022] According to further another aspect of the present invention, the earth line has a slack portion at a part in the bearing.
[0023] According to further another aspect of the present invention, the wind turbine further includes a shield member fixed in the rotor head and configured to cover the earth line and made of a conductive material.
[0024] According to the present invention, it is possible to ease the maintenance for lightning protection equipment of a wind turbine.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] The above objects, other objects, effects, and characteristics of the present invention will become clearer by the description of embodiments with the accompany drawings, in which:
[0026] FIG. 1 shows a rotor head and the root of a blade according to a first embodiment of the present invention;
[0027] FIG. 2 is a cross-sectional view of a rotor head and the root of a blade according to a second embodiment of the present invention;
[0028] FIG. 3 is a cross-sectional view around a blade bearing for explaining a problem to be solved according to a third embodiment of the present invention;
[0029] FIG. 4 shows an arrangement of an earth line according to the third embodiment of the present invention;
[0030] FIG. 5 is a cross-sectional view around a blade bearing for explaining a wind turbine according to a fourth embodiment of the present invention;
[0031] FIG. 6 shows the route of an earth line when a blade is the feather state in the fourth embodiment of the present invention;
[0032] FIG. 7 shows the route of an earth line when a blade is the fine state in the fourth embodiment of the present invention;
[0033] FIG. 8A shows an example of an attaching means of a blade attachment plate;
[0034] FIG. 8B shows an example of an attaching means of a blade attachment plate;
[0035] FIG. 8C shows an example of an attaching means of a blade attachment plate; and
[0036] FIG. 9 is a side view showing an example of a wind turbine.
[0037]
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DESCRIPTION OF EMBODIMENTS
[0038] Some embodiments of the present invention will be explained below. The total structure of the wind turbine according to a first embodiment of the present invention is the same as that of the wind turbine explained with reference to FIG. 9 . FIG. 1 shows the rotor head and the root of blades of the wind turbine in the first embodiment. The rotor head 1 , the blade 2 , and the blade bearing 3 correspond to the rotor head 104 , the blade 105 , and the blade bearing 107 explained in FIG. 9 , respectively. In FIG. 1 , the profile of the rotor head 1 is drawn with dotted lines, and the inside thereof is represented by a transparent view. Only the roots of two blades among three blades are drawn.
[0039] The blade bearing 3 is a circular-shaped bearing which supports the blade 2 such that the blade 2 is rotatable to the rotor head 1 in the pitch angle direction. The blade attachment plate 4 is attached to the surface of the blade bearing 3 on the blade 2 side. The blade attachment plate 4 has a through hole. The hole is formed in, for example, the center part of the blade attachment plate 4 . The blade attachment plate 4 has a shape corresponding to the root of the blade 2 . In the root part of the blade 2 , a flange is formed. The flange is fixed to the blade attachment plate 4 by bolts so that the blade 2 is fixed to the blade attachment plate 4 .
[0040] The means for fixing the blade attachment plate 4 to the blade 2 is not limited to the above-explained case. FIGS. 8A to 8C are cross-sectional views of the means for fixing the blade attachment plate 4 to the blade 2 . In the case shown in FIG. 8A , the blade attachment plate 4 is fixed to the blade 2 at the edge surface of the blade. In the case shown in FIG. 8B , the blade attachment plate 4 b is fixed to the inner circumferential surface of the blade 2 near the blade edge. In this case, for example, an attachment part 23 such as a flange having a circumferential shape is formed on the outer circumferential surface of the blade attachment plate 4 b , and by attaching the attachment part 23 to the inner circumferential surface of the blade 2 , the blade attachment plate 4 b can be fixed. In the example shown in FIG. 8C , on the inner circumferential surface of the blade 2 near the root of the blade, an uneven step which protrudes to the internal side thereof is formed as an attachment part 24 . A blade attachment plate 4 c of a disc shape having a bit smaller profile than the inner circumferential surface of the blade 2 is fixed inside the blade 2 to the attachment part 24 from the side of the blade root. The blade attachment plate 4 a , 4 b , 4 c can be fixed to the blade 2 by the above-explained various means. For the fixing, any connection means such as a welding, a bolt fastening or the like can be adopted.
[0041] On the surface of the blade bearing 3 opposing to the blade 2 , a connection shaft attachment plate 5 being a plate-shaped member is attached. The connection shaft attachment plate 5 has a hole. The hole is formed at the center portion of the connection shaft attachment plate 5 , for example. A connection shaft 11 is attached to the connection shaft attachment plate 5 . The connection shaft 11 is attached to the pitch angle driving means 12 . The pitch angle driving means 12 drives the blade 2 to the pitch angle instructed by a control signal by pushing or pulling the connection shaft 11 by an actuator.
[0042] In the internal space of the blade 2 , a down conductor 7 being a conducting wire for conducting a lightning current is arranged. An end portion of the down conductor 7 is connected to a receptor corresponding to the receptor 110 in FIG. 9 . On the inner wall surface of the blade 2 , a connection bracket 8 is attached. On the surface of the blade attachment plate 4 on the blade side (the side opposite to the blade bearing 3 ), a fixing bracket 9 is attached. The end of the down conductor 7 on the blade root side is electrically connected to the earth line 7 a by the connection bracket 8 . A part of the earth line 7 a is wired along a predetermined route in the blade 2 by the fixing bracket 9 . Another part of the earth line 7 a is further conducted into the rotor head 1 through the hole 6 which is formed from the hole of the blade attachment plate 4 , the space of the internal side of the blade bearing 3 , and the hole of the connection shaft attachment plate 5 , and attached to the surface of the connection shaft attachment plate 5 on the opposite side of the blade 2 .
[0043] The earth 7 a is preferably an insulated cable covered by an electrically insulating member. From the viewpoint of suppressing the shape deformation caused by a continuous applying of a lightning current, EPR (Ethylene Propylene Rubber) or XLPE (Cross-Linked Polyethylene) is preferable used as the insulation covering. These members are preferable for the earth line 7 a of the present embodiment in the characteristics of the electrical insulating performance, the weathering resistance, the flame resistance, and the twist resistance (robustness to torsion or bending). Further, the oil resistance characteristic is also required for the earth line 7 a since lubrication oil is used around the bearings. The above members are also preferable from this viewpoint because they have high oil resistance.
[0044] The blade 2 rotates relatively to the rotor head 1 . As a result, accompanying to the blade rotation, torsion of the earth line 7 a occurs. For permitting this torsion, the earth line 7 a is fixed to have a slack (in the state being longer than the strain state) in the part of the blade bearing 3 . Alternatively, as the earth line 7 a , a wiring formed by connecting the earth line in the blade 2 and the earth line in the rotor head 1 to be rotatable to each other by a slip ring, a rotatable connector device, and the like.
[0045] In the example of FIG. 1 , a fixing bracket 10 is attached in the surface of the connection shaft attachment plate 5 on the opposite side of the blade bearing 3 . The earth line 7 a derived from the hole 6 into the rotor head 1 is wired along a predetermined route in the rotor head 1 by the fixing bracket 10 .
[0046] When lightning strikes the wind turbine having the above structure, the lightning current irrupted from a receptor is conducted in the blade 2 along the down conductor 7 to the direction of the blade root, and is passed to the earth line 7 a . The lightning current flowing through the earth line 7 a is conducted via the hole 6 to the route inside the rotor head 1 . The lightning current is further conducted via a route not shown in the drawings being a wiring in the nacelle and the tower to the ground electrode. In such a structure, the lightning current of the lightning received by the receptor of the blade 2 can be conducted to the internal space of the rotor head 1 without flowing the lightning current through the blade bearing 3 .
[0047] FIG. 2 is a cross sectional view showing the rotor head 1 and the blade root of one of the blades 2 according to the second embodiment of the present invention. Only the different points from the first embodiment are explained below. When lightning current passes through the earth line 7 a which is drawn into the internal space of the rotor head 1 via the hole 6 a of the blade attachment plate 4 , the blade bearing 3 , and the hole 6 b of the connection shaft attachment plate 5 , strong electromagnetic wave is generated. For suppressing the influence of the electromagnetic wave on the control devices and the like arranged in the rotor head 1 , a shield member 18 made of metal is attached in the internal space of the rotor head 20 . In the example of FIG. 2 , the shield member 18 is attached to the metal member 17 (such as a structural beam for mounting some kind of equipment or the like) in the internal space of the rotor head 20 by a mounting bracket 19 . The shield member 18 covers at least a part of the earth line 7 a in the extending direction of the earth line 7 a . Instead of the shield member 18 , a metal duct may be installed in the internal space of the rotor head 20 . The earth line 7 a drawn into the internal space of the rotor head 20 is conducted via the internal space of the shield member 18 to the outside of the rotor head 1 . The electromagnetic wave generated by the lightning current flowing through the earth line 7 a is blocked by the shield member 18 . As a result, the influence thereof to the control devices and the like in the internal space of the rotor head 20 is reduced.
[0048] When a lightning current is passing, a large potential difference is generated between the earth line 7 a and the metal members supporting the earth line 7 a . In a case where the tolerance width of the dielectric strength in the insulation covering of the earth line 7 a is not enough, for further enhancing the safety, it is preferable to cover the surface of the metal member on the side of the earth line 7 a by an electrically insulating member. In the example shown in FIG. 2 , the electrically insulating member 13 covers the surface of a part of the blade attachment plate 4 along the wiring route of the earth line 7 a . Further, the inner surfaces of the hole 6 a and hole 6 b are covered by the electrically insulating members 14 and 15 , respectively. Moreover, the above-mentioned shield member 18 is also fixed to the metal member 17 via the electrically insulating member 16 . According to such a structure, it is possible to set a route of the lightning current passing through the internal side of the blade bearing 3 with maintaining high safety and reliability.
[0049] Next, the third embodiment of the present invention is explained. Only the portions different from the first and second embodiments will be explained. FIG. 3 is a cross sectional view around the blade bearing 3 for explaining the problem to be solved in the third embodiment. In the example of this figure, the earth line 7 a is arranged such that a part on the blade 2 side of the blade attachment plate 4 and another part on the opposite side of the blade 2 of the connection shaft attachment plate 5 are parallel to each other (whose flow directions of the electric current are antiparallel to each other). By arranging the earth line 7 a to be parallel, in accordance with the Fleming's left hand rule, a repulsion force is generated between the parts of the earth line 7 a . In the case of the arrangement shown in FIG. 3 , a force in the direction of ripping the fixing bracket 9 from the blade attachment plate 4 is generated by the earth line 7 a . Therefore, strength tolerable against such a force is required for the fixing bracket 9 .
[0050] FIG. 4 shows the arrangement of the earth line 7 a according to the third embodiment of the present invention. In the example of this figure, the hole 6 c is formed on a peripheral area which is deviated from the center of the blade attachment plate 4 a , so that the position of the hole 6 c and the position of the hole 6 b of the connection shaft attachment plate 5 are deviated to each other. The earth line 7 a is derived from the internal space of the blade 2 to the internal space of the blade bearing 3 via the hole 6 c . A mounting bracket 22 is mounted on the surface of the blade attachment plate 4 a on the opposite side to the blade 2 , namely, on the surface facing to the space formed by the blade attachment plate 4 a , the inner surface part of the blade bearing 3 , and the connection shaft attachment plate 5 . The earth line 7 a is arranged along a predetermined route on the blade attachment plate 4 a by the mounting bracket 22 . The earth line 7 a is further conducted to the internal space of the rotor head 1 via the hole 6 b . In the example of FIG. 4 , the earth line 7 a on the route on the blade attachment plate 4 a and the earth line 7 a on the route in the rotor head 1 are parallel to each other. The flow directions of the electric current flowing in the earth line 7 a on the route on the blade attachment plate 4 a and on the route in the rotor head 1 are antiparallel to each other. For applying the insulating member explained in FIG. 2 to this structure, the insulating members are attached to the inner surface side of the hole 6 c , and the surface of the blade attachment plate 4 a on the route where the earth line 7 a is arranged.
[0051] When lightning strikes the wind turbine having the above structure, the lightning current 21 flows through the earth line 7 a . The route of the earth line 7 a on the blade attachment plate 4 a and the route thereof in the rotor head 1 are parallel to each other. As a result, the earth line 7 a on the blade attachment plate 4 a is pushed onto the blade attachment plate 4 a by the Lorentz force. The blade attachment plate 4 a has a high strength for fixing the blades 2 , and is fixed to the blade bearing 3 with high strength. Therefore, the blade attachment plate 4 a can receive the Lorentz force applied to the earth line 7 a with high strength. Since the force applied to the mounting bracket 22 is reduced, the strength required for the mounting bracket 22 is permitted to be smaller than the example shown in FIG. 3 . According to such a structure, even when a large Lorentz force is applied to the earth line 7 a , it is possible to support the force reliably.
[0052] FIG. 5 is a cross sectional view around the blade bearing 3 for explaining the wind turbine according to the fourth embodiment of the present invention. Only the portions different from the third embodiment will be explained. In this embodiment, the hole 6 a of the blade attachment plate 4 and the hole 6 b of the connection shaft attachment plate 5 may be formed at the same position correspondingly in the planar direction to each other, namely, in the center of each plate for example, similarly to the first embodiment. On the surface of the blade attachment plate 4 of the blade 2 side, the earth line 7 a is fixed along a predetermined route by fixing brackets not shown in the drawings. The earth line 7 a is conducted to the internal space of the rotor head 1 through the holes 6 a and 6 b . In the internal space of the rotor head 1 , the earth line 7 a is arranged along a predetermined route on the connection shaft attachment plate 5 by fixing brackets not shown in the drawings.
[0053] From the vertical (the direction normal to the connection shaft attachment plate 5 ) viewpoint, namely, in the planar arrangement viewed from the rotational axis of the blade bearing 3 , the route of the earth line 7 a on the blade attachment plate 4 and the route of the earth line 7 a on the connection shaft attachment plate 5 are on a single straight line. In such a structure, when a lightning current 21 flows through the earth line 7 a , since the earth line 7 a on the blade attachment plate 4 side and the earth line 7 a on the connection shaft attachment plate 5 side are not overlapped and separated to each other from the vertical view, the Lorentz force applied between each other is small. Therefore, the force applied to the fixing brackets can be reduced.
[0054] It is not required for the earth line 7 a of the side of the blade attachment plate 4 and the earth line 7 a of the side of the connection shaft attachment plate 5 to be accurately on a single straight line. It is enough for the earth line 7 a on the side of the connection shaft attachment plate 5 to be arranged to be in the direction of extending (the direction of the flowing current therein) whose angle with at least a part of the earth line on the side of the blade attachment plate 4 is less than 90 degree. Further, it is possible for the earth line 7 a to arrange such that the earth line 7 a has a planar arrangement shown in FIG. 5 from the vertical viewpoint, and the route along the blade attachment plate 4 is on the surface of the blade attachment plate 4 opposite to the blade 2 as shown in FIG. 4 .
[0055] Referring to FIGS. 6 and 7 , the arrangement of the earth line 7 a according to the fourth embodiment is explained in detail. FIG. 6 is a view of the arrangement of the earth line 7 a shown from the connection shaft attachment plate 5 when the pitch angle of the blade 2 is controlled to the feather state. FIG. 7 shows the case where the pitch angle of the blade 2 is controlled to the fine in the normal operation. The earth lines 7 b , 7 c show the first part and the second part of the earth line 7 a in FIG. 5 , respectively. The earth line 7 b of the side of the blade attachment plate 4 (the blade root part of the blade 2 ) is drawn in a dotted line, and the earth line 7 c of the side of the connection shaft attachment plate 5 (in the rotor head) is drawn in a solid line.
[0056] When the weather is in the condition that the lightning strike may occur, the normal operation of the wind turbine is stopped. The pitch angle driving means 12 drives the connection shaft 11 for controlling the pitch angle of the blade 2 to the feather state. In this state, for suppressing the Lorentz force applied to the earth line 7 a , it is preferable for the angle between the route of the earth line 7 b and the route of the earth line 7 c to be 90 degree or less, and more preferably, it is approximately parallel (their planar arrangement forms approximately a single straight line). Even though the whole earth line 7 a satisfies the above angle condition, when the angle condition is satisfied for the earth line 7 a in the range within a predetermined length from the hole 6 a and the hole 6 b , the Lorentz force operated between the earth line 7 b and the earth line 7 c can be suppressed. Specifically, the angle between the earth line 7 b and the earth line 7 c is preferably in the range of ±30 degree or less which is the level where the influence of the electromagnetic force generated in the passing of the lightning current becomes ignorable level.
[0057] In the normal operation of the wind turbine, the pitch angle driving means 12 rotates the blade 2 (the blade attachment plate 4 ) relatively to the rotor head 1 (the connection shaft attachment plate 5 ) so that the blades 2 become fine. In this state, the earth line 7 b passing a route predetermined to the blade attachment plate 4 rotates relatively to the earth line 7 c in the rotor head 1 as shown in FIG. 7 . In the normal operation, since there is no anxiety of lightning strike, there occurs no problem even the direction of the current flow of the earth line 7 b and the earth line 7 c is deviated significantly from 0 degree.
[0058] In the above, some embodiments are explained. Those embodiments can be applied to the yaw bearing 109 between the tower 102 and the nacelle 103 of the wind turbine shown in FIG. 9 . In this case, the earth line in the internal space of the nacelle 103 is conducted to the side of the tower 102 through the yaw bearing 109 . According to this structure, the earth line can be grounded without flowing the lightning current through the yaw bearing 109 .
[0059] In the above, the present invention is explained with reference to some embodiments. However, the present invention is not limited to those above embodiments. The above embodiments can be variously modified. For example, any combination of the above embodiments, if there is no contradiction, can be another embodiment of the present invention.
[0060] The present application claims a priority based on Japanese Patent Application No. 2011-105629, which was filed on May 10, 2011, and the disclosure of which is hereby incorporated into the present application by this reference.
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In lightning protection equipment of a wind turbine, it is required to ease the maintenance with maintaining high safety. The lightning current received by a receptor of a blade is conducted to an earth line in the blade. The earth line is conducted to the internal space of the rotor head via the internal side space of the bearing for changing the pitch angle of the blade. It is possible to conduct the lightning current to the rotor head side without using the bearing as the current route and without using a sliding or wearing member such as a brash or the like.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a divisional of U.S. patent application Ser. No. 12/582,126, filed Oct. 20, 2009, which is a divisional of U.S. patent application Ser. No. 11/426,109, filed Jun. 23, 2006, which is based on and claims priority to U.S. Provisional Patent Application No. 60/760,665, filed Jan. 20, 2006, and is a continuation-in-part of U.S. patent application Ser. No. 10/117,007, filed Apr. 5, 2002, which is based on and claims priority to U.S. Provisional Patent Application Ser. No. 60/281,852, filed Apr. 5, 2001. The entire disclosure of each of the foregoing documents is hereby expressly incorporated herein by reference.
TECHNICAL FIELD
[0002] This patent generally relates to emergency shutdown systems used in process control environments and more particularly to a versatile controller for use in the testing and diagnostics of emergency shutdown devices and supporting equipment used in a process control environment.
BACKGROUND
[0003] Safety instrument systems typically incorporate emergency shutdown valves which are normally in a fully opened or a fully closed state and are controlled by a logic solver, a Programmable Logic Controller (PLC), or an emergency shutdown controller of some type to change states in the event of an emergency situation. To ensure that these valves can function properly, process control system operators typically periodically test the emergency shutdown valves by running these valves through a stroke test, which partially or completely opens or closes the valve. Because these tests are typically performed while the process is operating on-line or is operational, it is important to perform any test reliably and then return the valve to its normal state as quickly as possible. In this context, the term “normal state” refers to the position or state of the emergency shutdown valve when there is no emergency and the emergency shutdown valve is not being tested, i.e., when the process is operating normally.
[0004] In many cases, the emergency shutdown tests are performed at predetermined intervals by remotely located controllers. For example, emergency shutdown tests may be performed only a few times each year due to cumbersome test procedures and issues related to manpower. Also, during emergency shutdown tests, the emergency shutdown valve, or other emergency shutdown device being tested, is not available for use if an actual emergency event were to arise. However, limited, periodic testing is not an efficient way of verifying the operability of an emergency shutdown test system. As a result, digital valve controllers have been, in some cases, programmed to assist in the operation of the valve test to make the testing more automatic, user friendly and reliable.
[0005] Additionally, it is typically important that any emergency shutdown system be able to activate an emergency shutdown device (an emergency shutdown valve, for example) to its safe condition even when commanded by the emergency shutdown controller to do so in the unlikely but possible situation where an emergency event occurs during an emergency shutdown device test. In this context, the term “safe condition” refers to the position of the emergency shutdown device that makes the process plant or portion of the process plant “safe.” Typically, this safe position is associated with a position of the shutdown device that shuts down or halts some portion of the process plant.
[0006] While there are many systems that test the ultimate emergency shutdown device, such as an emergency shutdown valve, itself, in many cases there is supporting equipment associated with the emergency shutdown device that should also be tested to assure the complete operability of the emergency shutdown capabilities at any particular plant location. For example, in some pneumatic valve configurations, a solenoid valve is connected between a pneumatic valve actuator of an emergency shutdown valve and an emergency shutdown controller to redundantly control the operation of the valve actuator in response to signals from the emergency shutdown controller. While the emergency shutdown valve may be functional, it is possible for the solenoid device to become defective and therefore not operate properly as a redundant method of actuating the emergency shutdown valve. In some cases, an improperly operating solenoid device may even prevent the emergency shutdown valve from actuating properly when the emergency shutdown controller sends a shut-down signal to the valve controller for the emergency shutdown valve.
[0007] While it is possible to develop and provide specialized equipment at each emergency shutdown location within a plant to perform testing of each different emergency shutdown device and its supporting equipment, it is more desirable to provide a universal or generic set of equipment that may be used in many different situations to test different types of emergency shutdown devices and the supporting equipment associated therewith or to perform other functions in the plant. For example, it is desirable if such versatile equipment is able to control and test different types of emergency shutdown valves and solenoid valve configurations while simultaneously or alternatively operating as part of a closed loop distributed process control system.
SUMMARY
[0008] A multi-functional or versatile emergency shutdown device controller, such as an emergency shutdown valve controller, may be used in various different emergency shutdown configurations to enable the control and testing of different types and configurations of emergency shutdown devices and the supporting equipment associated therewith while also being able to be used in other plant configurations, such as in closed loop process control configurations. In one example, a digital valve controller for use with an emergency shutdown valve includes two pressure sensors and is adapted to be connected to a pneumatic valve actuator and to a solenoid valve device to assist in the on-line testing of the valve actuator as well as the on-line testing of the solenoid valve.
[0009] To perform testing of the solenoid device, the valve controller may measure the pressure at different ports of the solenoid valve as the solenoid valve is actuated for a very short period of time. The valve controller may determine whether the solenoid device is fully functional or operational based on the derivative of the difference between the measured pressure signals, i.e., based on the rate of change of the difference between the measured sensor signals over time. In this case, the digital valve controller, or an emergency shutdown test system connected to the digital valve controller, may determine that the solenoid is in acceptable operational condition if the absolute value of the determined derivative is greater than a predetermined threshold and may determine that a problem exists with the solenoid valve if the absolute value of the determined derivative is less than the same or a different predetermined threshold.
[0010] In one case, the digital valve controller may be used as a pressure transducer to control a valve based on measurements of the pressure supplied to the valve actuator which may be, for example, a spring and diaphragm type of valve actuator. In this case, the digital valve controller may use both of the pressure sensors, one to perform control of the valve and the other to perform testing of the solenoid. Alternatively, the digital valve controller may use one of the pressure sensors to perform pressure based control, i.e., within the servo control loop of the valve, and may use the other pressure sensor, not to test the solenoid valve, but to measure some other pressure signal within the process plant. This other pressure signal need not be associated with the control or testing of the emergency shutdown device or its associated equipment. In another case, the digital valve controller can use one of the pressure sensors to control or limit an amount of force used to test the valve. So configured, the digital valve controller can minimize inadvertent effects on the process by overmodulating the valve position during the test.
[0011] In another case, the digital valve controller may be used as a positioner and control movement of the valve based on position measurements provided to the digital valve controller by position sensors. In this case, the digital valve controller may use one of the pressure sensors to perform testing of the solenoid or other equipment associated with the emergency shutdown device and may use the second pressure sensor to sense a further pressure signal not needed within the servo control loop of the emergency shutdown device or for the testing of the emergency shutdown device. In this case, for example, the second pressure sensor of the digital valve controller may be connected to another location within the process plant, such as to a fluid line output from the emergency shutdown valve, to provide a process variable signal to the emergency shutdown controller or even to a process controller associated with normal control of the process.
[0012] Still further, the same digital valve controller may be used outside of an emergency shutdown device configuration and may control a valve using either pressure control (i.e., as a pressure transducer) or position control (i.e., as a positioner). In the former case, one of the sensors may be used to measure the pressure in the pneumatic loop of the valve for control purposes, i.e., as a pressure feedback, while the other of the sensors may be used to measure a pressure not associated with the valve or needed for controlling or testing the valve. In the latter case, both of the sensors may be used to measure pressures not associated with the valve or needed for controlling or testing the valve
[0013] The emergency shutdown device controller may include a processor, a memory coupled to the processor, and a communication input coupled to the processor that is adapted to receive a test activation signal from, for example, an emergency shutdown controller, a user, etc. One or more first test routines are stored in the memory and each is adapted to be executed on the processor to cause an emergency shutdown test of some kind to be performed in response to the receipt of an appropriate test initiation signal from, for example, the emergency shutdown controller. These test routines may be, for example, partial or full stroke test routines for the valve, test routines for the solenoid valve, etc. One or more second routines are stored in the memory and are adapted to be executed on the processor during the emergency shutdown test of, for example, a solenoid valve, to cause the one or more sensor outputs to be stored in the memory for subsequent retrieval and/or to be processed to determine the operational functionality of one or more devices, such as the solenoid valve, associated with the emergency shutdown device.
[0014] As noted above, the emergency shutdown device controller may include a communication unit, wherein the communication unit is coupled to the processor and communicates with a diagnostic device or a controller via a communication network or line using an open communication protocol, such as the HART protocol, the FOUNDATION® Fieldbus communication protocol or any other desired proprietary or non-proprietary communication protocol. The communication unit may, in some configurations, send one or more of the collected sensor signals to a further device within the process control system via the communication network or communication line.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a schematic diagram of several components of an example emergency shutdown system including a pneumatic emergency shutdown valve, a valve actuator, a digital valve controller and a solenoid valve configured to perform emergency shutdown operations and tests;
[0016] FIG. 2 is a block diagram of a digital valve controller associated with the emergency shutdown system of FIG. 1 ;
[0017] FIG. 3 is a schematic diagram of an example emergency shutdown system including the digital valve controller of FIGS. 1 and 2 configured to operate within the emergency shutdown system as well as to collect a pressure signal not used by or associated with the emergency shutdown system; and
[0018] FIG. 4 is a schematic diagram of a typical valve configuration including the digital valve controller of FIGS. 1 and 2 configured to operate to perform valve control within a distributed control system of a process plant to thereby perform closed loop control of a valve as well as to collect one or more auxiliary pressure signals not used for the closed loop control of the valve.
DETAILED DESCRIPTION
[0019] In a multitude of industries, valves and other mechanical devices are used in process control systems to bring a variety of processes quickly into a safe state if an emergency situation arises. It is important to periodically test these valves and associated electro/mechanical devices to ensure that they are in proper functioning condition. For example, to verify the performance of an emergency shutdown valve, mechanical movement of the valve needs to be verified in a reliable and secure manner without unduly affecting the process. Additionally, if the valve has supporting equipment, such as attendant solenoids, etc., it is desirable to be able to test this supporting equipment in a safe and reliable manner while the process is operating on line, but in a manner that does not unduly upset the process.
[0020] FIG. 1 illustrates an example emergency shutdown system 10 that may be used to test the operation of an emergency shutdown valve 12 connected within a process plant. It will be appreciated by those skilled in the art that, while an emergency shutdown valve system is illustrated in the embodiment of FIG. 1 , the emergency shutdown system 10 may include or be used to control other types of emergency shutdown devices, including other types of control devices, other types of valve devices, etc.
[0021] As illustrated in FIG. 1 , the emergency shutdown valve 12 may be disposed within a fluid line in a process plant, such as in a pipeline 13 having a portion that supplies fluid to an inlet 12 a of the emergency shutdown valve 12 and having a portion that receives fluid from an outlet 12 b of the emergency shutdown valve 12 . The emergency shutdown valve 12 , which is actuated by a valve actuator 14 , may be located normally in one of two positions, i.e., in a fully open position which permits fluid to flow freely between the inlet 12 a and the outlet 12 b, or in a fully closed position which prevents fluid from flowing between the inlet 12 a and the outlet 12 b . To ensure that the emergency shutdown valve 12 will properly function in a true emergency shutdown condition, the emergency shutdown valve 12 may be periodically tested by causing the valve actuator 14 to partially open or close the emergency shutdown valve 12 , which is referred to as a partial stroke test. Of course, other types of tests may be performed to test the operational capabilities of the valve 12 .
[0022] In the example system of FIG. 1 , the emergency shutdown system 10 includes the valve actuator 14 , illustrated as a pneumatically controlled actuator, and further includes a digital valve controller (DVC) 16 and a solenoid valve 18 which are pneumatically connected to the valve actuator 14 to control the operation of the valve actuator 14 . Additionally, the DVC 16 and the solenoid valve 18 are communicatively connected to an emergency shutdown controller 20 via communication lines and/or power lines 22 and 24 . In one embodiment, the DVC 16 may be the DVC6000 valve controller sold by Fisher Controls International LLC. In the embodiment of FIG. 1 , the solenoid valve 18 has a solenoid S that is energized via a 24 volt DC power signal sent from the emergency shutdown controller 20 on the lines 22 , while the DVC 16 communicates with the emergency shutdown controller 20 via a 4-20 milliamp communication line 24 , which may be for example, a traditional 4-20 ma control line, a HART protocol line, etc. Of course, if desired, the DVC 16 could be communicatively connected to the emergency shutdown controller 20 via any other desired proprietary or non-proprietary communication network, such as a FOUNDATION® Fieldbus network, a Profibus communication network, or any other known or later developed communication network. Likewise, the solenoid S of the solenoid valve 18 may be connected to and receive control signals from the emergency shutdown controller 20 using any other desired communication or power signals provided on any desired or suitable communication or power lines.
[0023] The valve actuator 14 of FIG. 1 is illustrated as a spring and diaphragm type actuator which is configured to receive a pneumatic signal on one side (referred to herein as the top side) of a spring biased diaphragm (not shown), to cause movement of a valve stem 28 of the valve 12 . If desired, however, the valve actuator 14 could be a one-sided or a two-sided piston type actuator or could be any other type of known pneumatic valve actuator. To control the actuator 14 , the DVC 16 receives a pneumatic supply pressure signal from a supply line 30 and provides a pneumatic signal via a pneumatic line 34 , a valve portion of the solenoid valve 18 and a pneumatic line 36 to the top side of the valve actuator 14 . As will be understood, the DVC 16 controls movement of the valve actuator 14 by controlling the pressure provided to the top side of the actuator 14 to thereby control movement of the valve stem 28 . Of course, the DVC 16 may cause movement of the diaphragm of the valve actuator 14 in response to control signals sent to the DVC 16 by the emergency shutdown controller 20 via the communication lines 24 .
[0024] The DVC 16 may include a memory which stores one or more stroke tests, such as partial stroke tests or full stroke tests, for testing the valve 12 , and the DVC 16 may initiate these tests in response to one or more test signals sent by the emergency shutdown controller 20 , input by a user or an operator at the DVC 16 itself or provided to the DVC 16 in any other desired manner. Of course, the DVC 16 may be used to perform any known or desired test(s) on the valve 12 and the valve actuator 14 to assure the operability of these devices.
[0025] In safety instrumented systems that employ air-operated valve actuators, such as that illustrated in FIG. 1 , the pneumatic solenoid valve 18 is often used as a redundant means of assuring that all air is evacuated from the actuator 14 when an emergency demand occurs, to thereby cause the valve/actuator combination to be forced to the emergency seat, i.e., into the safe state. Under normal, non-emergency conditions, the valve actuator 14 is pressurized to force the valve 12 against the normal or non-emergency seat, and the solenoid valve 18 is positioned to maintain pneumatic pressure in the actuator 14 , and to allow the DVC 16 to adjust that pressure via the pneumatic line 34 . In particular, in the embodiment of FIG. 1 , during the normal operation of the emergency shutdown valve 12 (i.e., the normal, non-safe or non-shutdown state), the solenoid valve 18 connects a port A thereof, as shown in FIG. 1 , to a port B to enable the DVC 16 to control the pressure in the line 36 and thereby control the pressure at the associated input of the valve actuator 14 . However, during an emergency shutdown operation, the solenoid valve 18 actuates (usually based on the removal of the 24 volt DC power signal from the lines 22 ) to connect the port A to a port C of the solenoid valve 18 while simultaneously disconnecting the line 34 from the line 36 . It will be understood that the port C is vented to the atmosphere. When this action occurs, the pressure supplied to the valve actuator 14 via the line 36 is vented to the atmosphere, causing the spring biased diaphragm and associated linkage within the valve actuator 14 to move the valve stem 28 and the valve plug from the normal seat to the emergency seat.
[0026] Thus, in normal operation, power is applied to and maintained at the input of the solenoid valve 18 to actuate the solenoid valve 18 , allowing air, or other gas, to freely pass between solenoid ports A and B, which allows the DVC 16 to exchange air with the actuator 14 and thereby control the internal pressure at the top side of the valve actuator 14 . When an emergency shutdown occurs, power is removed from the solenoid S of the solenoid valve 18 , allowing a healthy solenoid valve 18 to move to the opposite position. This action closes off port B, and connects port A to port C, thereby allowing air within the valve actuator 14 to escape to the atmosphere. This operation can occur in conjunction with or as a redundant operation to the DVC 16 removing pressure from the line 34 (such as by venting this pressure to the atmosphere) which would also cause the valve actuator 14 to move the valve 12 to the emergency seat in the absence of movement of the solenoid valve 18 .
[0027] As noted above, it is desirable to periodically test the solenoid valve 18 during normal operation of the plant to assure that, in the event of an actual emergency, the solenoid valve 18 will actuate as expected to actually disconnect the DVC 16 from the valve actuator 14 and to allow all or most gas/air to escape from the top side of the valve actuator 14 , thus moving the valve 12 to the emergency seat position.
[0028] To assist in this testing procedure, the DVC 16 is provided with two pressure sensors 40 and 42 which are positioned to monitor the flow of air or other gas through the solenoid valve 18 . In particular, the pressure sensor 40 monitors the valve controller output pressure provided at the solenoid valve port B, i.e., in the line 34 , while the sensor 42 is fluidly connected to and monitors the valve actuator pressure at the solenoid valve port A. As illustrated in FIG. 1 , the sensor 42 is fluidly connected to the port A of the solenoid valve 18 via a line 45 . Additionally, the DVC 16 may be provided with a testing routine that may collect, store and process the measurements made by the sensors 40 and 42 to determine the operational capabilities of the solenoid valve 18 based on the measured pressure signals, as discussed in more detail below.
[0029] Generally speaking, during a test of the solenoid valve 18 , the emergency shutdown controller 20 may remove power from the solenoid S of the solenoid valve 18 for a short period of time, thereby causing a healthy solenoid valve to actuate. At this time, the controller output pressure measured by the sensor 40 should remain nominally constant (because the DVC 16 will not vent the pressure in the line 34 to the atmosphere), while the pressure at port A measured by the sensor 42 will fall rapidly as the valve actuator 14 evacuates. Generally speaking, the mechanical health of the solenoid valve 18 may be estimated by inferring the rate and extent of travel as the solenoid valve 18 transitions from one position to the other. This inference may be made by continuously monitoring or determining the absolute value of the difference between pressures measured by the sensors 40 and 42 as a function of time.
[0030] More particularly, if the solenoid valve 18 only partially actuates, it will not fully open or close the ports A, B and/or C. Such attenuated solenoid travel will reduce the rate of the evacuation of the valve actuator 14 , causing a slower rate of change in pressure at port A than would occur with a healthy or normally operating solenoid valve 18 . Depending on solenoid valve constructions, such partial actuation may also partially open the port B to the atmosphere, causing the port B pressure, as measured by the senor 40 , to drop as well (instead of staying the same). Either of these phenomena reduces the rate of change in the pressure difference between ports A and B. Likewise, if the solenoid valve 18 actuates more slowly due to friction caused by a degraded physical condition, the solenoid valve 18 will also open and close the ports A, B and/or C thereof more slowly, which will also affect the rate of change with respect to time of the pressure difference between ports A and B.
[0031] As a result, during the test of the solenoid valve 18 (i.e., when power is removed from the solenoid S of the solenoid valve 18 ), the DVC 16 may collect and store pressure measurements made by the sensors 40 and 42 . During or after the test, the DVC 16 may process these measurements to determine the operational condition of the solenoid valve 18 . In particular, the DVC 16 may implement a discrete time domain, digital algorithm as generally defined by equation (1) below to determine the health of the solenoid valve 18 .
[0000] DP= abs ((S1−S2) dt ) (1)
[0000] where: DP=the derivative of the differential pressure with respect to time;
[0032] S 1 =the measurement of the pressure sensor 40 ; and
[0033] S 2 =the measurement of the pressure sensor 42 .
[0000] It will be understood, however that other implementations of the same basic calculation or equation are possible and may be used instead.
[0034] Equation (1) above may be performed periodically during the solenoid valve test or at separate times associated with the solenoid valve test, to calculate the absolute value of the derivative with respect to time of the differential pressure between the two ports A and B of the solenoid valve 18 . The output of this equation reflects the rate of change of the pressure drop of port A with respect to port B of the solenoid valve 18 . As will be understood, the value DP will be larger when the pressure difference changes more rapidly, meaning that the solenoid valve operated more quickly in response to the removal of the power from the lines 22 . Comparing the quantity DP to an expected threshold, MinDP, provides if this pressure transition is sufficient to constitute a healthy solenoid condition. In other words, solenoid valves which are operating properly and which are free of obstructions, or other binding friction, will rapidly “snap” to the new position, producing a sharp, rapid transition in pressure, resulting in a larger value for DP. Solenoid valves which are clogged, slow to travel, or which do not fully actuate, will produce more sluggish, rounded pressure waveforms, or attenuated pressure differences, thus producing a time-based derivative (DP) which is smaller in amplitude. Solenoid valves which produce a DP valve less than MinDP may be determined to be at risk of failing to perform as expected when required during an actual emergency, and thus may be determined to be faulty or in need of repair or replacement.
[0035] In practice, i.e., during an actual test, an external system such as the emergency shutdown controller 20 may command the DVC 16 to initiate a solenoid valve test, which begins by collecting sensor measurements from the sensors 40 and 42 and watching for a pressure pulse at the input of one or more of the sensors 40 and 42 . The receipt of this pressure pulse may start the periodic evaluation of equation (1) above. After sending the test signal to the DVC 16 , the emergency shutdown controller 20 may then interrupt the solenoid power on the lines 22 for a brief instant. The actual time of the power interruption will depend on the dynamics of the system, but may typically be on the order of tens or hundreds of milliseconds. The time should be long enough to cause full travel of a healthy solenoid at normal operating pressure, but not long enough to cause significant actual movement of the valve 12 , thus preventing the introduction of a significant disturbance within the process being controlled. In particular, the sensors 40 and 42 , as well as the pneumatic lines connecting these sensors to the ports A and B of the solenoid valve 18 are configured to determine a drop or change in pressure at these ports, but the solenoid valve 18 is not actuated long enough to allow the valve actuator 14 to move very much or to actually move the valve 12 a significant amount. That is, the solenoid valve 18 may be de-energized an amount of time less than or on the order of the dead-time associated with the operation of the solenoid valve, valve actuator, and valve stem configuration, so that by the time the valve 12 actually begins to move, the solenoid valve 18 is re-energized and returned to its normal, non-emergency, condition or state. Of course, this operation assumes that the solenoid valve 18 operates much faster (e.g., orders of magnitude faster) than the valve 12 , which is typically the case.
[0036] In any event, after power is restored to the solenoid valve 18 , the DVC 16 may be polled by, for example, the emergency shutdown controller 20 via the communication network 24 to determine if the signal DP was ever large enough to exceed the expected criterion MinDP. If so, the solenoid valve 18 may be deemed to be healthy. Of course, the calculations of equation (1) above may be made while the solenoid valve is moving from one position to another in response to de-energization of the solenoid S, when the solenoid valve 18 is sitting in the emergency position (i.e., has connected port A to port C) and/or when the solenoid valve 18 is moving from one position to another in response to a re-energization of the solenoid S.
[0037] Generally speaking, it will be understood that the value MinDP may be user adjustable or selectable based on the solenoid type, the pressures involved, and the dynamics of the system and may be determined in any desired manner, such as by experimental testing. Still further, the description provided herein is provided in the context of solenoids that are normally powered, and actuators that are normally pressurized. However, the technique described herein can also be applied in systems where the solenoid is normally unpowered, with power being applied only during an emergency demand condition, and/or where the valve actuator is normally unpressurized, with pressure being applied only during an emergency, or any combination thereof. Still further, while the pressure calculations are described as being performed by the DVC 16 during the test, the pressure calculations may be made based on collected (i.e., stored) pressure signals after the solenoid valve 18 has actuated, i.e., after the test, and/or may be made by any other device, such as by the emergency shutdown controller 20 . In this case, the DVC will provide pressure signals from the sensors 40 and 42 either in real time or as stored pressure signals to the emergency shutdown controller 20 . Still further, any means of performing the derivative calculation in equation (1) may be performed, including, for example, using periodic digital sampling and digital calculations, using mechanical devices or using analog electronic circuitry.
[0038] Referring now to FIG. 2 , a block diagram of the DVC 16 is illustrated to show some of the internal components associated with the DVC 16 . In particular, in addition to the pressure sensors 40 and 42 illustrated in FIG. 1 , the DVC 16 includes a processor 50 , a memory 52 , one or more analog-to-digital (A/D) converters 54 , one or more digital-to-analog (D/A) converters 56 , and a current-to-pressure converter 58 . The memory 52 is utilized to store instructions or scripts, including tests 60 for testing the valve 12 and the valve actuator 14 , and tests 62 for testing the solenoid valve 18 and any other associated devices. The memory 52 may also store collected sensor signals and diagnostic data. The A/D converters 54 convert analog sensor inputs, such as signals from the sensors 40 and 42 , into digital signals which the processor 50 may process directly and/or store in the memory 52 . Other examples of sensor inputs that may be acquired and stored by the DVC 16 include valve stem travel or position signals (or valve plug travel or position signals), output line pressure signals, loop current signals, etc.
[0039] The D/A converters 56 may convert a plurality of digital outputs from the processor 50 into analog signals which, in some cases, may be used by the current to pressure converter 58 to control a pressure or pneumatic switch 64 . The pneumatic switch 64 couples the pressure supply line 30 (of FIG. 1 ) to one or more output lines, such as the line 34 of FIG. 1 . Of course, the pneumatic switch 64 may also or in some cases, connect the line 34 to an atmospheric line 65 to vent pressurized gas to the atmosphere. Alternatively, the current-to-pressure converter 58 may receive digital signals directly from the processor 50 , or may receive analog current signals, such as 4-20 ma current signals from a communication unit 70 , to perform pressure switching and controlling functions.
[0040] The communication unit 70 serves as an interface to the communication network 24 of FIG. 1 . The communication unit 70 may be or include any desired type of communication stack or software/hardware combination associated with any desired communication protocol. As is known, the communication unit 70 may serve to enable signals received by the processor 50 to be communicated to the emergency shutdown controller 20 or any other device connected to the communication network 24 , such as a process controller responsible for controlling one or more portions of the process not associated with the valve 12 , a user interface or any other device. In particular, the processor 50 may receive and process the pressure signals from the sensors 40 and 42 and may provide one or more of these signals as digital data to be sent via the communication unit 70 and the communication network 24 to other devices. In this manner, one or more of the sensors 40 and 42 may be used to perform measurement activities within the process plant that are not needed for the control and/or testing of the emergency shutdown system 10 of FIG. 1 . This feature makes the DVC 16 more versatile and useful in processes or emergency shutdown devices that do not need both of the sensors 40 and 42 for control and/or testing of the components within the emergency shutdown device.
[0041] As illustrated in FIG. 2 , the DVC 16 may also include a clock 72 and an auxiliary input interface 74 which may be used by the processor 50 to monitor or receive auxiliary inputs such as inputs from electrical switches or other devices connected directly to the DVC 16 via the auxiliary interface 74 . Additionally, if desired, the DVC 16 may include a housing 76 which may be an explosion proof housing used to prevent sparks from reaching explosive gasses in a plant, and thus reduce the likelihood that the emergency shutdown system 10 will cause an explosion.
[0042] While the DVC 16 has been described as storing and performing stroke tests and integrity tests on the valve 12 , the valve actuator 14 and the solenoid valve 18 of FIG. 1 , it will be understood that the DVC 16 can also store and implement any other types of or any additional tests that are based on or that use other diagnostic data collected by the DVC 16 in addition to or alternatively to the data collected by the sensors 40 and 42 . Sensor or diagnostic data collected during, for example, an emergency shutdown test may be collected by other types of sensors not shown in FIG. 2 and/or may be retrieved using a handheld computing device that may communicate with the DVC 16 via the auxiliary interface 74 or via the communication unit 70 . Many possible tests are described in United States Patent Application Publication No. US 2002-0145515 A1, which is hereby expressly incorporated by reference herein. Additionally or alternatively, if desired, the DVC 16 may send collected data back to a main control room via, for example, the emergency shutdown controller 20 , for processing by other devices.
[0043] FIG. 3 illustrates a different configuration of an emergency shutdown system 100 that uses the DVC 16 of FIGS. 1 and 2 in a slightly different manner. This configuration and that of FIG. 4 described below are provided to indicate only a couple of examples of the many ways in which the DVC 16 described herein is versatile enough to be used in different process plant configurations without being significantly altered. The emergency shutdown system 100 of FIG. 3 is similar to the system 10 of FIG. 1 , with like elements having the same reference numbers. In the system 100 of FIG. 3 , however, the DVC 16 is not set up to perform the solenoid valve test discussed above, but is instead configured to use the output of the sensor 40 to perform closed loop pressure control of the valve actuator 14 to cause the valve actuator 14 to actuate in any desired manner in response to the receipt of, for example, an emergency shutdown signal at the DVC 16 or to perform testing, such as partial stroke testing, of the valve actuator 14 . In this case, the DVC 16 uses the sensor 40 to operate as a pressure transducer for the valve actuator 14 and may provide any type of control of the valve 12 .
[0044] However, as illustrated in FIG. 3 , the second sensor 42 of the DVC 16 may be connected to any desired fluid line within the process to acquire process variable measurements not needed for the control and/or testing of the valve 12 , the valve actuator 14 or the solenoid valve 18 . While the sensor 42 is illustrated in FIG. 3 as being connected to the outlet 12 b of the valve 12 , it could instead be connected to any other fluid line or pressure take-off associated with any other process control device or equipment. This other process equipment may, but need not be, associated with the emergency shutdown device 100 . Additionally, it will be understood that the output of the sensor 42 , which is a process variable, may be stored in and sent by the DVC 16 to other devices, such as to the emergency shutdown controller 20 via the communication network 24 , to a handheld device via the main communications controller or the auxiliary interface 74 ( FIG. 2 ), to a distributed controller or a user interface not associated with the emergency shutdown system 100 via the communication network 24 or the auxiliary interface 74 , etc. Thus, collection and use of the sensor data from the sensor 42 is not limited to use in an emergency shutdown device or system in which the DVC 16 is located. This feature makes the DVC 16 , when used as part of an emergency shutdown system, more versatile because it enables the DVC 16 to provide an auxiliary pressure input to a distributed process control system or to a maintenance system associated with a process plant.
[0045] Alternatively, the emergency shutdown device 100 can be configured as shown in FIG. 3 , wherein the DVC 16 operates to perform position control of the valve 12 , i.e., wherein the DVC 16 operates as a positioner. In this case, however, the sensor 40 may be connected as shown in FIG. 3 to perform pressure control as a fallback control method if a problem occurs with the position control servo loop, such as if a position sensor associated with this loop fails. This fallback control method is described in more detail in U.S. patent application Ser. No. 11/195,281, entitled “System and Method for Transfer of Feedback Control for a Process Control Device,” which was filed Aug. 2, 2005, the disclosure of which is hereby expressly incorporated by reference herein. In this case, however, the additional sensor 42 may still be used to measure a pressure signal external to the valve 12 and valve actuator 14 configuration. While the sensor identified by reference numeral 40 has just been described as performing the pressure control in FIG. 3 , an alternate embodiment can include either the sensor identified by reference numeral 40 or the sensor identified by reference numeral 42 performing the pressure control as a fallback control method. Additionally, the sensor identified by reference numeral 40 may alternately be used as a pressure sensor for measuring a pressure external to the valve 12 and actuator 14 configuration. Thus, it should be appreciated that either sensor may perform any of the above-described functions, as necessary for a desired application.
[0046] Likewise, FIG. 4 illustrates the DVC 16 of FIGS. 1 and 2 being used in a closed loop valve control configuration 110 to control a valve 12 and a valve actuator 14 combination which are not part of an emergency shutdown device. The closed loop valve control configuration 110 includes elements that are the same as or similar to the system 10 of FIG. 1 , with like elements having the same reference numbers. In the configuration 110 of FIG. 4 however, the DVC 16 is illustrated as being connected to a process controller 200 and is used to provide standard servo control of the valve 12 which, in this case, may be a process valve not associated with an emergency shutdown device or system. In this configuration, the sensor 40 of the DVC 16 may be connected to the input of the valve actuator 14 (e.g., may be connected to the pneumatic line 34 ) to perform pressure control of the valve actuator 14 . Here, the DVC 16 operates as a traditional pressure transducer for controlling the valve 12 . However, as shown in FIG. 4 , the pressure sensor 42 is connected outside of the valve and valve actuator configuration to acquire an external pressure measurement not needed for controlling the valve 12 . Thus, in a manner similar to the earlier described configurations, the DVC 16 may allow the process controller 200 to use the sensor 42 as another pressure transmitter disposed within the process plant.
[0047] Alternatively, the valve control configuration 110 can be configured as shown in FIG. 4 , wherein the DVC 16 operates to perform position control of the valve 12 , i.e., so that the DVC 16 operates as a positioner within the process control scheme. In this case, however, the sensor 40 may still be connected as shown in FIG. 4 to perform pressure control as a fallback control method if a problem occurs with the position control loop, such as if a position sensor fails. This fallback control method is described in more detail in U.S. patent application Ser. No. 11/195,281 as noted above.
[0048] Still further, while not shown in FIG. 4 , if the DVC 16 is used to perform position control of the valve 12 , i.e., if the DVC 16 operates as a positioner within the process control scheme, both of the sensors 40 and 42 may be used as external or auxiliary pressure transmitters to measure any desired pressure signals associated with or present within the process plant, including pressure signals not associated with the controlling or testing the valve 12 or the valve actuator 14 . Of course, the outputs of the sensors 40 and 42 may be stored in the DVC 16 and/or may be sent to other devices, such as to the process controller 200 , to user interface devices (not shown), etc. via for example, the communication network 24 .
[0049] It will be understood from the description provided above that the DVC 16 may be used in many different process plant configurations and scenarios to provide different pressure measurements for different uses, and that the DVC 16 may be used as part of an emergency shutdown device or as part of a distributed process control device when performing these pressure measurements. While the DVC 16 has been described and illustrated as including two pressure sensors 40 and 42 , it will be understood that the DVC 16 is not limited to the use of two pressure sensors, but instead that additional pressure sensors could be provided on the DVC 16 to perform other pressure measurements within the process plant.
[0050] While the present invention has been described with reference to specific examples, which are intended to be illustrative only and not to be limiting of the invention, it will be apparent to those of ordinary skill in the art that changes, additions and/or deletions may be made to the disclosed embodiments without departing from the spirit and scope of the invention.
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A method of monitoring a fluid process control system having a control loop for controlling the flow of a material through a path in the fluid process control system. The control loop a control valve, a valve controller, and a fluid control line. The control valve is disposed in the path and is movable between an open position and a closed position. The valve controller is for controlling movement of the control valve. And, the fluid control line couples the valve controller to the control valve. The method detects a first pressure in the control loop with a first pressure sensor. Then, a second pressure can be detected at a location that is external to the control loop with a second pressure sensor. Finally, the method can include determining a characteristic of the control loop based on the first pressure.
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This Appln. Claims Benefit of 60/079,347 Mar. 24, 1998.
BACKGROUND
a. Field of the Invention
The present invention relates generally to installation of underground pipelines and similar conduits, and, more particularly, to an apparatus for installing fill material around a pipeline after this has been placed in an excavated trench.
b. Related Art
Underground pipelines are used for many purposes, including oil and natural gas lines, water lines, sewer lines and electrical power conduits, for example. In most instances, such pipelines are installed by excavating a trench in the earth, laying the pipe in the trench, and then placing protective fill material around and over the pipe.
The protective fill material is normally one of two types. For oil and gas lines and similar types of high-strength pipe, the fill material is ordinarily a soil or gravel material which is screened for size, but which does not necessarily include a cement or other binder component. The padding in such installations serves mostly to protect the pipe from coming into contact with large/sharp rocks in the subterranean formation or in overlying layers of backfill. The padding also protects the pipe from vertical loads, such as the weight of the overlying fill or that of a vehicle crossing over the trench, by directing these loads outwardly into the earth along the sides of the trench. Still further, the padding serves to protect the pipe against excessive pressures in the event of a shifting or collapse of the earth along the trench, as due to an earthquake for example, and also protects the cathodic protection coating on the pipeline material itself.
In order to serve these functions, the fill material must be screened to exclude pieces of rock greater than a predetermined size, and the material must then be distributed carefully in a predetermined profile over and around the pipe. Also, depending on the specifications for the installation, different (e.g., coarser or finer) grades of material may need to be installed in layers to form the fill, and cement and/or fly ash may also be included in one or more of the layers to provide a stronger, more coherent padding. Furthermore, in some installations it is necessary to add a certain amount of water to the padding material so as to form a slurry which is able to flow in and fill completely around and underneath the pipeline (e.g., see FIG. 3).
To obtain the fill material, excavated earth (often, the native spoils excavated from the trench itself) is trucked or otherwise transported to a screening plant. After screening, the material is transported back to the trench, where it is dumped onto the pipe using a truck or loader. Not only is such a process time consuming and inefficient, but simply dumping the material onto the pipe in this manner makes it very difficult to provide the fill with the proper contour.
Certain machines have been developed for the specific purpose of screening and installing pipeline padding, but these have generally been unsatisfactory in one or more respects. To illustrate these problems, a typical prior art pipeline padder 10 is shown in FIG. 1; machines of this type are available from several sources, including Ozzie's Pipeline Padder Co., 1545 West Watkins, Phoenix, Ariz.
As can be seen in FIG. 1, prior art padders typically include some form of tracked carriage 12 which propels the vehicle alongside the trench 14 (in some instances there is a separate bulldozer or other tracked vehicle which carries or propels the assembly), in the direction indicated by arrow 16. As the machine moves along, an on-board conveyor 18 picks up excavated backfill lying alongside the trench and discharges this on top of a vibrating screen shaker 22. Fines in the backfill pass through the screen shaker, while larger rocks and debris roll off the screen and are discarded as indicated at 24.
The screened material falls onto a transverse belt 26 which transports the material sideways towards the trench at a comparatively high speed. A deflector plate 28 mounted at the end of the conveyor assembly intercepts the material and redirects this downwardly on top of the pipeline 30 so as to form the padding 32.
While machines of this type are in widespread use, their efficiency is limited by a number of problems which are inherent in the basic configuration. One of the most serious drawbacks is the inability of the operator to effectively control placement of the material in trench. As can be seen, the operator 34 is located well off to the side of the trench, in a position where he is viewing the pipe at an angle and where his sight is partially obstructed by the upper edge of the trench. As a result, it is difficult or impossible for the operator to see whether the fill is being placed correctly at any given point. Moreover, the operator has only limited control over the position of the conveyor assembly, and the transverse alignment of the conveyor (shooting crosswise onto the trench) makes it very difficult to direct the flow of material with any degree of accuracy.
These deficiencies have become more acute with the development of more sophisticated pipeline padding or bedding techniques, some of which require the installation of several layers of fill material, each of which has its own specified depth and profile. For example, FIG. 2 shows an installation in which the first layer of fill 36 is formed of a comparatively fine material which surrounds the pipe and has a domed profile 38 along its upper surface, while the subsequent layers 40 and 42 vary in thickness and coarseness of the material. It will be appreciated that this form of padding requires precise, controllable placement of the different grades of fill material, which has been very difficult to accomplish using existing types of machines.
Furthermore, certain installations call for mixing water with the fill material, so as to make it more flowable, or for mixing in Portland cement or other cementitious material to form a stronger, more coherent fill. In particular, most water lines require the use of a cementitious fill material, commonly referred to as Controlled Low Strength Material (CLSM). Water lines are typically much thinner walled and weaker than gas or oil lines, and the shape and strength of the fill material, forms a significant part of the design strength of the pipe.
Existing types of pipeline padding machines, such as that described above, have no provision for adding and mixing water and cement with the fill so as to form a CLSM material. As a result, CLSM fill has typically been made at a local concrete ready-mix plant and then trucked to the installation site, where it is placed using the discharge chute of the mixer truck. This practice is extremely inefficient in several respects. Firstly, if the native spoils which have been excavated from the trench are to be used in the CLSM fill, these must be trucked from the excavation site to the to the ready-mix plant; otherwise, the excavated material must be disposed of and new aggregate material purchased to form the CLSM.
Furthermore, the CLSM begins to set immediately after mixing and must be deposited in the trench within a comparatively short time. Not infrequently, however, the bedding operation is interrupted for one reason or another (e.g., to make a repair or correction), or the operation has advanced to a section of the pipeline where the fill material is not needed. When this happens, the CLSM material from the ready-mix plant must be disposed of in short order, before it sets up inside the mixer truck. Not only does this cause the material to be wasted, but it is also necessary to find (or excavate) a hole or other cavity into which the material can be dumped.
Accordingly, there exists a need for a pipeline padding/bedding machine which enables the operator to accurately place the fill material in the desired positions and contour around and over a pipeline. Furthermore, there exists a need for such an apparatus in which water can be added to the fill material in an efficient, continuous manner, when this is needed in order to form a slurry or flowable padding which will flow completely under and around a pipeline and/or pipeline appurtenance. Still further, there exists a need for such an apparatus in which Portland cement or other cementitious materials can be incorporated in the fill material in an efficient, manner when these are needed, and on a continuous or interrupted basis as necessary.
SUMMARY OF THE INVENTION
The present invention has solved the problems cited above, and is an apparatus for preparing and installing pipeline padding or bedding material in a controllable manner.
The apparatus includes a tracked platform which straddles the trench, with the operator cab being mounted near the midpoint of the platform to provide a clear view looking down into the trench. A screen assembly sorts raw backfill material to exclude excessively large pieces, and the screened material is fed to a conveyor belt which extends at a forward angle towards the trench. The fill material is directed downwardly into the trench though a hopper assembly at the discharge end of the belt.
When adding water and/or cementitious material to the padding material, a horizontal auger is mounted to the lower end of the hopper assembly. Preferably, the lower portion of the hopper assembly is rotatable about a vertical axis, with the auger being mounted to this lower portion and extends forwardly towards the trench. The forward end of the auger is supported from an extensible crane assembly, so that by rotating and/or extending/retracting the crane assembly, the operator is able to precisely control the discharge point of the horizontal auger, thereby achieving precise placement of the padding, bedding or slurry material.
The apparatus may also include means for mixing water with the padding material so as to form a flowable slurry. This may comprise a water supply line which discharges into the rearward end of the horizontal auger, so that the padding material and water are thoroughly mixed before being discharged into the trench.
The apparatus may also include means for mixing a cementitious slurry with the padding material. This may comprise a cement silo which discharges cement dust into the intake end of the swivel hopper, along with water from the supply line. The cement dust and water combine with the screened backfill material in the hopper and enter the intake end of the horizontal auger, in which they are mixed so as to form a cementitious slurry prior to being discharged into the trench.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective, environmental view of a prior art pipeline padding machine, showing the manner in which this discharges fill material into the trench from the transversely extending conveyor assembly;
FIG. 2 is a cross-sectional view of a pipeline installed in an excavated trench, this having an exemplary multi-layer padding fill installed around and over the pipe;
FIG. 3 is a front elevational view of a pipeline padding and bedding machine in accordance with the present invention, showing this straddling a trench so as to install fill material therein; and
FIG. 4 is a plan view of the apparatus of FIG. 3, showing the configuration of the pivotable discharge assembly, and also the mechanism by which cement is selectively added and mixed with the fill material before this is discharged into the trench.
DETAILED DESCRIPTION
FIG. 3 shows a pipeline padding or bedding installation apparatus 50 in accordance with the present invention. As can be seen, this includes a wide-track crawler carriage 52 having a first and second propulsion tracks 54a, 54b which are spaced apart by a distance sufficient to enable the carriage to straddle a pipeline trench 56 of ordinary width. For example, a track spacing of approximately 221/2 feet is eminently suitable for most conventional applications (although the width can be adjusted by adding sections to the carriage, to approximately 38 feet wide, for example).
An example of a tracked undercarriage suitable for use in the embodiment of the invention which is illustrated in FIGS. 3-4 is available from Henry Machine Company, Inc., Pierce, Colo. An on-board diesel engine (not shown) serves as the prime mover, and the tracks are independently controllable by means of a conventional pedal mechanism. The diesel engine also drives the hydraulic pumps (not shown) which provide hydraulic pressure to operate the other on-board systems. Suitable hydraulic coolers and controls are provided for controlling the operation of the various systems, such controls being well known to those skilled in the art of design and manufacture of hydraulic systems.
An operator station 58 (in the form of an enclosed cab in the embodiment which is illustrated) is mounted proximate the midpoint of the main platform 60 of the tracked carriage. Because the carriage spans the trench, this location provides the operator with a clear, unobstructed view looking down on the trench and pipeline, so that the operator is able to observe exactly where the fill material needs to be placed. The operator station also houses the controls (not shown) for operating the principal subsystems of the apparatus.
A vibrating screen mechanism 62 is mounted on one side of the platform 60 (to the left in FIG. 3). In this position, the screen mechanism is readily accessible from the side, so that this can receive backfill material which is dumped into the top of the vibrator in the direction indicated by arrow 64, using a front-end loader, for example.
Although a single-deck vibrating screen mechanism may be used in the assembly, FIG. 3 shows a two-deck mechanism having upper and lower screens 66 and 68. The two-deck mechanism has the advantage of providing a large screen area without occupying an excessive area on the platform 60. As a result, the upper end of the two-deck mechanism provides a large "target" for the loader operator to hit with the material, while the lower end funnels down to a comparatively small area on the carriage itself.
As can be seen, the upper and lower screens 66, 68 of the two-deck mechanism extend parallel to one another, at an outwardly sloped angle relative to the machine 50. The upper and lower screens are joined by a series of "C"-shaped springs 70, and a rotating shaft 72 is mounted to the upper screen 66. The shaft carries a plurality of bob weights 74, and is driven via belt 76 from a hydraulically powered pulley 78. Operation of shaft 72 thus causes the upper and lower screens to vibrate on springs 70. Moreover, a pivot connection 80 at one end of the screens and an adjustable leg 82 at the other allow the angle of the screens to be adjusted as needed, depending on the nature of the excavated material and other factors.
Materials below a predetermined size pass through the vibrating screen mechanism 62 (see also FIG. 4) and fall into the underlying hopper section 84, while larger pieces roll down the screens and are discarded in the direction indicated by arrow 90.
Because (unlike the prior-art padder described above) the apparatus 70 of the present invention is fed by a loader, the padding/bedding operation is not dependent on maintaining forward motion of the machine. In other words, the machine 70 can remain stationary if necessary, while fill material is brought to it by the loader. Moreover, the loader can avoid larger boulders and other objects in the excavated material which might otherwise interfere with the screen mechanism, and if necessary can bring additional material to the padding/bedding machine from areas away from trench itself.
The comparatively fine fill material passes through to the hopper section 84 is discharged through chute 92 onto the rearward end of a longitudinal conveyor 94. As can be seen in FIG. 4, the forward end of the longitudinal conveyor 94 is positioned just above the rearward end of a second, angled conveyor 96, so that fill material from the first conveyor is discharged onto the second conveyor and travels in a forward and inward direction, as indicated by arrow 98. To aid in controllable placement of the fill, the rearward end of the longitudinal conveyor is mounted for pivoting movement in the horizontal plane, as indicated at 99 in FIG. 3; moreover, the angle of the second conveyor 96 is somewhat parallel to the trench, rather than crosswise to the trench as in the prior art machines described above.
As can be seen in FIGS. 3 and 4, the second conveyor 96 is inclined upwardly and has its discharge end 100 positioned in vertical alignment above the open top of a swivel hopper 102. The comparatively large diameter of the upper end of the hopper allows a certain amount of shifting movement to take place between the hopper and its respective feed lines without the discharge ends of the feed lines moving out of register with the hopper. The lower chute portion 104 of hopper 102 is pivotally mounted to the upper portion so that the latter is able to rotate about a vertical axis.
The lower end of the chute portion 104 is mounted to and discharges into the rearward end of an auger trough 106, a shield panel 108 being mounted around the rearward end of the trough to prevent material from splashing over the edges in this area. A hydraulic motor 110 at the rearward end of the trough drives a horizontal mix auger 112 (see FIG. 4) which extends axially the full length of the trough. The mix auger is somewhat similar to an Archimedes' screw, and is driven by the motor so that the fill material is pushed in a generally longitudinal direction through the trough. The auger also preferably includes a plurality of short paddle members 114 which are mounted along the auger shaft intermediate the flights 116; the paddle members serve to break up clumps in the fill material, thereby ensuring more even mixing and also reducing wear on the auger screw.
Suitable sizes for the mix auger in the embodiment which is illustrated in FIGS. 3-4 may be approximately 12-16" in diameter and approximately 12' in length. After mixing in the auger trough, the fill material is discharged at the forward end thereof through a bottom opening 118, as indicated by arrow 120 in FIG. 3.
The connection to the pivoting hopper at its rearward end provides the auger trough with a pivot connection 121 which enables the trough to swing back and forth in a horizontal plane. The forward end of the auger trough, in turn, is supported from a knuckle-boom crane 122 which is mounted on a turntable 124 (see FIG. 4) for rotation about the vertical axis, and which includes an articulated arm 126 having extensible hydraulic cylinders 128, 130. Cranes of this general type are available from various manufacturers/suppliers of pipe laying equipment, including the Henry Machine Company noted above. It should also be noted that in instances when water and/or cement are not being added to the fill material, so that there is no need for mixing the components in the horizontal auger, the auger can simply be removed and the crane can be attached to the outer end of the forwardly-extending conveyor 96 for directing the discharge of material into the trench therefrom.
The auger trough is supported from the end 132 of the crane arm by a bridle 134 which accommodates changes in angular orientation between the two members. Moreover, as was noted above, the auger and feed conveyor are mounted to the chassis by pivot connections 99 and 121 which permit pivoting movement in the horizontal plane. Thus, by turning the crane back and forth and/or increasing/decreasing the effective length of the articulated arm, the operator is able to swing the discharge end of the auger trough through a horizontal arc to precisely controlled positions, as indicated by arrows 136a and 136b in FIG. 4.
This precise control, in combination with the direct, unobstructed line of sight looking down into the trench from the operator's station 58, enables the operator to accurately place the padding fill where this is needed to uniformly cover the pipeline 138 and develop the proper contour, as that indicated by 140 in FIG. 3.
As was noted above, the apparatus 50 also includes a system for adding a cement slurry component to the padding fill. As can be seen in FIG. 2, a silo 142 is included for holding a supply of cement dust; a suitable capacity for silo 142 is approximately 10,000 lbs. of cement dust. The dust is supplied to the assembly from an adjacent source, such as a truck or trailer (not shown), through a feed line 144 as indicated by arrow 146 in FIG. 3. The cement feed line discharges into a bag house 148 for dust control, and is fed therefrom to the top of silo 142 through a supply line 148.
A feed auger draws cement dust from the silo and discharges this through a line 150 which is mounted to the lower end of the silo, the other end 152 of the line being positioned to discharge the dust into the open upper end of the pivot hopper 182. A close tolerance, 61" diameter feed auger is suitable for the embodiment of apparatus which is shown in FIGS. 3-4.
The water component of the slurry, in turn, is provided from an adjacent source through water supply line 154, in the direction indicated by arrow 156 in FIG. 4. The end 158 of the water supply line also discharges into the open upper end of the pivot hopper 102, so that the water and cement dust combine with the flow of screened backfill material passing therethrough.
The screened fill, cement dust, and water pass vertically from hopper 102 through chute 104 and into the intake end of the auger trough 106. The rotation of the auger 112 thoroughly mixes the constituents and also moves them longitudinally through the trough, in the manner described above. Consequently, the cementitious slurry which forms the fill is thoroughly mixed by the time it is discharged through opening 118 into the trench.
Selective control of the water supply is provided by a valve mechanism (not shown), which is preferably operable from within the operator station 58; similarly, the rate of the cement dust feed can be controlled by means of a variable speed drive for the feed auger or other suitable mechanism, again preferably controlled from within the operator station. The water and cement supplies can be operated independently, so that water alone can be added in those instances where a flowable slurry is desired but a cementitious mix is not required.
The mixing can thus be performed in a consistent, efficient, and controllable manner on a continuous or periodic basis, as desired. Cementitious material may be added to replenish the silo as necessary, without affecting the mix ratio. This enables the machine to batch or produce continuously. For example, in an apparatus having the exemplary dimensions described above, mixing and batching can be controllably adjusted over a range from about 0-3 cubic yards per minute, with any desired slump. Moreover, if the filling operation must be interrupted for some reason, only the small amount of CLSM material which has already been mixed in the trough need be disposed of, rather than having to waste an entire truckload of ready-mix material as in the past.
It is to be recognized that various alterations, modifications, and/or additions may be introduced into the constructions and arrangements of parts described above without departing from the spirit or ambit of the present invention.
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An apparatus for depositing fill material over a pipeline. A wide-track carriage is provided for straddling the pipeline trench, and this includes a shaker screen mechanism for screening aggregate fill material, such as excavated native spoils. The screened fill material is fed into the trench via a pivoting conveyor which is controlled by means of a pivotable and extensible boom. A mix auger is also provided for mixing water and cement with the fill material to form a cementitious Controlled Low Strength Material fill in those installations where this is needed.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This is a continuation-in-part of Ser. No. 08/040,261, filed on Mar. 30, 1993, now U.S. Pat. No. 5,432,062, which is incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
The present invention relates to a method for controlled proteolysis. More particularly, the invention concerns a method for obtaining enzymes by the proteolytic cleavage of proenzymes or proforms of blood coagulation factors in the presence of a detergent or a chaotropic substance.
Methods for producing enzymes from proenzymes are known to those of skill in the art. As an illustration, thrombin can be obtained by isolating prothrombin from plasma, adsorbing prothrombin on a solid carrier, such as methacrylic and acrylic copolymers, and by treating the adsorbate with plasma-derived proteases and Ca 2+ ions to release thrombin from the adsorbate. See, for example EP-A-0 378 798.
While trypsin also can be used to cleave prothrombin, under standard conditions trypsin digestion may degrade prothrombin to fragments of low molecular weight, leading to a complete loss of thrombin activity. Biochim. Biophys. Act. 329: 221 (1973).
These methods provide various prothrombin cleavage products, depending upon particular protease and treatment conditions. Such cleavage products may be used for therapy (e.g. thrombin), for diagnosis, or for the production of specific antibodies against the protein fragments. Since all known cleavage methods lead to a plurality of fragments, the preparation of the cleavage product for therapy or diagnosis is very labor-intensive. A further disadvantage of these multi-stage and time-consuming purification methods is that they necessarily involve high losses of yield.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide an improved method for recovering enzymes or fragments from proteins.
It is a further object of this invention to provide a method for producing active blood coagulation factors.
These and other objects are achieved, in accordance with one embodiment of the present invention, by the provision of a method of proteolytically cleaving a proenzyme or proform of a blood coagulation factor comprising the step of incubating the proenzyme or proform with a protease in the presence of a detergent or a chaotropic substance, wherein the chaotropic substance is selected from the group consisting of urea, guanidinium hydrochloride and a thiocyanate, and wherein the protease treatment produces an active blood coagulation factor.
In addition, the present invention is directed to a method of proteolytically cleaving a proenzyme or proform of a blood coagulation factor, further comprising the step of immobilizing the proenzyme or proform on a solid carrier material prior to the incubation step. In such a method, the solid carrier material can be a slightly soluble salt or a chelate of a bivalent metal. A suitable bivalent metal is an alkaline earth metal.
The detergent used in these methods is selected from the group consisting of deoxycholate, dodecylsulfate, CHAPS, Brij® (polyethyleneglycolethers of lauryl-, cetyl-, stearyl- and oleyl-alcohols), Tween® (polyoxyethylene derivatives of sorbitanesters), Triton® (4-(1,1,3,3-tetramethylbuthyl) phenol) and Pluronic® (polyalkylenglycols based on ethylene and propylene oxide). Moreover, the protease is selected from the group consisting of trypsin, chymotrypsin, plasmin, kallikrein, dispase, endoproteinase Glu-C, endoproteinase Lys-C and endoproteinase Asp-N.
A suitable proenzyme or proform of a blood coagulation factor for the claimed methods is selected from the group consisting of Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII and protein C.
The present invention also is directed to a method of activating a blood coagulation factor, comprising the steps of:
(a) providing a solution containing a proenzyme or proform of a blood coagulation factor;
(b) contacting the proenzyme-containing solution with a solid carrier to immobilize the proenzyme or proform on the carrier;
(c) treating the immobilized proenzyme or proform with a protease in the presence of a detergent or a chaotropic substance to obtain a solution that contains active blood coagulation factor;
(d) separating the carrier from the solution of step (c);
(e) isolating active blood coagulation factor from the solution of step (d); and
(f) purifying the isolated active blood coagulation factor to homogeneity to obtain pure active blood coagulation factor.
A suitable proenzyme or proform of a blood coagulation factor for such a method is selected from the group consisting of Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII and protein C. Moreover, the solid carrier can be a slightly soluble salt or a chelate of a bivalent metal, such as an alkaline earth metal.
Such activation methods can be performed with a protease that is selected from the group consisting of trypsin, chymotrypsin, kallikrein, dispase, endoproteinase Glu-C, endoproteinase Lys-C and endoproteinase Asp-N. Furthermore, a suitable detergent is selected from the group consisting of deoxycholate, dodecylsulfate, CHAPS, Brij®, Tween®, Triton® and Pluronic®. In addition, the chaotropic substance is selected from the group consisting of urea, guanidinium hydrochloride and a thiocyanate.
The present invention is further directed to a method of producing a pharmaceutical composition containing an active blood coagulation factor, comprising the steps of:
(a) obtaining a purified preparation of active blood coagulation factor by the methods described above; and
(b) combining the active blood coagulation factor with a pharmaceutically acceptable vehicle.
The present invention also includes pharmaceutical compositions comprising purified active blood coagulation factor obtained by the above-described methods and a pharmaceutically acceptable vehicle.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows the effect of deoxycholate (DOC) on the yield of active thrombin.
FIG. 2 shows the fragment composition of a peptide digest produced by treatment of prothrombin with trypsin in the presence of deoxycholate.
FIG. 3 shows the effect of sodium dodecylsulfate on the activation of protein C by plasmin.
DETAILED DESCRIPTION
The methods described herein provide an improved approach for isolating certain fragments of proteins. These methods are particularly suited for preparing active blood coagulation factors from proenzymes or proform of a blood coagulation factor. Examples of blood coagulation factors that are proteolytically activated include prothrombin (Factor II), Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, Factor XIII and protein C. See, for example, Campbell et al., Phil. Trans. R. Soc. Lond. B. 332: 165 (1991), Hemker et al., Haemostasis 21: 189 (1991), and Kurachi, Biotechnology 19: 177 (1991). Although protein C plays an important role in the anticoagulant pathway, researchers have considered protein C to be a "coagulation factor." See, for example, Kurachi, supra. Accordingly, the term "blood coagulation factor," as used herein, includes protein C. In addition to such blood coagulation factors, the methods described herein can be used to prepare plasmin from plasminogen.
The present invention takes advantage of the discovery that the proteolytic cleavage of proteins, such as proenzymes or proforms, can be controlled if carried out in the presence of either a detergent or a chaotropic substance. As shown herein, the cleavage pattern of proteins varies according to the type and concentration of protease, detergent and chaotropic substance. This finding opens up the possibility of selecting the reaction environment such that only a few and precisely selected protein fragments are formed during proteolysis.
A plurality of proteases can be used to cleave proenzymes or proforms, including chymotrypsin, dispase, endopeptidase Arg-C, endoproteinase Lys-C, endoproteinase Glu-C, endoproteinase Asp-N, factor Xa, kallikrein, papain, pepsin, plasmin, pronase, proteinase K, staphylocoagulase, subtilisin, thrombin, trypsin (in particular, human, bovine, porcine), trypsin-like proteases from arthropods or microorganisms (e.g. Streptomyces griseus-trypsin), and serine-proteases from venomous snakes (such as Angkistrodon rhodostoma, Bothrops atrox, Dispholidus typus, Echis carinatus, Naja nigrocollis, Oxyuranus scutellatus scutellatus). Trypsin, chymotrypsin, kallikrein, dispase or the endoproteinase Glu-C, Lys-C or Asp-N, are preferably used as the protease. Such proteases can be isolated from natural sources or can be obtained by recombinant methodology.
In the presence of a detergent, a proenzyme can be cleaved so selectively that the desired enzyme product forms the dominant portion of the proteolytic digest. Suitable detergents include deoxycholate (DOC), dodecylsulfate (SDS), CHAPS and polyoxyethylene derivatives, such as Brij®, Tween®, Triton® and Pluronic®. DOC is a preferred detergent. In addition to controlling proteolysis, the presence of a detergent further facilitates the desorption of protein fragments from a solid carrier.
Suitable chaotropic substances include urea, guanidinium hydrochloride and thiocyanates. However, the chaotropic substance should not be a calcium salt if the substrate is a proenzyme or proform of the blood coagulation cascade. This is so because calcium salts are "coagulatively active" in the sense that they could activate the proenzymes. Accordingly, the inclusion of a calcium salt will cause a loss of control of proteolysis.
In a preferred variation of the present method, a proenzyme substrate is immobilized on a solid carrier material. This variation facilitates recovery of the active enzyme because the inactive portion of the proenzyme will remain adsorbed to the solid carrier, which can be separated from the reaction solution.
European patent application No. EP-A-0 378 798 describes a method in which copolymers are used as carriers for prothrombin.
As shown herein, it is possible to control the cleavage of a proenzyme that has been immobilized either on a solid carrier of a slightly soluble salt or as a chelate of a bivalent metal. Suitable salts include Ca 3 (PO 4 ) 2 , CaSO 4 , CaCo 3 , BaSO 4 , BaCO 3 or barium citrate. For example, such salts can be added to a prothrombin-containing solution, or they may be formed in situ by precipitation of the salt in a prothrombin-containing solution. Preferably, the bivalent metal is an alkaline earth metal.
A particular advantage of using bivalent ions for the carrier is that they selectively bind proenzymes or proforms of certain blood coagulation factors via a gamma-carboxy-glutamic acid terminus. For example, proteolytic activation of prothrombin results in the formation of thrombin and a protein fragment that contains the gamma-carboxy-glutamic acid terminus. Consequently, newly-formed thrombin can be easily separated from the protein fragment which remains adsorbed to the bivalent ions of the carrier. Other blood coagulation factors that have a gamma-carboxy-glutamic acid terminus include Factor VII, Factor IX, Factor X and protein C.
Additional suitable carriers include hydroxylapatite, a hydroxylapatite gel or a metal chelate-affinity chromatographic carrier loaded with a bivalent cation (e.g. Pharmacia Chelating Sepharose®). See, generally, Woodward (ed.), IMMOBILIZED CELLS AND ENZYMES: A PRACTICAL APPROACH (IRL Press 1985).
Following proteolysis, the desired product in the reaction supernatant can be subjected to further purification steps. For example, gel permeation chromatography or affinity chromatography can be used to concentrate and to isolate the protein product. Preferably, affinity chromatography is used to obtain concentrated samples of the desired product. Dye ligand affinity chromatographic carriers with ligands of the Cibacron®-Blue F3GA-type (produced by Ciba Geigy) or Procion®-Red HE-3B (produced by ICI) or related dyes have proved to be suitable.
Proteins may be adsorbed on the respective affinity matrix (e.g. Fractogel® TSK AF-Blue (produced by Merck), Blue-Sepharose® CL-6B (produced by Pharmacia) in the batch or in the packed column directly from the desorption supernatant after the solid phase activation step. Subsequently, protein fragments are separated from detergent by washing with a buffer, and the product is eluted with a highly molar (e.g. 1M) chaotropic substance (e.g. KSCN or NH 4 SCN).
The eluate may be freed from the chaotropic substance by gel permeation chromatography (e.g. via Sephadex® G25), diafiltration or dialysis. After reconstituting the protein product in a suitable buffer or a salt solution, the protein can be purified to homogeneity using well-known techniques such as reverse phase chromatography, affinity chromatography or gel permeation chromatography.
Examples 1-6 show that the method of the present invention can be used to obtain pure thrombin. Similarly, Example 7 demonstrates that pure, activated protein C can be prepared by the methods described herein. More generally, the present methods can be used to obtain purified, active blood coagulation factors for the preparation of pharmaceutical compositions.
Active blood coagulation factors can be formulated as pharmaceutical compositions according to known methods, whereby the purified, active factors are combined with a pharmaceutically acceptable vehicle. A composition is said to contain a "pharmaceutically acceptable vehicle" if its administration can be tolerated by a recipient patient. Sterile phosphate-buffered saline is one example of a pharmaceutically acceptable vehicle. Other suitable vehicles are well-known to those in the art. See, for example, REMINGTON'S PHARMACEUTICAL SCIENCES, 18th Ed. (1990).
For purposes of therapy, an active blood coagulation factor and a pharmaceutically acceptable vehicle are administered to a patient in a therapeutically effective amount. A pharmaceutical composition is said to be administered in a "therapeutically effective amount" if the amount administered is physiologically significant. An agent is physiologically significant if its presence results in a detectable change in the physiology of a recipient patient. In the present context, for example, a pharmaceutical composition comprising Factor V, Factor VII, Factor VIII, Factor IX, Factor X, Factor XI, Factor XII, or Factor XIII is physiologically significant if its presence enhances blood coagulation. In contrast, a pharmaceutical composition comprising protein C is physiologically significant if its presence inhibits blood coagulation.
A particular advantage of the presently described methods is that detergent treatment markedly inactivates any virus potentially present in a starting material that has been obtained from a virus-contaminated pool. In one case it was found that no vaccinia viruses were detectable in a thrombin preparation produced according to the method of the invention, although the starting material (a fermentation supernatant) had contained vaccinia. Those of skill in the art are aware that additional measures can be used to inactivate infectious agents in the starting material, such as vapor-heat treatment of a lyophilized product.
The present invention, thus generally described, will be understood more readily by reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present invention.
EXAMPLE 1
Effect of Detergent or Chaotropic Substance on the Tryptic Cleavage of Immobilized Prothrombin
In these studies, samples of prothrombin were incubated with trypsin in the absence or presence of a detergent or a chaotropic substance. A cell culture supernatant medium containing recombinant human prothrombin was obtained as described in international application No. WO 91/11519. To immobilize prothrombin, an aliquot of the medium was mixed with five grams of powdered Ca 3 (PO 4 ) 2 per 100 IU of prothrombin, and the mixture was slightly stirred at 4° C. for one hour. Subsequently, the solid phase of the mixture was pelleted by centrifuging at 5000 xg, the pellet was resuspended in 40 ml of 20 mM Tris-HCl buffer (pH 7.4), stirred for 10 minutes, and again the mixture was centrifuged at 5000 xg. This procedure was repeated once with Tris-HCl buffer that contained 40 ml of 5% (W/V) ammonium sulfate, and once again with 40 ml of Tris-HCl buffer without ammonium sulfate.
In the same manner, a partial prothrombin complex, e.g. a mixture of Factors II, IX and X, can be used as the prothrombin-containing starting material for preparing the immobilized prothrombin.
To determine the effect of chaotropic substances and detergents on the tryptic cleavage of prothrombin, the following four solutions were prepared:
Solution A: 20 mM Tris-HCl buffer (pH 8.3) with 0.5M urea,
Solution B: 20 mM Tris-HCl buffer (pH 8.3) with 0.05M sodium deoxycholate,
Solution C: 20 mM Tris-HCl buffer (pH 8.3) with 0.05M sodium dodecylsulfate, and
Solution D: 20 mM Tris-HCl buffer (pH 8.3).
Two hundred milligrams of buffer-moist, washed prothrombin-containing pellet were added to one milliliter of each of the four solutions. After adding 20 μl of 20 mM Tris-HCl buffer with 1 mg/ml trypsin, the mixtures were shaken at room temperature. Aliquots of each mixture were removed after one, two and three hours, the solid phase of each aliquot was pelleted by centrifugation, and the supernatants were examined for protein fragment composition by Western blot analysis. The results were measured by densitometric scans of Western blots.
Table 1 shows the peak area integrals of the protein fragment bands at 12, 19, 23, 25.5, 33, 35 and 44 kD. The fragments at 33 kD and at 35 kD correspond to thrombin, with the 33 kD form representing active thrombin. In contrast to the three-hour incubation in pure Tris-HCl buffer (i.e. solution D), all solutions with a detergent or a chaotropic substance contained a majority of protein fragments that were greater than 30 kD. Even after three hours of incubation with trypsin, active thrombin was the major component in the sample that contained sodium deoxycholate (i.e., solution B).
These results demonstrate that tryptic cleavage produced fragments of different sizes, and that the amount of the various fragments varies according to the presence of a detergent or chaotropic substance.
TABLE 1______________________________________Molecular Mass (kD) 12 19 23 25.5 33 35 44Solution Reaction time (h) Peak Area Integral:______________________________________A 1 26 19 22 14 94 95 2 22 20 13 54 20 3 24 27 14 51 17B 1 31 165 90 2 15 175 25 3 18 170C 1 53 11 2 35 2 3 9D 1 25 132 117 22 2 25 120 34 3 42 129______________________________________
EXAMPLE 2
Cleavage of Immobilized Prothrombin by Various Proteases in the Presence of a Detergent
An aliquot of a prothrombin-containing cell culture supernatant was treated with Ca 3 (PO 4 ) 2 , and immobilized prothrombin was washed with buffer.
Eight samples of 250 mg of buffer-moist adsorbate were each suspended in one milliliter of 20 mM Tris-HCl buffer (pH 8.3) containing 200 mM sodium deoxycholate. Fifty microliters of the following eight enzymes, dissolved in 20 mM Tris-HCl (pH 8.3) with 0.9% sodium chloride ("TBS"), were added to the one milliliter samples: 250 U/ml porcine pancreas kallikrein, 1 mg/ml Bacillus polymyxa dispase I, 350 U/ml bovine pancreas α-chymotrypsin, 0.76 mg/ml porcine pancreas trypsin, 1 mg/ml Staphylococcus aureus V8 endoproteinase Glu-C, 0.1 mg/ml Lysobacter enzymogenes endoproteinase Lys-C, 0.04 mg/ml Pseudomonas fragi endoproteinase Asp-N, and 20 U/ml human Factor Xa.
The mixtures were incubated at room temperature with shaking for two hours with the exception of the kallikrein-containing solution which was incubated for 20 hours. After incubation, aliquots of the mixtures were mixed (1:1) with sodium dodecylsulfate sample buffer and examined for protein fragment composition by Western blot analysis.
Table 2 shows the peak area integrals of the fragment bands at 12, 18, 19, 20, 23, 33, 34, 35, 44, 47, 50, 52, 54, 55, 71 and 75 kD. The results demonstrate that a series of fragments in the molecule mass range of 12 to 71 kD can be produced by digestion with the above-mentioned proteases. The fragment corresponding to active thrombin (33 kD) can be obtained in a particularly high yield by tryptic cleavage of prothrombin.
TABLE 2__________________________________________________________________________Molecular Mass(kD) 12 18 19 20 23 33 34 35 44 47 50 52 54 55 71 75Protease Peak Area Integral__________________________________________________________________________Kallikrein 12 31 15 16 16 59Dispase 36 27 8 39α-Chymotrypsin 7 57 9 18 44Trypsin 20 14 56Endoproteinase 13 28 39 17 13 17 78Glu-CEndoproteinase 6 51 21Lys-CEndoproteinase 21 83 11 11 19Asp-NFactor Xa 12 10 31 98__________________________________________________________________________
EXAMPLE 3
Cleavage of Immobilized Prothrombin in the Presence of Various Concentrations of Deoxycholate
A pellet containing recombinant prothrombin immobilized on Ca 3 (PO 4 ) 2 was obtained from a prothrombin-containing cell culture, as described above. Five 0.6 gram samples of moist adsorbate were suspended in 3 ml of 20 mM Tris-HCl buffer (pH 8.3) containing 50 mM, 100 mM, 250 mM, 350 mM or 500 mM sodium deoxycholate. Sixty microliter aliquots of 0.76 mg/ml trypsin were added to each sample, and the mixtures were incubated for three hours at room temperature with shaking. After incubation, the buffers of the samples were changed against 0.9% NaCl.
Samples were examined for thrombin activity using normal plasma in a coagulation test and in an amidolytic assay. Amidolytic activity was determined photometrically with the chromogenic substrate TH-1 (2 AcOH.-D-CHG-ala-arg-p-nitroanilide) against an international thrombin standard. FIG. 1 shows that the maximum yield of active thrombin (i.e., 33 kD-fragment) was obtained with 350 mM sodium deoxycholate. Active thrombin was not further degraded by trypsin during an incubation of at least 20 hours.
EXAMPLE 4
Purification of Protein Fragments of Cleaved Prothrombin
One and one-half milliliters of the prothrombin fragment-containing solution obtained in Example 3 were adsorbed with 0.1% trifluoroacetic acid in water (solvent A) on a reverse phase HPLC column (Nucleosil 100-5C18, 125×4 mm; flow rate: 1.7 ml/min). Protein fragments were eluted from the column with 0.1% trifluoroacetic acid in acetonitrile (solvent B) with a linear gradient of 30% to 70% acetonitrile over 30 minutes at a flow rate of 1.7 ml/min. Six main peaks were detected at 220 nm (retention times: 10.01 minutes; 11.96 minutes; 12.68 minutes; 13.47 minutes; 13.94 minutes; 14.47 minutes). The peaks were collected separately and lyophilized. The protein fragments were analyzed using SDS-PAGE with Coomassie staining, as well as by Western blot analysis with a polyclonal rabbit-anti-human prothrombin-antiserum. The molecular masses of the fragments in the six main peaks were determined to be 9 kD, 16 kD, 21 kD, 23 kD, 12 kD and 33 kD.
EXAMPLE 5
Recovery of Thrombin
Approximately 10 gm of a buffer-moist, prothrombin-containing pellet were resuspended in 50 ml of 0.76 mg/ml porcine trypsin (Sigma T-0134) in 20 mM Tris-HCl buffer (pH 8.3) which contained 200 mM sodium deoxycholate. The suspension was incubated for one hour at room temperature with slight stirring. After incubation, calcium phosphate was separated by centrifugation. The supernatant was found to contain primarily thrombin and a few other prothrombin fragments.
Thrombin was purified from the supernatant using column chromatography. A column having a cross-sectional area of 8 cm 2 was packed with Fractogel® TSK-AF Blue (Merck) at a height of 12 mm (gel volume˜9.6 ml) in 20 mM Tris-HCl buffer (pH 8.3) and washed with the same buffer. These and all subsequent steps were performed at 4° C.
The thrombin-containing supernatant (approximately 50 ml) was pumped over the gel at a flow rate of 2 ml/min to effect adsorption. Thereafter, nonspecifically bound prothrombin fragments were eluted with 20 ml of 0.5M sodium chloride solution, 40 ml of 1.0M sodium chloride solution and 20 ml of 20 mM Tris-HCl buffer (pH 7.4) at a flow rate of 6 ml/min. In reverse flow direction, prothrombin fragments were then eluted at 1 ml/min with 20 mM Tris-HCl buffer which contained 1M KSCN. The eluate was photometrically measured at 280 nm with a flow cell, and a total of 15 ml was collected.
The protein content of the eluate was 188 mg/ml according to the method of Bradford. FIG. 2 shows the fragment composition, as determined by densitometric scan of a Western blot. About 30% of recovered protein was thrombin, and the dominant portion was the 33 kD fragment of active thrombin. The thrombin had a specific activity of approximately 2200 IU/mg protein, as determined by a thrombin time assay. Thus, approximately 100 IU of thrombin were obtained from 1 IU of prothrombin by tryptic solid phase activation.
The thrombin-containing solution obtained by the present methods can be further purified in a known manner, concentrated and processed to a pharmaceutical composition.
EXAMPLE 6
Cleavage of Dissolved Prothrombin
Two 1 ml samples of a prothrombin-containing fermentation supernatant were mixed with 1 ml of 40 mM Tris-HCl buffer (pH 8.3) which contained either 0.1M sodium deoxycholate or 0.1M sodium dodecylsulfate. The final concentration of either detergent was 0.05M. For comparison, a third 1 ml sample of prothrombin-containing fermentation supernatant was mixed with 40 mM Tris-HCl buffer that did not contain a detergent. Fifteen milliliters of a solution containing 1 mg trypsin/ml in 20 mM Tris-HCl buffer (pH 8.3) with 0.9% NaCl were added to each sample, and the mixtures were incubated at room temperature for four hours with shaking.
After one, two, three and four hours, 50 μl aliquots of each sample were diluted with Laemmli buffer (1:1), boiled and fractionated using a 12% sodium dodecylsulfate-polyacrylamide gel. Western blot analysis was performed using anti-human-factor II rabbit serum as the first antibody and goat-anti-rabbit IgG peroxidase conjugate as the second antibody. Western blots were developed with 4-chloro-1-naphthol, and densitometrically examined in the impinging light. The results are shown in Table 3.
TABLE 3______________________________________Molecular mass (kD) 19 25.5 33 35 ReactionAddition Time (h) Peak Area Integral______________________________________Deoxycholate 1 10 2 9 3 7 4 6Dodecylsulfate 1 8 68 2 6 67 3 5 69 4 4 67Blank Value 1 4 9 4 2 3 1 0 3 0 0 0______________________________________
EXAMPLE 7
Activation of Protein C
The activation of human protein C by the proteolytic enzyme, plasmin, is difficult to control. See, for example, Bajaj et al., Prep. Biochem. 13: 191 (1983). Plasmin initially activates, and then, degrades protein C. An experiment was performed to determined whether the activation process could be controlled with detergent.
In this study, a solution of protein C was prepared at a concentration of 9 U/ml in 20 mM Tris-buffered saline (pH 7.35). After adding plasmin to a final concentration of 1.25 nM, the mixture was incubated at 37° C. Samples were removed from the incubation mixture at various times and were diluted ten-fold with 20 mM Tris-buffered saline (pH 7.35).
The extent of plasmin-induced activation of protein C was determined by measuring the prolongation of clotting time in the activated partial thromboplastin time (APTT) assay of Dahlback et al., Proc. Nat'l Acad. Sci. USA 90: 1004 (1993). Briefly, 50 μl of APTT reagent (APTT-Automated or Platelin LS Organon Tecknika!) was incubated with an equal volume of normal human plasma for five minutes at 37° C. The coagulation reaction was initiated by the addition of 100 μl of a mixture containing 50 μl of 10 mM Tris-HCl, 50 mM NaCl, 30 mM CaCl 2 (pH 7.5) and 50 μl of test sample. Incubations were performed either in the absence or in the presence of 0.1M sodium dodecylsulfate. The anticoagulant activity of activated protein C was determined by the extent of prolongation of APTT in relation to the starting level.
As shown in FIG. 3, treatment of protein C with plasmin in the absence of sodium dodecylsulfate resulted in an initial activation of protein C, followed by inactivation of protein C after 30 minutes. In contrast, samples incubated in the presence of sodium dodecylsulfate contained anticoagulant activity even after a 60 minute incubation. Thus, the methods described herein can be used to control the activation of protein C.
Although the foregoing refers to particular preferred embodiments, it will be understood that the present invention is not so limited. It will occur to those of ordinary skill in the art that various modifications may be made to the disclosed embodiments and that such modifications are intended to be within the scope of the present invention, which is defined by the following claims.
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Proenzymes or proforms of blood factors can be cleaved in the presence of a detergent or a chaotropic substance to produce active blood factors selected from the group consisting of Factor Va, Factor VIIa, Factor VIIIa, Factor IXa, Factor Xa, Factor XIa, Factor XIIa, Factor XIIIa and activated protein C. The chaotropic substance can be urea, guanidinium hydrochloride or a thiocyanate salt. Under these conditions, proteolytic activation occurs in a controlled and restricted manner. Consequently, it is possible to isolate high yields of active blood factor, while minimizing the production of inactive degradation products. Immobilization of the proenzyme or proform on a solid support prior to activation facilitates the separation of active blood factor from the proenzyme or proform and inactive peptide fragments.
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BACKGROUND OF THE INVENTION
Among the known herbicides there are included 1-(1,3,4-thiadiazol-2-yl)-urea derivatives, which are disclosed in Germans DT-PS Nos. 1,816,696 and 2,118,520. However, these herbicides exhibit only a very limited selectivity spectrum toward cultivated plants.
The object of the present invention is therefore the provision of herbicidal agents which will exhibit excellent activity against weeds, and at the same time a broad selectivity spectrum toward cultivated plants.
GENERAL DESCRIPTION OF THE INVENTION
The present invention concerns novel 2-(dimethylcarbamoyl-imino)-1,3,4-thiadiazolin-3-carboxylic acid esters, methods for their preparation, and herbicidal compositions containing these compounds.
The objects are achieved, in accordance with the invention, by a novel herbicidal agent which is broadly a compound of the formula: ##STR2## in which R and R 1 are aliphatic hydrocarbon groups which can, if desired, be halogenated, and n is 0, 1 or 2.
The compounds of the invention are characterized by a broad herbicidal activity against per-emerged portions of leaves of weeds. They can be applied to the destruction of mono- and dicotylodenous weeds.
By their use, weeds occurring in fields in cultivation, both in pre-emergence and post-emergence stages may be destroyed, such weeds including Sinapis ssp., stellaria media, Senecio vulgaris, Matricaria chamomilla, Ipomoea purpurea, Chrysanthemum segetum, Lamium amplexicaule, Centaurea cyanus, Amaranthus retroflexus, Alopecurus myosuroides, Echinchloa crus galli, Setaria italica, Sorghum halepense, Lolium perenne, and many others.
For the control of seminal weeds there are applied amounts ranging from about 1 kg per hectare to about 5 kg per hectare of active agent. In this way there is achieved the aforementioned selective activity toward useful plants, such as potatoes, corn, peanuts, soybeans, peas and other legumes, wheat, barley, sorghum (seed) as well as copse, ornamental shrubbery, and nursery crops.
In larger applications, the compounds of the invention are suitable as complete herbicides for the destruction or suppression of desert plants during a vegetation period.
The agents of the invention can be applied either alone or in admixture with one or more other agents. If desired other plant protecting or pesticidal agents, such as, for example, fungicides, nematocides, and similar agents, depending upon the objective desired, can be added. The addition of fertilizers is also possible.
From the standpoint of broadening the action spectrum, other herbicides can also be added. For example, herbicides which are suitable as active partners include triazines, aminotriazoles, anilides, diazines, uracils, aliphatic carboxylic acids and halogenated carboxylic acids, halogenated benzoic acids, and the hydrazides, amides, nitriles, and esters of these acids, carbamide and thiocarbamide acid esters, ureas, 3,2,6-trichlorobenzyloxypropanol, agents containing thiocyanate groups, and the like. There may also be added other materials, such as non-phytotoxic additives which may provide a synergistic action with the herbicides, including wetting agents, emulsifiers, solvents and oils.
The agents of the invention or their admixtures may be applied in the form of preparations, such as powders, dusts, granules, solutions, emulsions or suspensions, with addition of liquid and/or solid carriers or diluents, and if desired in connection with wetting agents, adhesives, emulsifiers and/or dispersing agents.
Especially suitable as liquid carriers are water, aliphatic and aromatic hydrocarbons, such as benzene, toluene, xylene, cyclohexanone, isophorone, dimethyl sulfoxide, dimethyl formamide, and mineral oil fractions.
As solid carriers there are suitable, mineral earths, such as tonsil, silica gel, talc, kaolin, attaclay, limestone, silica acid, and vegetable products such as flour.
As surface-active agents there can be employed, for example, calcium ligninsulfonate, polyoxyethylene-alkylphenyl ethers, naphthalenesulfonic acids and their salts, phenolsulfonic acids and their salts, formaldehyde condensates, fatty alcohol sulfates, and benzenesulfonic acids and their salts.
The content of the active herbicides of the invention in the foregoing preparations can vary over a wide range. For example, the herbicidal preparations contain from about 10% to about 80% by weight of active ingredient, and from about 90% to about 20% by weight of liquid or solid carrier, as well as, if desired, up to 20% by weight of a surface-active agent.
The application of the herbicides can be made in conventional ways, for example as a spray with water as the carrier, in amounts from about 100 to about 1000 liters per hectare. The products may be used in so-called "low volume" and "ultra-low-volume" processes, as well as in the form of so-called microgranules.
Compounds according to the invention which exhibit an especially favorable activity are those having the aforementioned general formula, wherein R is an alkyl, alkenyl or alkinyl group, each having 1 to 6 carbon atoms; R 1 is a halogenated alkyl, alkenyl or alkinyl group, each having 1 to 6 carbon atoms; and n signifies the numerals 0, 1 or 2.
Examples of the alkyl, alkenyl and alkinyl groups as defined for R include: methyl, ethyl, propyl, isopropyl, allyl, 2-propinyl, butyl, isobutyl, sec.-butyl, tert,-butyl, 2-butenyl, 2-methyl-2-propenyl, n-pentyl, isopentyl, neopentyl, tert.-pentyl, 1-methylbutyl, 1-ethylpropyl, hexyl, isohexyl and the like.
As examples of R 1 there are included: methyl, ethyl, 2,2,2-trichloroethyl, propyl, isopropyl, allyl, 2-propinyl, 3-chloropropyl, n-butyl, isobutyl, sec.-butyl, 2-butenyl, tert.-butyl, pentyl, isopentyl, n-hexyl, and the like.
The novel compounds of the invention can be advantageously prepared, for example, by
(a) reacting metal compounds of the general formula: ##STR3## with haloformic acid esters of the general formula;
Hal--CO--O--R.sub.1
or (b) by reacting compounds of the general formula: ##STR4## with a haloformic acid ester of the general formula:
Hal--CO--O--R.sub.1
in the presence of an acid-binding agent; or
(c) by treating a compound of the general formula: ##STR5## with an oxidizing agent.
In these foregoing reactions, R, R 1 and n have the meaning given above, Hal is a halogen atom, such as chlorine or bromine, and B is a monovalent metal equivalent, for example, lithium, sodium, potassium cations.
The reactions are performed at temperatures in the range of 0° to 120° C., but generally at room temperature. For the synthesis of the compounds of the invention, the reactants are used in approximately equimolecular amounts. As reaction media there are suited polar organic solvents, alone or in admixture with water. Their choice depends upon the metal compounds or the acid binding agents used. As solvents or suspensions media there may be employed acid amides such as dimethylformamide, acid nitriles such as acetonitrile, ethers such as dioxan, ketones such as acetone, and many others.
As acid binding agents there can be employed the usual agents for this purpose. For this purpose there are suited organic bases such as tertiary amines, for example triethylamine or N,N-dimethylaniline, pyridine bases or suitable inorganic bases such as oxides, hydroxides, carbonates, and alkanoic acid salts of the alkali or alkaline earth metals, such as those of sodium, potassium and calcium.
Bases such as pyridine can serve simultaneously as solvents.
As oxidizing agents there may be employed suitable inorganic or organic substances. For the preparation of the compounds of the present invention, when n=1, the oxidizing agents can be organic hydroperoxides, such as, for example, tert.-butyl hydroperoxide or per-acids, such as, for example, m-chloroperbenzoic acid, or N-halogenic acid amides, such as, for example, N-bromosuccinimide, or inorganic compounds such as, for example, hydrogen peroxide, sodium periodate and the like.
There are added two oxidation equivalents of the oxidizing agent or a small excess, to 1 mol of the thio-compound at temperatures between about 0° and about 60° C.
For the preparation of the compounds of the invention where n is 2, there can be employed besides the oxidizing agents already mentioned, inorganic agents such as potassium permanganate or chromic acid and their salts, or nitric acid or halogens, within a temperature range of about 0° to about 120° C. For 1 mol of thio-compound there are employed analogously, 4 oxidation equivalents or an excess, but at least double the amount with the above described sulfo-oxidation where n is 1.
There may be employed for this purpose, as oxidation media, organic solvents, such as carboxylic acids, for example acetic or formic acid, ethers, for example dioxan, ketones such as acetone, acid amides such as dimethylformamide, carboxylic acid nitriles, such as acetonitrile, or other solvents which are inert toward the above-named oxidizing agents, and these alone or in admixture with water.
The isolation of the produced compounds of the invention takes place either by distilling off the solvent or by precipitation with water.
The starting materials for the preparation of the novel compounds of the invention are generally known compounds.
Those metal compounds not heretofore described in the literature, can be prepared, for example,
(a) by reacting dimethylcarbamoyl chloride of the formula: ##STR6## with 1,3,4-thiadiazolylamides of the formula: ##STR7## in presence of acid binding agents, to form 2-(dimethylcarbamoylimino)-1,3,4-thiadiazolin-3-carboxylic acid dimethylamino derivatives of the general formula: ##STR8## and then reacting this with a metal compound of the formula:
BY (V)
(b) or by reacting a 1-(1,3,4-thiadiazolyl-2-yl)-3,3-dimethylurea derivative of the general formula: ##STR9## with a metal compound of the general formula:
BY (V)
if necessary with use of a solvent, wherein R, B and n have the aforesaid meanings, and Y is hydrogen, hydroxy, lower alkoxy or amino.
For the synthesis of the compounds according to the invention the reactants are brought together in approximately equimolar amounts. As reaction media there may be used polar organic liquids, alone or in admixture with water. The choice depends upon the type of metal compound BY which is employed. As solvents or suspension media there may be employed acid amides such as dimethylformamide, acid nitriles such as acetonitrile, alcohols such as methanol or ethanol, ethers such as tetrahydrofuran, and the like.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The following examples serve to illustrate the practice of the invention, but are not to be regarded as limiting.
EXAMPLE 1
80.5 g of 2-(dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazol-3-id, sodium salt, were suspended in 300 ml of acetonitrile and treated dropwise with stirring with 36.5 g of ethyl chloroformate at room temperature. The mixture was further stirred for 2 hours, treated with ice water, the precipitated substance separated by suction filtration, and recrystallized from acetonitrile. There is obtained 84.5 g (86.9% of theory) of 2-(dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid ethyl ester of m. pt. 129° C.
Analysis: Calculated: C 37.23%; H 4.86%; N 19.30%. Found: C 37.27%; H 4.87%; N 19.16%.
EXAMPLE 2
To a solution of 10.9 g of 1,1-dimethyl-3-(5-methylthio-1,3,4-thiadiazol-2-yl)-urea in 50 ml pyridine there were added dropwise with stirring 11 g of methyl chloroformate, whereupon the temperature of the reaction mixture rose to 50° C. After further stirring for one-half hour the reaction product is precipitated by addition of 300 ml water, filtered by suction, washed with water, and recrystallized from ethanol.
Yield: 11.5 g (83.4% of theory) of 2-(dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid methyl ester.
M. pt. 142° C.
Analysis: Calculated: C 34.77%; H 4.38%. Found: C 35.12%; H 4.90%.
EXAMPLE 3
33.2 g of 2(dimethylcarbamoylimino)-5-propylthio-1,3,4-thiadiazolin-3-carboxylic acid isopropyl ester were dissolved in 100 ml glacial acetic acid and 40 ml water. To this solution there is added, at 40° C., 22 g of potassium permangamate, in portions, followed by stirring for 30 minutes and final reduction of the mixture, cooled to 50° C., of precipitated manganese dioxide, by dropwise addition of a solution of 20 g sodium metabisulfite in 200 ml water.
The precipitated substance is precipitated by addition of 500 ml ice water, filtered by suction, washed with water and recrystallized from ethanol. Yield: 30.0 g (82.5% of theory) of 2-(dimethylcarbamoylimino)-5-propylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid isopropyl ester.
M. pt. 127° C.
Analysis: Calculated: C 39.55%; H 5.53%; N 15.37%. Found: C 39.43%; H 5.76%; N 15.35%.
In analogous manner, the compounds shown in Table 1 may be prepared, in accordance with the invention:
Table 1______________________________________Name Physical Constants______________________________________2-(Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-methylester M. pt. 178° C.5-Ethylthio-2-(dimethylcarbamoyl-imino)-1,3,4-thiadiazolin-3-carboxylic acid-methylester M. pt. 126° C.5-Ethylsulfonyl-2-(dimethylcarbamoyl-imino)-1,3,4-thiadiazolin-3-carboxylicacid-methylester M. pt. 144° C.2-(Dimethylcarbamoylimino)-5-propyl-thio, 1,3,4-thiadiazolin-3-carboxylic acid-methylester M. pt. 79° C.5-Ethylthio-2-(dimethylcarbamoyl-imino)-1,3,4-thiadiazolin-3-carboxylic acid-ethylester M. pt. 89° C.5-Ethylsulfonyl-2-(dimethylcarbamoyl-imino)-1,3,4-thiadiazolin-3-carboxylic acid-ethylester M. pt. 130° C.2-(Dimethylcarbamoylimino)-5-methyl-sulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-ethylester M. pt. 149° C.2-(Dimethylcarbamoylimino)-5-propyl-thio, 1,3,4-thiadiazolin-3-carboxylic acid-isopropylester M. pt. 67° C.2-(Dimethylcarbamoylimino)-5-propylthio-1,3,4-thiadiazolin-3-carboxylic acid-pentylester M. pt. 68° C.2-(Dimethylcarbamoylimino)-5-propyl-sulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-pentylester M. pt. 106° C.2-Dimethylcarbamoylimino)-5-propyl-thio-1,3,4-thiadiazolin-3-carboxylicacid-(3-chlorpropyl)-ester M. pt. 77° C.2-(Dimethylcarbamoylimino)-5-methyl-thio-1,3,4-thiadiazolin-3-carboxylic acid-isopropylester M. pt. 97° C.5-Ethylthio-2-(dimethylcarbamoylimino)-1,3,4-thiadiazolin-3 carboxylicacid-isopropylester M. pt. 87° C.2-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylicacid-isobutylester M. pt. 92° C.2-(Dimethylcarbamoylimino)-5-methyl-sulfonyl-1,3,4-thiadiazolin-3-carboxylicacid-isobutylester M. pt. 125° C.2-(Dimethylcarbamoylimino)-5-methyl-sulfonyl-1,3,4-thiadiazolin-3-carboxylicacid-isopropylester M. pt. 135° C.5-Ethylsulfonyl-2-(dimethylcarbamoyl-imino)-1,3,4-thiadiazolin-3-carboxylicacid-isopropylester M. pt. 133° C.5-Ethylthio-2-(dimethylcarbamoylimino)-1,3,4-thiadiazolin-3-carboxylicacid-pentylester M. pt. 70° C.2-(Dimethylcarbamoylimino)-5-(2-propenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-methylester M. pt. 72° C.2-(Dimethylcarbamoylimino)-5-iso-propylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester M. pt. 64° C.2-(Dimethylcarbamoylimino)-5-methyl-thio-1,3,4-thiadiazolin-3-carboxylicacid-butylester M. pt. 125° C.2-(Dimethylcarbamoylimino)-5-methyl-thio-1,3,4-thiadiazolin-3-carboxylicacid-(2-propenyl)-ester M. pt. 101° C.2-(Dimethylcarbamoylimino)-5-iso-propylthio-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 54° C.2-(Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 137° C.2-(Dimethylcarbamoylimino)-5-methyl-thio-1,3,4-thiadiazolin-3-carboxylicacid-pentylester M. pt. 97° C.2-(Dimethylcarbamoylimino)-5-isopropyl-sulfonyl-1,3,4-thiadiazolin-3-carboxylicacid-butylester M. pt. 104° C.2-(Dimethylcarbamoylimino)-5-methyl-sulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester M. pt. 113° C.2-(Dimethylcarbamoylimino)-5-iso-propylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester M. pt. 125° C.2-(Dimethylcarbamoylimino)-5-methyl-sulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-pentylester M. pt. 106° C.2-(Dimethylcarbamoylimino)-5-iso-propylthio-1,3,4-thiadiazolin-3-carboxylic acid-pentylester M. pt. 63° C.2-(Dimethylcarbamoylimino)-5-iso-butylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester M. pt. 55° C.2-(Dimethylcarbamoylimino)-5-iso-butylthio-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 51° C.2-(Dimethylcarbamoylimino)-5-pentyl-thio-1,3,4-thiadiazolin-3-carboxylicacid-methylester M. pt. 101° C.2-(Dimethylcarbamoylimino)-5-hexyl-sulfinyl-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 83° C.2-(Dimethylcarbamoylimino)-5-(2-propenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 59° C.2-(Dimethylcarbamoylimino)-5-(2-butenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 58° C.2-(Dimethylcarbamoylimino)-5-(2-butenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-methylester M. pt. 96° C.2-(Dimethylcarbamoylimino)-5-(2-butenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester M. pt. 59° C.2-(Dimethylcarbamoylimino)-5-hexyl-thio-1,3,4-thiadiazolin-3-carboxylicacid-methylester M. pt. 86° C.2-(Dimethylcarbamoylimino)-5-hexylthio-1,3,4-thiadiazolin-3-carboxylicacid-ethylester M. pt. 62° C.2-(Dimethylcarbamoylimino)-5-hexyl-thio-1,3,4-thiadiazolin-3-carboxylicacid-isopropylester M. pt. 56° C.2-(Dimethylcarbamoylimino)-5-hexyl-thio-1,3,4-thiadiazolin-3-carboxylicacid-propylester M. pt. 55° C.2-(Dimethylcarbamoylimino)-5-hexyl-thio-1,3,4-thiadiazolin-3-carboxylicacid-isobutylester M. pt. 60° C.2-(Dimethylcarbamoylimino)-5-hexyl-thio-1,3,4-thiadiazolin-3-carboxylicacid-butylester M. pt. 70° C.2-(Dimethylcarbamoylimino)-5-iso-propylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-pentylester M. pt. 91° C.2-(Dimethylcarbamoylimino)-5-iso-butylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 64° C.2-(Dimethylcarbamoylimino)-5-iso-butylsulfonyl-1,3,4-thiadiazolin-5-carboxylic acid(2-propenyl)-ester M. pt. 94° C.2-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-ethylester M. pt. 74° C.2-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-isopropylester M. pt. 70° C.2-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-isobutylester M. pt. 91° C.2-(Dimethylcarbamoylimino)-5-isobutylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propinyl)-ester M. pt. 103° C.5-Ethylthio-2-(dimethylcarbamoyl-imino)-1,3,4-thiadiazolin-3-carboxylic acid-(2-propinyl)-ester M. pt. 111° C.5-Ethylsulfonyl-2-dimethyl-carbamoylimino)-1,3,4-thiadiazolin-3 carboxylic acid-benzylester M. pt. 117° C.5-Butylsulfonyl-2-(dimethyl-carbamoylimino)-1,3,4-thiadiazolin-3 carboxylic acid-butylester M. pt. 74° C.2-(Dimethylcarbamoylimino)-5-(2-propinylthio)-1,3,4-thiadiazolin-3 carboxylic acid-methylester M. pt. 101° C.2-(Dimethylcarbamoylimino)-5-pentylthio-1,3,4-thiadiazolin-3-carboxylic acid-benzylester M. pt. 82° C.2-(Dimethylcarbamoylimino)-5-isobutylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-(2-propinyl)-ester M. pt. 146° C.5-Ethylsulfonyl-2-(dimethylcarbamoyl-imino)-1,3,4-thiadiazolin-3-carboxylicacid-(2-propinyl)-ester M. pt. 156° C.2-(Dimethylcarbamoylimino)-5-pentylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-(2-propinyl)-ester M. pt. 148° C.2-(Dimethylcarbamoylimino)-5-pentylthio-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 48° C.2-(Dimethylcarbamoylimino)-5-(2-methyl-2-propenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-ethylester M. pt. 65° C.2-(Dimethylcarbamoylimino)-5-(2-methyl-2-propenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-propylester M. pt. 54° C.2-(Dimethylcarbamoylimino)-5-(2-methyl-2-propenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 47° C.2-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester M. pt. 145° C.2-(Dimethylcarbamoylimino)-5-(2-methyl-2-propenylsulfonyl)-1,3,4-thiadiazolin-3-carboxylicacid-ethylester M. pt. 126° C.2-(Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-(2-propinyl)-ester M. pt. 155° C.2-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-2,2,2-trichlor-ethylester M. pt. 120° C.2(Dimethylcarbamoylimino)-5-ethylthio-1,3,4-thiadiazolin-3-carboxylic acid-benzylester M. pt. 89° C.2-(Dimethylcarbamoylimino)-5-isopropylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propinyl)-ester M. pt. 117° C.2-(Dimethylcarbamoylimino)-5-butylthio-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 61° C.2-(Dimethylcarbamoylimino)-5-butylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester M. pt. 43° C.2-(Dimethylcarbamoylimino)-5-butylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester M. pt. 96° C.2-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-butylester M. pt. 80° C.2-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,5-thiadiazolin-3-carboxylic acid-propylester M. pt. 66° C.2-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-phenylester M. pt. 142° C.2-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-hexylester M. pt. 94° C.2-(Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-hexylester M. pt. 101° C.2-(Dimethylcarbamoylimino)-5-(2-methyl-2-propenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-methylester M. pt. 91° C.______________________________________
The compounds according to the invention form colorless and odorless crystalline substances, which are slightly soluble in water, but which dissolves well in organic solvents such as hydrocarbons, halogenated hydrocarbons, ethers, ketones, alcohols, carboxylic acids, esters, carboxylic acid amides and carboxylic acid nitriles.
In the following Examples there is described the preparation of useful metal compounds from the starting compounds:
EXAMPLE 4
To a suspension of 30.3 g of 5-ethylthio-2-(dimethylcarbamoylimino)-1,3,4-thiadiazolin-3-carboxylic acid dimethylamide (m.pt. 91° C.) in 200 ml methanol there are added dropwise, with stirring, at room temperature, 6.68 g. of 85% potassium hydroxide dissolved in 100 ml methanol. After standing overnight the reaction mixture is dried in vacuo, the residue digested twice with isopropanol and dried in vacuo.
Yield: 25.2 g (93.4% of theory) of 5-ethylthio-2-(dimethylcarbamoylimino)-1,3,4-thiadiazolin-3-id, potassium salt. M. pt. 250° C.
Analysis: Calculated: C 31.09%; H 4.10%; N 20.72%; K 14.46%. Found: C 30.89%; H 4.31%; N 20.43%; K 14.72%.
The following examples serve to illustrate the utility of the compounds according to the invention:
EXAMPLE 5
The compounds set forth in the following tables were applied in the greenhouse in an amount of 5 kg per hectare, suspended in 500 liters of water per hectare, to sugar beets and tomatoes as test plants, by spraying before and after emergence. Three weeks after treatment, the results were rated on a scale according to which 0=no action and 4=destruction of the plant. As can be seen from Table 2, in general, no destruction of the test plants occurred.
Table 2__________________________________________________________________________Compound of the Pre-emergence Post-emergenceInvention Sugar Beet Tomato Sugar Beet Tomato__________________________________________________________________________2-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadia-zolin-3-carboxylic acid-methyl-ester 4 4 4 45-Ethylthio-2-(dimethylcarba-moylimino)-1,3,4-thiadia-zolin-3-carboxylic acid-methylester 4 4 4 42-(Dimethylcarbamoylimino)-5-propylthio-1,3,4-thiadia-zolin-3-carboxylic acid-methylester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadia-zolin-3-carboxylic acid-ethylester 4 4 4 45-(Ethylthio-2-dimethyl-carbamoylimino)-1,3,4-thiadiazolin-3-carboxylicacid-ethyl-ester 4 4 4 42-Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thiadiazolin-3-carboxylicacid-methyl-ester 4 4 4 45-Ethylsulfonyl-2-(di-methyl-carbamoylimino)-1,3,4-thiadiazolin-3-carboxylic acid-methyl-ester 4 4 4 45-Ethylsulfonyl-2-(di-methyl-carbamoylimino)-1,3,4-thiadiazolin-3-carboxylic acid-ethyl-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-ethyl-ester 4 4 4 42-(Dimethylcarbamoylimino)-imino)-5-propylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-isopro-pyl-ester 4 4 4 42-(Dimethylcarbamoyl-imino)-5-propyl-sulfonyl-1,3,4-thia-diazolin-3-carboxylicacid-pentyl-ester 4 4 4 42-(Dimethylcarbamoyl-imino)-5-propylthio-1,3,4-thiadiazolin-3-carboxylic acid-isopro-pylester 4 4 4 42-(Dimethylcarbamoyl-imino)-5-propylthio-1,3,4-thiadiazolin-3-carboxylic acid-penty-lester 4 4 4 42-(Dimethylcarbamoyl-imino)-5-propylthio-1,3,4-thiadiazolin-3-carboxylic acid,(3-chloropropyl)-ester 4 4 4 42-(Dimethylcarbamoyl-imino)-5-propylthio-1,3,4-thiadiazolin-3-carboxylic acid-isopropylester 4 4 4 45-Ethylthio-2-(dimethyl-carbamoylimino)-1,3,4-thiadiazolin-3-carboxylic acid-isopro-pylester 4 4 4 42-(Dimethylcarbamoyl-imino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-isobutylester 4 4 4 42-(Dimethylcarbamoyl-imino)-5-methylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-iso-butyl-ester 4 4 4 42-(Dimethylcarbamoyl-imino-5-methylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-isopropyl-ester 4 4 4 45-Ethylsulfonyl-2-(dimethylcarbamoyl-imino)-1,3,4-thiadia-zolin-3-carboxylicacid-isopropyl-ester 4 4 4 45-Ethylthio-2-(dimethyl-carbamoylimino)-1,3,4-thiadiazolin-3-carboxylicacid-pentyl-ester 4 4 4 4__________________________________________________________________________
EXAMPLE 6
The plants listed below were treated before emergence with the named agents in an amount of 1 kg per hectare. The agent for this purpose was applied to the soil as aqueous suspension with 500 liters water per hectare. The results shown are three weeks after treatment, and demonstrate that the compounds of the invention exhibit a higher selectivity than the comparison compounds. The scale used in Table 3, are 0=total destruction to 10=no injury.
Table 3 Compounds of the Seed- Invention Peanut Potato Pea Corn Wheat Barley Rice Sorghum 2-(Dimethylcarbamoylimino)-5- methylthio-1,3,4-thiadiazolin- 3-carboxyl ic acid-methylester 10 10 8 9 8 8 9 8 5-Ethylthio-2-(dimethylcarbamoyl- imino)-1,3,4-thiadiazolin-3- carboxylic acid-methylester 10 10 8 9 8 9 10 9 2-(Dimethylcarbamoylimino)-5- propylthio-1,3,4-thiadiazolin- 3-carboxylic acid-methylester 10 10 10 10 10 9 10 9 2-(Dimethylcarbamoyli mino)-5- methylthio-1,3,4-thiadiazolin- 3-carboxylic acid-ethylester 10 10 10 10 9 9 9 8 5-Aethylthio-2-(dimethylcarba- moylimino)-1,3,4-thiadiaz olin- 3-carboxylic acid-ethylester 10 10 10 8 8 10 10 8 Cent- Chrysan- Echino- Lamium Compounds of the Stellaria Senecio Matricharia aurea Amaranthus themum Impomoea Polygonum Avena chloa Setaria Digitaria Sorghum Poa amplexi- Invention media vulgaris chamomilla cyanus retroflexus segetum purpurea lapathifolium fatua crus galli italica sanguinalis halapense anua caule 2-(Dimethylcarbamoylimino)- 5-methylthio-1,3,4-thiadia- zolin-3-carboxy lic acid- methylester 0 0 0 0 0 0 0 0 0 2 0 0 1 1 0 5-Ethylthio-2-(dimeth yl- carbamoylimino)-1,3,4- thiadiazolin-3-carboxylic acid-methylester 0 0 0 0 0 0 0 0 0 0 0 0 2 1 0 2-(Dimethylcarbamoyl- imino)-5-propylthio- 1,3,4-thiadiazolin-3- carboxylic acid-methyl- ester 0 0 0 0 0 0 0 0 2 2 0 0 4 2 0 2-(Dimethylcarbamoyl- imino)-5-methylthio- 1,3,4-thiadiazolin-3 - carboxylic acid- ethylester 0 0 0 0 0 0 0 0 1 1 0 0 2 1 0 5-Ethylthio-2 -(dimethyl- carbamoylimino)-1,3,4- thiadiazolin-3-carboxylic acid-ethyles ter 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Compounds of the Seed- Invention Peanut Potato Pea Corn Wheat Barley Rice Sorghum 2-(Dimethylcarbamoylimino) 5-methylsulfonyl-1,3,4- thiadiazolin-3-carboxylic acid-methylester 10 8 9 10 8 9 9 -- 5-Ethylsulfonyl-2-(dimethyl- carbamoylimino-1,3,4- thiadiazolin-3-carboxylic acid-methylester 10 10 8 10 8 8 10 9 5-Ethylsul fonyl-2-(dimethyl- carbamoylimino)-1,3,4-thia- diazolin-3-carboxylic acid- ethylester 10 10 9 10 -- -- 10 9 2-(Dimethylcarbamoylimino)- 5-methylsulfonyl-1,3,4-thia- diazolin-3-carboxylic acid- ethylester 10 9 9 10 9 9 10 9 2-(Dimethylcarbamoylimino)- 5-propylsulfonyl-1,3,4-thia- diazolin-3-carboxylic acid- isopropyl-ester 10 10 -- 8 -- -- -- -- Cent- Chrysan- Echiono- Lamium Compounds of the Stellaria Senecio Matricharia aurea Amaranthus themum Impomoea Polygonum A vena chloa Setaria Digitaria Sorghum Poa amplexi- Invention media vulargis chamomilla cyanus retroflexus segetum purpurea lapathifolium fatua crus galli italica sanguinalis halapense anua caule 2-Dimethylcarbamoyli- mino)-5-methylsulfonyl- 1,3,4-thiadiazolin-3- carboxylic acid- methylester 0 0 0 0 0 1 0 0 0 0 0 0 0 1 0 5-Ethylsulfony l-2- dimethylcarbamoyli- mino)-1,3,4-thiadia- zolin-3-carboxylic acid-methyl-ester 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 5-Ethylsulfonyl-2- (dimethylcarbamoylimino)- 1,3,4-thiadiazolin-3- carboxylic acid-ethyl- ester 0 0 0 0 0 0 -- 0 0 0 0 0 0 -- 0 2-(Dimethylcarbamoyl- imino)-5-meth ylsul- fonyl-1,3,4-thiadia- zolin 3-carboxylic acid- ethyl-ester 0 0 0 0 1 0 0 0 0 2 0 0 0 0 0 2-(Dimethylcarbamoyl- imino)-5-propylsulfonyl- 1,3,4-thiadiazolin-3- carboxylic acid-isopro- pyl-ester 0 0 0 0 0 0 10 1 0 1 0 0 1 1 0 Compounds of the Seed- Invention Peanut Potato Pea Corn Wheat Barley Rice Sorghum 2-(Dimethylcarbamoylimino) 5-propylsulfonyl 1-1,3,4-thia- diazolin-3-carboxylic acid- pentyl-ester 10 10 -- 8 8 -- 8 8 2-(Dimethylcarbamoylimino) 5-propylthio-1,3,4-thiadia- zolin-3-carboxylic acid-iso- propylester 10 10 -- -- -- -- -- -- 2-(Dimethylcarbamoylimino) 5-propylthio-1,3,4-thiadia- zolin-3-carboxylic acid- pentylester 10 10 -- -- -- -- 8 -- 2-(Dimethylcarbamoylimino) 5-propylthio-1,3,4-thia- diazolin-3-carboxylic acid- 3-chlorpropyl)-ester 1010--9-- --9 8 2-(Dimethylcarbamoylimino) 5-methylthio-1,3,4-thia- diazolin-3-carboxylic acid- isopropylester 10 6 8 9 8 9 10 10 Cent- Chrysan- Echiono- Lamium Compounds of the Stellaria Senecio Matricharia aurea Amaranthus themum Impomoea Polygonum Avena chloa Setaria Digitaria Sorghum Poa amplexi- Invention media vulgaris chamomill a cyanus retroflexus segetum purpurea lopathifolium fatua crus galli italica Sanguinails halapense anua caule 2-(Dimethylcarbamoyl- imino)-5-propylsulfonyl- 1,3,4-thiadiazolin-3- carboxylic acid- pentyl- ester 0 0 0 0 0 1 -- 4 0 1 1 0 3 2 0 2-(Dimethyl carbamoyl- imino)-5-propylthio-1, 3,4-thiadiazolin-3- carboxylic acid-iso- propylester 0 0 0 0 4 0 0 0 0 1 0 0 2 0 0 2-(Dimethylcarbamoyl- imino)-5-propylthio-1, 3,4-thiadiazolin-3- carboxylic acid-penty- lester 0 0 0 0 4 0 0 0 1 0 0 0 4 1 0 2-(Dimethylcarbamoyl- imino)-5-propy lthio- 1,3,4-thiadiazolin-3- carboxylic acid-(3- chlorpropyl)-ester 0 0 1 0 1 0 0 1 1 2 1 0 0 1 1 2-(Dimethylcarbamoyl- imino)-5-methylthio- 1,3,4-thiadiazolin- 3-carboxylic acid- isopropylester 0 0 0 0 0 0 0 0 -- 2 1 1 -- 2 0 Compounds of the Seed- Invention Peanut Potato Pea Corn Wheat Barley Rice Sorghum 5-Ethylthio-2-(dimethyl- carbamoylimino)-1,3,4- thiadiazolin-3- carboxylic acid-isopropy- lester 10 6 -- 6 6 7 7 7 2-(Dimethylcarbamoylim ino)- 5-methylthio-1,3,4-thiadia- zolin-3-carboxylic acid- isobutylester 10 10 10 10 9 8 10 10 2-(Dimethylcarbamoylimino) methylsulfonyl-1,3,4- thiadiazolin-3-carboxy lic acid-isobutyl-ester 10 8 6 8 8 8 8 8 2-(Dimethylcarbamoylimino) 5-methylsulfonyl-1,3,4- thiadiazolin-3-carboxylic acid-isopropyl-est er 10 -- -- 9 -- 8 -- 7 5-Ethylsulfonyl-2-(dimethyl- carbamoylimino)-1,3, 4-thia- diazolin-3-carboxylic acid- isopropyl-ester 10 -- 6 7 6 7 7 8 Cent- Chrysan- Echiono- Lamium Compounds of the Stellaria Senecio Matricharia aurea Amaranthus themum Impomoea Polygonum A vena chloa Setaria Digitaria Sorghum Poa amplexi- Invention media vulgaris chamomilla cyanus retroflexus segetum purpurea lapathifolium fatua crus galli italica sanguinalis halapense anua caule 5-Ethylthio-2-(dimethyl- carbamoylimino)-1,3,4- thiadiazzthiadiazolin-3 -carboxylic acid-isopropylester 0 0 0 0 0 0 0 0 1 0 0 0 1 0 0 2-(Dimethyl carbamoyl- imino)-5-methylthio-1,3,4- thiadiazolin-3-carboxylic acid-isob utylester 0 0 0 0 0 0 0 0 4 3 0 1 -- 0 0 2-(Dimethylcarbamoylimino) 5-methylsulfonyl-1,3,4- thiadiazolin-3-carboxylic acid-isobutyl-este r 0 0 0 0 0 0 -- 0 2 0 0 0 0 1 0 2-(Dimethylcarbamoylimino) 2-(Dimethylca rbamoylimino) 5-methylsulfonyl-1,3,4- thiadiazolin-3-carboxylic acid-isopropyl-ester 0 0 0 0 0 0 1 0 1 0 0 0 0 0 0 5-Ethylsulfonyl-2- (Dimethylcarbamoylimino) 1,3,4-thiadiazolin-3- carboxylic acid-isopropyl- ester 0 0 0 0 0 0 -- 0 0 0 0 0 0 0 0 Compounds of the Seed- Invention Peanut Potato Pea Corn Wheat Barley Rice Sorghum 5-Ethylthio-2-(dimethyl- carbamoylimino)1,3,4- thiadiazolin-3-carboxyli c acid-pentylester 10 7 6 9 9 8 8 8 Comparison Compound 1,3-Dimethyl-1-(5 -tert.- butyl-1,3,4-thiadiazol- 2-yl)-urea 3 3 0 2 0 0 7 0 1,3-Dimethyl-1-(5-tri- fluor-methyl-1,3,4-thia- diazol-2-yl)-urea 8 6 0 3 0 0 3 0 Untreated 10 10 10 10 10 10 10 10Cent- Chrysan- Echiono- Lamium Compounds of the Stellaria Senecio Matricharia aurea Amaranthus themum Impomoea Polygonum Avena chloa Setaria Digitaria Sorghum Poa Amplexi- Invention media vulgaris chamomilla cyanus retroflexus segetum purpurea lopathifolium fatua crus galli italica sanguinalis halapense anua caule 5-ethylthio-2-(dimethyl- carbamoylimino)-1,3,4-thiadia- zolin-3-carboxy lic acid- pentylester 0 0 0 0 0 0 0 0 2 1 0 0 2 0 0 Comparison Compound 1,3-Dimethyl-1-(5-tert.- bhutyl-1,3,4-thiadiazol) 2-yl-)-urea 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1,3-Dimethyl-1-(5- trifluormeth yl-1,3,4- thiadiazol-2-yl)-urea 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 Untreated 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10
EXAMPLE 7
The plants listed in Table 4 were treated in the greenhouse after emergence with the listed agents in application amounts of 1 kg agent per hectare. The agent was applied for this purpose as a spray of an aqueous suspension in 500 liters water per hectare. Three weeks after treatment the compounds according to the invention exhibited good selectivity in comparison with the known compounds, on a scale on which 0=total destruction to 10=no injury.
Table 4 Compounds of the Seed- Invention Peanut Potato Pea Corn Wheat Barley Rice Sorghum 2-(Dimethylcarbamoylimino)- 5-methylthio-1,3,4- thiadiazolin-3-carboxyl ic acid-methylester 10 8 8 8 9 10 10 10 5-Ethylthio-2-(dimethyl- carbamoylimino)-1,3,4- thiadiazolin-3-carboxylic acid-methylester 10 8 -- 8 -- 8 8 -- 2-(Dimethylcarbamoylimino)- 5-propylthio-1,3,4-thia- diazolin-3-carboxylic acid- methylester 10 8 10 9 8 8 10 8 2-(Dimethylcarbamoylimino)- 5-methylthio-1,3,4-thia- diazolin-3-carboxylic acid- ethylester 10 8 8 8 8 8 10 8 5-Ethylthio-2-(d imethyl- carbamoylimino)-1,3,4- thiadiazolin-3-carboxylic acid-ethylester 10 8 9 -- 9 8 10 8 Amaran- Poly- Alope- Stell- Lamium Cent- thus Chrysan- gonum curus Compounds of the aria Senecio Matricharia amplexi- aurea retro- Galium themum Ipomoea lapathio- Avena myosur- Echinochloa Setaria Digitaria Sorghum Poa Invention media vulgaris chamomilla caule cyanus flexus aparine segetum purpurea folium fatua oides crus galli italica sanguinalis halapense anua 2-(Dimethylcarbamoyl- imino)-5-methyl-thio- 1,3,4-thiadiazolin-3- carboxylic acid- methylester 0000000000 2 1 0 0 0 0 2 5-Ethylthio-2-(dime thyl- carbamoylimino)1,3,4- thiadiazolin-3- carboxylic acid-methyl- ester 0000000000 1 0 0 0 0 0 1 2-(Dimethylcarbamoyl- imino)-5-propylthio- 1,3,4-thiadiazolin-3- carboxylic acid- methylester 0000000000 2 2 0 0 0 0 1 2-(Dimethylcarbamoyl)- imino)-5-methylthio- 1,3,4-thiadiazolin- 3-carboxylic acid- ethylester 0 0 0 0 0 0 2 0 0 0 3 2 0 0 0 1 2 5-Ethylth io-2-(di- methylcarbamoyl- imino)-1,3,4-thia- diazolin-3-carboxylic acid-ethylester 0000000000 3 3 1 0 0 0 2Compounds of the Seed- Invention Peanut Potato Pea Corn Wheat Barley Rice Sorghum 2-(Dimethylcarbamoylimino)- 5-methylsulfonyl-1,3,4- thiadiazolin-3-carb oxylic acid-methylester 10 -- -- 8 -- -- 8 -- 5-Ethylsulfonyl-2-(dimethyl - carbamoylimino)-1,3,4- thiadiazolin-3-carboxylic acid-methyl-ester 10 10 -- 8 -- -- 8 -- 5-Ethylsulfonyl-2-(dimethyl- carbamoylimino)-1,3,4-thi a- diazolin-3-carboxylic acid- ethylester 10 9 8 9 9 9 9 9 2-(Dimethylcarbamoylimino)- 5-methylsulfonyl-1,3,4- thiadiazolin-3-carboxylic acid-ethylester 10 9 -- 9 9 9 10 8 2-(Dimethylcarbamoylimino)- 5-propylsulfonyl-1,3,4- thiadiazolin-3-ca rboxylic acid-isopropyl-ester 10 10 8 10 10 10 10 8 Amaran- Poly- Alope- Stell- Lamium Cent- thus Chrysan- gonum curus Compounds of the aria Senecio Matricharia amplexi- aurea retro- Galium themum Ipomoea lapathio- Avena myosur- Echinochloa Setaria Digitaria Sorghum Poa Invention media vulgaris chamomilla caule cyanus flexus aparine segetum purpurea folium fatua oides crus galli italica sanguinalis halapense anua 2-(Dimethylcarbamoyl- imino)-5-methyl- sulfonyl-1,3,4-thia- diazolin-3- carboxylic acid-methylester 0 0 0 0 0 0 1 0000000000 5-Ethylsulfonyl-2- (dimethylcarbamoyl- imino)-1,3,4-thia- diazolin-3-carboxylic acid-methyle ster 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 5-Ethylsulfonyl-2- (dimethylcarbam oyl- imino)-1,3,4-thiadia- zolin-3-carboxylic acid-ethylester 0000000000 0 1 0 0 0 0 2 2-(Dimethylcarbamoyl- imino)-5-methyl- sulfonyl-1,3,4-thia- diazolin-3-carboxylic acid-ethylester 0000000000 1 1 0 0 0 0 2 2-(Dimeth ylcarbamoyl- imino)-5-propyl- sulfonyl-1,3,4-thia- diazolin-3-carboxylic acid-isopropylester 0 0 0 0 0 0 0 2 1 0 1 3 0 0 0 2 -- Compounds of the Seed- Invention Peanut Potato Pea Corn Wheat Barley Rice Sorghum 2-(Dimethylcarbamoylimino)- 5-propylsulfonyl-1,3,4- thiadiazolin-3-carb oxylic acid-pentyl-ester 10 10 -- 10 10 8 8 8 2-(Dimethylcarbamoylimino)- 5-propylthio-1,3,4- thiadiazolin-3-carboxylic acid-isopropylester 10 10 -- 8 8 8 8 9 2-(Dimethylcarbamoylimino)- 5-propylthio-1,3,4-thia- diazolin-3-carboxylic acid-pentylester 10 10 10 10 10 8 8 10 2-(Dimethylcarbamoylimino)- 5-propylthio-1,3,4-thia- diazolin-3-carboxy lic acid- (3-chlorpropyl)-ester 10 10 -- 9 -- -- -- -- 2-(Dimethylcarbamoyl- imino)-5-methylthio-1,3,4- thiadiazo lin-3-carboxylic acid-isopropylester 9 8 -- -- -- -- 8 -- Amaran- Poly- Alope- S tell- Lamium Cent- thus Chrysan- gonum curus Compounds of the aria Senecio Matricharia amplexi- aurea retro- Galium themum Ipomoea lapathio- Avena myosur- Echinochloa Setaria Digitaria Sorghum Poa Invention media v ulgaris chamomilla caule cyanus flexus aparine segetum purpurea folium fatua oides crus galli italica sanguinalis halapense anua 2-(Dimethylcarbamoyl- imino)-5-propylsulfonyl- 1,3,4-thiadiazolin-3- carboxylic acid- pentylester 0 0 0 0 0 0 0 0 5 0 1 3 0 0 0 1 -- 2-(Dimeth ylcarbamoyl- imino)-5-propylthio- 1,3,4-thiadiazolin- 3-carboxylic acid- isopropylester 0000000000 3 1 0 0 0 5 0 2-(Dimethylcarbamoyl- imino)-5-pr opylthio- 1,3,4-thiadiazolin- 3-carboxylic acid- pentylester 0 0 0 0 0 0 1 0 0 0 4 2 0 0 0 0 0 2-(Dimethylcarbamoyl- imino)-5-propylthio- 1,3,4-thiadiazolin-3- carboxylic acid-(3- chlorpropyl)-ester 0 0 0 1 0 0 0 0 0 -- 3 3 2 0 1 0 4 2-(Dimethylcarbamoyl- imino)-5-methylthio- 1,3,4-thiadiazolin- 3-carboxylic acid- isopropyl-ester 0000000000 0 3 4 0 0 4 1 Compounds of the Seed- Invention Peanut Potato Pea Corn Wheat Barley Rice Sorghum 5-Ethylthio-2-(dimethyl- carbamoylimino)-1,3,4- thiadiazolin-3-carboxyl ic acid-isopropylester 9 8 -- 6 -- -- 7 -- 2-(Dimethylcarbamoyl- imino)-5-methyl-thio- 1,3,4-thiadiazolin-3- carboxylic acid- isobutyleste r 8 -- -- -- -- -- -- -- 2-(Dimethylcarbamoyl- imino)-5-methyl-sulfonyl- 1,3,4-thiadiazolin-3- carboxylic acid-isobuty- lester -- 6 -- -- -- -- -- -- 2-(Dimethylcarbamoyl- imino)-4-methyl-sulfonyl- 1,3,4-thiadiazolin- 3- carboxylic acid-isopropyl- ester 10 8 0 -- -- -- -- -- 5-Ethylsulfonyl-2-(dimethyl- carbamoylimino)-1,3,4-t hia- diazolin-3-carboxylic acid-isopropylester 9 -- -- -- -- -- -- -- Amaran- Poly- Alope- Stell- Lamium Cent- thus Chrysan- gonum curus Compounds of the aria Senecio Matricharia - amplexi aurea retro- Galium themum Ipomoea lapathio- Avena myosur- Echinochloa Setaria Digitaria Sorghum Poa Invention media vulgaris chamomilla caule cyanus flexus aparine segetum purpurea folium fatua oides crus galli italica sanguinalis halapense anua 5-Ethylthio-2-(dimethyl- carbamoylamino)-1,3,4- thiadiazolin-3-carboxyl ic acid-isopropylester 0 0 0 0 2 0 0 0 0 0 0 1 1 0 0 1 0 2-(Dimethylcarba moyl- imino)-5-methylthio- 1,3,4-thiadiazolin- 3-carboxylic acid-iso- butylester 0 0 0 0 0 0 4 0000000000 2-(Dimethylcarbamoyl- imino)-50methyl sulfonyl- 1,3,4-thiadiazolin-3- carboxylic acid-isobutyl- ester 0 0 0 0 0 0 2 0 -- 0 0 0 0 0 0 0 0 2-(Dimethylcarbamoyl- imino)-5-methylsulfonyl- 1,3,4-thiadiazolin-3- carboxylic acid-iso- propyl-ester 0 0 0 0 0 0 3 0 -- 0 0 0 0 0 0 0 1 5-Ethylsulfonyl-2- dimethyl-carbamoyl- imino)-13,4,-th iadia- zolin-3-carboxylic acid-isopropyl-ester 0 0 0 0 0 0 1 0 -- 0 0 0 0 0 0 0 0 Compounds of the Seed- Invention Peanut Potato Pea Corn Wheat Barley Rice Sorghum 5-Ethylthio-2-(dimethylcarbamoyl- imino)-1,3,4-thiadiazolin-3- carboxylic acid-pentylester -- 9 -- 6 -- -- 8 -- Comparison Compounds 1,3-Dimethyl-1-(5-tert.-butyl- 1,3,4-thiadiazol-3-yl)-urea 6 0 0 1 0 0 0 0 1,3-Dimethyl-1-(5-Trifluor- methyl-1,3,4-thiadiazol-2- yl)-urea 4 0 0 3 0 0 0 0 Untreated 10 10 10 10 10 10 10 10 Amaran- Poly- Alope- Stell- Lamium Cent- thus Chrysan- gonum curus Compounds of the aria Senecio Matricharia amplexi- aurea retro- Galium themum Ipomoea lapathio- Avena myosur- Echinochloa Setaria Digitaria Sorghum Poa Invention media vulgaris chamomilla caule cyanus flexus aparine segetum purpurea folium fatua aides crus galli italica sanguinalis halapense anua 5-Ethylthio-2-(dimethyl- carbamoylimino)-1,3,4- thiadiazolin-3-carboxyl ic acid-pentylester 0 0 0 0 0 0 4 0 0 0 0 1 0 0 0 4 1 Comparison Compounds 1,3-Dimethyl-1-(5-tert.- butyl-1,3,4-thiadiazol- 2-yl)-urea 0000000000 0 0 0 0 0 0 0 1,3-Dimethyl-1-(5-tri- fluormethyl-1,3,4-thia- diazol-2-yl)-urea 0000000000 3 0 0 0 0 0 0 Untreated 110 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10
EXAMPLE 8
The compounds listed in Table 5 were applied in the greenhouse in amounts of 5 kg agent per hectare, suspended in 500 litwer of water per hectare, to Sinapis sp. and Solanum sp. as test plants by spraying before and after emergence. Three weeks after the treatment the results were measured according to a scale on which 0=no action to 4=destruction of the plant. As can be seen from the table, as a rule, no injury to the test plants resulted.
Table 5__________________________________________________________________________Compounds of the Pre-emergence Post-emergenceInvention Sinapis sp. Solanum sp. Sinapis sp. Solanum sp.__________________________________________________________________________2-(Dimethylcarbamoyl-imino)-5-pentylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-(2-pro-pinyl)-ester 4 4 4 42-(Dimethylcarbamoyl-amino)-5-pentylthio-1,3,4-thiadiazolin-3-carboxylic acid-butylester -- 3 4 42-(Dimethylcarbamoyl-imino)-5-ethylthio-1,3,4-thiadiazolin-3-carboxylic acid-benzylester 4 4 4 45-Ethylsulfonyl-2-(dimethyl-carbamoylimino)-1,3,4-thiadiazolin-3-carboxylicacid-benzylester 4 4 4 45-Butylsulfonyl-2-(dimethyl-carbamoylimino)-1,3,4-thiadiazolin-3-carboxylicacid-butylester 4 4 4 42-(Dimethylcarbamoylimino)-5-(2-propinylthio)-1,3,4-thiadiazolin-3-carboxylicacid-methylester -- -- -- --2(Dimethylcarbamoylimino)-5-pentylthio-1,3,4-thiadiazolin-3-carboxylic acid-benzy-lester -- -- 4 --2-(Dimethylcarbamoylimino)-5-isobutylsulfonyl-1,3,4-thia-diazolin-3-carboxylic acid-(2-propinyl)-ester 4 4 4 45-Ethylsulfonyl-2-(dimethyl-carbamoylimino)-1,3,4-thiadiazolin-3-carboxylicacid-(2-propinyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-(2-methyl-2-propenylsulfonyl)-1,3,4-thiadiazolin-3-carboxylicacid-ethylester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-(2-propinyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-2,2,2-trichlor-ethylester 4 4 4 42-(Dimethylcarbamoylimino)-5-isopropylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propinyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-isobutylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propinyl)-ester 4 4 4 45-Ethylthio-2-(dimethylcarbamoyl-imino)-1,3,4-thiadiazolin-3-carboxylic acid-(2-propinyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thia-diazolin-3-carboxylic acid-hexylester 4 4 4 42-(Dimethylcarbamoylimino)-5-(2-methyl-2-propenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-methylester 4 4 4 42-(Dimethylcarbamoylimino)-5-(2-methyl-2-propenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-ethylester 4 4 4 42-(Dimethylcarbamoylimino)-5-(2-methyl-2-propenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-propylester 4 4 4 42-(Dimethylcarbamoylimino)-5-(2-methyl-2-propenylthio)-1,3,4-thiadiazolin-3-carboxylic acid-butylester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-butylthio-1,3,4-thiadiazolin-3-carboxylic acid-butylester 4 4 4 42-(Dimethylcarbamoylimino)-5-butylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester 3 -- 4 42-(Dimethylcarbamoylimino)-5-butylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-butylester 4 4 4 42-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,4-thiadiazolin-3-carboxylic acid-propylester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-phenylester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-hexylester 4 4 4 42-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,4-thiadia-zolin-3-carboxylic acid-ethylester -- -- 4 42-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,4-thiadia-zolin-3-carboxylic acid-ethylester -- -- 4 42-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,4-thiadia-zolin-3-carboxylic acid-isopropylester -- -- 4 42-(Dimethylcarbamoylimino)-5-hexylsulfonyl-1,3,4-thiadia-zolin-3-carboxylic acid-isobutylester -- -- 4 42-(Dimethylcarbamoylimino)-5-hexylthio-1,3,4-thiadiazolin-3-carboxylic acid-propylester -- -- 4 42-(Dimethylcarbamoylimino)-5-hexylthio-1,3,4-thiadiazolin-3-carboxylic acid-isobutylester -- -- 4 42-(Dimethylcarbamoylimino)-5-hexylthio-1,3,4-thiadiazolin-3-carboxylic acid-butylester -- -- 4 42-(Dimethylcarbamoylimino)-5-isopropylsulfonyl-1,3,4-thiadia-zolin-3-carboxylic acid-pentylester -- -- 4 42-(Dimethylcarbamoylimino)-5-isobutylsulfonyl-1,3,4-thiadia-zolin-3-carboxylic acid-butylester -- -- 4 42-(Dimethylcarbamoylimino)-5-isobutylsulfonyl-1,3,4-thiadia-zolin-5-carboxylic acid-(2-propenyl)-ester -- -- 4 42-(Dimethylcarbamoylimino)-5-(2-butenylthio)-1,3,4-thia-diazolin-3-carboxylic acid-butylester 4 4 4 42-(Dimethylcarbamoylimino)-5-(2-butenylthio)-1,3,4-thiadia-zolin-3-carboxylic acid-methylester 4 4 4 42-(Dimethylcarbamoylimino)-5-(2-butenylthio)-1,3,4-thiadia-zolin-3-carboxylic acid-(2-propenyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-hexylthio-1,3,4-thiadiazolin-3-carboxylic acid-methylester -- -- 4 42-(Dimethylcarbamoylimino)-5-hexylthio-1,3,4-thiadiazolin-3-carboxylic acid-ethylester -- -- 4 42-(Dimethylcarbamoylimino)-5-hexylthio-1,3,4-thiadiazolin-3-carboxylic acid-isopropyl-ester -- -- 4 42-(Dimethylcarbamoylimino)-5-isopropylthio-1,3,4-thiadia-zolin-3-carboxylic acid-pentylester 4 4 4 42-(Dimethylcarbamoylimino)-5-isobutylthio-1,3,4-thiadia-zolin-3-carboxylic acid-(2-propenyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-isobutylthio-1,3,4-thiadiazolin-3-carboxylic acid-butylester 4 4 4 42-(Dimethylcarbamoylimino)-5-pentylthio-1,3,4-thiadiazolin-3-carboxylic acid-methylester -- -- 4 42-(Dimethylcarbamoylimino)-5-hexylsulfinyl-1,3,4-thiadia-zolin-3-carboxylic acid-butylester 4 4 4 42-(Dimethylcarbamoylimino)-5-(2-propenylthio)-1,3,4-thiadia-zolin-3-carboxylic acid-buty-lester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thia-diazolin-3-carboxylic acid-butylester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadia-zolin-5-carboxylic acid-pentylester 4 4 4 42-(Dimethylcarbamoylimino)-5-isopropylsulfonyl-1,3,4-thia-diazolin-3-carboxylic acid-butylester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thiadia-zolin-3-carboxylic acid-(2-propenyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-isopropylsulfonyl-1,3,4-thia-diazolin-3-carboxylic acid-(2-propenyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylsulfonyl-1,3,4-thiadia-zolin-3-carboxylic acid-pentylester 4 4 4 42-(Dimethylcarbamoylimino)-5-(2-propenylthio)-1,3,4-thia-diazolin-3-carboxylic acid-methylester 4 4 4 42-(Dimethylcarbamoylimino)-5-isopropylthio-1,3,4-thiadia-zolin-3-carboxylic acid-(2-propenyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-butylester 4 4 4 42-(Dimethylcarbamoylimino)-5-methylthio-1,3,4-thiadiazolin-3-carboxylic acid-(2-propenyl)-ester 4 4 4 42-(Dimethylcarbamoylimino)-5-isopropylthio-1,3,4-thiadia-zolin-3-carboxylic acid-(2-propenyl)-ester -- -- 4 42-(Dimethylcarbamoylimino)-5-isopropylthio,1,3,4-thiadia-zolin-3-carboxylic acid-butylester 4 4 4 4__________________________________________________________________________
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2-(Dimethylcarbamoylimino)-1,3,4-thiadiazolin-3-carboxylic acid esters of the formula: ##STR1## in which R and R 1 are aliphatic hydrocarbon groups which may be halogenated, and n is 0, 1 or 2, are effective herbicides, and exhibit a high degree of selectivity toward cultivated plants.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the priority, under 35 U.S.C. §119, of German application DE 10 2006 007 181.6, filed Feb. 16, 2006; this application also claims the priority, under 35 U.S.C. §119(e), of provisional application No. 60/777,246 filed Feb. 27, 2006; the prior applications are herewith incorporated by reference in their entireties.
BACKGROUND OF THE INVENTION
Field of the Invention
[0002] The present invention relates to a method and an apparatus for controlling a printing press having a plurality of printing units, a plurality of cylinders which are coupled mechanically to one another and a control computer for controlling at least one drive motor which drives the mechanically coupled cylinders.
[0003] Sheet-fed rotary offset printing presses have a plurality of printing units which in each case apply a separation of a printed image onto the printing material in a defined color. There are usually at least four printing units, in order for it to be possible to print the three primary colors red, yellow, blue, and also black. However, still further printing units can be provided for special colors, such as gold or silver. It is additionally possible to apply a varnish to the printing material with a special varnishing unit after the printing units. In addition, sheet-fed rotary printing presses can process the front and rear sides of a printing material, with the result that double the number of printing units and varnishing units are to be provided in this case. In printing presses for recto and verso printing having a plurality of special colors and subsequent varnishing units, this leads to a considerable number of printing and varnishing units. Therefore, a number of sixteen printing and varnishing units is therefore no longer unusual in packaging material.
[0004] As all the printing units print their color separations over one another, it is important that the overprinting takes place with accurate register, that is to say there may not be any deviation in the positioning if possible between the individual color separations on the printing material, as otherwise visible image errors occur for the observer of the finished printed product. The individual printing and varnishing units in sheet-fed rotary printing presses are usually connected to one another via a gearwheel train, in order to also to achieve this register accuracy during overprinting of different color separations. In this case, the plate cylinders, blanket cylinders, impression cylinders and transport cylinders, as well as turner drums of the printing press are coupled mechanically to one another and are driven jointly by one or more drive motors. Here, the mechanically coupled cylinders represent a system with a finite rigidity, with the result that torsion phenomena are produced at defined loads. Moreover, adjustment possibilities for the register adjustment are provided in the printing units of each sheet-fed offset printing press, in order for it to be possible if required to correct register deviations between the individual color separations, as the deviations depend, inter alia, on the printing speed, and the latter is not identical in every print job. It has been proven that the setting of the registers is dependent not only on the printing speed but also on the torque of the drives or other operating parameters of the printing press.
[0005] German patent DE 31 48 449 C1, discloses a method for reducing register errors in multiple-color offset printing presses, the printing units of which are driven by a common motor and have a device for register adjustment. This invention is based on the functional relationship between the torque which is supplied by the drive motor of the printing press or a variable which is characteristic of the torque and the register adjustment in the printing press which is necessary for maintaining satisfactory register. The functional relationship between the torque and the necessary register setting is stored in a computer of the printing press. During continuous operation of the printing press, the torque which is supplied by the drive motor is monitored and the register adjustment is performed as a function of the respective torque. Here, the relationship between the torque and the register adjustment is either determined during a test run of the printing press and stored in the form of a value table, or calculations are carried out which result in value pairs containing the torque and the register adjustment. There is also a value table in this case, which value table can be made use of during printing operation. The advantage of a procedure of this type lies in the fact that there does not have to be a complicated control computer, as only a comparison between the currently determined torque and the value table has to take place, whereupon the corresponding register adjustment values are then called up in the control computer and used. However, the method has the great disadvantage that it cannot react to changes within the printing press, which changes occur after delivery of the printing press to the customer, as the value table which is stored in the printing press cannot take the changes into consideration.
SUMMARY OF THE INVENTION
[0006] It is accordingly an object of the invention to provide control of a printing press using a torsion model and printed press controlled by the torsion model, which overcomes the herein-mentioned disadvantages of the heretofore-known methods and devices of this general type, with which the maintenance of register can be improved further in offset printing presses and which can react to changes in operating parameters of the printing press during printing operation.
[0007] With the foregoing and other objects in view there is provided, in accordance with the invention, a method for controlling a printing press having a plurality of printing units, at least one drive motor, a plurality of cylinders coupled mechanically to one another, and a control computer for controlling the at least one drive motor driving the cylinders mechanically coupled to one another. The method includes storing a torsion model in the machine computer for describing a torsion state of the cylinders in the printing press, as a function of at least one measurable operating parameter or at least one variable of the printing press known to the machine computer. The printing press is controlled, via the control computer, on a basis of values calculated by the torsion model.
[0008] The present invention can be used in all printing presses, in which a plurality of impression cylinders, blanket cylinders, plate cylinders or transport cylinders are coupled mechanically to one another. The mechanical coupling has the effect that changes in one of the cylinders necessarily also have an effect on the other cylinders which are coupled to the former. The invention is almost predestined to be used in sheet-fed offset printing presses, in which all the cylinders or at least the majority of the cylinders are connected to one another by a mechanical coupling, such as a continuous gear train or a longitudinal shaft. In addition, the printing press according to the invention has at least one drive motor which drives the mechanically coupled cylinders and a control computer, in which a mathematical torsion model is stored in the form of software for describing the torsion state of the cylinders which are coupled rotatably and mechanically to one another in the control computer of the printing press. The torsion model represents an algorithm which can constantly recalculate the mechanical rotation and position with respect to one another of the individual cylinders which are coupled to one another, as a function of at least one measurable operating parameter or a variable which is known to the control computer, also during operation of the printing press. The operating parameters and the known variables can be, for example, a current torque of one or more drives, the power usage of the drives, operating temperatures, used printing units, components which are switched on, settings of inking zone openings in the printing units, etc. The control computer can then intervene in the control of the printing press on the basis of the values which are calculated by the torsion model during operation of the printing press. This procedure has the great advantage that changes in the torsion state of the printing press can also be taken into consideration during printing operation, which changes are produced, for example, on account of the change in environmental conditions such as temperature and air humidity. Furthermore, the running of the printing press can become easier or stiffer during operation, so that changes can also result in the torsion state of the cylinders which are coupled to one another. If the corresponding operating parameters of the printing press are detected by sensors and fed to the machine computer with the torsion model, corresponding values can be calculated for correcting settings of the printing press and the corresponding setting processes can be triggered.
[0009] There is provision in a first refinement of the invention for at least one variable which is characteristic of the power requirement of the at least one drive motor to be measured as an operating parameter and to be fed to the control computer of the printing press. The power requirement of the printing press can be detected, for example, via measurement of the current of the drive motor. The greater the detected current is, the more electrical power the drive motor is drawing from the electrical network. The power requirement of the drive motor can change, for example, as a result of a change in the printing speed. If the printing speed is increased, the power requirement of the drive motor also changes necessarily, because correspondingly more drive power is required for a higher printing speed. However, the power requirement of the printing press can also change at a constant printing speed, for example as a result of warming. However, the settings do not remain unaffected by the change in the power requirement of the printing press. With consideration of the measured power requirement of the drive motor, the effects on the torsion state of the printing press can be calculated by the torsion model in the machine computer. Corresponding changes to the settings of the printing press can then be initiated by the control computer.
[0010] Furthermore, there is provision for the torque which is fed into the cylinders by the at least one drive motor to be measured as an operating parameter and to be fed to the control computer of the printing press. In addition to the measurement of the power requirement of the drive motor or as an alternative, the torque which is fed into the cylinders of the printing press can also be detected. The torque can likewise be detected via the drive motor or via additional torque sensors which measure the torque at individual cylinders of the printing press or at gearwheels of the gearwheel train. The detected torque values are likewise fed to the torsion model in the machine computer of the printing press, so that the torsion state of the printing press can be calculated there as a function of the respectively detected torque. The corresponding, necessary settings of the printing press can therefore also be performed by the control computer.
[0011] There is provision in one particularly advantageous refinement of the invention for an adjustment of the registers and/or an adjustment of the front lay in the printing units to be performed by the values which are calculated by the torsion model. If there is a varnishing unit, it goes without saying that the maintenance of register can also be adjusted in a varnishing unit of this type. As was mentioned in the introduction, the maintenance of register is particularly sensitive during overprinting of the different color separations in order to achieve a high print quality, which relates to changes in the operating state of the printing press. This relates, above all, to changes in the torsion state of the cylinders which are connected to one another in the printing press. For instance, the gear train can be relieved during heating and during the processing of a print job, which has the consequence of a change in the register setting. In practice, the printer learns of a register setting of this type only by the fact that he pulls test sheets and notices the change in the registers there, or has installed an automatic register monitoring device in the printing press, which register monitoring device automatically regulates the register deviation. However, an automated register monitoring device of this type is expensive and not available for every printing press. Moreover, corresponding special measuring marks have to be provided on the printing material, which special measuring marks correspondingly take up space on the printing material, which space could otherwise be used for the printed image itself. However, it is possible with the use of the torsion model to constantly recalculate the torsion state in the printing press in a current manner using operating parameters such as the changed power requirement or torque change, and to perform an adjustment of the registers in the individual printing units or varnishing units on this basis. In this case, a complicated automated register regulating device is not necessary, and it is sufficient to control the registers using the values which are calculated by the torsion model. If the printer so desires, the changed values of the register adjustment can be displayed first on a display screen of the printing press, with the result that the printer can decide himself whether he would like to perform the register adjustment by hand or desires to leave it to the printing press. In the latter case, the work of the printer can be made easier by the fact that the register adjustment is performed automatically by the control computer of the printing press. In this case, the printer no longer has to consider the transfer of the correct values for the register adjustment. In addition to the register adjustment, an adjustment of the front lay on the feeder is also possible. This adjustment ensures that the paper edge in the transport gripper on a reference cylinder, preferably in the machine center or near the main drive, is tracked to form a reference state if the operating state changes. This increases the reproducibility of the sheet transfer as a result of the paper projecting length on the reference cylinder being made more uniform, the paper projecting length also being changed in the front printing units, however. In the following text, the adjustment of the front lay is also always possible in addition to the register adjustment.
[0012] There can advantageously be provision for the printing press to have a measuring device for monitoring the registers, and for, during the detection of register deviations in the control computer by the torsion model, the register adjustment and/or the adjustment of the front lay in the printing units to be corrected. In this case, regulation of the registers is provided in addition to the controller, by register marks on the printing materials being detected in the printing press or on a separate measuring table and being fed to the control computer of the printing press. In order to improve the regulation of the register adjustment, the detected deviations in the registers of the individual printing units or varnishing units are likewise fed, however, to the torsion model in the control computer of the printing press, with the result that the torsion state in the printing press can also be taken into consideration in the calculation of the actuating variables for the correction of the register deviation in the control computer. This leads to a considerable improvement in comparison with conventional register regulation, as the correction of the register deviation can be carried out in a more targeted manner, with the result that fewer regulating steps are necessary for correcting the register deviation by the control computer. However, a reduction of regulating steps in the correction of register deviations leads to it being possible for the register deviations to be adjusted more rapidly. This in turn has the consequence that fewer printing materials are produced, on which corresponding register deviations of the individual color separations can be seen, with the result that waste paper is reduced.
[0013] Moreover, there is advantageously provision for the register adjustment and/or the adjustment of the front lay to be set correctly for at least one selected operating state of the printing press, and for the correct setting values of the register adjustment and/or the adjustment of the front lay to be stored in the control computer of the printing press in conjunction with the associated selected operating state. The selected operating state can be, for example, a defined machine configuration or a defined printing speed. In this case, the printer can set the registers himself in the individual printing units in a setup mode which is carried out at a low printing speed, until the result corresponds to his wishes. In this case, the selected printing speed is the setup speed. In this way, influences from the printing plate exposure, the clamping process of the printing plates and the torsion state of the machine can be corrected at the setup speed. When the result corresponds to the wishes of the printer, he can acknowledge this to the control computer of the printing press by a corresponding input. A storage process is triggered by this acknowledgement signal, in which storage process register adjustment values which have been set, the currently consumed drive power or the torque and additional other data are stored in the printing press controller. After this, the printer can then switch the printing press to printing operation and bring it up to full machine speed. As a function of the machine speed which is then reached, the machine controller calculates corresponding register adjustment values using the torsion model and the stored register adjustment values at setup speed, in order also to ensure satisfactory printing at full machine speed. This dispenses with the manual tracking of register adjustment values which is otherwise customary for the printer, if the printing speed of the printing press is changed. This can go so far that, if the printing speed is changed, the register adjustment is corrected automatically at a changed printing speed on the basis of the register adjustment which is set correctly for the selected printing speed, with the torsion model being taken into consideration. As soon as the printer operates his machine at another speed, a corresponding correction of the register adjustment is performed by the torsion model, without it being necessary for the printer to intervene.
[0014] There is provision in one refinement of the invention for a plurality of components or printing units of the printing press to be influenced by the detection of one operating parameter. As has already been mentioned, an operating parameter of this type can be the power consumption or the torque requirement of the printing press. In order for it to be possible to perform the register adjustment correctly in individual printing units or varnishing units, the corresponding register deviations normally have to be detected via sensors. This is then no longer necessary if the control computer with an implemented torsion model is used, as it is sufficient for a plurality of printing units of the printing press to be influenced using a single detected variable, such as the power requirement of the printing press. As the torsion model takes into consideration and describes the torsion state and therefore the coupling of the cylinders in the individual printing units of the printing press, the effect of the adjustment of registers in the individual printing units with respect to one another is also taken into consideration. The effect of an operating variable such as the power requirement on all the printing units or varnishing units of the printing press can be calculated by the torsion model, with the result that the machine controller can then perform the corresponding corrections on all printing units or varnishing units via the register adjustment device.
[0015] Furthermore, it is possible for the torsion state of the printing press to be detected using measuring technology at at least two locations, by use of sensors. Sensors are to be provided in the printing press at least two locations, which sensors, for example, additionally measure the torsion via the respectively prevailing torque or the differential rotation between the sensors. The measured values can be included in the torsion model, in order to check it at least two locations for any correction requirement. In this case, not only are values calculated using the torsion model, but measured values are also used for checking purposes, which increases the accuracy. The measured values can be used for interpolation of values which lie between them by the torsion model. The measured values which are determined by the sensors can also be used to optimize the torsion model during operation. In this case, the measured values are taken into consideration in a type of adaptive controller, by the parameters of the torsion model correspondingly being adapted continuously or at defined time intervals.
[0016] There is advantageously provision for it to be possible for the torque distribution in the printing units of the printing press to be set in a variable manner or to take place as a function of the machine configuration. In addition to the register adjustment in the individual printing units, register corrections can also be carried out by the torque distribution in the individual printing units being changed, for example, as a function of the printing speed. This can take place by braking in the printing units, or additional drive motors can be provided, with which the torque distribution can be changed. It has proven particularly advantageous if the torque distribution of the drive motor in the printing units takes place as a function of the respective configuration of the printing units. The torque requirement in the individual printing units is dependent, inter alia, on how many printing units are actually used for the respective print job, whether the machine is operated, for example, in recto printing or in verso printing, and the nature in each case of the inking zone opening. All these configurations which are dependent on the respective print job have the consequence of a changed torque requirement in the individual printing units. This requirement can also be calculated by the torsion model, in order thus to improve the print quality on the printing materials.
[0017] There is provision in a further refinement of the invention for positional deviations with regard to the front and rear side of a printing material to be corrected, by the torsion model, by the register adjustment after a turner drum during recto and verso printing. The torsion state is also set at every printing speed in recto and verso printing, exactly as in pure recto printing. If this torsion state changes on account of a changed power consumption or a changed torque requirement, this is also associated here with register changes, as in pure recto printing. However, in recto and verso printing, the register accuracy between the printed images on the front and rear sides of the printing material also changes additionally. However, there must also not be any register deviation if possible between the printed image on the front side and the rear side, as otherwise edgeless trimming of the printing material is not possible, for example, without parts being cut off either in the printed image on the front side or in the printed image on the rear side on account of the different position. Register deviations which are as small as possible between the front side and the rear side are therefore also desired. These deviations can also be calculated by the torsion model in the machine controller, and the corresponding corrections can therefore be performed in the printing press.
[0018] There is provision in one particularly advantageous refinement of the invention for the changing torsion state of the printing press to be calculated, for the register deviation which has been experienced by a printing material in the printing press before the turner drum to be calculated from the calculated torsion state, and for the register adjustment for the printing units after the turner drum to be loaded with twice the value of the paper edge loss in relation to the printing units before turning, in order to correct the register deviation. In this case, the register deviation between the front side and the rear side of the printing material is corrected via the register adjustment device on the printing units and varnishing units after the turning device. The current torsion state is calculated by the torsion model, which results in the paper edge loss of the printing material being summed over the printing units before turning. Register adjustment values are calculated therefrom accordingly, and as in pure recto printing, by the torsion model. For the printing and varnishing units after the turning device, all the register adjustment values are corrected by twice the determined paper edge loss, with the result that register deviations no longer occur between the printed images on the front side and the rear side. It is therefore also possible by the present invention to avoid register deviations reliably in recto and verso printing.
[0019] A further advantageous refinement of the invention results from an improvement in the model results by a calibration test which is individual to the machine. As both the compliance of the gear train and the current/torque characteristics of the drive can have relatively small variances, the individual result on one machine can be improved by a standardized printing test being carried out under real conditions before delivery of the machine to the customer, and by the results of the torsion model then being improved, such as scaled, with the aid of the values discovered by the standardized printing test. In the simplest case, a scaling factor is superimposed on all values here for correction. The calibration is required only once.
[0020] Other features which are considered as characteristic for the invention are set forth in the appended claims.
[0021] Although the invention is illustrated and described herein as embodied in control of a printing press using a torsion model and printed press controlled by the torsion model, it is nevertheless not intended to be limited to the details shown, since various modifications and structural changes may be made therein without departing from the spirit of the invention and within the scope and range of equivalents of the claims.
[0022] The construction and method of operation of the invention, however, together with additional objects and advantages thereof will be best understood from the following description of specific embodiments when read in connection with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIG. 1 is a diagrammatic, side-sectional view of a sheet-fed offset printing press, in which a register adjustment in printing units and in a varnishing unit is controlled via a torsion model stored in a machine controller according to the invention;
[0024] FIG. 2 is a block diagram of the machine controller of the printing press shown in FIG. 1 ; and
[0025] FIG. 3 is a diagram of a paper edge loss in recto and verso printing in a printing press having ten printing units.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0026] Referring now to the figures of the drawing in detail and first, particularly, to FIG. 1 thereof, there is shown a printing press 1 which processes sheet-shaped printing materials 22 in rotary offset printing. The printing press 1 has five printing units 6 and one varnishing unit 7 . Here, the first four printing units 6 serve to apply the four primary colors yellow, red, blue and black in recto printing, while the fifth printing unit 6 is filled with special colors such as silver, gold or the like. The colors which are used in the printing units 6 are completely irrelevant, however, for the functioning of the present invention. After the fifth printing unit 6 , the printed sheets 22 are provided with a varnish coat in the varnishing unit 7 . The sheets 22 which are finished in the varnishing unit 7 are gripped by gripper bars on a deliverer transport chain 8 and deposited onto a deliverer stack 4 in the deliverer 3 . When the deliverer stack 4 has reached its maximum height, it is removed and transported for further processing. The feeder 2 which removes sheet-shaped printing materials 22 from the feeder stack 5 and feeds them to the first printing unit 6 of the printing press 1 via a feed table 15 is situated on the opposite side of the printing press 1 . The sheet-shaped printing materials 22 are transported from the first printing unit 6 to the varnishing unit 7 by cylinders 9 , 10 .
[0027] Each of the printing units 6 has an impression cylinder 10 which, together with a blanket cylinder 13 , forms the press nip, in which the ink is applied to the sheet 22 in the printing unit 6 . The printing ink itself is situated in every printing unit in an inking unit 11 which meters the printing ink in accordance with the settings of the current print job. In order to influence the print properties of the ink, a damping unit 12 is situated in every printing unit 6 , moreover, with which damping unit 12 damping solution can be added in a targeted manner. The printing ink which is dampened this way is transferred in the printing unit 6 onto a plate cylinder 14 which carries a printing plate and transfers the applied printing ink onto the blanket cylinder 13 by a rolling movement. In principle, all the printing units 6 are of identical construction, this not necessarily needing to be the case. The sheets 22 in FIG. 1 are transported between the individual printing units 6 by a turner drum 9 . The turner drums 9 allow the printing press 1 to be operated in recto and verso printing operation. The printed sheet 22 can be turned between each of the printing units 6 by the turner drum 9 , with the result that both the front side and the rear side can be printed.
[0028] The varnishing unit 7 is situated behind the fifth printing unit 6 , in which varnishing unit 7 a varnish coat can be applied in addition to the finished sheet 22 . The printing press 1 in FIG. 1 is configured in such a way that all the cylinders 9 , 10 , 13 , 14 and the inking units 11 and the damping units 12 are coupled mechanically to one another via a gearwheel train. It is possible here that individual printing units 6 or else cylinders 9 , 10 , 13 , 14 can be decoupled from the continuous mechanical gear train by clutches. During printing operation, however, all the cylinders 9 , 10 , 13 , 14 are coupled to one another in a fixed and mechanical manner and are driven by a common main drive motor 16 . In FIG. 1 , the main drive motor 16 drives a gearwheel of the impression cylinder 10 in the third printing unit 6 , from where the force is transmitted via the gearwheel train to the other cylinders 9 , 10 , 13 , 14 of the printing press 1 .
[0029] The individual color separations and the varnish coat are printed over one another in the printing units 6 and in the varnishing unit 7 . It is necessary for an optimum printed result that all the color separations and the varnish coat are printed over one another as exactly as possible, as otherwise image errors occur. This exact positioning over one another is called register maintenance in the printing industry. Although the cylinders 10 , 13 , 14 in the individual printing units 6 are coupled mechanically to one another, the gearwheel train has a certain elasticity, it being possible for individual cylinders, such as the plate cylinders 14 in the printing units 6 , to be rotated with respect to one another within certain limits by a non-illustrated motor for register adjustment. The rotation of the cylinders 9 , 10 , 13 , 14 of the machine which are coupled to one another depends, above all, on the operating state of the printing press 1 . Here, the printing speed, in particular, plays a large role, but operating parameters such as surrounding temperature, air humidity, etc. are also to be taken into consideration. The rotation in the drive train of the printing press 1 can therefore change its state depending on the operating conditions. A torsion state results from the rigidity and the loading of the cylinders 9 , 10 , 13 , 14 which are coupled to one another and can always be rotated a little with respect to one another, even if only to a small extent. The torsion state of the printing press 1 has the direct consequence of a change in the register maintenance of the sheets 22 . During startup of the printing press 1 , the printer therefore sets the register maintenance of the individual color separations in the printing units 6 and of the varnish coat in the varnishing unit 7 at the beginning of a print job, initially at a selected printing speed which usually lies considerably lower than the final production speed. This is effected in that some sheets 22 are produced which are then evaluated by the printer by a measuring device or a magnifying glass with the naked eye. The determined register deviations are corrected by an adjustment of the registers in the individual printing units 6 and in the varnishing unit 7 .
[0030] In order to correct the register adjustment, the printing press 1 in FIG. 1 has a machine controller 20 which controls all the components of the printing press 1 . The machine controller 20 has a computer which controls, for example, the main drive motor 16 of the printing press 1 and, moreover, is provided for controlling non-illustrated register adjustment motors in the individual printing units 6 and in the varnishing unit 7 . For this purpose, the register adjustment devices in the printing units 6 and in the varnishing unit 7 are connected to the machine controller 20 via a communication link 21 . The machine controller 20 in turn is connected to a non-illustrated input apparatus, such as a display screen and a keyboard, with the result that the printer can set up the printing press 1 in accordance with his stipulations. The printer can therefore perform the register adjustment in the individual printing units 6 and in the varnishing unit 7 manually via the machine controller 20 . If there are corresponding register sensors in the printing press 1 , the register adjustment can also be performed in a closed control loop. However, this is not necessary for the functioning of the present invention.
[0031] The present invention namely ensures that, if possible, regulating interventions are not necessary at all. The invention relates to a control measure which can precalculate register deviations which occur during operation using one or more operating parameters of the printing press 1 and can perform the register adjustment automatically.
[0032] Moreover, there is an adjustable front lay 23 on the feeder 2 of the printing press 1 . The front lay 23 is also controlled by a machine computer 18 . The front lay usually permits a change in the sheet position by +/−1 mm, as a result of which the sheet position in all further transport grippers on the cylinders 8 , 9 , 10 is also influenced at the same time. A calculation can then be carried out by the torsion model for one reference cylinder, for example one of the turner drums 9 , as to how much the front lay 23 has to be adjusted, in order to have a desired sheet position in the transport gripper on the selected reference cylinder. There is therefore a further correction possibility as a result of the torsion model.
[0033] The machine controller 20 from FIG. 1 is explained in greater detail in FIG. 2 . The machine controller 20 contains the machine computer 18 which calculates and controls all the operating processes of the printing press 1 . The machine computer 18 monitors and controls first a drive controller 17 which regulates the power requirement of the main drive motor 16 of the printing press. Second, the machine computer 18 also controls a register controller 19 which performs register adjustments in the individual printing units 6 and in the varnishing unit 7 . The machine computer 18 is therefore the heart of the machine controller 20 .
[0034] According to the invention, a torsion model of the printing press 1 is stored in the machine computer 18 in the form of software which makes it possible to calculate the torsion state of the printing press 1 as a function of the different parameters. Here, the torque which is output by the main drive motor 16 or the output performance can be suitable as operating parameters, or else the surrounding temperature or operating temperature of the printing press 1 and settings of the configuration in the individual printing units 6 of the printing press 1 . It has been shown that it is sufficient to detect, for example, the power requirement of the main drive motor 16 constantly and to feed it to the torsion model in the machine computer 18 , in order for it to be possible to determine the torsion state of the printing press 1 . Adjustment values for the register adjustment in the individual printing units 6 and in the varnishing unit 7 can then be calculated using the determined torsion state, which adjustment values are then effected by the register controller 19 . It is possible in this way to correct the register adjustment by the torsion model as a function of changing operating parameters, without it being necessary for the complicated regulating device to be provided in the printing press 1 .
[0035] A correct register setting which was performed at a low setup speed can be converted by the printer by the torsion model to any other desired printing speeds of the printing press 1 , with the result that the printer does not have to input any new values for the register adjustment in the event of changes to the printing speed.
[0036] If the printing press 1 operates in verso and recto printing operation, the coordination of the positions of the printed image on the front side and the rear side, what is known as the turning register, is also dependent on the torsion state of the printing press 1 , in addition to the register maintenance. The printing press 1 in FIG. 1 can be operated, for example, in recto and verso printing by the printing materials 22 being turned on the third turner drum 9 and therefore also being printed on the rear side in the fourth and fifth printing units 6 . In order to achieve register maintenance of the printed image on the front side and rear side of the sheet 22 , register adjustments have to be performed on the first three printing units 6 , as in pure recto printing. It is to be noted in numbers four and five of the printing units 6 that the rear side is printed here, with the result that register deviations have a different effect on the register. The spacing of the printed image of the front side from the edge of the sheet 22 can be calculated using the torsion model in the machine computer 18 , with the result that the spacing is available for the adjustment of the registers in numbers four and five of the printing units 6 . Here, numbers four and five of the printing units 6 are loaded with twice the calculated paper edge loss of the sheet 22 after turning, with the result that ultimately the printed images on the front side and rear side of the sheet 22 lie over one another with accurate register.
[0037] The profile of the paper edge loss over all the printing units 6 of a printing press 1 is shown in FIG. 3 using the example of a 10-color printing press. Here, the turning device is situated between the fourth and the fifth printing units. The paper edge loss is plotted on the vertical axis in relation to the first printing unit. The first paper edge loss is set in the second printing unit and is increased in recto and verso printing operation as far as the fourth printing unit. After turning, a paper edge gain of the same magnitude as the overall sum on the recto printing side is set at the fifth printing unit. This gain is reduced as far as the tenth printing unit. In order to counteract this, the register adjustment has to counteract the values which are shown in FIG. 3 , that is to say there must be a negative register adjustment on the recto printing side and a positive register adjustment on the verso printing side. In pure recto printing, positive correction is required only at numbers nine and ten of the printing units, whereas negative correction is required at numbers two to eight of the printing units. The correction values are calculated by the torsion model.
[0038] The present invention therefore makes particularly accurate control possible of the register maintenance in sheet-fed rotary printing presses 1 having a pure controller, without complicated regulation with register sensors being necessary. Simple retrofitting of already existing printing presses 1 with the technology according to the invention is therefore also possible, in order for it to be possible to improve their printing operation decisively.
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A method and an apparatus control a printing press having a plurality of printing units, a plurality of cylinders which are coupled mechanically to one another and a control computer for controlling at least one drive motor which drives the mechanically coupled cylinders. A torsion model is stored in the machine computer for describing the torsion state of the cylinders in the printing press which are rotatably coupled mechanically to one another, as a function of at least one measurable operating parameter or at least one variable of the printing press which is known to the machine computer. A control of the printing press is performed by the control computer on the basis of the values which are calculated by the torsion model.
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RELATED APPLICATION
This application is a continuation of application Ser. No. 08/106,910, filed Aug. 13, 1993, now abandoned, which is a divisional of application Ser. No. 07/826,839, filed Jan. 28, 1992, now U.S. Pat. No. 5,300,073, which is a continuation-in-part of application Ser. No. 07/593,196, filed Oct. 5, 1990, now U.S. Pat. No. 5,127,912.
BACKGROUND OF THE INVENTION
The present invention relates to sacral implants, and more particularly to an improved implant system for fixing a stabilizing appliance to the sacrum and to the lumbar vertebrae.
Spinal fusion, especially in the lumbar and sacral region is regularly employed to correct and stabilize spinal curves, to prevent recurrence of spinal curves and to stabilize weakness in trunks that result from degenerative discs and joint disease, deficient posterior elements, spinal fracture, and other debilitating problems. Spinal implant systems have been used regularly to stabilize the lumbar and sacral spine temporarily while solid spinal fusions develop.
Several temporary stabilization systems are currently in use. All perform adequately, however leave room for improvement. For example, an implant system for attaching the superior most lumbar vertebra (L 1 ) to the implant without interfering with normal motion of the next superior vertebra needs to be developed. Additionally, implant systems that achieve stronger sacral fixation, easier use for multiple segment fixation, and easier use with spinal deformity are needed. Further, better implant systems for rigidly tying the base of the system to the sacrum must be developed.
SUMMARY OF THE INVENTION
The present invention provides a sacral implant system that rigidly affixes the base of the implant system to the sacrum while allowing ease of installation and flexibility of design. Moreover, the present system provides apparatus for securing the upper portion of the implant system to, for example, the L- 1 vertebra, without interfering with the next superior most vertebra (T- 12 ) and any or all vertebrae in between. The sacral implant system of the present invention comprises first and second sacral plates for mounting on opposite sides of the sacrum adjacent the lumbosacral junction. Each of the sacral plates has at least a pedicle and oblique mounting means for rigidly affixing each of the sacral plates to the sacrum. The system also includes first and second rods extending in a superior direction and generally parallel relationship from respective ones of the sacral plates. The rods are situated on opposite sides of the sagittal plane. Means are also provided for rigidly affixing the rods to respective sacral plates. At least one connecting member is employed to rigidly interconnect the rods at a location superior to the sacral plates. Finally, a superior fixation plate having a lateral portion and a medial portion is employed to affix the superior most vertebra to be fused to the implant system. A pedicle screw is fixed to and through the pedicle of the vertebra. The lateral portion of the fixation plate is rigidly affixed to the pedicle screw. The medial portion of the fixation plate is offset in an inferior direction sufficiently far so that it avoids the inferior articulate process of the next superior vertebra. In this manner the next superior vertebra can move in a normal fashion relative to the vertebra to be fused during the temporary stabilization. Preferably, a lateral fixation plate is also used for pedicle fixation of intermediate vertebrae.
In another aspect of the invention, a specialized pedicle screw is provided for attachment of the offset and lateral fixation plates to the vertebra. The screw includes a first threaded portion for threading into the vertebra, a subhead portion and a second threaded portion projecting above the subhead. The second threaded portion is adapted to receive a nut. The subhead has a diameter greater than the second threaded portion and an upwardly facing shoulder lying in a plane substantially orthogonal to the axis of the screw. In use, the shoulder engages the anterior surface of the fixation plate while the nut is threaded on the second threaded portion and bears down against the posterior surface of the plate to secure the plate and screw together.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing aspects and many of the attendant advantages of this invention will become more readily appreciated as the same becomes better understood by reference to the following detailed description, when taken in conjunction with the accompanying drawings, wherein:
FIG. 1 is an isometric view of the spinal implant system of the present invention as applied to the lumbar spine;
FIG. 2 is an isometric view of a right lateral sacral plate constructed in accordance with the present invention;
FIG. 3 is a plan view (in the sacral plane) of a sacral plate shown in FIG. 2;
FIG. 4 is a cross-sectional view taken along section line 4 — 4 of FIG. 3;
FIG. 5 is a cross-sectional line taken along broken cross-sectional line 5 — 5 of FIG. 3;
FIG. 6 and FIG. 7 are elevation views of fixation screws for use with the sacral plate;
FIG. 8 is a plan view of the offset fixation plate that is constructed in accordance with the present invention;
FIG. 9 is a elevation view of a pedicle screw for use with the fixation plate of FIG. 8;
FIG. 10 is an exploded isometric view of the fixation plate and screw of FIG. 9 shown in conjunction with a fixation rod and fastening system used in accordance with the present invention;
FIG. 11 is a plan view of a straight fixation plate;
FIG. 12 is an enlarged dorsal view of a superior portion of the sacrum showing the sacral plates implanted in accordance with the present invention;
FIG. 13 is an enlarged cross-sectional view taken along section line 13 — 13 of FIG. 1 through the sacrum looking in an inferior direction at the sacral implant system of the present invention;
FIG. 14 is an enlarged cross-sectional view taken along section line 14 — 14 of FIG. 1 of the pedicle screw and offset fixation plate implanted in accordance with the present invention looking in an inferior direction;
FIG. 15 is a lateral view looking from right to left of the offset fixation plate shown in FIG. 14;
FIG. 16 is a plan view (in the sacral plane) of a second embodiment of the sacral plate shown in FIGS. 2 and 3; and
FIG. 17 is a cross-sectional view taken along broken cross-sectional line 17 - 17 of FIG. 16 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
Referring first to FIG. 1, the spinal implant system 20 constructed in accordance with the present invention is affixed to the lumbar spine, generally designated 22 . The implant system includes a pair of sacral plates 24 and 26 affixed to the sacrum 28 adjacent the lumbosacral joint. A pair of fixation rods 30 and 32 extend in a superior direction on opposite sides of the sagittal plane from the sacral plates posterior to the lumbar vertebrae L 5 , L 4 , L 3 , L 2 and L 1 . Rods 30 and 32 terminate adjacent the superior portion of vertebra L 1 . Conventional fasteners 34 and 36 securely affix the rods 30 and 32 , respectively, to the sacral plates 24 and 26 .
At the superior end of the rods, a pair of offset fixation plates 40 and 42 affix the upper ends of the rods to the L 1 vertebra. Inferior to that location, a pair of conventional inferior hooks 44 and 46 grasp the inferior portion of the L 1 vertebra to secure it relative to the rods 30 and 32 . At intermediate locations a straight fixation plate 48 is employed to affix vertebra L 3 to the rods 30 and 32 . Immediately superior to the sacral plates, a connecting member 50 rigidifies the rods 30 and 32 relative to each other. One of ordinary skill in this technique will readily recognize that one or more connecting members 50 , straight fixation plates 48 , and hooks 44 can be employed as needed.
The implant system 20 constructed and employed in accordance with the present invention provides a rigid stabilization system for the lumbar spine. The system rigidly ties the sacrum to one or more of the lumbar vertebrae. Moreover, the offset fixation plates 40 and 42 allow the upper portion of the implant system to be rigidly affixed to the superior lumbar vertebra L 1 while avoiding contact with the inferior processes of the next superior vertebra T 12 . In this manner the T 12 vertebra can move in a normal manner while stabilization of the lumbar spine occurs.
Referring now to FIGS. 2, 3 , 4 and 5 , the right sacral plate is illustrated. The right sacral plate is a mirror image of the left sacral plate; therefore, only the right plate will be described in detail. The right sacral plate 26 has a base 60 having a posterior surface and an anterior surface. The anterior surface of the plate is designed to intimately contact the posterior surface of the sacrum adjacent the lumbosacral joint. In position, the base 60 lies generally in a plane generally tangential to the portion of the sacrum adjacent the lumbosacral joint. For purposes of this description, that plane will be referred to as the sacral or dorsal plane.
A U-shaped flange 62 extends posteriorly from the medial portion of the base 60 . The medial surface of the flange 62 carries a groove 64 oriented in a superior/inferior direction for receiving a fixation rod 32 . A conventional rod clamp 68 is employed to securely and rigidly affix the rod 32 in the groove 64 on the flange 62 . The lateral portion of the sacral plate 26 carries three bores that extend from the posterior surface of the base 60 in a generally anterior direction. These bores are the pedicle bore 70 , the lateral bore 72 and the oblique bore 74 . The bores 70 , 72 and 74 , while extending in an anterior direction, are not orthogonal to the sacral plane.
Instead, the pedicle bore 70 has a cylindrical section 80 having an axis 82 extending in an anterior and medial direction that is offset in the medial direction preferably at an angle of 15 degrees to a line orthogonal to the sacral plane. A countersink bore 81 is located posterior to the cylindrical section 80 and emerges onto the posterior surface of the sacral plate. This angle can be varied from 0 degrees to 20 degrees, depending upon the particular sacral anatomy being fixed. However, it is understood that the screw that extends through this opening extends through the pedicle of the sacrum and must always lie within the pedicle. It has been found that 15 degrees is the angle most universally acceptable for this orientation. In the present embodiment, the axis 82 is not inclined in a superior or inferior direction relative to a plane perpendicular to the sacral plate. It however can be inclined superiorly so that the vertebral end plate, rather than the anterior cortex, can be engaged by the end of the screw.
The lateral bore 72 has a cylindrical section 84 having an axis 86 extending in an anterior and lateral direction that is preferably offset in the lateral direction at an angle of 30 degrees from a line orthogonal to the sacral plane. If desired, one of ordinary skill may also vary the lateral angle from 30 degrees up to 45 degrees. Preferably the axis 86 is not canted in either an inferior or superior direction relative to the sacral plate. However, depending upon the sacral anatomy, the axis can be canted from 0 degrees to 15 degrees in the superior direction when viewed in the sacral plane. A countersink bore 85 is located posterior to the cylindrical section 85 and emerges onto the posterior surface of the sacral plate.
The oblique bore 74 also has a cylindrical section 88 having an axis 90 having two offsets in the lateral and inferior directions. The axis 90 when viewed in the sacral plane is first preferably offset 45 degrees from a lateral line, but may be varied from 30 degrees to 60 degrees. Secondly, the axis 90 is offset in the lateral direction preferably 30 degrees from a line orthogonal to the sacral plane but again may be varied from 30 degrees to 45 degrees. A countersink 89 is located posterior to the cylindrical section 88 and also emerges onto the posterior surface of the sacral plate.
Referring now to FIG. 6, the pedicle screw 94 employed with the sacral plate has a unique construction. It has a lower threaded portion 96 , an upper flared head 98 and a cylindrical section 100 immediately below the head 98 . The head also carries an allen socket 102 so that the screw can be rotated into a hole drilled in the pedicle. The bone engaging threads on the lower threaded portion 96 are of conventional design. The cylindrical section 100 has a diameter slightly less than the diameter of the cylindrical section 80 of pedicle bore 70 . The diameters are chosen such that when the cylindrical section 100 is in the cylindrical section 80 , the screw 94 can rotate and reciprocate. However, the tolerances are such that the screw cannot angulate or toggle relative to the axis 82 . The upper flared portion 98 is configured to mate with countersink 81 when the screw is completely threaded into the sacrum.
Referring to FIG. 7, the same screw 106 is employed in both the lateral bore 72 and the oblique bore 74 . Screw 106 also has a lower threaded portion 108 , a flared head 110 and a cylindrical section 112 . Cylindrical section 112 is sized relative to the cylindrical sections 84 and 88 to allow rotation and reciprocation but not angulation. The flared head 110 is configured to mate with the countersinks 85 and 89 when the screws are completely threaded into the sacrum.
Referring now to FIGS. 8 and 10, the offset fixation plate 40 includes a medial portion 122 and a lateral portion 124 . The fixation plate of FIG. 8 is employed on the left side of the fixation system. A similar fixation plate, having the mirror image of plate 40 , is employed on the right side; however, it is not shown in the drawings. The lateral portion 124 carries a bore 126 that extends in a posterior/anterior direction when installed. The medial portion 122 is offset in an inferior direction from the lateral portion 124 . The medial portion 122 carries a lateral slot 127 . The anterior surface of the medial portion 122 carries a plurality of grooves 128 that extend in an inferior/superior direction and intersect the slot 127 . These grooves have a diameter equivalent to the fixation rod 30 . A conventional rod to clamp fastener 58 is employed to secure the fixation plate 40 to the fixation rod 30 .
A special pedicle screw 129 is employed with the offset fixation plate. Referring to FIG. 9, the pedicle screw includes a lower threaded portion 130 , a subhead portion 132 and an upper threaded portion 134 . The upper threaded portion 134 has an allen socket 136 extending axially into its upper end. The subhead has a diameter larger than the upper threaded portion 134 and terminates in its upward end in a shoulder 138 that is positioned in a plane orthogonal to the axis of the screw. Referring now to FIG. 10, the pedicle screw 129 is received by the bore 126 , which is sized just slightly larger than the upper threaded portion 134 so that the pedicle screw can reciprocate relative to the offset fixation plate 40 , but cannot angulate relative to the screw axis when engaging the bore 126 . A conventional nut 140 is threaded onto the upper portion 134 of the pedicle screw 129 securing the shoulder 138 against the anterior surface of the fixation plate while the nut 140 snugs against the posterior surface, thus rigidly interlocking the pedicle screw 129 and the fixation plate.
A straight fixation plate 48 is illustrated in FIG. 11 . The straight fixation plate 48 is similar in construction to the offset fixation plate 40 except that it does not contain the offset. It carries a similar bore 144 for receiving a pedicle screw similar to screw 129 , a lateral slot 146 and rod engaging grooves 148 for securing the plate 48 to a fixation rod.
Referring to FIGS. 12 and 13, in use, the sacral plates 24 and 26 are affixed to the sacrum 28 adjacent the lumbosacral junction. As desired and as necessary, the anterior surface of the sacrum can be smoothed so as to receive the anterior surface of the sacral plates 24 and 26 in snug relationship. The pedicle screws 94 and 94 ′, for use in the pedicle bores of the sacral plates, are threaded into appropriate bores made by the surgeon through the pedicle of the sacrum. The pedicle screws are snugged down so that the flared heads are seated firmly in the countersinks in the respective plates. A torque ranging from 6 to 10 in./lb. can be used to snug the screws. The physician also makes appropriate bores into the sacrum that are aligned with the lateral bores 72 and 72 ′ and with the oblique bores 74 and 74 ′. Screws 106 are inserted through the lateral and oblique bores 72 and 74 in the right plate, and bores 72 ′ and 74 ′ in the left plate. All the screws 106 are snugged down so that the flared heads seat snugly in the countersinks in the anterior surface of the sacral plates. Again a torque of 6 to 10 in./lb. is appropriate for snugging the screws into the plate.
In this manner, the three screws in each sacral plate all diverge from each other. As a result, the screws cannot be easily pulled from the bores in the bone. A force in the direction of the axis of one of the screws will be partially distributed over the bone on which the remaining two screws bear. In this manner, full force cannot be exerted in the direction of the axis of a single screw and thus a single screw cannot be sheared from its bore in an easy manner. This construction provides significant advantages over the prior art while allowing independent placement of a sacral plate on each side of the sacrum. For example, screw placement is designed to achieve fixation in the proximal part of the sacrum, which has the strongest bone. The oblique screw is designed to be proximal to and parallel the S 1 foramin, thereby avoiding damage to the S 1 nerve. The medial screw is inclined medially to allow bicortical fixation while avoiding neurovascular structures directly anterior to the S 1 pedicle. The lateral screw is also designed to allow bicortical fixation lateral to the significant neurovascular structures.
Referring now to FIGS. 14 and 15, offset fixation plates 40 and 42 are shown affixed by conventional fasteners 58 to fixation rods 30 and 32 . The pedicle screws 129 are threaded into suitable bores in the left and right pedicle 150 and 152 of the L 1 vertebra. Nuts 140 are threaded onto the upper portions of the pedicle screws 129 and tightened against the anterior surfaces of the fixation plates 40 . The fasteners 58 thereafter are tightened to secure the other end of the plate to the fixation rods 30 and 32 . In this manner, the upper end of the lumbar spine implant system can be secured to the L 1 vertebra without interfering with the next superior vertebra.
Referring now to FIGS. 16 and 17, a second embodiment of a right sacral plate 150 according to the present invention is shown. A left sacral plate is configured as a mirror image of the right sacral plate; therefore, only the right sacral plate will be described in detail. The sacral plate 150 has a base 152 having a posterior surface and an anterior surface. The anterior surface of the plate is designed to intimately contact the posterior surface of the sacrum adjacent the lumbosacral joint. In position, the base 152 lies in a plane generally tangential to the portion of the sacrum adjacent the lumbosacral joint.
A U-shaped flange 154 is configured in the same way as flange 64 shown in FIG. 2 . The medial surface of the flange 154 carries a groove 156 oriented in a superior/inferior direction for receiving a fixation rod 32 that is held in place with a conventional rod clamp 68 as shown in FIG. 2 . The lateral portion of the sacral plate 150 carries two bores that extend from the posterior surface of the base 152 in a generally anterior direction. These bores are the pedicle bore 158 and the oblique bore 160 . The bores 158 and 160 , while extending in the anterior direction, are not orthogonal to the sacral plane.
The pedicle bore has a cylindrical section 162 having an axis 164 extending in an anterior and medial direction that is offset in the medial direction preferably at an angle of 15 degrees to a line orthogonal to the sacral plane. A countersink bore 166 is located posterior to the cylindrical section 162 and emerges onto the posterior surface of the sacral plate. The angle of the axis 164 can be varied from 0 degrees to 20 degrees, depending upon the particular sacral anatomy being fixed. However, it is understood that a screw that extends through this opening into the pedicle of the sacrum must always lie within the pedicle. In the present embodiment of the sacral plate 150 , the axis 164 is not inclined in the superior or inferior direction relative to a plane perpendicular to the sacral plate. However, the axis can be inclined superiorly so that the vertical end plate rather than the anterior cortex can be engaged by the end of the screw.
The oblique bore 160 also has a cylindrical section 166 having a axis 168 having two offsets in the lateral and inferior directions. The axis 168 when viewed in the sacral plane is first preferably offset at 45 degrees from a lateral line, but may be varied from 30 degrees to 60 degrees. Secondly, the axis 168 is offset in the lateral direction preferably 30 degrees from a line orthogonal to the sacral plane but again may be varied from 30 degrees to 45 degrees. A countersink 170 is located posterior to the cylindrical section 166 and also emerges onto the posterior surface of the sacral plate.
The sacral plate 152 is designed for patients having a lumbosacral joint that is too small to accept the sacral plate 26 shown in FIGS. 2 and 3. By providing a sacral plate 150 having only the pedicle bore and oblique bore, the sacral implant system according to the present invention can be adapted to fit patients having smaller skeletal structures.
The present invention has been described in connection with the preferred embodiment. However, one of ordinary skill will be able to effect various alterations, substitutions of equivalents and other changes without departing from the broad concepts imparted herein. It is, therefore, intended that the letters patent issued hereon be limited only by the definition contained in the appended claims and equivalents thereof.
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An implant system for spinal fixation includes a fastener having an upper portion, a lower portion configured to engage a vertebra, and a shoulder between the upper and lower portions. A connector is provided for engaging the fastener to an elongated rod that is positionable along the spinal column laterally from a line containing the axis of the fastener. The connector includes a first portion for engaging the upper portion of the fastener adjacent the shoulder, and an integral second portion having a surface for engaging the elongated spinal rod. The connector further includes an elongated slot between the first portion and the second portion to permit relative lateral adjustment between the rod and the upper portion of the fastener. A threaded fastener is provided for clamping the rod against the surface of the connector. In one embodiment, the fastener includes an eyebolt defining an aperture for receiving the spinal rod. In another embodiment of the invention, the connector includes an elongated plate that defines a slot through which the second portion of the fastener is received. This slot includes a plurality of grooves on a surface of the plate facing the rod, each of the grooves configured to receive a portion of the rod therein.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a passenger conveyer, and in particular to a driving pulley which drives a hand rail and more particular to a driving pulley which is capable of controlling a moving speed of a hand rail.
2. Description of Related Art
Generally, a passenger conveyer is installed in an airport, subway, building, etc. and is an apparatus for effectively conveying passengers from a position to another position. As examples of a passenger conveyer, an escalator is known for conveying passengers from one position to another position at a different height, or a moving walkway for conveying passengers horizontally from one position to another position.
The above-described passenger conveyer includes a plurality of steps on which a passenger steps, a pair of balustrades each of which are installed uprightly and continuously near each side of the steps from a boarding position to a taking-off position, hand rails movably installed on the balustrade and moving along a predetermined loop, and a driving apparatus for driving the steps and the hand rails.
The conventional passenger conveyer will be explained with reference to the escalator.
First, FIG. 1 is a schematic lateral cross-sectional view illustrating a conventional escalator. As shown therein, reference numeral 11 represents a plurality of steps 11 on which passengers stand. The steps 11 are connected with a step chain 44 and move along a predetermined loop depending on a driving operation of the step chain 44. The connection of the steps 11 and the step chain 44 will be explained in more detail with reference to FIGS. 2A and 2B.
A pair of balustrades 21 are installed uprightly and continuously near side edges of the steps, from the boarding position of the passengers to the stepping-off position of the passengers for providing a lateral boundary of the passenger conveyor. A hand rail guide(not shown) is fixedly installed at each upper surface of the balustrades 21.
The hand rail 20 is guided by the hand rail guide and surrounds the balustrades 21. Reference numeral 32A is a transmission output sprocket connected with an output shaft of the transmission which increase the rotation driving torque of a driving motor(not shown). The transmission output sprocket 32A, and the connection and driving force transfer structure of the transmission and the motor will be explained with reference to FIGS. 3A and 3B.
The transmission output sprocket 32A is driven by a pair of step driving sprockets 42a and 42b via driving chain 33.
The step driving sprockets 42a and 42b are connected with pair of step driven sprockets 46a and 46b installed below the lower balustrades 21 of the escalator. The step driving sprockets 42a and 42b are drivingly connected with a hand rail driving pulley 60 through a driving force transfer chain(not shown).
A part of the loop of the hand rail 20 is wound on the driving pulley 60 and is moved by the rotation of the hand rail driving pulley 60.
The operation of the conventional escalator will be explained.
When rotating the motor shaft by supplying power to the motor, the transmission connected with the output shaft of the motor increases or decreases the driving torque of the motor by using the gears installed therein. The transmission output sprocket 32A connected with the output shaft of the transmission is rotated, and the rotation force of the transmission sprocket 32A is transferred to the step driving sprockets 42a and 42b through the driving chain 33. Therefore, the step driving sprockets 42a and 42b are rotated, and the step chain 44 and the step driven sprockets 46a and 46b connected with the step driving sprockets 42a and 42b are rotated. The steps 11 connected with the step chain 44 are moved upwardly or downwardly. Since the hand rail driving pulley 60 is connected with the step driving sprockets 42a and 42b, when the step driving sprockets 42a and 42b are rotated, the hand rail driving pulley 60 is rotated thereby moving the hand rail 20. As a result, when passenger boards on the step 11, the passenger is conveyed upwardly or downwardly with his hands holding the hand rail 20.
FIGS. 2A and 2B are front and lateral views illustrating a connection between the step 11 and the step chain 44.
As shown therein, the step 11 includes a pair of horizontally extending front wheel roller rotation shafts 11c passing through the step chain 44 from a predetermined position of the upper sides of the step 11, and a pair of horizontally extending rear wheel roller rotation shafts 11d from lower sides of the step.
A pair of front wheel rollers 11a are rotatably installed on the front wheel roller rotation shafts 11c, and a pair of rear wheel rollers 11b are rotatably installed on the rear wheel roller rotation shafts 11d. Therefore, when the step chain 44 rotates, since the front wheel roller rotation shafts 11c are connected with the step chain 44, the step 11 moves in the same direction as the step chain 44.
FIG. 3A is a schematic perspective view illustrating a step and a driving unit which drives the step, and FIG. 3B is a plan view illustrating a driving connection relationship between a driving unit and a hand rail driving unit of FIG. 3A.
As shown therein, the motor 31 is connected with the transmission 32. A plurality of transmission gears(not shown) of transmission 32 are connected with an output shaft of the motor 31, so that the rotation torque from the output shaft of the motor 31 is increased and the rotation velocity of the output shaft is decreased.
The transmission output sprocket 32a is connected with an output of the transmission 32 and is rotated by the rotation torque from the transmission 32.
The main sprocket 43 is drivingly connected with the transmission output sprocket 32a through the driving chain 33.
Therefore, when the transmission output sprocket 32a is rotated, rotation torque is transferred to the main sprocket 43 through the driving chain 33 for rotating the main sprocket 43. The main sprocket 43, the step driving sprockets 42a and 42b and one hand rail driving sprocket 52 are coaxially connected with the main driving shaft 41, so that they are all rotated together with the main driving shaft 41. The main driving shaft 41 is supported by a support and rotates as the main sprocket 43 rotates. The hand rail driving sprocket 52 is drivingly connected with the hand rail driven sprocket 53 through the hand rail chain 54. Therefore, when the hand rail driving sprocket 52 is rotated, the rotation torque is transferred to the hand rail driven sprocket 53. The hand rail driven sprocket 53 is rotatably engaged to the hand rail driving shaft 51, and a pair of hand rail driving pulleys 60 are coaxially engaged to the hand rail driving shaft 51.
Therefore, when the motor 31 is rotated, the rotation torque of the motor is increased or decreased by the transmission for rotating the transmission output sprocket 32a. The rotation torque of the transmission output sprocket 32a is transferred to the main sprocket 43 through the driving chain 33 for rotating the main sprocket 43. The rotation torque of the main sprocket 43 is transferred to a pair of the step driving sprockets 42a and 42b and one hand rail driving sprocket 52 through the main driving shaft 41.
Therefore, as the step chain 44 rotates, the step 11 is moved upwardly or downwardly, so that passengers are moved to a predetermined floor or destination. When the hand rail driving sprocket 52 is rotated, the rotation torque is transferred to the hand rail driven sprocket 53 through the hand rail chain 54 for rotating the hand rail driven sprocket 53.
Therefore, the hand rail driving pulleys 60 coaxially connected with the hand rail driven sprocket 53 and the hand rail driving shaft 51 are rotated thereby rotating the hand rail 20.
The driving connection relationship between the hand rail driving pulley 60 and the hand rail 20 will be explained in detail with reference to FIG. 4.
The transmission output sprocket 32a is drivingly connected with the main sprocket 43 through the driving chain 33. The hand rail driving sprocket 52 is coaxially connected with the main sprocket 43. The hand rail driving sprocket 52 is drivingly connected with the hand rail driven sprocket 53 through the hand rail chain 54. A first tension compensating roller 54a is installed at an upper location between the hand rail driving sprocket 52 and the hand rail driven sprocket 53 for compensating the tension of the hand rail chain 54. As a result, the hand rail chain 54, which receives a driving force from the hand rail driving sprocket 52 moves to the hand rail driven sprocket 53 through the tension compensating roller 54a in a state that the tension is tightly compensated. The second tension compensating roller 20a is installed at a location between the hand rail driving pulley 60 and the balustrades 21 for tightly compensating the tension of the hand rail 20. Reference numerals 62a and 62b represent pressure belt rollers which support the pressure belt 63 which is installed to contact the hand rail 20 below the hand rail driving pulley 60 so as to increase a friction force between the hand rail driving pulley 60 and the hand rail 20. Therefore, the rotation torque from the transmission output sprocket 32a is transferred to the main sprocket 43 through the driving chain 33, so that when the main sprocket 43 is rotated, the hand rail driving sprocket 52 coaxially connected with the main sprocket 43 is rotated. The rotation torque of the hand rail driving sprocket 52 is transferred to the hand rail driven sprocket 53 through the hand rail chain 54 in a state that the tension is compensated by the first tension force control roller 54a. When the hand rail driven sprocket 53 is rotated, the driving pulley 60 coaxially connected with the sprocket 53 is rotated therefore, the hand rail 20 closely contacts with the driving pulley 60 by a pressure of the pressurizing belt 63 and rotates along the balustrades 21 by a friction force with the driving pulley 60.
The construction and operation of the conventional hand rail driving pulley unit, hand rail and pressurizing belt will be explained with reference to FIGS. 5A and 5B.
The conventional hand rail driving pulley unit includes a hand rail driving shaft 51. A boss portion 60a has a through hole into which the hand rail driving shaft 51 is inserted. A spoke member 60 has three spoke portions 60b extending radially extended from the boss portion 60a. A main wheel 66 has a flange portion 66. Three support members 64, (namely, engaging members), engage for engaging the main wheel 66 and the spoke members 60. A bolt 65a supports the head portion to the support member 64 and passes through the main wheel 66 and the spoke member 60. A nut 65b is engaged with the threaded portion of the bolt inserted through the main wheel 66 and the spoke member 60. A ring-shaped elastic friction member 61 is adhered on the outer circumferential surface of the main wheel 66.
As shown in FIG. 5A, the main wheel 66 is ring-shaped, and as shown in FIG. 5B, the lateral cross-section of the same is L-shaped. The main wheel 66 includes three bolt insertion holes each of which formed at about an angle of 120 degrees so that the bolts 65a are inserted thereinto. The main wheel 66 is preferably made of a metallic material having a good mechanical strength. The support member 64 is used in order to increase the mechanical durability of the main wheel 66 which may be decreased because of the holes of the bolt insertion holes after the spoke member 60 is connected with the main wheel 66 using the bolt 60a and the nut 60b. The spoke member 60 is used for drivingly coupling the hand rail driving shaft 51 to the main wheel 66. One hole in which the bolt 60a is inserted is formed at a portion contacting the main wheel 66 among the spokes. Therefore, the bolt which passes through a center hole among three bolts inserted into one support member 64 passes through the main wheel 66 and the spoke member 60. The remaining two bolts only pass through the main wheel 66. The hand rail driving pulley unit frictionally contacts the hand rail 20 for moving the hand rail 20, so that the friction member 61 is formed by winding a band formed of an elastic resin material such as rubber onto an outer circumferential surface of the main wheel 66. The upper surface of the friction member 61 which contacts the outer circumferential surface of the main wheel 66 is flat in order to increase a bonding force with the outer surface of the main wheel 6. In addition, the outer surface of the main wheel 66 is flat in order to implement a full contact with the friction member 61.
The pressure belt 63 is positioned higher than the portion of the friction member 61 in which the belt surface contacts with the hand rail 20 in order to increase the contact area of the hand rail 20 contacting with the friction member 61, so that as shown in FIG. 5A, the pressure belt 63 is downwardly deflected by the hand rail driving pulley unit.
In this state, an elastic restoring force of the upper surface of the pressure belt 63 is applied to upwardly press the hand rail 20 between the pressure belt 63 and the friction member 61. Therefore, the hand rail 20 closely contacts with the friction member 61. The pressure belt 63 is supported by the belt rollers 62a and 62b which maintain tension in the pressure belt 63. The pressure belt 63 reciprocates between the belt rollers 62a and 62b by the friction force of the hand rail 20 when the hand rail 20 is moved by the rotation of the friction member 61.
The operation of the conventional hand rail driving pulley unit will be explained.
When the driving force is applied through the hand rail chain 54, and the hand rail driven sprocket 53 is rotated, the spoke member 60b drivingly connected with the hand rail driven sprocket 53 through the hand rail driving shaft 51 is rotated.
Therefore, the main wheel 66 connected with the spoke member 60b by the engaging member is rotated, and the friction member 61 fixed to the outer surface of the main wheel 66 is rotated. The hand rail 20 is rotated along the frames by the friction with the friction member 61 which is rotated by the pressure from the pressure belt 63.
In the thusly constituted conventional passenger conveyer, it is very important to move the step 11 and the hand rail 20 at a same speed so that safety of the passengers may be protected.
The motor 31, the transmission 32, the driving force transfer driving chain 33, and the main driving shaft 41 are used as a common driving unit for driving the step 11 and the hand rail 20 at the same speed. Furthermore, the diameters of the hand rail driving sprocket 52 and the hand rail driven sprocket 53 are same and the driving operation of the same is implemented by the chain 54. The hand rail 20 is driven by the main wheel 66 which is coaxially connected with the hand rail driven sprocket 53.
By above mentioned construction, the step 11 and the hand rail 20 may be moved at the same speed.
However, the friction member 62 and the hand rail 20 may wear down over time, so the friction force between the friction member 61 and the hand rail 20 decreases. Therefore, a speed difference occurs between the moving speeds of the step 11 and the hand rail 20. In particular, since the circumference of the friction member 61 is very short relative to the entire length of the hand rail 20, wearing down of the friction member 61 may occur quickly compared to wearing down of the hand rail 20. Thus, moving speed difference between the step 11 and the hand rail 20 is mainly due to the wear of the friction member 61.
However, in the conventional passenger conveyer, since the wear of the friction member is not compensated for, in order to compensate for the resultant speed difference, the worn-down friction member 61 must be removed from the main wheel 60 and replaced with a new friction member bonded on an outer surface of the main wheel 60 to compensate the speed difference. In addition, there no other way for overcoming the speed difference problem except for substituting a new hand rail when the old hand rail is worn.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a passenger conveyer which is capable of compensating for a speed difference between a hand rail and steps without having to replace a friction member or a hand rail.
It is another object of the present invention to provide a passenger conveyer in which a friction member can be quickly replaced.
Therefore, a passenger conveyer including: a motor for generating a driving torque; a transmission for shifting the driving torque from the motor; a driving sprocket drivingly coupled with the transmission and being rotated by the driving torque transferred from the transmission; a driven sprocket rotatable in correspondence with the rotation of the driving sprocket; an endless loop step chain wound onto the driving sprocket and the driven sprocket and being moved between the sprockets by the rotation of the driving sprocket; a plurality of steps drivingly coupled with the step chain and moving along the movement of the step chain; a pair of balustrades for providing a lateral boundary of the passenger conveyor; a pair of endless loop shaped hand rails each of which moves in the same direction as the moving direction of the steps along the balustrade; a hand rail guide member continuously installed on the upper surfaces of the balustrades for providing a guide surface on which the hand rails move; a hand rail driving pulley assembly rotatable in correspondence the rotation of the driving sprocket for providing a driving force to the hand rail by contacting with the hand rail and having an adjustable radius between the rotation center and a surface contacting with the hand rail for adjusting a moving speed of the hand rail; and a driving force transfer member for transferring a rotation force of the driving sprocket to the hand rail driving pulley assembly.
More particularly, a hand rail driving pulley according to the present invention includes: a driving shaft rotating by a rotation force transferred from the driving force transfer member for rotating the hand rail driving pulley assembly; a main wheel rotating by the rotation of the driving shaft, with the driving shaft passing through the center portion of the main wheel; a movable member disposed to be opposite to one surface of the main wheel and being movable between a position which is spaced-apart from the main wheel in an axial direction and a approached position to the main wheel in an axial direction, wherein a groove having a variable width is formed between opposing surfaces of the main wheel and the movable member; an elastic member positioned between the main wheel and the movable member for biasing the movable member away from the main wheel; a clamping mechanism for adjusting the width of the groove and clamping the main wheel, the movable member and the elastic member for maintaining the adjusted width of the groove; and a contacting ring having at least one surface variable in depth which is inserted into the groove depending on the adjusted width and another surface for providing a friction force to the hand rail and to move the hand rail.
According to the present invention, a hand rail driving pulley mechanism may comprise; a driving shaft which rotates by the rotation force transferred from the driving force transfer member, thereby rotating the hand rail driving pulley assembly; a main wheel mounted on the driving shaft and being rotated by the rotation of the driving shaft; a pair of movable members opposing each other, each of which is movable between a position axially spaced-apart from the main wheel in an axial direction and a approached position to the main wheel in an axial direction, wherein a variable width groove is formed between both opposing surfaces of the movable member; a pair of elastic members disposed between the main wheel and the movable members for biasing the movable members to be apart from the main wheel; a clamping mechanism for clamping the main wheel, the movable member and the elastic member for adjusting the width of the groove and maintaining the adjusted state; and a contacting ring having at least one surface variable in depth which is inserted into the groove depending on the adjusted width and another surface for providing a friction force to the hand rail and to move the hand rail.
Additional advantages, objects and features of the invention will become more apparent from the description which follows.
BRIEF DESCRIPTION OF THE DRAWINGS
The present invention will become more fully understood from the detailed description given hereinbelow and the accompanying drawings which are given by way of illustration only, and thus are not limitative of the present invention, and wherein:
FIG. 1 is a schematic lateral cross-sectional view illustrating a conventional escalator;
FIGS. 2A and 2B are front and side views illustrating respectively a connection structure of a step and a step chain;
FIG. 3A is a schematic perspective view illustrating a step and a driving unit which drives the step;
FIG. 3B is a plan view illustrating a driving connection relationship between a driving unit and a hand rail driving unit of FIG. 3A;
FIG. 4 is a partial cross-sectional view illustrating a driving connection relationship between a hand rail driving pulley and a hand rail;
FIGS. 5A and 5B are front and partial lateral cross-sectional views illustrating the construction of a conventional hand rail driving pulley unit, hand rail and pressure belt;
FIG. 6A is a front view illustrating the construction of a hand rail driving pulley unit, hand rail and pressure belt according to the present invention;
FIG. 6B is a lateral cross-sectional view illustrating a hand rail driving pulley unit according to the present invention;
FIG. 7 is an partially enlarged side cross-sectional view of a portion of FIG. 6B with respect to a hand rail driving pulley unit according to the present invention;
FIG. 8A is a lateral cross-sectional view illustrating a hand rail driving unit in order to explain a state that the radius from the center of a main wheel to an outer surface of a contact ring is decreased by adjusting a movable member to be apart from a main wheel in a hand rail driving pulley unit according to the present invention;
FIG. 8B is a partial lateral cross-sectional view illustrating a hand rail driving pulley unit in order to explain a state that the radius from the center of a main wheel to an outer surface of a contact ring is increased by adjusting a movable member closely to a main wheel in a hand rail driving pulley unit according to the present invention;
FIG. 9 is a partial lateral cross-sectional view illustrating a hand rail driving pulley unit according to another embodiment of the present invention;
FIG. 10 is a partial lateral cross-sectional view illustrating a contact ring according to the present invention;
FIG. 11 is a partially enlarged side cross-sectional view similar to that shown in FIG. 7 of another embodiment of the present invention; and
FIG. 12 is a partially enlarged side cross-sectional view similar to that shown in FIG. 9, but of yet another embodiment of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The embodiments of the present invention will be explained with reference to the accompanying drawings.
The passenger conveyer according to the present invention is similar to the conventional passenger conveyer in their construction and operation except for the hand rail driving pulley unit. Therefore, only the construction and operation of the hand rail driving pulley unit will be explained. The parts and elements which are similar to those in the conventional art will be assigned identical reference numerals and their repeated detailed description will be omitted.
Referring to FIG. 6A illustrating the construction of a hand rail driving pulley unit, hand rail and pressure belt according to the present invention as a front view and FIG. 6B illustrating a hand rail driving pulley unit according to the present invention as a lateral cross-sectional view, the present invention will be explained as followed.
The hand rail driving pulley unit according to the present invention includes a driving shaft 51 rotated by a rotation torque transferred from a chain 54 of FIG. 3B, which is a torque transferring member for rotating the hand rail driving pulley unit. A main wheel 110 is installed on the driving shaft 51 and is rotated by the driving shaft. A movable member 120 is disposed to be opposite to one surface of the main wheel 110 and is movable between a position which is spaced-apart from the main wheel 110 in an axial direction and proximate to the main wheel 110 in an axial direction. A variable width groove 143 is defined between opposing surfaces of the main wheel 110 and the movable member 120. An elastic member 150 is positioned between the main wheel 110 and the movable member 120 for biasing the movable member away from the main wheel 120. A clamping mechanism 131, 132 is provided for adjusting the width of the groove 143 and clamping the main wheel 110, the movable member 120 and the elastic member 150 to maintain the adjusted width of the groove 143. Finally, a contacting ring having slant surfaces 160a, 160b variable in depth is inserted into the groove 143 depending on the adjusted width thereof and having another surface 160c for providing a friction force to the hand rail to move the hand rail.
Since the construction and operation that the rotation torque is generated for rotating the driving shaft 41 and is transferred to the driving shaft 51 are described in FIG. 3B, the description thereof will not be repeated.
The main wheel 110 includes a boss portion 110a for transferring the rotation torque of the driving shaft 51 to the main wheel 11 having a center portion into which the driving shaft 51 is inserted. Three spoke portions 110b radially extend from the boss portion 110a at about 120 degrees. A ring-shaped flange portion 110c integrally connects the extended portions of the spoke portions 110b. Therefore, when the driving shaft 51 is rotated, the rotation torque is transferred to the flange portion 110c through the boss portion 110a and the spoke portions 110b, so that the main wheel 110 is rotated together with the driving shaft 51.
The flange portion 110c includes one surface stepped from the spoke portions 110b. The ring-shaped movable member 120 is axially movable between a position spaced-apart from the surface of the main wheel 110 and a position proximate to the surface of the main wheel 110.
A groove is defined between one surface of the opposite flange portion 110c and the movable member 120 along the outer surface of the main wheel 110. A part of the elastic contact ring 160 is inserted into the groove.
The clamping units 131 and 132 include a plurality of bolts 131 and a plurality of nuts 132. The bolt 131 has a threaded portion passing through the flange portion 110c and the movable member 120 that is engaged with the nut 132 to thereby clamp the movable member 120 and the main wheel 110. A plurality of clamping units 131 and 132 are installed along the ring-shaped upper surface of the movable member 120 and the flange portion 110c at predetermined intervals.
The hand rail driving pulley unit according to one embodiment of the present invention illustrated in FIGS. 6A, 6B now will be explained with reference to FIG. 7.
The surface of the flange portion 110c of the main wheel 110 opposite to the movable member 120 includes plane surface 112 and slant surface 142. The movable member 120 includes plane surface 122 and the slant surface 141 which are opposite to plane surface 112 and slant surface 142 of the main wheel 110.
An elastic member 150 is installed between plane surface 112 of the main wheel 110 and plane surface 122 of the movable member 120.
The elastic member 150 may be formed of a rubber, a spring (see FIGS. 11 and 12), etc.
A through hole 111, a through hole 151, and a through hole 121 are axially formed at the flange portion 110c of the main wheel 110, the elastic member 150 and the driving member 120.
The head portion of the bolt 131 is supported by the upper surface of the movable member 120, and the threaded portion passes through the through holes 121, 151 and 111. The nut 132 is engaged with the threaded portion, so that main wheel 110, the elastic member 150 and the movable member 120 are clamped by the clamping members 131 and 132.
Since the boss portion 110a in the main wheel 110 is axially fixed to the driving shaft 51, the elastic member 150 biases the movable member 120 away from the main wheel 110. Therefore, the movable member 120 is spaced-apart from the main wheel 110 or becomes close to the main wheel 110 by adjusting the engagement of clamping members 131 and 132.
The elastic force of the elastic member 150 is zero when the movable member 120 is most spaced-apart from the main wheel 110, and the elastic energy of the elastic member 150 is largest at the position nearest the main wheel 110.
Slant surface 142 of the main wheel 110 and slant surface 141 of the movable member 120 form a groove 143 into which a part of the contact ring 160 is inserted. The contact material 160 is formed of an elastic ring such as a rubber, etc. When the elastic energy is zero, (i.e., when the contact ring 160 is not deflected by an external force), it is desirable for the diameter of the contact ring 160 to be smaller than the main wheel 110.
When moving the movable member 120 towards or away from to the main wheel 110 by controlling the clamping members 131 and 132, the width of the groove 143 changes. Therefore the insertion depth that the contact ring 160 is inserted into the groove 143 changes depending on the width of the groove 143. The contact ring 160 includes a surface inserted into the groove 143 and another surface for applying a friction force for moving the hand rail. The surface of the contact ring 160 inserted into the groove 143 has slant surfaces 160a and 160b corresponding to slant surface 141 of the movable member 120 and slant surface 142 of the main wheel 110. There is another plane surface 160c in the contact ring 160 for providing a friction force for moving the hand rail.
Since slant surfaces 160a and 160b are inserted into the groove 143 correspondence with slant surfaces 141 and 142 of the movable member 120 and the main wheel 110, the contact ring 160 smoothly into or slides out from the groove 143.
FIG. 8A is a lateral cross-sectional view illustrating a hand rail driving pulley unit in order to explain decreasing the radius from the center of a main wheel to an outer surface of a contact ring by adjusting the spacing between movable member 120 and main wheel 110. FIG. 8B is a partial lateral cross sectional view illustrates increasing the radius from the center of a main wheel to an outer surface of a contact ring by adjusting the spacing between movable member 120 and main wheel 110 to become close.
Referring to FIG. 8A and FIG. 8B, the operation and effects of the speed control of the hand rail according to the present invention will be explained.
When moving the movable member 120 away from the main wheel 110 by controlling the clamping units 131 and 132, the width of the groove 143 increases, and the depth that the contact ring 160 slides into the groove 140 increases. As the depth that the contact ring 160 slides into the groove 140 increases, the radius from the rotation center of the main wheel 110 to the plane surface 160c of the contact ring 160 contacting with the hand rail 20, (i.e., the rotation radius of the hand rail driving unit R1) decreases.
The above-described state is shown in FIG. 8A. At this time, the length of the elastic member 150 is G1. In this state, since the friction force between the contact ring 160 and the hand rail 20 is decreased, the moving speed of the hand rail 20 thus becomes slower.
When moving the movable member 120 towards the main wheel 110 by adjusting the clamping units 131 and 132, the width of the groove 143 decreases, and the depth that the contact ring 160 slides into the groove 143 decreases. As the depth that the contact ring 160 slides into the groove 143 decreases, the radius from the rotation center of the main wheel 110 to the plane 160c of the contact ring 160 contacting with the hand rail 20, (i.e., the rotation radius of the hand rail driving pulley unit) increases. The above-described state is shown in FIG. 8B. At this time, the length of the elastic member 150 is G2. In this state, since the friction force between the contact ring 160 and the hand rail 20 is increased, the moving speed of the hand rail 20 is increased.
FIG. 9 is a partial lateral cross-sectional view illustrating the hand rail driving pulley unit according to another embodiment of the present invention.
The main wheel 210 includes a flange portion 210a stepped down from the outer end portion, a boss portion(not shown) axially fixed to the driving shaft 51 for drivingly coupling the main wheel 210 and the driving shaft 51, and three spoke portions(not shown) radially extending from the boss portion for connecting the flange portion 210a and the boss portion.
The flange portion 210a includes planes 210b and 210c which are opposite to flat surfaces 242a and 242b of the movable members 220a and 220b.
A pair of axially movable members 220a and 220b are disposed between a position spaced-apart from the planes 242a and 242b of the flange portion 210a and the position proximate to the planes 242a and 242b. The movable member 220a has a plane 242a and a slant surface 241a, and the movable member 220b has a plane 242b and a slant surface 241b.
A elastic member 212a is disposed between the plane 242a of the movable member 220a and the plane 210b of the flange portion 210a, and another elastic member 212b is disposed between the plane 242b of the driving member 220b and the plane 210c of the flange portion 210a, The main wheel 210 is installed on the driving shaft 51 fixedly in the axial direction so that the center portion of the boss portion passes through the driving shaft 51. Therefore, the elastic member 212a provides an elastic force so that the movable member 220a is biased away from the plane 210b of the flange portion 210a, and the elastic member provides an elastic force so that the movable member 220b is biased away from the plane 210c of the flange portion 210a.
Shaft holes are formed in the movable members 220a and 220b, the flange portion 210a, and the elastic members 212a and 212b. The clamping units 231 and 232 are installed for variably adjusting the movable members 220a and 220b between a position spaced-apart from the planes 242a and 242b of the flange 210a and a position proximate to the planes 242a and 242b with respect to the flange portion 210a and for maintaining the adjusted position by clamping the movable members 220a and 220b, the flange portion 210a, and the elastic members 212a and 212b. The clamping units 231 and 232 each include a bolt 231 having its head portion supported by the movable member 220a and passing through the shaft hole, and a nut 232 engaged with the threaded portion formed on the bolt 231 passing through the shaft hole.
Therefore, the movable members 220a and 220b are axially movable by adjusting the clamping units 231 and 232.
The elastic force of the elastic members 212a and 212b, is zero when the movable members 220a and 220b are most spaced-apart from the main wheel 110, and the elastic energy of the elastic members 212a and 212b is largest when the movable members 220a and 220b are nearest the main wheel 210.
Slant surfaces 241a and 241b of the movable members 220a and 220b define a groove 243 into which a part of the contact ring 260 is inserted. The contact ring 260 is made of an elastic member such as a rubber. When the elastic energy is zero, (i.e., when the contact ring 260 is not extended), the radius of the contact ring 260 is smaller than the radius which is obtained by adding the radius from the center of the main wheel 210 and the distance to the outer diameter of the movable members 220a and 220b.
When moving the movable members 220a and 220b, the width of the groove 243 changes, and the depth that the contact ring 260 is inserted into the groove 243 changes depending on the width of the groove 243.
The contact ring 260 includes a surface inserted into the groove 243 and another surface contacting the hand rail 20, thereby generating a friction force for moving the hand rail 20. The surface of the contact ring 160 inserted into the groove 243 includes slant surfaces 260a and 260b corresponding with slant surfaces 241a and 241b of the movable members 220a and 220b, and another surface by which a friction force is generated for moving the hand rail is a plane 260c.
Slant surfaces 260a and 260b of the contact ring 260 inserted into the groove 243 and the opposite slant surfaces 241a and 241b of the movable members 220a and 220b are formed correspondingly with one another, so that the contact ring 260 smoothly and quickly slides radially into or out from the groove 243.
When moving the movable members 220a and 220b by adjusting the clamping units 231 and 232, the width of the groove 243 increases, so that the depth that the contact ring 260 slides into the groove 243 increases. When the depth that the contact ring 260 slides into the groove 243 increases, the radius from the rotation center of the main wheel 210 to the plane 260c of the contact ring 260 contacting with the hand rail 20, (namely, the rotation radius of the hand rail driving wheel unit) decreases. In this state, since the friction force between the contact ring 260 and the hand rail 20 is decreased, the moving speed of the hand rail 20 will be slower.
When moving the movable members 220a and 220b to the main wheel 210 by adjusting the clamping units 231 and 232, the width of the groove 243 decreases, so that the depth that the contact ring 260 slides into the groove 243 is decreases.
Therefore, the radius from the rotation center of the main wheel 210 to the plane 260c of the contact ring 260 contacting with the hand rail 20, (namely, the rotation radius of the hand rail driving wheel unit) increases. In this state, since the friction force between the contact ring 260 and the hand rail 20 increases, the moving speed of the hand rail 20 will be faster.
FIG. 10 is a partial lateral view illustrating a contact ring according to the present invention. The construction and operation of the contact ring according to the present invention will be explained with reference to FIG. 10.
As shown in FIGS. 8A, 8B and 9, in the contact ring according to one and another embodiment of the present invention, the contact rings 160 and 260 each preferably include concave portions 160c', 260c' and convex portions 160c" and 260c". The concave portions 160c' and 260c' and the convex portions 160" and 260c" increase the friction force between the contact rings 160 and 260 and the hand rail 20.
The procedure for changing the contact rings according to the present invention will be explained.
In a state that the contact rings 160 and 260 are inserted into the grooves 143 or 243 by a shallow depth by adjusting the clamping unit when exchanging the contact rings 160 and 260, a part of the contact rings 160 and 260 is manually pulled, the contact rings 160 and 260 made of an elastic material such as a rubber are extended, so that the contact rings 160 and 260 are separated from the groove 143 or 243. Thereafter, the remaining parts of the contact rings 160 and 260 are removed. When inserting new contact rings 160 and 260, parts of the contact rings 160 and 260 are inserted into an upper portion among the surrounding portions of the groove 143 or 243, and parts of the contact rings 160 and 260 are manually pulled, so that the contact rings 160 and 260 are extended for thereby exchanging the same.
As described above, in the present invention, it is possible to compensate for the speed difference by providing a passenger conveyer including a hand rail driving pulley unit without exchanging the parts when a speed difference occurs between the hand rail and step, so that the maintenance cost and time are significantly decreased compared to the conventional art.
In addition, the passenger conveyer including a hand rail driving pulley unit according to the present invention is implemented by inserting the contact ring contacting with the hand rail based on an inventive insertion method. When the contact ring is worn, the worn contact ring is easily exchanged with a new one, so that the contact ring exchanging cost and time is easily implemented.
Although the preferred embodiment of the present invention have been disclosed for illustrative purposes, those skilled in the art will appreciate that various modifications, additions and substitutions are possible, without departing from the scope and spirit of the invention as recited in the accompanying claims.
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Present invention relates to a hand rail driving pulley for a passenger conveyor. According to the invention, when difference between the moving velocity of a step and the moving velocity of a hand rail generates, by adjusting the radius of the driving pulley, the velocity difference can be synchronized without any change of new part. And present invention discloses a new installing method of elastic contacting ring inserted into a groove not the conventional adhering method, so when a worn contacting ring is changed, changing work can be done easily and simply.
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RELATED APPLICATIONS
The present application is related to U.S. Provisional Patent Application Ser. No. 60/377,915, filed on May 3, 2002, which is incorporated herein by reference and to which priority is claimed pursuant to 35 USC 119.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method whereby the data rate that can be passed through a single radio frequency channel using phase shift or missing cycle modulation can be effectively doubled without increasing the bandwidth of the channel.
2. Description of the Prior Art
“Digital Modulation Device in A System And Method of Using the Same”. U.S. Pat. No. 6,445,737, which issued to the present inventor, and which is incorporated herein by reference, describes a modulation method which transmits a single radio frequency with phase changes at bit period intervals in one to three cycles of the carrier frequency. The modulation is accomplished by either reversing the RF phase for one or more cycles, or by removing one or more cycles from the RF frequency which is transmitted. The method is described as ‘Pulse Position Phase Reversal Keying’ (PPPRM) or (3PRK), or as ‘Missing Cycle Modulation’ (MCM).
The spectrum of these modulation methods is a single frequency line containing more than 95% of the transmitted energy, plus a plurality of sinx/x spectral lines which spread over a wide bandwidth containing less than 5% of the radiated energy. The sinx/x spikes do not contain any useful phase modulation information and can be removed by filtering.
The detector circuit detects the missing cycle, or phase change pulse, or the reversing phase cycle. The detected output is a very narrow pulse one to three RF cycles wide.
The pulses are created in a modulation circuit shown in FIG. 1 that creates a pulse one RF cycle wide at the RF frequency on the rising edge of the data rate clock. This pulse (at time 1 ) is created only for a digital one. If a digital zero is to be represented, a delay is inserted to cause the zero pulse to occur late (at time 2 ) with respect to the clock. A decoding circuit utilizes this pulse delay as an indication of a digital one or zero.
In FIG. 1 , the pulses for a digital one pass through gates 11 and 12 to the one shot generator 15 . The one shot generator 15 creates a pulse having a time duration of one or two RF cycles. This is then applied to a modulator. If phase reversal keying is to be used, the XOR gate 16 is used. If the pulse is to be removed, the AND gate 17 is used. A digital zero passes through gates 13 , 14 and 12 , to cause a pulse delayed by one bit period plus a small delay amount.
It is not necessary to transmit a pulse representing a zero, since the decoding circuitry ( FIG. 2 ) responds only to the digital ones. A sequence of 10000000100-bits would have a pulse for the 1's, followed by a period of seven bit periods where there would be no alteration in the RF cycles. The decoder recognizes the phase shifts representing the ones, and the RF cycles in which there is no change will be decoded as zeros. The presence of a digital one sets the data clock. If there is a pulse at the start of the data clock, the data is decoded as a one. If there is no pulse the information is read and decoded as a zero.
BRIEF SUMMARY OF THE INVENTION
The invention is an improvement in a method for phase pulse position modulating signals comprising the step of utilizing abrupt pulse phase changes in a carrier frequency. The phase changes have a very short duration to mark the presence of digital ones only. The carrier is a single frequency that does not change in frequency or phase except at the time of the abrupt phase change pulses. Additional abrupt phase changes of the same carrier, spaced in time, are used to carry information relative to additional independent data channels.
The invention is also an improvement in an apparatus for pulse position modulating signals comprising a means for generating abrupt time spaced phase changes in a carrier frequency which has the phase changes of a very short duration to mark the presence of digital ones only. The improvement further comprises gating means for generating an optimal adjustable temporal spacing between the abrupt phase change pulses.
The improvement also comprises a decoding means employing gating periods to separate the phase pulse position modulated channels and reject all signals not within the gate period. The improvement further comprises separate decoding means for each channel to decode the digital ones and zeros, and to provide a data clock for the individual channels.
The invention can also be defined as a method for phase pulse position modulating signals which are synchronized to clocked bit periods using a clock comprising the steps of utilizing abrupt phase changes of pulses in a carrier signal at a carrier frequency in which the phase changes have a very short duration to mark the presence of digital ones only. A first signal is generated to mark the presence of digital ones during a first time slot. A second signal is generated to mark the presence of digital ones during a second time slot subsequent to the first time period. The first and second time slots occur during the same bit period. The first and second signals are combined into a single data channel.
The improvement further comprises the step of generating a common gate pulse in an encoder and gating the first and second signals by the common gate pulse to modulate the carrier signal.
The improvement further comprises the step of providing a first clock signal in a decoder linked to the arrival of the first signal to generate a first gate pulse derived from a clock pulse linked to the arrival of the first signal. The arrival of the first signal during the first gate pulse is decoded as a digital one and otherwise is decoded as a digital zero in a first data channel output in all other timing conditions. A delayed second clock signal is generated in the decoder. The arrival of the second signal during the second gate pulse derived from the delayed second clock signal is decoded as a digital one and is otherwise decoded as a digital zero in a second separate data channel output during all other timing conditions.
The improvement further comprises the step of gating the detected first signal into the first half of the bit period and gating the second signal into the second half of the same bit period. In one embodiment the step of gating the first signal and second signals comprises the step of gating the signal and second signals using a 2-times clock signal.
The improvement further comprises the steps of receiving in a two-bit shift register a 2-times data rate signal combined into a single data channel, sampling both bits of the shift register at a 1-times data rate and separately storing each bit in a separate memory circuit, and outputting the separately stored bits as a two separate 1-times data channels.
The single data channel is a modulated RF data signal having the first and second signals combined into the single data channel so that the method further comprises the step of detecting the modulated phases of the RF signal, low pass filtering the detected phases, differentiating the filtered phases to generate spikes to mark an abrupt phase change, and forming stretched square wave pulses from the spikes. The step of detecting the modulated phases of the RF data signal comprises amplifying or signal conditioning the modulated RF signal, generating a phase reference signal from the RF data signal and gating an unaltered form of the modulated RF data signal with the phase reference signal to generate a pulse corresponding to a detected abrupt phase change of the RF data signal.
While the apparatus and method has or will be described for the sake of grammatical fluidity with functional explanations, it is to be expressly understood that the claims, unless expressly formulated under 35 USC 112, are not to be construed as necessarily limited in any way by the construction of “means” or “steps” limitations, but are to be accorded the full scope of the meaning and equivalents of the definition provided by the claims under the judicial doctrine of equivalents, and in the case where the claims are expressly formulated under 35 USC 112 are to be accorded full statutory equivalents under 35 USC 112. The invention can be better visualized by turning now to the following drawings wherein like elements are referenced by like numerals.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic diagram of a prior art, one and zero encoder with an RF modulator.
FIG. 2 is a schematic diagram of a prior art, data decoder for one channel.
FIG. 3 is a timing diagram showing the timing sequences for adding a second pulse.
FIG. 4 is a schematic diagram of an encoder for two channels with an RF modulator.
FIG. 5 is a timing diagram showing the timing sequence for two channels.
FIG. 6 is a schematic diagram for added circuitry for second channel detection.
FIG. 7 is a schematic diagram for a conversion circuit of double pulses to double data rate.
FIG. 8 is a schematic diagram for a conversion circuit of double data rate to dual pulses.
FIG. 9 is a timing diagram showing the timing for double data rate.
FIG. 10 is a schematic diagram for a phase detector for pulse position phase reversal keying.
The invention and its various embodiments can now be better understood by turning to the following detailed description of the preferred embodiments which are presented as illustrated examples of the invention defined in the claims. It is expressly understood that the invention as defined by the claims may be broader than the illustrated embodiments described below.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the prior art, a delayed pulse was used to indicate a zero. Since the zeros are not needed or used, the time position of the zero pulse can be used to carry a second or additional data channel(s). In fact, a series of time delayed pulses can be used to represent two, three or more channels by selectively gating the pulses, thus increasing the data throughput of the RF channel accordingly.
FIG. 3 shows the pulse timing applicable in part to both the prior art and to the present invention. Pulses 102 from a detector are shown on line 100 . There is a pulse 102 only when a digital one is transmitted, coinciding with the rising edge of the clock. At position or time 160 there is no pulse and the decoder will decode this as a digital zero. On Line 104 , a gate circuit pulse 112 opens the decoder to the incoming pulses for a short time period only, typically ⅛ the bit period. If the gate is open and the detected pulse 102 occurs, it is decoded as a one and the data clock on line 106 is set to decode the data stream. Gating is used to reduce the effects of noise and multipath signals.
In line 108 , a second pulse 110 representing a second channel has been added. The decoder circuit will see both pulses 110 and 102 if they occur within the gate pulse 112 . The detector circuit will automatically lock to the first pulse 110 of these pulses, ignoring the second pulse 102 . The data clock will be reset by the leading pulse 110 . If there are three or more pulses, the decoder will ‘slip’ to respond to the first pulse in the sequence, thereby keeping the clock timing at a fixed position.
In line 114 , the second pulse 102 , which will not reset the clock, is shown outside the gate pulse 112 . A second gate 116 on line 118 can now be used to pass the delayed pulse 102 , which represents the second data channel. The decoder circuit for the first data channel, including clock restoration, is shown in the prior art circuit of FIG. 2 . The decoder circuit 120 for the second channel is shown in FIG. 6 .
FIG. 4 is a schematic of a modified encorder 122 which schematic shows the changes made to the encoder of FIG. 1 to enable either one or two channel use. The AND gates 11 and 14 of FIG. 1 have been replaced by one shot generators 124 and 126 to create a very narrow pulse that passes through the OR gate 44 to cause the single cycle altering one shot 45 to alter the RF modulation via gates 46 or 47 .
A switch 48 (S 1 ) has been provided to allow changing from the single pulse method with ones and zeros to a double pulse with ones only. With the switch in position (b), there are two altered cycles for each of two channels, representing ones-only in the RF stream. The earliest of these to occur is the change for channel one, while the delayed pulse is for channel 2 . This is seen in the detected pulses shown in line 114 of FIG. 3 . The clock delay is made slightly less than the gate width so that both pulses can occur initially within the gate pulse 116 .
FIG. 2 shows the prior art decoder circuit for a single channel. The very narrow pulses from the phase detector in FIG. 10 are input to a pulse stretcher 21 . The stretched pulse is used as an input to the ‘D’ input of data detector 22 . The leading edge of the stretched pulse is also applied to a one shot delay circuit 24 , whose output drives a spike generator 25 that resets a a divide by 64 counter 26 . The output of this counter can provide both 1X and 2X clocks. Counter 26 resets the data clock to have a rising edge only slightly delayed from the incoming pulse. In order to prevent noise and unwanted signals such as multiplath signals from resetting the clock, a gating circuit 23 is used. A time delay period of approximately ⅞ bit period is followed by a gate open period of approximately ⅛ bit period. The gate closes with the rising edge of the clock. This gating pulse, which is applied to the ‘D’ input of the delay latch 24 , prevents any signal outside the gate period from resetting the clock.
The data from the stretcher 21 is clocked into the data detector 22 . If there is a pulse present, the detector 22 outputs a one and holds it until the next clock rise. If there is no pulse, or the second pulse is too late, a digital zero is clocked out. The delayed pulses representing zeros are not used. Thus making it possible to use that time slot for a second channel.
The timing required for decoding the second channel is shown in FIG. 5 . The decoder 128 of FIG. 2 provides a clock which is linked to the timing of the first pulse to arrive, which must occur within the gate period shown as pulse 130 on line 132 . By delaying this clock, a second gate 134 on line 136 can be created. If a pulse occurs during this gate period 134 , it will preset the data decoder to a one. This preset is automatically cleared by the undelayed clock as shown as implemented in the circuit of FIG. 6 .
FIG. 6 shows the added circuitry used to detect the second channel. The recovered clock from FIG. 2 is delayed slightly to the second gate 64 . If a spike or pulse representing the timing for channel 2 appears, the gate 64 plus the pulse appear at the output of the AND gate 62 to preset the RS flip flop 138 as shown on line 140 of FIG. 5 . This is automatically cleared by the undelayed clock at the start of the next clock cycle at time 142 .
If there is no repeated one, the RS flip flop 138 remains in the clear position. If there is a repeated one, the RS flip flop 138 is preset to a one as shown at time 144 .
The channel 1 clock is inverted by inverter 146 and applied to a ‘D’ flip flop 66 to compare with the ‘D’ input and to output a one or zero for channel 2 , which is delayed from the data output of channel 1 by ½ clock period.
FIG. 7 shows how the two channels can be combined to produce one channel at double the data rate. The method essentially sends the bits from channels one and two alternately in a single data stream. The data from channel one is combined with the data clock in the AND gate 71 to produce an output which is present for one half clock cycle. This output sets the ‘D’ input of the ‘D’ flip flop 75 so that a 2X clock will cause a corresponding one or zero output on each 2X clock rise. The data clock is inverted by inverter 148 for channel two and it's associated AND gate 73 , so that channel 2 appears at the ‘D’ input of flip flop 75 for the other half data clock cycle. In this manner, channels one and two are combined in alternating sequence to produce a data rate at twice the data rate of the individual channels. The 1X and 2X clocks are obtainable from the original clock frequency oscillator 27 and dividing counter 26 .
FIG. 8 shows how the double data rate can be converted back to two individual channels if desired. The upper two ‘D’ flip flops 81 , 83 form a shift register to accept the incomming 2X data rate. The original 2X clock is divided by two in flip flop 82 to obtain a 1X clock, which is used to sample the outputs of the shift register 81 , 83 once every two incoming bits. The first bit to arrive at the shift register 81 , 83 is shifted to the second stage 83 as the next bit arrives. Both the first and second bits are then sampled by the output ‘D’ flip flops 84 , 85 respectively to become the data for channels one and two respectively.
FIG. 9 shows the timing for FIGS. 7 and 8 . Channel two data 95 is delayed behind channel one data 94 by ½ of the 1X clock cycle 150 , or by one full 2X clock cycle 152 . By switching between the two at the 2X clock rate and adding them in sequence, the 2X data rate 93 is achieved. Conversely, when two bits at the 2X rate are stored in the shift register 81 , 83 and read out by the 1X clock, two separate channels are obtained.
FIG. 10 shows a phase detector applicable to the present invention. The limiting amplifier 101 raises the incoming RF signal to CMOS levels. The signal is split to follow two different paths. The path through the crystal 103 and the tuning capacitor 105 creates a phase reference to be applied to one input of the XOR gate 107 , used as a phase detector. The other path, via the inductor 109 , passes the signal unaltered to the other input of the phase detector 107 . A low pass filter 111 removes any remaining RF signals to result in a pulsed output shown in the inset as pulse 113 . This output can be differentiated by differentiator 115 to yield spikes 117 which are used by the pulse stretcher 21 .
It is obvious to those skilled in the art that minor time delays must often be inserted in the clocking of the above circuitry so that the data being sampled is steady at the time of sampling.
Many alterations and modifications may be made by those having ordinary skill in the art without departing from the spirit and scope of the invention. Therefore, it must be understood that the illustrated embodiment has been set forth only for the purposes of example and that it should not be taken as limiting the invention as defined by the following claims. For example, notwithstanding the fact that the elements of a claim are set forth below in a certain combination, it must be expressly understood that the invention includes other combinations of fewer, more or different elements, which are disclosed in above even when not initially claimed in such combinations.
The words used in this specification to describe the invention and its various embodiments are to be understood not only in the sense of their commonly defined meanings, but to include by special definition in this specification structure, material or acts beyond the scope of the commonly defined meanings. Thus if an element can be understood in the context of this specification as including more than one meaning, then its use in a claim must be understood as being generic to all possible meanings supported by the specification and by the word itself.
The definitions of the words or elements of the following claims are, therefore, defined in this specification to include not only the combination of elements which are literally set forth, but all equivalent structure, material or acts for performing substantially the same function in substantially the same way to obtain substantially the same result. In this sense it is therefore contemplated that an equivalent substitution of two or more elements may be made for any one of the elements in the claims below or that a single element may be substituted for two or more elements in a claim. Although elements may be described above as acting in certain combinations and even initially claimed as such, it is to be expressly understood that one or more elements from a claimed combination can in some cases be excised from the combination and that the claimed combination may be directed to a subcombination or variation of a subcombination.
Insubstantial changes from the claimed subject matter as viewed by a person with ordinary skill in the art, now known or later devised, are expressly contemplated as being equivalently within the scope of the claims. Therefore, obvious substitutions now or later known to one with ordinary skill in the art are defined to be within the scope of the defined elements.
The claims are thus to be understood to include what is specifically illustrated and described above, what is conceptionally equivalent, what can be obviously substituted and also what essentially incorporates the essential idea of the invention.
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The invention is a method for pulse position modulating signals which are synchronized to clocked bit periods using a clock comprising the steps of generating two, three or n signals to mark the presence of digital ones during corresponding n time slots occurring during the same bit period. The two, three or n signals are combined into a single data channel to utilize abrupt phase changes of pulses in a carrier signal at a carrier frequency, the phase changes having a very short duration to mark the presence of digital ones only. The combination of the n signals into a single data channel comprises gating each of the n signals in a sequence of serially delayed time slots corresponding to each of the n signals during a portion of the same bit period in the single data channel during time positions reserved for unexpressed zeroes.
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This invention was made with government support under Grant No. 5 P51 RR00163 "Support for Regional Primate Research Center" awarded by the Department of Health and Human Services, Division of Research Resources. The government has certain rights in this invention.
BRIEF SUMMARY OF THE INVENTION
The invention relates to synthetic compounds which, when administered orally to warm-blooded animals, inhibit the absorption of cholesterol.
Certain water/alcohol soluble extracts from plant sources have been found to reduce cholesterolemia in chicks, pigs and rats (P. Griminger, et al., "Dietary Saponin and Plasma Cholesterol in the Chick." Proc. Soc. Exp. Biol. Med. 99:424-426, 1958; H. A. I. Newman, et al. "Dietary Saponins, a Factor Which May Reduce Liver and Serum Cholesterol Levels." Poultry Sci. 37:42-46, 1958; B. Morgan, et al., "The Interactions Between Dietary Saponin, Cholesterol and Related Sterols in the Chick." Poultry Sci. 51:677-682, 1972; D. L. Topping, et al, "Effects of Dietary Saponins in Fecal Bile Acids and Neutral Sterols, Plasma Lipids, and Lipoprotein Turnover in the Pig." Am. J. Clin. Nutr. 33:783-786, 1980; D. G. Oakenfull, et al., "Effects of Saponins on Bile-acids and Plasma Lipids in the Rat." Br. J. Nutr. 42:209-216, 1979; and D. L. Topping, et al., "Prevention of Dietary Hypercholesterolemia in the Rat by Soy Flour High and Low in Saponins." Nutr. Rep. Int. 22:513-519, 1980.)
More specifically, extracts from alfalfa hay are known to be active in reducing the absorption of dietary cholesterol. Although such alfalfa extracts are of unknown composition, they are found to contain saponins identifiable by thin-layer chromatography. The alfalfa extracts contain, in addition to saponins, unspecified amounts of carbohydrates, amino acids, peptides, pigments, and free aglycones removed from alfalfa hay by the water:alcohol solvent used during their preparation. Such crude extracts are sometimes referred to herein as "alfalfa saponins" as an operational definition. These alfalfa extracts reduce the intestinal absorption of cholesterol in rats and monkeys (M. R. Malinow, et al., "Cholesterol and Bile Acid Balance in Macaca fascicularis: Effects of Alfalfa Saponins." J. Clin. Invest. 67:156-162, 1981). The capacity of such alfalfa extracts to interfere with cholesterol absorption is enhanced by partial acid hydrolysis as reported in M. R. Malinow, et al., "Effect of Alfalfa Saponins on Intestinal Cholesterol Absorption in Rats." Am. J. Clin. Nutr. 30:2061-2067, 1977; and U.S. Pat. No. 4,242,502 (Malinow, et al.)).
Digitonin binds cholesterol in vitro, inhibits the intestinal absorption of cholesterol, and prevents the hypercholesterolemia expected in monkeys ingesting high-fat, highcholesterol foods (M. R. Malinow, et al, "Prevention of Hypercholesterolemia in Monkeys (Macaca fascicularis) by Digitonin, Am. J. Clin. Nutr., 31:814-818, 1978). But, digitonin is costly. Diosgenin has also been reported to inhibit the absorption of cholesterol in rats when given in a massive dose (1000 mg/kg) (M. N. Cayen, et al., "Effect of Diosgenin on Lipid Metabolism in Rats.", J. Lipid Res. 20: 162-174, 1979).
It was previously reported that toxicity of plant saponins is decreased in rats, mice, and birds by cholesterol in the diet (J. O. Anderson, "Effect of Alfalfa Saponin on the Performance of Chicks and Laying Hens." Poult. Sci. 36:873-876, 1957; I. Ishaaya, et al., "Soyabean Saponins. IX. Studies of Their Effects on Birds, Mammals and Cold-blooded Organisms." J. Sci. Food Agric., 20:433-436, 1969; G. Reshef, et al., "Effect of Alfalfa Saponins on the Growth and Some Aspects of Lipid Metabolism of Mice and Quails." J. Sci. Food Agric. 27:63-72, 1976; E. B. Wilcox, et al., "Serum and Liver Cholesterol, Total Lipids and Lipid Phosphorus Levels of Rats Under Various Dietary Regimes." Am. J. Clin. Nutr., 9:236-243, 1961).
Despite these encouraging results, it has remained a problem that plant extracts, which are of variable composition, contain a volume of nonuseful chemical substances. It is difficult, due to the variations in composition, to set a standard dosage or predict the impurities present. Thus, such extracts are not well suited for use by humans. Furthermore, purification of plant extract substances and synthesis of saponins suspected to exist in plants are likely to be very costly due to the anticipated complexity of the required procedures.
It has now been discovered that certain synthetically produced, pure "sapogenin-derived" compounds, e.g., substances compounded from spirostane, spirostene, or sterol-derived" compounds are nontoxic. Such compounds depress cholesterol absorption more effectively than alfalfa extracts on a weight basis and thus can be administered in reasonably sized doses. Because the chemical compositions of these substances are known and because they can be synthesized at a high degree of purity, they are suitable for use by any warm-blooded animal, including humans. Precursor substances for use in the synthesis are available as by-products of present industrial processes. For example, one spirostane compound (tigogenin) is currently a wasted by-product of digitalis manufacture.
Unless administered in massive amounts, pure sapogenins do not significantly bind cholesterol or inhibit its absorption. It is only when compounded with another moiety that sapogenins have the desired effect. Examples of such sapogenin compounds are compounds of tigogenin and diosgenin, particularly glycosides having tigogenin or diosgenin as an aglycone. Although it is not established that the size of the nonsapogenin moiety has any effect on a compound's ability to inhibit cholesterol absorption, at least one glycoside with a relatively longer sugar moiety has an increased biological activity in regard to cholesterol absorption. Specifically, cellobiose-sapogenins are more active than glucose-sapogenins having the same aglycone. Of such substances, cellobiose-tigogenin is particularly active to inhibit cholesterol absorption. Somewhat less active is cellobiose-diosgenin, perhaps due to the presence of a double bond in C 5 of the spirostene aglycone of diosgenin.
DETAILED DESCRIPTION
Certain synthetic compounds, when administered orally, inhibit the absorption of cholesterol by warm-blooded animals, and consequently may lower plasma cholesterol levels and induce regression of atherosclerosis. These include compounds of sterols and of "spirostane substances" such as diosgenin, tigogenin, smilagenin and the like. One group of such compounds includes compounds of diosgenin (5,20α,22α,25d-spirostan-3β-ol) as represented by the following formula: ##STR1##
Another group according to the invention include compounds of tigogenin (5α,20α,22α,25D-spirostan-3β-ol) represented by formula: ##STR2##
A. Esters
Esters of the above formulas can be prepared by reacting an anhydride with the "spirostane substance". Any of numerous organic anhydride substances could be used in such molecules, although not all such molecules would be effective or be sufficiently nontoxic for general use.
Esters have been formed from the following anhydrides which react with the hydroxyl group of the sapogenin or sterol:
______________________________________Anhydrides Used in the Synthesis of Sapogenin and Sterol______________________________________Estersphtalyl-DL-glutamic cis-1,2-cyclobutane dicarboxylic1-octenyl-succinic citraronicglutaric 3-nitrophtalicnonenylsuccinic methylsuccinictrans-1,2-cyclohexane 3-methylglutaricdicarboxyliccix-1,2-cyclohexanedicarboxylic 2,3-dimethyl maleic3,3-dimethyl glutaric 1,2,3,4-cyclobutane tetracarboxylictrans-1,2-cyclohexanedi- diphenylcarboxylic2-dodecen-1-ylsuccinic maleicdichloromaleic______________________________________
Of the esters produced, only maleic esters proved to be effective in the inhibition of intestinal absorption of cholesterol in laboratory animals.
Such maleic esters were synthesized by combining maleic anydride and the desired sapogenin or sterol substance in chloroform at 50° for a period of four days. The result was a maleic ester of the formula: ##STR3## wherein R is a sapogenin such as diosgenin or tigogenin or a sterol such as cholesterol.
Tests were performed on laboratory animals according to the procedure outlined in M. R. Malinow, et al., "Effect of Alfalfa Saponins on Intestinal Cholesterol Absorption in Rats." Am. J. Clin. Nutr., 30, December 1977, pps. 2061-2067. The tests were performed in groups of six animals each (mean±SE). The result of the tests are summarized in Table I:
TABLE I______________________________________Effect of Sapogenin Esters on Intestinal Absorption ofCholesterol in Rats. Tests performed in groups ofsix animals each (mean ± SE) Intestinal absorption of cholesterol (% of I.D.)Substance mg/rat Controls Experimental -P______________________________________tigogenin maleate 15 80.5 ± 0.6 62.9 ± 1.0 0.001diosgenin maleate 15 79.6 ± 1.4 56.0 ± 2.2 0.001tigogenin 15 79.1 ± 1.5 81.2 ± 1.1 N.S.diosgenin 15 73.5 ± 2.0 76.4 ± 2.6 N.S.maleic acid 15 79.1 ± 1.5 78.1 ± 0.8 N.S.maleic acid/tigogenin 5/10 77.0 ± 2.1 78.1 ± 0.8 N.S.Maleic acid/diosgenin 5/10 77.0 ± 2.1 71.2 ± 2.8 N.S.______________________________________
In vitro tests for micellar cholesterol binding were performed according to the method of M. R. Malinow, et al., "Prevention of Hypercholesterolemia in Monkeys (Macaca fascicularis) by Digitonin." Am. J. Clin. Nutr. 31:814-818, 1978. These tests confirmed that cholesterol was bound by the sapogenin maleates. The results of these in vitro tests appear in Table II:
TABLE II______________________________________In Vitro Micellar Cholesterol Binding Bound cholesterolSubstance (mg/mg substance)______________________________________Tigogenin maleate 0.20diosgenin maleate 0.24digitonin 0.33alfalfa saponins 0.24tigogenin 0diosgenin 0______________________________________
When tested in primates, however, the sapongenin maleates induced vomiting when administered orally. Thus, the maleates may be unacceptable for administration to humans, or even be toxic.
B. Glycosides
Sapogenin and sterol compounds according to the invention, specifically glycosides of tigogenin, diosgenin and cholesterol successfully bind cholesterol and inhibit its absorption by the digestive system of warm-blooded animals. Thus far, no toxic effect has been associated with such substances. And, due to their structure, it is likely that they are substantially nontoxic.
The glucosidic compounds were formed by reacting a carbohydrate-containing molecule with the hydroxyl group of the aglycone substance. The carbohydrate-containing molecule can, for example, be α-D-(+)-glucose of the formula: ##STR4## or β-D-(+)-glucose of the formula: ##STR5## or longer carbohydrate molecules such as (+)-cellobiose(β-anomer) otherwise known as 4-O-(β-D-glucopyranosyl-D-glucopyranose): ##STR6##
The glycosidic bonds between the carbohydrate-containing molecule and the aglycone could be either an α glycosidic bond: ##STR7## or a β glycosidic bond: ##STR8##
For compounds which are to bind cholesterol, it is anticipated that a β glycosidic bond will be preferred in most instances since compounds having a β glycosidic bond are less likely to be hydrolyzed in the intestine of the subject animal.
Thus, although an α-cellobiose-tigogenin of the following formula might be suitable, ##STR9## it is anticipated that a β-cellobiose-tigogenin, such as one of the following formula, would be more effective: ##STR10##
Glucosides having tigogenin and diosgenin aglycones were synthesized and tested according to the following procedures.
EXAMPLE 1
Synthesis
A series of saponins were synthesized by glycosylation of the hydroxyl group of the two sapogenins, tigogenin (5α,20α,22α,25D-spirostan-3β-ol) and diosgenin (5α,20α,22α,25D-spirosten-3β-ol). Synthesis of the saponins was accomplished with a modified version of the method described by Rosevear at al., "Alkyl Glycoside Detergents" A Simpler Synthesis and Their Effects on Kinetic and Physical Properties of Cytochrome C Oxidase." Biochemistry, 19:4108-4115, 1980.
a. Weigh 1 mmol (678 mg) of cellobiose octoacetate (β-anomer) or 1 mmol (390 mg) of glucose pentaacetate (β-anomer) into a foil-covered reaction vessel. While stirring magnetically, add 5 ml of glacial acetic acid and stir for a few minutes. Quickly add 5 ml of 31% HBr in glacial acetic acid. Immediately shut in the fumes with a stopper and stir vigorously for 45 to 55 min (cellobiose) or 30 to 40 min (glucose).
b. Add 10 ml of choloform for cellobiose or dichloromethane for glucose. Pour into a separating funnel containing 30 ml of ice and water. Shake for 2 min and extract the bottom nonaqueous layer into 30 ml of a cold saturated sodium bicarbonate solution previously saturated with chloroform or dichlormethane. Shake for 2 min. Repeat NaHCO 3 extraction twice or until the pH of the aqueous layer is >7.0. Wash the nonaqueous phase three times with cold solvent-saturated distilled water.
c. Dry the extracted solvent layer over 500 mg. of magnesium sulfate while stirring for 30 min. Centrifuge and wash the precipitate with dry solvent.
d. Pour the dried filtrate into a foil-covered, 50-ml screw-cap tube and evaporate to about 10 ml with N 2 at low heat.
e. Keeping the reaction vessel protected from light and air moisture as much as possible, add: 1 mmol of tigogenin or diosgenin; 200 mg of dry silver carbonate; one small iodine crystal; and 1 g of 4 Å molecular sieves. Stir in the dark for 12 to 24 h.
f. Centrifuge at a low speed for 10 min. and transfer the supernatant to a foil-covered, 50-ml screw-cap tube. Wash the precipitate twice with 5 ml of solvent and combine the solvents.
g. Evaporate the combined solvent with N 2 to a cloudy syrup of about 1 to 2 ml. Add a stir bar and 10 ml of a solution of triethylamine:methanol:water (1:2:1). Stir for 30 min. and let stand overnight.
h. Transfer the solution quantitatively into dialyzing tubing with 40 ml of water. Dialyze it against tap water for 48 h.
i. Transfer the solution to a container for freeze-drying. Evaporate the water overnight.
j. Dissolve the resulting white powder in dichloromethane-methanol (10:1, vol/vol) and transfer to a chromatography column filled with silica gel type 60 (230-400 mesh, E. Merck Reagents). Separate 7 ml fractions with the above solvent and after 150 ml, use methanol to elute the saponins.
k. Perform thin-layer chromatography (TLC) on a small amount (around 10 .sub.μ g) with chloroform:methanol:water (65:38:10) as the solvent. Use a Cu acetate solution for charring. Saponins typically have retardation factor (R f ) values around 0.6 to 0.8 and give a bluish or brownish color.
This procedure probably synthesized saponins with β-glycosidic bonds, or, in the case of cellobiose, a mixture of β- and α-glycosides. It was possible to synthesize the α-isomer, by using glucose pentaacetate (α-anomer) and ZnCl 2 instead of AgCO 3 as catalyst.
Glucosides having tigogenin and diosgenin aglycones were tested for in vitro binding of cholesterol according to the following procedure:
EXAMPLE 2
In Vitro Binding of Cholesterol
a. Prepare a micellar suspension of cholesterol by placing in a flask caprylic acid (1.2×10 -3 M), glyceryl monoleate (0.6×10 -3 M), and [4- 14 C] cholesterol (0.3×10 -3 M; specific activity˜25,000 dpm/mg), and agitating these for 1 h at 38° C. with sodium taurocholate (10×10 -3 M) in 0.1M phosphate buffer, pH 6.2 (20). The suspension contains approximately 58 μg of cholesterol/ml. Centrifuge the suspension at 10,000 rpm for 30 min. before use.
b. Place 100 μg of the synthetic saponin dissolved in methanol in a 50-ml screw-cap tube and evaporate the solvent under N 2 in a warm-water bath.
c. Add 4 ml of the micellar suspension and shake it for 2 h at room temperature.
d. Transfer the medium to centrifuge tubes. Centrifuge at 3,000 rpm for 20 min.
e. Determine the radioactivity in 0.5 ml of the upper solvent phase with 10 ml of toluene-based scintillation fluid.
f. Treat blanks as above without adding the synthetic saponin.
Results of these tests showed that binding of cholesterol occurs with the synthetic saponins. Representative data from the test appears in Table III:
TABLE III______________________________________In Vitro Binding of Cholesterol by Synthetic Saponins.sup.a Mass/flask Cholesterol boundSaponin (μg) (μg)______________________________________None.sup.b 0 0Cellobiose-tigogenin.sup.b 250 21Cellobiose-tigogenin.sup.b 500 37Cellobiose-tigogenin.sup.b 750 46Cellobiose-tigogenin.sup.b 1000 60Cellobiose-diosgenin.sup.b 1000 26Glucose-diosgenin.sup.c 1000 49Glucose-tigogenin.sup.c 1000 40______________________________________ .sup.a Results are average of three determinations. .sup.b Mixture of and glycosides. .sup.c Mainly glycoside.
Further experimentation was conducted to determine the effect of the synthesized saponins on living animals.
EXAMPLE 3
Effects of Synthetic Glycosides in Vivo
Effects of the synthetic glycosides on the intestinal absorption of cholesterol in rats were tested according to the procedure of M. R. Malinow, et al., "Effect of Alfalfa Saponins on Intestinal Cholesterol Absorption in Rats." Am. J. Clin. Nutr. 30:2061-2067, 1977. The animals were fed semipurified cholesterol-free food from 8 a.m. to 10 a.m. for ten days. On the day of the experiment, the rats were anesthetized at about 10:30 a.m. and the test substance, as well as a pulse dose of radioactive cholesterol, were given per gastric tube. The excretion of 14 C-neutral steroids was determined in feces collected for 72 h after intragastric administration of the test substances and 2 mg of [4- 14 C] cholesterol (specific activity˜0.25 μCi/mg).
As shown in Table IV, these rate experiments demonstrated that the synthetic glycosides inhibit the intestinal absorption of cholesterol. No significant inhibition was observed with sapogenins. Better results were obtained with a longer sugar moiety (cellobiose) than with a shorter moiety (glucose).
TABLE IV__________________________________________________________________________Effects of Sapogenins and Synthetic Glycosides on Cholesterol Absorptionin Rats.sup.a Intestinal Student's Number Absorption of .sub.- t test, Substance of Weight Dose cholesterol .sub.-- P versus RelativeSeries administered rats (g) (mg/rat) (I.D.) controls Absorption__________________________________________________________________________I none 6 242 ± 3 0 74.6 ± 2.3 100 glucose- 6 246 ± 7 14 46.2 ± 1.8 <0.001 62 tigogenin glucose- 6 245 ± 5 14 52.6 ± 3.7 <0.001 71 diosgenin alfalfa 6 249 ± 9 14 60.2 ± 3.7 <0.01 81 extractII none 6 290 ± 7 0 74.8 ± 1.6 100 cellobiose- 6 291 ± 12 14 39.6 ± 1.8 <0.001 53 tigogenin cellobiose- 6 287 ± 4 14 53.7 ± 1.3 <0.001 72 diosgenin alfalfa 6 275 ± 8 14 56.3 ± 1.1 <0.01 75 extractIII none 6 268 ± 5 0 78.0 ± 2.1 100. tigogenin 6 259 ± 5 15 80.4 ± 1.4 N.S. 103IV none 6 328 ± 4 0 73.5 ± 2.0 100 diosgenin 6 330 ± 4 15 76.4 ± 2.6 N.S. 104V none 6 276 ± 7 0 77.7 ± 2.2 100 cellobiose- 6 282 ± 3 15 69.5 ± 1.3 0.01 89 cholesterol glucose- 6 273 ± 8 15 72.5 ± 1.0 N.S. 93 cholesterol alfalfa 6 277 ± 5 15 68.4 ± 2.3 0.02 88 extract__________________________________________________________________________ Values are mean ± SE. Abbreviations: I.D., injected dose; N.S., not significant. .sup.a The excretion of .sup.14 Cneutral steroids was determined in feces collected for 72 h after intragastric administration of glycosides or sapogenins and 2 mg of [4.sup.14 Ccholesterol.
The mechanism whereby cholesterol absorption is inhibited by sapogenin and sterol compounds is unknown. However, it is possible that the compounds form an insoluble complex with cholesterol in the intestinal lumen and thereby prevent the absorption of dietary cholesterol. Additionally, the compounds may bind biliary cholesterol and cholesterol from desquamated intestinal cells and, thus, may induce negative cholesterol balance through the increased excretion of endogenous cholesterol.
In the above described experiments, synthetic sapogenin and sterol compounds inhibited the absorption of exogenous cholesterol in laboratory animals. It is thus anticipated that they will also be effective in preventing atherosclerosis or inducing its regression without toxic effects. It is an advantage that such synthetic compounds are pure substances with known or determinable chemical structures and may be synthesized in sufficient purity so as to be used to treat human beings. As indicated by their ability to prevent the absorption of cholesterol, synthetic sapogenin and sterol compounds may reduce deaths due to atherosclerotic disease, a most significant cause of death in the adult population of the Western world.
Having given examples of preferred embodiments of my invention, it will be apparent to those skilled in the art that changes and modifications may be made without departing from my invention in its broader aspects. I therefore intend the appended claims to cover all such changes and modifications as fall within the true spirit and scope of my invention.
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Synthetic sapogenin and sterol compounds, administered orally to warm-blooded animals, inhibit the absorption of cholesterol and are useful in the treatment of hypercholesterolemia. Particular compounds suitable for such purposes include glycosides with spirostane, spirostene, or cholesterol aglycones, and esters of spirostanes, spirostenes and cholesterol.
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[0001] The present application claims the benefit of U.S. Provisional Patent Application No. 60/736,411, filed Nov. 14, 2005, titled “Fuel Filler Neck.”
FIELD OF THE INVENTION
[0002] The invention relates to fills for conveyance of fluid and, in particular, to a fuel fill for conveyance of fuel to a fuel tank permitting pressure equilibration with the atmosphere via a vent.
BACKGROUND
[0003] A fill is a device typically mounted on a vehicle and, more specifically to the present application, to a watercraft such as a boat. The fill provides access for filling a fuel tank of the boat with fuel and, more specifically, is secured with one or more tubes leading to a fuel tank so that fuel is pumped into an opening in the fill, the tubes being in fluid communication with the fuel tank. A closure or cap is secured with or on the fill to substantially close the opening of the fill. Most commonly, the cap is removable to provide access to the opening, and is securable to close substantially the opening.
[0004] A typical fill system, the closure and the fill itself, includes a vent to the atmosphere to balance pressure within the fuel tank. During operation of the boat, the fuel will be drawn from the fuel tank by the fuel line and into the engine. In a closed system, a negative pressure would be experienced due to the drop in fuel level. This negative pressure makes it difficult for the boat's fuel pump to force fuel into the engine for normal operation. Alternatively, when the boat is idle for an extended period of time, the volatile fuel turns to a gaseous or vaporous state, the amount of which is dependent on the pressure and temperature in the tank. In a closed system, this may result in a positive pressure in the fuel tank, when compared with atmosphere. A positive pressure can result in too much fuel being driven into the engine, resulting in poor engine performance, and can result in injuries if fuel spray is released when the closure is opened by a person in order to pump fuel into the fuel tank. The vent addresses these problems by allowing fluid/gaseous communication from the atmosphere outside of the fuel storage system with the volume within the fuel storage system.
[0005] A vent system usually consisted of a much smaller tubular passage than the fill pipe, and it is constructed with a fuel tank to eliminate fuel splashes caused by the trapped air in the tank during fueling. This vent line is either connected to an independent vent or to the fill itself at a point where the opening is not obstructed by the fueling device. Splashing or spillage of fuel through the vent results in fuel loss, and its attendant economic cost and environmental impact, and can damage the boat itself. For the case where the vent is constructed into the fill, if the openings are not properly engineered, splashed fuel could also injure the fueling operator.
[0006] There have been a number of solutions to the problem of fuel leakage or splashing. One manner is having a one-way valve, which does not alleviate both negative and positive pressures. Another, more common manner, is providing a fuel cap with a member that easily shifts to close the vent. Were fuel to be forced upward to the opening, the member is contacted by the fuel so that the member is forced into a position that covers the vent port. While this is a reasonable solution, it is not a perfect solution, and generally requires a number of components.
[0007] As examples of the shifting member design, reference is made to U.S. Pat. No. 5,327,946, to Perkins, and to U.S. Pat. No. 5,507,324, to Whitley II, et al. In each of these, several components need be manufactured and assembled in multiple stages to allow a member to shift when contacted by fuel to cover a vent port. Nonetheless, the movable members are not immediately reactive to the fuel contact, so that a small amount of fuel may be able to pass through the vent. For instance, the '946 patent describes an auxiliary biasing spring that could be provided, the bias of which need be overcome. Such a spring would, on the other hand, assist in forcing the otherwise gravity-biased movable member downward which: in the absence of the spring, the cap would risk the movable member being stuck upward.
[0008] Another expensive and inconvenient design for addressing spillage is shown in U.S. Pat. No. 6,237,645, to Pountney. In the '645 patent, a system is shown having a first cap and fill arrangement for filling a tank, a second cap and fill arrangement where spillage is contained for recovery, and a vent line leading from the spillage recovery arrangement. This requires a significant number of components, and a significant amount of effort to assembly and mount in a boat.
[0009] Accordingly, there has been a need for a vent for a fill and closure that is simpler and more reliable.
SUMMARY
[0010] In accordance with an aspect, a closure for a fill is disclosed, the closure including a unitary component having a first portion connectable with the fill and a second portion for spanning across the first portion to substantially close the fill, wherein a vent opening is formed between the first and second portions and extends laterally outwardly therefrom to provide fluid communication with the fill and atmosphere outside of the closure. The vent opening may include a series of vent ports to the atmosphere. The vent opening may be positioned outboard of a vent tube opening in the fill.
[0011] The closure may include an exterior surface bearing indicia indicating an orientation for the closure when secured with the fill. The orientation may indicate a desirable orientation of the vent opening relative to an opening in a vent tube of the fill.
[0012] The closure may include a compressible sealing member located around the first portion for preventing liquid passage between the closure and the fill.
[0013] The closure may include a cavity in the first portion in fluid communication with an opening in the fill, and a passageway in fluid communication with the cavity and with the vent opening. The unitary component may further include a recessed portion in fluid communication with the cavity and with the passageway.
[0014] In another aspect, a fill system is disclosed including a fill member and a unitary closure member, the a fill member including a fill passage for fluid conveyance, the closure member being connectable with the fill member for substantially closing the fill passage, the closure member including a vent passageway in fluid communication from an interior of the fill member and an atmospheric exterior of the closure when secured with the fill member. The closure member may have a first portion connectable with the fill member and a second portion for spanning across the first portion to substantially close the fill member, wherein the vent passageway is formed between the first and second portions and extends laterally outwardly therefrom to provide fluid communication with the fill member and the atmospheric exterior.
[0015] The fill system may further include a compressible sealing member located around the first portion of the closure member to prevent fluid flow between the fill and closure members.
[0016] The vent passageway may include a vent opening to the atmosphere. The fill system may further include a compressible sealing member located around the first portion of the closure member to prevent fluid flow between the fill and closure members, the sealing member providing a gap between the fill and closure members to permit venting to the atmosphere therethrough. The vent opening may include a series of vent ports.
[0017] The fill member may include a vent tube having an opening into the fill passage, and the closure member vent opening is positioned outboard of the vent tube opening in the fill passage.
[0018] The fill member may include a vent tube having a fire arrestor therewithin, the fire arrestor including porous incombustible material that renders little resistance to gas flow through the vent tube.
[0019] The closure member may include an exterior surface bearing indicia indicating an orientation for the closure member when secured with the fill member. The fill member may include a vent tube having an opening into the fill passage, the vent passageway may include a vent opening, and the indicia may indicate a desirable orientation of the vent opening relative to the vent tube opening.
[0020] The closure member may include a cavity in fluid communication with the fill passage, and may include a vent passageway in fluid communication with the cavity and with the vent opening. The closure member may further include a recessed portion in fluid communication with the cavity and with the vent passageway.
BRIEF DESCRIPTION OF THE DRAWINGS
[0021] FIGS. 1A and 1B are perspective views of a fill allowing access to a fuel tank for pumping fuel thereinto and a closure for generally closing the fill, the closure having a tab movable from a recessed position shown in FIG. 1A to an extended position in FIG. 1B for grasping to rotate the closure during securing and releasing of the closure with the fill;
[0022] FIG. 2 is a side elevational view in cross-section of the fill and closure of FIG. 1A with the closure disconnected from the fill;
[0023] FIG. 3 is a side elevational view in cross-section similar to that of FIG. 2 showing the closure connected and secured with the fill;
[0024] FIG. 4 is a perspective view showing an interior passageway of the fill and a bottom side of the closure, and showing a connector for retaining the closure with the fill;
[0025] FIG. 5 is a top plan view of the fill showing portions of the interior passageway therethrough; and
[0026] FIG. 7 is a front side elevational view of the fill with portions of the interior passageway shown in phantom.
DETAILED DESCRIPTION
[0027] Referring initially to FIGS. 1A, 1B , and 2 , a fill system 10 is shown having a fill 12 and a closure 14 secured thereto. Fuel is poured or pumped into the fill 12 for conveyance to a fuel tank (not shown), and the closure 14 is secured or connected with the fill 12 to generally close the fill 12 and is removed or disconnected from the fill 12 to permit access for the fuel conveyance. As used herein, the term fuel refers generally to liquid and the term gas refers generally to materials in a gaseous form, whether that is vaporized or gaseous fuel, air, or a mixture thereof. It should also be noted the fill system 10 and fill 12 are equally usable for other liquids, such as water, and the use of the term fuel herein is obviously used for convenience.
[0028] When installed, preferably in a marine application, the fill 12 is in fluid communication with the fuel tank through major and inferior passageways 20 a , 22 a (see FIG. 2 ). The major passageway 20 a , defined by a fill tube 20 , is principally used as the direct conduit through which fuel is conveyed to the fuel tank. The inferior passageway 22 a , defined by a vent tube 22 , principally allows gas (and, in an overflow situation, fuel) to pass from the fuel tank back to the fill 12 . The fill 12 has a large upper opening 24 , referred to herein as the mouth 24 , from which both of the fill tube 20 and vent tube 22 branch. In operation, a fuel nozzle (not shown) would be inserted into the mouth 24 and, preferably, at least a short distance into the fill tube 20 for conveying fuel into the fuel tank via the fill tube 20 . During this time, gas that is present in the fuel tank is displaced therefrom, and this gas is forced through the vent tube 22 to the mouth 24 for release to the atmosphere.
[0029] It should be noted that the fill tube 20 and vent tube 22 would be typically constructed as shown in the Figs., and then connected with other tubes or passageways that lead to the fuel tank. However, for simplicity's sake, the terms fill tube 20 and vent tube 22 will be used to refer to the structure as shown as well as the connecting tube intermediate the shown structure and the fuel tank.
[0030] A fire arrestor 23 is located in the vent tube 22 , as best seen in FIGS. 2 and 3 . The fire arrestor 23 includes a screen 23 a or other structure that is porous and incombustible so that flow therethrough is permitted. An arrestor frame 23 b retains the screen 23 a and secures with the vent tube 22 . As shown, the vent tube 22 narrows at it leads upward toward the mouth 24 , and the arrestor frame 23 b is inserted into the vent tube 22 and pressed into this narrowing portion so that it and the screen 23 a are retained therein. Thus, the fire arrestor 23 renders little resistance to the gas flow in the passage yet is able to quench fire started from the mouth 24 or outside the fill system 10 . It should be noted that the fire arrestor 23 is accessible or removable for changing and/or cleaning.
[0031] The vent tube 22 , in cooperation with the closure 14 , also serves to provide pressure balance with the atmosphere. As discussed above, the pressure within the fuel storage system (including the fuel tank, the fill 12 , and passageways therebetween) is desirably balanced with the atmosphere. In order to achieve this, the vent tube 22 is connected to a portion of the fuel tank that, preferably, is above an expected fuel level. In this manner, gas from the fuel tank can escape through the vent tube 22 while fuel generally does not pass therethrough.
[0032] Under some operating conditions the fuel may be forced upwardly through the vent tube 22 . For instance, inertial or centripetal forces on the fuel during sharp and high speed maneuvers in a boat may force the fuel into the vent tube 22 . In some instances, the fuel would only move a partial distance through the vent tube 22 to move upward. However, in other instances, the fuel passes through the vent tube 22 and into the mouth 24 . With the closure 14 in place, the fuel simply flows back down into the fuel tank via the fill tube 20 .
[0033] The pressure balance with the atmosphere is not achieved by the vent tube 22 and fill tube 20 alone, instead necessitating a vent port 30 in the closure 14 (see also FIG. 4 , showing a series of vent ports 30 a ). As noted above, the prior art makes use of multi-component systems for allowing an opening to the atmosphere outside of the closure. As described herein, the present closure 14 may be formed principally of a single component, which may be cast or molded, for example, thus eliminating the manufacture and assembly of these components, and thus being simpler, cheaper, and more reliable than those of the prior art.
[0034] The closure 14 includes an upper cover portion 40 from which a lower cylindrical portion 42 depends. A vent passageway 44 is formed in the closure 14 that, when the closure 14 is secured with the fill 12 , allows the vent port 30 to be in fluid communication with the fill mouth 24 and, therefore, the vent tube 22 .
[0035] The closure cylindrical portion 42 and fill 12 include cooperating structure for securing the closure 14 with the fill 12 . As shown, the cylindrical portion 42 has external male threads 50 that are received by female threads 52 located on the inner surface of the fill 12 and around the mouth 24 . Accordingly, the closure 14 is threadably coupled (connected) or disconnected with the fill 12 .
[0036] A gasket 54 is provided on the cylindrical portion 42 of the closure 14 for assisting in securing the closure 14 with the fill 12 . The gasket 54 fulfills a number of purposes including restricting any flow of fuel that may pass between the threads from flowing out from the fuel fill system 10 in general. It should be made clear that the gasket 54 does not provide a complete seal between the closure 14 and the fill 12 , due to the presence of the vent port 30 . However, the gasket 54 is elastic or rubberized material. Therefore, it is compressed between the fill 12 and the closure 14 . This provides resistance to any tendency of the closure 14 to back-out or unthread from the fill 12 , and does so without excessive pressure needing to be applied to the threads 50 , 52 themselves, thus prolonging the life of the threads. Importantly, this allows for greater tolerance or clearance between the threads so that connection/disconnection of the closure 14 minimally wears on the threads 50 , 52 and stripping due to mismatch of the threads is reduced. For instance, T-threading may be used.
[0037] Above and around the mated threads, the gasket 54 is intended to seal the closure 14 with the fill 12 to prevent fuel leakage thereacross. Towards this end, the fill 12 includes a beveled shoulder 60 angling upwardly and outwardly formed around the mouth 24 above the fill threads 52 . The closure cover portion 40 extends radially outwardly from the cylindrical portion 42 , and an annular channel 66 is positioned at the juncture therebetween so that the cover portion 40 and cylindrical portion 42 form a shoulder 68 . While a portion of the gasket 54 is inserted into the channel 66 , the gasket 54 is sized so that it extends beyond the channel 66 . When the closure 14 is threaded into the fill 12 , the gasket 54 is compressed between the shoulders 60 and 68 .
[0038] With specific reference to FIG. 3 , the vent passageway 44 communicating with the vent port 30 and the fill mouth 24 can be seen. The closure cylindrical portion 42 has an internal cavity 70 that is open to the mouth 24 . The interior or bottom side of the cover portion 40 has an excavated or recessed portion 72 that rises above the cylindrical portion 42 , and the vent passageway 44 passes through the cover portion 40 from the recessed portion 72 to the vent port 30 . As a result, gas is free to pass from the vent port 30 to the mouth 24 , and vice versa, through the vent passageway 44 . As can be seen in FIG. 3 , a small gap 74 is provided between the cover portion 40 and the fill 12 at an outboard position from the threaded portions thereof. As can also be seen, in order for gas to pass therethrough, the gas must proceed upward into the interior of the recessed portion 72 , then pass through the vent passageway 44 , and finally exit through the vent port 30 and the gap 74 .
[0039] Though not necessary, the ability of the construction to restrict fuel spillage through the vent port 30 benefits from providing a specific orientation to the closure 14 when secured with the fill 12 . With reference to FIG. 5 , the mouth 24 of the fill 14 is shown so that a vent opening 22 b into the mouth 24 can be seen; in comparing FIG. 5 (as well as FIG. 4 ) with FIG. 3 , it can be seen how the angle and direction of the fuel, if such were to pass through the vent tube 22 and the vent opening 22 b into the mouth 24 , would result in the fuel being deflected back toward the center of the mouth 24 and toward the center of the closure cylindrical portion cavity 70 . In order to reach the vent passageway 44 in the recessed portion 72 , the fuel would then need to reverse its direction and move back outwardly. An occurrence that allows any appreciable amount of fuel to pass through the vent port 30 is unlikely, due to the nature of the forces which are forcing the fuel upward and generally against gravity.
[0040] With reference to FIGS. 1A and 1B , indicia 76 such as that depicting a fuel pump may be presented on the exterior of the closure 14 which indicates a proper orientation of the vent port 30 when the closure 14 is secured with the fill 12 . In the present embodiment, a wall 77 is provided (see FIGS. 3 and 4 ) as a splash guard. The wall 77 extends inwardly into the mouth 24 at a position just above the opening of the vent tube 22 to deflect fuel away from the closure 13 , reducing the likelihood of passing into the recessed portion 72 , vent passageway 44 , and vent port 30 , and serving to protect a person pumping fuel into the fuel tank from an overflow/splashing occurrence. In embodiments utilizing the splash guard wall 77 , the indicia 76 may indicate the vent port 30 being aligned with the wall 77 so that splashing fuel is directed by the wall 77 away from the vent port 30 , vent passageway 44 , and recessed portion 72 . In the absence of the splash guard wall 77 , the indicia 76 may be positioned to indicate the vent port 30 being non-aligned with the opening 22 b of the vent tube 22 so that splashing fuel does not go directly toward the recessed portion 72 , vent passageway 44 , and vent port 30 .
[0041] As noted, the closure 14 can be a single piece cast or molded component. The gasket 54 is simply installed around/in the channel 66 , and the fill 12 may be a separate molded component (though the wall 77 may be a second piece mounted in the molded fill 12 ). The manufacture of the closure 14 , being a single component, is much easier than the prior art devices requiring multiple components and shifting valves. Furthermore, the present fuel fill system 10 is much more reliable than the prior art devices as the lack of moving parts minimizes faulty operation of the vent feature provided by the vent port 30 . The construction of the closure 14 including the vent port 30 and vent passageway 44 obviates much of the need for structure in the fill 12 itself to deflect fuel away from the closure 14 . It should also be noted that the fuel fill system 10 shows the fill tube 20 and vent tube 22 set at a 45 degree angle relative to the mouth 24 and the closure 14 , though this angle may be varied, such as being at zero degrees.
[0042] It should be noted that the fill 12 may be provided with bolt holes 80 ( FIG. 4 ) for receiving bolts 82 ( FIG. 5 ) so that fill 12 may be secured with the vehicle, such as a boat. The bolt holes 80 are positioned outside of the mouth 24 and away from the gasket 54 so that other features of the operation of the fuel fill system 10 are not impeded, and the gasket 54 does not wear against the bolt holes 80 and bolts 82 . It should also be noted that the internal cavity 70 of the closure cylindrical portion 42 preferably has a depending post 84 adapted for securing an end of a chain 96 ( FIG. 4 ) or other retainer, the other end of the chain 96 being connected with the interior of fill 12 around or in the mouth 24 . In this manner, the chain 96 keeps the closure 14 from being separated from the fill 12 , which may result simply from careless handling or from rocking of a boat while being fueled with the closure 14 disconnected to allow access into the mouth 24 by a fuel nozzle.
[0043] The closure 14 is equipped with an ergonomically shaped finger recess 100 to allow a finger grip 102 to be pivoted from a recessed position ( FIG. 1A ) within the exterior surface of the closure 14 to an extended position ( FIG. 1B ) allowing a user to rotatably manipulate the closure 14 . In the recessed position, the finger grip 102 is preferably flush or below the exterior surface of the closure 14 so that the risk of the grip 102 (or the closure 14 itself) is minimized. As can be seen in FIG. 3 , the exterior surface of the closure 14 includes a recess 104 for the finger grip 102 which conveniently helps to define the cavity 70 of the closure 14 leading to the vent passageway 44 , thereby minimizing materials.
[0044] While the invention has been described with respect to specific examples including presently preferred modes of carrying out the invention, those skilled in the art will appreciate that there are numerous variations and permutations of the above described systems and techniques that fall within the spirit and scope of the invention as set forth in the appended claims.
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A fill system, particularly for use as a fuel fill system for filling a tank of a vehicle such as a boat, is disclosed including a fill device for mounting on the vehicle and a closure for substantially closing an opening of the fill. The closure is generally a unitary component provided a vent to the atmosphere for pressure balance between the atmosphere and the fuel tank of the vehicle. The closure includes a vent passageway leading to one or more vent ports, and the construction of the vent passageway and ports minimizes fuel splashing through the closure.
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CROSS-REFERENCE
[0001] This application claims priority from Non-Provisional patent application Ser. No. 14/662/342 filed on Mar. 19, 2015 and from Provisional Patent Application Ser. Nos. 62/062,441 filed on Oct. 10, 2014 and 62/067,612 filed on Oct. 23, 2014.
FIELD OF THE INVENTION
[0002] This invention relates to a quick release attachment for mounting accessories (e.g., a scope, light, bayonet, etc.) on the Picatinny or tactical rail of a firearm.
BACKGROUND
[0003] Many individuals and firearm enthusiasts desire to mount one or more interchangeable accessories, such as a scope, light, bayonet and the like, onto their firearms. Historically, this has been accomplished by fixedly mounting the accessory to the Picatinny or tactical rail of the firearm, which is essentially a bracket that can be attached to a firearm and which provides a standard mounting platform for a desired attachment. However, heretofore, the process of mounting such accessories to the Picatinny rail has required the use of external tools, and has been both awkward and time-consuming. Moreover, the inability to timely attach a desired accessory to a firearm, or switch accessories, can be dangerous for the user. For example, in combat, a soldier's inability to quickly attach a bayonet to his firearm could result in death or serious injury to the soldier.
[0004] Consequently, there is a long felt need in the art for a device that enables a user to quickly and securely attach/detach an accessory (e.g., a scope, light, bayonet, etc.) to the Picatinny or tactical rail of a firearm without the use of external tools. There is also a long felt need for a device that is capable of being locked/unlocked with a single hand, thereby allowing the user to retain possession of the firearm with his remaining hand. Finally, there is a long felt need for a device that accomplishes all of the forgoing objectives, and that is relatively inexpensive to manufacture and safe and easy to use.
SUMMARY
[0005] The following presents a simplified summary in order to provide a basic understanding of some aspects of the disclosed innovation. This summary is not an extensive overview, and it is not intended to identify key/critical elements or to delineate the scope thereof. Its sole purpose is to present some concepts in a simplified form as a prelude to the more detailed description that is presented later.
[0006] The subject matter disclosed herein, in one aspect thereof, is a device for enabling a user to quickly and securely attach/detach an accessory (e.g., a scope, light, bayonet, etc.) to the Picatinny or tactical rail of a firearm. In a preferred embodiment of the present invention, the device comprises a lower portion, an upper portion, and a locking mechanism, wherein said locking mechanism further comprises a handle portion, at least one latch with a spring attached thereto, and at least one lock that is repositionable by the movement of said at least one latch.
[0007] To the accomplishment of the foregoing and related ends, certain illustrative aspects of the disclosed innovation are described herein in connection with the following description and the annexed drawings. These aspects are indicative, however, of but a few of the various ways in which the principles disclosed herein can be employed and is intended to include all such aspects and their equivalents. Other advantages and novel features will become apparent from the following detailed description when considered in conjunction with the drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] FIG. 1 is a perspective view of one embodiment of the present invention securely attached to a Picatinny rail of a firearm.
[0009] FIG. 2 is a perspective view of the device of FIG. 1 detached from a Picatinny rail of a firearm.
[0010] FIG. 3A is a side elevational view of the device of FIG. 1 securely attached to a Picatinny rail of a firearm.
[0011] FIG. 3B is a cross-sectional view of the device depicted in FIG. 3A at cut line 3 B- 3 B.
[0012] FIG. 4A is a front elevational view of the device of FIG. 1 .
[0013] FIG. 4B is a cross-sectional view of the device depicted in FIG. 4A at cut line 4 B- 4 B.
[0014] FIG. 5 is a perspective view of the lower portion and locking mechanism of the device depicted in FIG. 1 .
[0015] FIG. 6 is a perspective view of an alternative embodiment of the present invention wherein the locking mechanism further comprises a button lock to reduce the likelihood of an accidental release of the locking mechanism.
[0016] FIG. 7A is a rear elevational view of the alternative embodiment of the present invention depicted in FIG. 6 .
[0017] FIG. 7B is a side cross-sectional view of the device depicted in FIG. 7A at cut line 7 B- 7 B.
[0018] FIG. 8 is an exploded view of the alternative embodiment of the present invention depicted in FIG. 6 .
[0019] FIG. 9 is a partially exploded view of an alternative embodiment of the present invention.
[0020] FIG. 10A is a front elevational view of the additional alternative embodiment of the present invention depicted in FIG. 9 .
[0021] FIG. 10B is a side cross-sectional view of the device depicted in FIG. 9 at cut line 10 B- 10 B.
[0022] FIG. 11A is a top perspective view of the lower portion and locking mechanism of the device depicted in FIG. 9 in a locked position.
[0023] FIG. 11B is a top perspective view of the lower portion and locking mechanism of the device depicted in FIG. 9 in an unlocked position.
[0024] FIG. 12A is a bottom perspective view of the lower portion and locking mechanism of the device depicted in FIG. 9 in a locked position.
[0025] FIG. 12B is a bottom perspective view of the lower portion and locking mechanism of the device depicted in FIG. 9 in an unlocked position.
DETAILED DESCRIPTION
[0026] The innovation is now described with reference to the drawings, wherein like reference numerals are used to refer to like elements throughout. In the following description, for purposes of explanation, numerous specific details are set forth in order to provide a thorough understanding thereof. It may be evident, however, that the innovation can be practiced without these specific details.
[0027] Referring initially to the drawings, FIG. 1 depicts a perspective view of the side slide lock and quick release device 100 of the present invention securely attached to a Picatinny rail 20 of a firearm (not shown), and FIG. 2 depicts a perspective view of the device 100 of the present invention detached from Picatinny rail 20 . By way of background, Picatinny rail 20 is an elongated bracket that may be attached to a firearm to provide a standard mounting platform for accessories and attachments such as a scope, light, bayonet and the like. Rail 20 is typically comprised of a plurality of raised, spaced apart lugs or ridges 22 along its top or upper surface, with channels 24 located between and formed by said ridges 22 , and a rail flange 26 extending along each side of rail 20 .
[0028] The side slide lock and quick release device 100 of the present invention is preferably comprised of a lower portion 110 , an upper portion 120 removably attached to said lower portion 110 through the use of fasteners 130 , and a locking mechanism 140 for detachably securing device 100 to rail 20 without the need for external tools. As best illustrated in the FIGS., lower portion 110 is an elongated member having a top surface 111 , a bottom surface 112 , opposing side surfaces 113 , a rear 115 , a front 116 , a rear fence 117 and a forward fence 118 , wherein said rear fence 117 and said forward fence 118 extend downwardly from said bottom surface 112 for mating engagement with rail 20 , as described more fully below.
[0029] Lower portion 110 further comprises one or more continuous openings 1112 that extend between top surface 111 and bottom surface 112 , and from a first side surface 113 in the direction of a second side surface 113 , for receipt of a portion of locking mechanism 140 , as described more fully below. Top surface 111 may also comprise a plurality of spaced apart openings 1114 for receipt of fasteners 130 to fixedly attach lower portion 110 to upper portion 120 .
[0030] As previously described, lower portion 110 is comprised of a pair of generally parallel, spaced apart fences 117 , 118 that extend downwardly from said bottom surface 112 for mating engagement with rail 20 . More specifically, rear fence 117 protrudes downwardly from one side of bottom surface 112 towards the front 116 of lower portion 110 and extends substantially along the length of lower portion 110 . Similarly, forward fence 118 protrudes downwardly from the opposite side of bottom surface 112 towards the rear 115 of lower portion 110 and is generally parallel to rear fence 117 , but that only extends partially along the length of lower portion 110 , as best shown in FIG. 5 , due to the presence of one or more continuous openings 1112 . Rear fence 117 further comprise a generally v-shaped groove 119 extending along a substantial portion of the length of rear fence 117 for mating engagement with rail flange 26 of rail 20 . Likewise, when locking mechanism 140 is engaged, forward fence 118 and a portion of locking mechanism 140 also form a generally v-shaped groove extending along a portion of the length of said forward fence 118 for mating engagement with rail flange 26 of rail 20 , as best shown in FIG. 4A .
[0031] Upper portion 120 is also a generally elongated member that is comprised of a top 121 , an opposing bottom 122 , a pair of opposing side slots 124 , a rear end 125 and a front end 126 . Similar to Picatinny rail 20 , top 121 is also comprised of a plurality of raised, spaced apart lugs or ridges 1210 , with channels 1212 located between and formed by said ridges 1210 .
[0032] Bottom 122 is generally flat and preferably corresponds in shape and size with top surface 111 of lower portion 110 as shown in the Figures, with the exception of (i) an elongated longitudinal opening or channel 1220 formed therein for receipt of a portion of locking mechanism 140 and (ii) one or more spring channels 123 formed therein for receipt of a spring, both of which are explained more fully below. Channel 1220 preferably extends along a partial length of bottom 122 from rear 115 in the direction of front 116 . Each of said spring channel(s) 123 also preferably extends a partial length of bottom surface 122 to coincide with the positioning of springs, as described more fully below.
[0033] Opposing side slots 124 are similar to rail flanges 26 in rail 20 , and preferably extend between rear end 125 and front end 126 and are useful for attaching accessories (such as a scope, light, bayonet, etc.) to device 100 in generally the same manner that accessories (not shown) would ordinarily be attached to rail 20 . Opposing side slots 124 may further comprise a plurality of spaced apart openings 1240 extending through bottom 122 . The number and placement of openings 1240 preferably correspond to the number and placement of openings 1114 in lower portion 110 for receipt of fasteners 130 , which are used to fixedly attach upper portion 120 to lower portion 110 , as best shown in FIGS. 1-3 .
[0034] Locking mechanism 140 is preferably comprised of an elongated arm portion 142 , a handle portion 144 for engaging or dis-engaging locking mechanism 140 , one or more locks 146 and one or more springs 147 . In a preferred embodiment of the present invention, arm portion 142 is further comprised of a front latch 1420 and a rear latch 1425 positioned in series and sized to fit and slide longitudinally within channel 1220 . Each of latches 1420 , 1425 further comprise a radially shaped continuous opening 1426 therein for receipt of a cam, as explained more fully below and depicted in FIG. 5 . Handle portion 144 may be attached to rear latch 1425 via fasteners 145 .
[0035] Each of locks 146 are generally block-like in shape and further comprise a cam 1460 that extends upwardly from a top surface 1462 of lock 146 , as best shown in FIG. 5 . More specifically cam 1460 is positioned in opening 1426 of latches 1420 , 1425 so that when said latches 1420 , 1425 are repositioned longitudinally within channel 1220 , cams 1460 cause each of locks 146 to move in and partially out of continuous openings 1112 in lower portion 110 .
[0036] A spring 147 is positioned atop of each of front latch 1420 and rear latch 1425 as shown in FIG. 5 and secured to said latches via a spring post 148 and a spring pin 149 . More specifically, each of springs 147 is comprised of a first end 1472 and a second end 1474 , with said first end 1472 being fixedly attached to said spring post 148 via spring pin 149 . Springs 147 are biased in the general direction of the length of device 100 , as best shown in FIG. 5 and, when fully assembled, springs 147 are contained and confined within spring channels 123 of upper portion 120 .
[0037] In the further preferred embodiment of the present invention depicted in FIGS. 6, 7A and 7B , locking mechanism 140 further comprises a button lock 150 for reducing the likelihood of an accidental or premature release of locking mechanism 140 . More specifically, button lock 150 comprises a button portion 152 , a pin 154 and an arm 156 , wherein button portion 152 and arm 156 are preferably integrally formed and pivot about pin 154 . Button lock 150 is engaged/disengaged by partially rotating button portion 152 about pin 142 , as described more fully below. Button portion 152 resides in a recess 159 in handle portion 144 , as best shown in FIG. 6 . When in the disengaged position, arm 156 resides in a recess 158 in arm portion 142 . When in the engaged position, arm 142 extends outwardly from recess 158 to contact rear end 125 of upper portion 120 to prevent locking mechanism 140 from accidentally or prematurely releasing, as described more fully below.
[0038] For purposes of further clarity, FIG. 8 is an exploded view of the alternative embodiment of the present invention depicted in FIG. 6 . As shown in FIG. 8 , device 100 may further comprise an insert device 180 that may be secured to, and extend downwardly from, the bottom surface 112 of lower portion 110 with fasteners 181 . Insert device 180 further comprises an insert portion 182 with an opening 1820 therein for receipt of a spring 184 and a ball 186 . As more fully described below, insert device 180 is inserted into a select one of channels 24 of Picatinny rail 20 when device 100 is installed on rail 20 , and biased spring 184 and ball 186 apply pressure against a select one of ridges 22 of rail 20 .
[0039] FIGS. 9 through FIG. 12B depict an additional alternative embodiment of the present invention in which locking mechanism 140 further comprises an arm 210 and related components for retaining handle portion 144 in a desired position while installing device 100 onto rail 20 , as more fully described below. More specifically, FIG. 9 is a partially exploded view of an alternative embodiment of the present invention and shows locking mechanism 140 further comprised of a pin 200 , arm 210 , a spring 220 and a pair of spacers 240 . In this particular embodiment, and as shown in FIG. 9 , lower portion 110 further comprises in top surface 111 a pin channel 202 for receipt of pin 200 , an arm channel 212 that preferably extends between top surface 111 and bottom surface 112 for receipt of arm 210 , and one or more spacer channels 242 for receipt of spacers 240 . Additionally, rear latch 1425 further comprises an aperture 1427 therein for receipt of a portion of arm 210 , as more fully described below.
[0040] As best shown in FIG. 9 , arm 210 is further comprised of a first end 2102 , an opposing second end 2104 , an opening 2105 for receipt of pin 200 and a spring seat 2106 for receipt of spring 220 , as more fully described below. More specifically, pin 200 is inserted into opening 2105 and extends from each side thereof to reside in pin channel 202 and permit arm 210 to pivot about pin 200 as arm 210 resides in arm channel 212 and extends beyond bottom surface 112 of lower portion 110 , as shown in FIG. 12B . Each of spacers 240 reside in a respective spacer channel 242 and prevent pin 200 from being prematurely removed from pin channel 202 . Further, spring 220 rests atop of spring seat 2106 adjacent to second end 2104 of arm 210 , and first end 2102 of arm 210 resides in arm channel 212 below aperture 1427 in rear latch 1425 , as explained more fully below.
[0041] More specifically, when device 100 is assembled and in the locked position (meaning the handle portion 144 is at its furthest point from rear 115 , as shown in FIGS. 10A &B, 11 A and 12 A), spring 220 , which is positioned in compression between spring seat 2106 on arm 210 and a spring channel 222 formed within bottom 122 of upper portion 120 , causes first end 2102 to pivot about pin 200 in the direction of rear latch 1425 , but is prevented from doing so until handle portion 144 is pushed in the direction of rear 115 thereby enabling aperture 1427 on rear latch 1425 to move into position to receive first end 2102 of arm 210 . Once received, handle portion 144 is prevented from moving out of the unlocked position (meaning that handle portion 144 is at its closest position to rear 115 , as shown in FIGS. 11B and 12B ) until such time as device 100 is placed onto rail 20 , which causes the portion of second end 2104 of arm 210 to pivot in the direction of spring 220 and spring 220 to compress between spring seat 2106 and spring channel 222 in upper portion 120 . As spring 220 compresses, first end 2102 of arm 210 leaves aperture 1427 and handle portion 144 returns to the locked position as shown in FIGS. 11A and 12A . In this manner, a user (not shown) is capable of installing device 100 onto rail 20 without having to both push the handle portion 144 towards device 100 and hold it there until device 100 is installed onto rail 20 at a desired location.
[0042] Having now described the general structure of a number of embodiments of device 100 , its function will now be described in general terms. A user (not shown) desiring to securely mount device 100 (as depicted in FIGS. 1-8 ) onto rail 20 would simply place device 100 (in an unlocked position—meaning the handle portion 144 is pushed in towards device 100 , as shown in FIGS. 1 and 2 ) at a desired position along and on top of rail 20 so that fences 117 , 118 clear rail flanges 26 and locks 146 and insert device 180 are capable of being inserted into a respective select one of said channels 24 . Once device 100 is placed on rail 20 , the user would then release handle portion 144 (which is compressing springs 147 ) in a direction opposite of rear 115 , thereby causing cams 1460 to travel clockwise within radial openings 1426 and each of locks 146 to securely engage Picatinny rail 20 . A user may then also desire to engage button lock 150 by partially rotating button portion 152 downwardly about pin 154 so that arm 156 extends upwardly from recess 158 to contact rear end 125 of upper portion 120 to prevent locking mechanism 140 from prematurely or accidentally disengaging.
[0043] Alternatively, a user (not shown) desiring to securely mount device 100 (as depicted in FIGS. 9 through 12B ) onto rail 20 would simply push handle portion 144 in the direction of rear 115 until first end of pivoting arm 210 engages aperture 1427 in rear latch 1425 and place device 100 (in an unlocked position—meaning the handle portion 144 is pushed in towards rear 115 , as shown in FIGS. 11B and 12B ) at a desired position along and on top of rail 20 so that fences 117 , 118 clear rail flanges 26 and locks 146 and insert device 180 are capable of being inserted into a respective select one of said channels 24 . Once device 100 is placed on rail 20 , arm 210 pivots about pin 200 so that first end 2102 of arm 210 leaves aperture 1427 thereby allowing handle portion 144 (which is compressing springs 147 ) to release in a direction opposite of rear 115 , thereby causing cams 1460 to travel clockwise within radial openings 1426 and each of locks 146 to securely engage Picatinny rail 20 . A user may then also desire to engage button lock 150 by partially rotating button portion 152 downwardly about pin 154 so that arm 156 extends upwardly from recess 158 to contact rear end 125 of upper portion 120 to prevent locking mechanism 140 from prematurely or accidentally disengaging.
[0044] Similarly, to unlock locking mechanism 140 (as depicted in FIGS. 1 through 8 ) to reposition device 100 along rail 20 or remove device 100 from rail 20 altogether, a user (not shown) would simply (i) disengage button lock 150 by partially rotating button portion 152 upwardly about pin 154 so that arm 156 retreats into recess 158 and (ii) push in handle portion 144 in the direction of rear 115 , thereby causing springs 147 to compress and cams 1460 to travel counter-clockwise within radial openings 1426 and each of locks 146 to disengage from Picatinny rail 20 . More specifically, as the user pushes in handle portion 144 and rear latch 1425 moves forward along channel 1220 it makes contact with front latch 1420 and causes the same to also move forward, thereby causing each of springs 147 to compress and the device 100 to become capable of being installed or removed from rail 20 . Once the device 100 has been installed, the compression force in the springs 147 causes each of front latch 1420 and rear latch 1425 to retreat to their original position.
[0045] Similarly, to unlock locking mechanism 140 (as depicted in FIGS. 9 through 12 ) to reposition device 100 along rail 20 or remove device 100 from rail 20 altogether, a user (not shown) would simply (i) disengage button lock 150 by partially rotating button portion 152 upwardly about pin 154 so that arm 156 retreats into recess 158 and (ii) push in handle portion 144 in the direction of rear 115 , thereby causing first end of pivoting arm 210 to engage aperture 1427 in rear latch 1425 and springs 147 to compress and cams 1460 to travel counter-clockwise within radial openings 1426 and each of locks 146 to disengage from Picatinny rail 20 . More specifically, as the user pushes in handle portion 144 and rear latch 1425 moves forward along channel 1220 it makes contact with front latch 1420 and causes the same to also move forward, thereby causing each of springs 147 to compress and the device 100 to become capable of being installed or removed from rail 20 . Once the device 100 has been installed, the compression force in the springs 147 causes each of front latch 1420 and rear latch 1425 to retreat to their original position.
[0046] Other variations are also within the spirit of the present invention. Thus, while the invention is susceptible to various modifications and alternative constructions, a certain illustrated embodiment thereof is shown in the drawings and has been described above in detail. It should be understood, however, that there is no intention to limit the invention to the specific form or forms disclosed, but on the contrary, the intention is to cover all modifications, alternative constructions, and equivalents falling within the spirit and scope of the invention, as defined in the appended claims.
[0047] The use of the terms “a” and “an” and “the” and similar referents in the context of describing the invention (especially in the context of the following claims) are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context. The terms “comprising,” “having,” “including,” and “containing” are to be construed as open-ended terms (i.e., meaning “including, but not limited to,”) unless otherwise noted. The term “connected” is to be construed as partly or wholly contained within, attached to, or joined together, even if there is something intervening. Recitation of ranges of values herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range, unless otherwise indicated herein, and each separate value is incorporated into the specification as if it were individually recited herein. All methods described herein can be performed in any suitable order unless otherwise indicated herein or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., “such as”) provided herein, is intended merely to better illuminate embodiments of the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as indicating any non-claimed element as essential to the practice of the invention.
[0048] Preferred embodiments of this invention are described herein. Variations of those preferred embodiments may become apparent to those of ordinary skill in the art upon reading the foregoing description. The inventor expects skilled artisans to employ such variations as appropriate, and the inventor intends for the invention to be practiced otherwise than as specifically described herein. Accordingly, this invention includes all modifications and equivalents of the subject matter recited in the claims appended hereto as permitted by applicable law. Moreover, any combination of the above-described elements in all possible variations thereof is encompassed by the invention unless otherwise indicated herein or otherwise clearly contradicted by context.
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An improved device for enabling a user to quickly and securely attach and detach an accessory (e.g., a scope, light, bayonet, etc.) to the Picatinny or tactical rail of a firearm. In a preferred embodiment of the present invention, the device comprises a lower portion, an upper portion and a locking mechanism. The device is relatively inexpensive to manufacture and safe and easy to use.
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FIELD
[0001] This invention relates to the field of integrated circuit design. More particularly, this invention relates to an efficient hardware implementation of a variable node processing unit (VNU) inside of a low-density parity check (LDPC) min-sum decoder.
BACKGROUND
[0002] Low density parity-check (LDPC) codes were first proposed by Gallager in 1962, and then “rediscovered” by MacKay in 1996. LDPC codes have been shown to achieve an outstanding performance that is very close to the Shannon transmission limit. However it is very difficult to build an efficient hardware implementation of a circuit for decoding LDPC codes. All existing hardware implementations of LDPC decoding algorithms suffer from low speed and large area and power requirements. It is very important to develop an LDPC-decoder that has better speed, area, and power characteristics than the existing implementations.
[0003] The most promising algorithm for decoding LDPC-codes is so the called min-sum algorithm. Generally speaking this algorithm performs two main operations
1. Find a minimum number among a given set of signed numbers, and 2. For a given group of signed numbers A 1 , . . . , A N and a signed number M calculate:
[0000] S i =S−A i , where i= 1, . . . N, S=A 1 + . . . +A N +M, and
[0000] SIGN=sign( S )={0, if S≧ 0; 1, if S< 0}.
[0006] A typical hardware implementation of this algorithm represents the LDPC decoder as a set of multiple node processing units performing operations (1) and (2) as given above. There are two types of units:
1. So-called “check node processing units” (CNU) that perform operation (1), and 2. So-called “variable node processing units” (VNU) that perform operation (2).
[0009] The decoder may contain up to thousands of these two units working in parallel. One hardware realization of a VNU as depicted in FIG. 1 contains N-input adder module (denoted by the “+” sign) for calculating the total sum S, and N two-input subtractor modules (denoted by the “−” sign) for calculating “partial” sums Si.
[0010] What is needed, therefore, is a VNU that improves—at least in part—the speed, area, and power characteristics of the VNU, and therefore enables the construction of a better LDPC decoder.
SUMMARY
[0011] The above and other needs are met by a variable node processing unit with N+1 inputs, having at least a first bank of two-input adders and a separate last bank of two-input adders, where the banks of adders are disposed in series. A sign module outputs a sign value. The unit has N+1 outputs, where one of the outputs is the sign value.
[0012] In various embodiments, the variable node processing unit is disposed in a low-density parity check min-sum decoder. In some embodiments, at least one of the two-input adders is a Signed Ripple-Carry adder, with a flip-flop interjected between two adjacent ones of the logic elements. In some embodiments the sign module includes a chain of majority cells that calculate the sign value without calculating a corresponding sum value, with a flip-flop interjected between two adjacent ones of the majority cells.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] Further advantages of the invention are apparent by reference to the detailed description when considered in conjunction with the figures, which are not to scale so as to more clearly show the details, wherein like reference numbers indicate like elements throughout the several views, and wherein:
[0014] FIG. 1 is a functional representation of a prior art VNU.
[0015] FIG. 2 is a functional representation of a VNU according to an embodiment of the present invention.
[0016] FIG. 3 is a functional representation of a prior art Ripple-Carry adder.
[0017] FIG. 4 is a functional representation of an enhanced prior art Ripple-Carry adder modified for signed numbers.
[0018] FIG. 5 is a functional representation of a two-stage signed Ripple-Carry adder according to an embodiment of the present invention.
[0019] FIG. 6 is a functional representation of a sign calculation submodule according to an embodiment of the present invention.
[0020] FIG. 7 is a functional representation of a two-stage sign calculation submodule according to an embodiment of the present invention.
DETAILED DESCRIPTION
[0021] Instead of using an N-input summator followed by subtractors, the embodiments of the present invention use simultaneous implementation of N partials sums Si and SIGN as shown in FIG. 2 . If N=4 (the most common value for a high-rate LDPC code) then the following equations are used to calculate the partial sums and the sign value:
[0000] y 1 =M+A 1
[0000] y 2 =M+A 2
[0000] y 3 =A 2 +A 3
[0000] y 4 =A 2 +A 4
[0000] y 5 =A 3 +A 4
[0000] S 1 =y 2 +y 5
[0000] S 2 =y 1 +y 5
[0000] S 3 =y 1 +y 4
[0000] S 4 =y 1 +y 3
[0000] SIGN=sign( A 4 +S 4)
Implementation of the Adder Submodule
[0022] To further reduce the circuit area, a Ripple-Carry implementation of two-input adders inside the VNU is used. Conventional Ripple-Carry adders use N logic elements to implement an addition of two N-bit unsigned numbers A and B, as shown in FIG. 3 . The output of the Ripple-Carry adder is (N+1)-bit unsigned number S such that S=A+B. Note that there is no overflow in the circuit because the sum width is greater then the items width.
[0023] An enhancement according to the basic Ripple-Carry adder depicted in FIG. 3 permits the addition of signed numbers, and is depicted in FIG. 4 . The enhanced adder uses N+1 logic elements to implement the addition of two N-bit signed numbers A and B in complement representation. The output of the Signed Ripple-Carry adder is (N+1)-bit signed number S in complement representation such that S=A+B. Note that again there is no overflow in the circuit because the sum width is greater then the items width.
[0024] Ripple-Carry adders are very small and power-efficient, but the circuit delay is relatively big (for example, delay from inputs A 0 and B 0 to output S N+1 ). To reduce the delay of the circuit, the Ripple-Carry adders are segmented by inserting a flip-flop somewhere in the middle of the chain of Full-Adders, as depicted in FIG. 5 . The exact position of the dividing flip-flop depends on various parameters and may be different for different instances of the Ripple-Carry adder disposed inside of the VNU.
Implementation of the Sign Calculation Submodule
[0025] As mentioned above, the SIGN value is calculated by the formula:
[0000] SIGN=sign( A 4 +S 4).
[0026] To calculate this value, a two-input adder can be used to find the sum S=A4+S4 and then take the uppermost bit of the sum to obtain the sign. However, in some embodiments an optimized circuit is used that calculates the sign of the sum without calculating the sum itself. The corresponding circuit is depicted in FIG. 6 , and consists of a chain of so-called majority cells.
[0027] To further optimize the circuit speed, the chain of majority cells is segmented by inserting a flip-flop in the same manner as for the Ripple-Carry adder described above. The corresponding circuit is depicted in FIG. 7 .
[0028] The circuits above use the following logic elements:
[0000]
HA (Half-Adder)
Inputs
Outputs
X (Left Upper)
Y (Right Upper)
C out (Left)
S (Bottom)
0
0
0
0
0
1
0
1
1
0
0
1
1
1
1
0
[0000]
FA (Full Adder)
Inputs
Outputs
X (Left Upper)
Y (Right Upper)
C in (Right)
C out (Left)
S (Bottom)
0
0
0
0
0
0
0
1
0
1
0
1
0
0
1
0
1
1
1
0
1
0
0
0
1
1
0
1
1
0
1
1
0
1
0
1
1
1
1
1
[0000]
XOR
Inputs
Output
X (Left Upper)
Y (Right Upper)
C in (Right)
C out
0
0
0
0
0
0
1
1
0
1
0
1
0
1
1
0
1
0
0
1
1
0
1
0
1
1
0
0
1
1
1
1
[0029] The foregoing description of preferred embodiments for this invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise form disclosed. Obvious modifications or variations are possible in light of the above teachings. The embodiments are chosen and described in an effort to provide the best illustrations of the principles of the invention and its practical application, and to thereby enable one of ordinary skill in the art to utilize the invention in various embodiments and with various modifications as are suited to the particular use contemplated. All such modifications and variations are within the scope of the invention as determined by the appended claims when interpreted in accordance with the breadth to which they are fairly, legally, and equitably entitled.
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A variable node processing unit with N+1 inputs, having at least a first bank of two-input adders and a separate last bank of two-input adders, where the banks of adders are disposed in series.
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[0001] The present application is a continuation-in-part of U.S. patent application Ser. No. 09/983,029, filed Oct. 22, 2001, which is a continuation-in-part of U.S. patent application Ser. No. 09/403,834, filed on Oct. 27, 1999 (now abandoned), which is a U.S. National Phase application of International Application No. PCT/JP98/05156, filed Nov. 16, 1998 and which claims priority from Japanese Application No. JP 10-287921, filed Oct. 9, 1998. The present application incorporates herein by reference the full disclosures of U.S. patent application Ser. No. 09/983,029, and of U.S. patent application Ser. No. 09/403,834, and of International Application No. PCT/JP98/05156, and of Japanese Application No. JP 10-287921.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present invention relates to free-cutting copper alloys.
[0004] 2. Prior Art
[0005] Among the copper alloys with a good machinability are bronze alloys such as that having the JIS designation H5111 BC6 and brass alloys such as those having the JIS designations H3250-C3604 and C3771. Those alloys are enhanced in machinability with the addition of 1.0 to 6.0 percent, by weight, of lead so as to give industrially satisfactory results as easy-to-work copper alloys. Because of their excellent machinability, those lead-containing copper alloys have been an important basic material for a variety of articles such as city water faucets and water supply/drainage metal fittings and valves.
[0006] In those conventional free-cutting copper alloys, lead does not form a solid solution in the matrix but disperses in granular form, thereby improving the machinability of those alloys. To produce the desired results, lead has to be added in as much as 2.0 or more percent by weight. If the addition of lead is less than 1.0 percent by weight, chippings will be spiral in form, as (D) in FIG. 1 . Spiral chippings cause various troubles such as, for example, tangling with the tool. If, on the other hand, the content of lead is 1.0 or more percent by weight and not larger than 2.0 percent by weight, the cut surface will be rough, though that will produce some results such as reduction of cutting resistance. It is usual, therefore, that lead is added to an extent of not less than 2.0 percent by weight. Some expanded copper alloys in which a high degree of cutting property is required are mixed with some 3.0 or more percent by weight of lead. Further, some bronze castings have a lead content of as much as some 5.0 percent, by weight. The alloy having the JIS designation H 5111 BC6, for example, contains some 5.0 percent by weight of lead.
[0007] However, the application of those lead-mixed alloys has been greatly limited in recent years, because lead contained therein is harmful to humans as an environment pollutant. That is, the lead-containing alloys pose a threat to human health and environmental hygiene because lead finds its way into metallic vapor that generates in the steps of processing those alloys at high temperatures such as melting and casting. There is also a danger that lead contained in the water system metal fittings, valves, and so on made of those alloys will dissolve out into drinking water.
[0008] For these reasons, the United States and other advanced nations have been moving in recent years to tighten the standards for lead-containing copper alloys to drastically limit the permissible level of lead in copper alloys. In Japan, too, the use of lead-containing alloys has been increasingly restricted, and there has been a growing call for the development of free-cutting copper alloys with a low lead content.
SUMMARY OF THE INVENTION
[0009] It is an object of the present invention to provide a free-cutting copper alloy that contains an extremely small amount (0.02 to 0.4 percent by weight) of lead as a machinability-improving element, yet which is quite excellent in machinability, that can be used as safe substitute for the conventional easy-to-cut copper alloys that have a large lead content, and that presents no environmental hygienic problems while permitting the recycling of chippings, thus providing a timely answer to the mounting call for the restriction of lead-containing products.
[0010] It is an another object of the present invention to provide a free-cutting copper alloy that has high corrosion resistance coupled with excellent machinability and is suitable as basic material for cutting works, forgings, castings and others, thus having a very high practical value. The cutting works, forgings, castings, and so on, including city water faucets, water supply/drainage metal fittings, valves, stems, hot water supply pipe fittings, shaft and heat exchanger parts.
[0011] It is yet another object of the present invention to provide a free-cutting copper alloy, with a high strength and wear resistance coupled with an easy-to-cut property, that is suitable as basic material for the manufacture of cutting works, forgings, castings, and other uses requiring high strength and wear resistance such as, for example, bearings, bolts, nuts, bushes, gears, sewing machine parts, and hydraulic system parts, and which therefore is of great practical value.
[0012] It is a further object of the present invention to provide a free-cutting copper alloy with an excellent high-temperature oxidation resistance combined with an easy-to-cut property, which is suitable as basic material for the manufacture of cutting works, forgings, castings, and other uses where a high thermal oxidation resistance is essential, e.g. nozzles for kerosene oil and gas heaters, burner heads, and gas nozzles for hot-water dispensers, and which therefore has great practical value.
[0013] The objects of the present inventions are achieved by provision of the following copper alloys:
[0014] 1. A free-cutting copper alloy with an excellent easy-to-cut feature which is composed of 69 to 79 percent, by weight, of copper, 2.0 to 4.0 percent, by weight, of silicon, 0.02 to 0.4 percent, by weight, of lead and the remaining percent, by weight, of zinc. For purpose of simplicity, this copper alloy will be hereinafter called the “first invention alloy.”
[0015] Lead does not form a solid solution in the matrix but instead disperses in granular form to improve machinability. Silicon improves the easy-to-cut property by producing a gamma phase (in some cases, a kappa phase) in the structure of metal. Silicon and lead are the same in that they are effective in improving machinability, though they are quite different in their contribution to other properties of the alloy. On the basis of that recognition, silicon is added to the first invention alloy so as to bring about a high level of machinability meeting industrial requirements while making it possible to greatly reduce the lead content. That is, the first invention alloy is improved in machinability through formation of a gamma phase with the addition of silicon.
[0016] The addition of less than 2.0 percent by weight of silicon cannot form a gamma phase sufficient enough to secure industrially satisfactory machinability. With an increase in the addition of silicon, machinability improves. But with the addition of more than 4.0 percent by weight of silicon, machinability will not go up in proportion. The problem is, however, that silicon is high in melting point and low in specific gravity and also liable to oxidize. If unmixed silicon is fed into the furnace in the melting step, silicon will float on the molten metal and is oxidized into oxides of silicon (silicon oxide), hampering the production of a silicon-containing copper alloy. In producing the ingot of silicon-containing copper alloy, therefore, silicon is usually added in the form of a Cu—Si alloy, which boosts the production cost. Due also to the cost of making the alloy, it is not desirable to add silicon in a quantity exceeding the saturation point or plateau of machinability improvement, that is, 4.0 percent by weight. An experiment showed that when silicon is added in the amount of 2.0 to 4.0 percent by weight, it is desirable to hold the content of copper at 69 to 79 percent by weight in consideration of its relation to the content of zinc in order to maintain the intrinsic properties of the Cu—Zn alloy. For this reason, the first invention alloy is composed of 69 to 79 percent by weight of copper and 2.0 to 4.0 percent by weight of silicon, respectively. The addition of silicon improves not only the machinability but also the flow of the molten metal in casting, strength, wear resistance, resistance to stress corrosion cracking, and high-temperature oxidation resistance. Also, the ductility and de-zinc-ing corrosion resistance will be improved to some extent.
[0017] The addition of lead is set at 0.02 to 0.4 percent by weight for this reason. In the first invention alloy, a sufficient level of machinability is obtained by adding silicon that has the aforesaid effect even if the addition of lead is reduced. Yet, lead has to be added in an amount not smaller than 0.02 percent by weight if the alloy is to be superior to the conventional free-cutting copper alloy in machinability, while the addition of lead in an amount exceeding 0.4 percent by weight would have adverse effect, resulting in a rough surface condition, poor hot workability such as poor forging behavior, and low cold ductility. Meanwhile, it is expected that such a small content of not higher than 0.4 percent by weight will be able to clear the lead-related regulations however strictly they are to be stipulated in the advanced nations including Japan in the future. For that reason, the addition range of lead is set at 0.02 to 0.4 percent by weight in the first and also second to eleventh invention alloys which will be described later.
[0018] 2. Another embodiment of the present invention is a free-cutting copper alloy also with an excellent easy-to-cut feature which is composed of 69 to 79 percent, by weight, of copper; 2.0 to 4.0 percent, by weight, of silicon; 0.02 to 0.4 percent, by weight, of lead; one additional element selected from among 0.02 to 0.4 percent, by weight, of bismuth, 0.02 to 0.4 percent, by weight, of tellurium, and 0.02 to 0.4 percent, by weight, of selenium; and the remaining percent, by weight, of zinc. This second copper alloy will be hereinafter called the “second invention alloy.”
[0019] That is, the second invention alloy is composed of the first invention alloy and, in addition, one element selected from among 0.02 to 0.4 percent, by weight, of bismuth, 0.02 to 0.4 percent, by weight, of tellurium, and 0.02 to 0.4 percent, by weight, of selenium.
[0020] Bismuth, tellurium, and selenium, as with lead, do not form a solid solution with the matrix but disperse in granular form to enhance machinability. That makes up for the reduction of the lead content. The addition of any one of those elements along with silicon and lead could further improve the machinability beyond the level obtained from the addition of silicon and lead. From this finding, the second invention alloy was developed, in which one element selected from among bismuth, tellurium, and selenium is mixed. The addition of bismuth, tellurium, or selenium as well as silicon and lead can make the copper alloy so machinable that complicated forms can be freely cut out at a high speed. But no improvement in machinability can be realized from the addition of bismuth, tellurium, or selenium in an amount of less than 0.02 percent by weight. However, those elements are expensive as compared with copper. Even if the addition exceeds 0.4 percent by weight, the proportional improvement in machinability is so small that addition beyond that level does not pay off economically. What is more, if the addition is more than 0.4 percent by weight, the alloy will deteriorate in hot workability such as forgeability and cold workability such as ductility. While there might be a concern that heavy metals like bismuth would cause a problem similar to that of lead, a very small addition of less than 0.4 percent by weight is negligible and would present no particular problems. From those considerations, the second invention alloy is prepared with the addition of bismuth, tellurium, or selenium kept to 0.02 to 0.4 percent by weight. In this regard, it is desired to keep the combined content of lead and bismuth, tellurium, or selenium to not higher than 0.4 percent by weight. That is because if the combined content exceeds 0.4 percent by weight, if slightly, then there will begin a deterioration in hot workability and cold ductility and also there is fear that the form of chippings will change from (B) to (A) in FIG. 1 . But the addition of bismuth, tellurium or selenium, which improves the machinability of the copper alloy though a mechanism different from that of silicon as mentioned above, would not affect the proper contents of copper and silicon. For this reason, the contents of copper and silicon in the second invention alloy are set at the same level as those in the first invention alloy.
[0021] 3. Another embodiment of the present invention is a free-cutting copper alloy, also with an excellent easy-to-cut feature, which is composed of 70 to 80 percent, by weight, of copper; 1.8 to 3.5 percent, by weight, of silicon; 0.02 to 0.4 percent. by weight, of lead; at least one element selected from among 0.3 to 3.5 percent, by weight, of tin, 1.0 to 3.5 percent, by weight, of aluminum, and 0.02 to 0.25 percent, by weight, of phosphorus; and the remaining percent, by weight, of zinc. This third copper alloy will be hereinafter called the “third invention alloy.”
[0022] Tin works the same way as silicon. That is, if tin is added, a gamma phase will be formed and the machinability of the Cu—Zn alloy will be improved. For example, the addition of tin in the amount of 1.8 to 4.0 percent by weight would bring about a high machinability in the Cu—Zn alloy containing 58 to 70 percent, by weight, of copper, even if silicon is not present. Therefore, the addition of tin to the Cu—Si—Zn alloy could facilitate the formation of a gamma phase and further improve the machinability of the Cu—Si—Zn alloy. The gamma phase is formed with the addition of tin in the amount of 1.0 or more percent by weight and the formation reaches the saturation point at 3.5 percent, by weight, of tin. If tin exceeds 3.5 percent by weight, the ductility will drop instead. With the addition of tin in an amount less than 1.0 percent by weight, on the other hand, an insufficient gamma phase will be formed. If the addition is 0.3 or more percent by weight, then tin will be effective in uniformly dispersing the gamma phase formed by silicon. Through that effect of dispersing the gamma phase, too, the machinability is improved. In other words, the addition of tin in an amount not smaller than 0.3 percent by weight improves the machinability.
[0023] Aluminum is, too, effective in facilitating the formation of the gamma phase. The addition of aluminum together with or in place of tin could further improve the machinability of the Cu—Si—Zn alloy. Aluminum is also effective in improving the strength, wear resistance, and high-temperature oxidation resistance as well as the machinability and also in keeping down the specific gravity. If the machinability is to be improved at all, aluminum will have to be added in an amount of at least 1.0 percent by weight. But the addition of more than 3.5 percent by weight could not produce the proportional results. Instead, that could lower the ductility as is the case with tin.
[0024] As to phosphorus, it has no property of forming the gamma phase as tin and aluminum. But phosphorus works to uniformly disperse and distribute the gamma phase formed as a result of the addition of silicon alone or with tin or aluminum or both of them. That way, the machinability improvement through the formation of gamma phase is further enhanced. In addition to dispersing the gamma phase, phosphorus helps refine the crystal grains in the alpha phase in the matrix, improving hot workability and also strength and resistance to stress corrosion cracking. Furthermore, phosphorus substantially increases the flow of molten metal in casting. To produce such results, phosphorus will have to be added in an amount not smaller than 0.02 percent by weight. But if the addition exceeds 0.25 percent by weight, no proportional effect will be obtained. Instead, there would be a decrease in hot forging property and extrudability.
[0025] In consideration of those observations, the third invention alloy is improved in machinability by adding to the Cu—Si—Pb—Zn alloy (first invention alloy) at least one additional element selected from among 0.3 to 3.5 percent, by weight, of tin, 1.0 to 3.5 percent, by weight, of aluminum, and 0.02 to 0.25 percent, by weight, of phosphorus.
[0026] Tin, aluminum, and phosphorus act to improve machinability by forming a gamma phase or dispersing that phase, and work closely with silicon in promoting the improvement in machinability through the gamma phase. In the third invention alloy to which silicon is added along with tin, aluminum, or phosphorus, thus the addition of silicon is smaller than that in the second invention alloy to which is added bismuth, tellurium, or selenium, which replaces silicon of the first invention in improving machinability. That is, those elements bismuth, tellurium, and selenium contribute to improving the machinability, not acting on the gamma phase but dispersing in the form of grains in the matrix. Even if the addition of silicon is less than 2.0 percent by weight, silicon along with tin, aluminum, or phosphorus will be able to enhance the machinability to an industrially satisfactory level as long as the percentage of silicon is 1.8 or more percent by weight. But even if the addition of silicon is not larger than 4.0 percent by weight, adding tin, aluminum, or phosphorus together with silicon will saturate the effect of silicon in improving the machinability, when the silicon content exceeds 3.5 percent by weight. For this reason, the addition of silicon is set at 1.8 to 3.5 percent by weight in the third invention alloy. Also, in consideration of the addition amount of silicon and also the addition of tin, aluminum, or phosphorus, the content range of copper in this third invention alloy is slightly raised from the level in the second invention alloy and copper is properly set at 70 to 80 percent by weight.
[0027] 4. A free-cutting copper alloy also with an excellent easy-to-cut feature which is composed of 70 to 80 percent, by weight, of copper; 1.8 to 3.5 percent, by weight, of silicon; 0.02 to 0.4 percent, by weight, of lead; at least one element selected from among 0.3 to 3.5 percent, by weight, of tin, 1.0 to 3.5 percent, by weight, of aluminum, and 0.02 to 0.25 percent, by weight, of phosphorus; one element selected from among 0.02 to 0.4 percent, by weight, of bismuth, 0.02 to 0.4 percent, by weight, of tellurium, and 0.02 to 0.4 percent, by weight, of selenium; and the remaining percent, by weight, of zinc. This fourth copper alloy will be hereinafter called the “fourth invention alloy.”
[0028] The fourth invention alloy has any one selected from among 0.02 to 0.4 percent, by weight, of bismuth, 0.02 to 0.4 percent, by weight, of tellurium, and 0.02 to 0.4 percent, by weight, of selenium in addition to the components in the third invention alloy. The grounds for mixing those additional elements and setting those amounts to be added are the same as given for the second invention alloy.
[0029] 5. A free-cutting copper alloy with an excellent easy-to-cut feature and with a high corrosion resistance which is composed of 69 to 79 percent, by weight, of copper; 2.0 to 4.0 percent, by weight, of silicon; 0.02 to 0.4 percent, by weight, of lead; at least one element selected from among 0.3 to 3.5 percent, by weight, of tin, 0.02 to 0.25 percent, by weight, of phosphorus, 0.02 to 0.15 percent, by weight, of antimony, and 0.02 to 0.15 percent, by weight, of arsenic, and the remaining percent, by weight, of zinc. This fifth copper alloy will be hereinafter called the “fifth invention alloy.”
[0030] The fifth invention alloy has, in addition to the first invention alloy, at least one element selected from among 0.3 to 3.5 percent, by weight, of tin, 0.02 to 0.25 percent, by weight, of phosphorus, 0.02 to 0.15 percent, by weight, of antimony, and 0.02 to 0.15 percent, by weight, of arsenic. Tin is effective in improving not only the machinability but also corrosion resistance properties (de-zinc-ification corrosion resistance) and forgeability. In other words, tin improves the corrosion resistance in the alpha phase matrix and, by dispersing the gamma phase, the corrosion resistance, forgeability, and stress corrosion cracking resistance. The fifth invention alloy is thus improved in corrosion resistance by the inclusion of tin and in machinability mainly by adding silicon. Therefore, the contents of silicon and copper in this alloy are set at the same as those in the first invention alloy. To raise the corrosion resistance and forgeability, on the other hand, tin would have to be added in the amount of at least 0.3 percent by weight. But even if the addition of tin exceeds 3.5 percent by weight, the corrosion resistance and forgeability will not improve in proportion to the increased amount of tin. Thus tin in excess of 3.5 percent would be uneconomical.
[0031] As described above, phosphorus disperses the gamma phase uniformly and at the same time refines the crystal grains in the alpha phase in the matrix, thereby improving the machinability and also the corrosion resistance properties (de-zinc-ification corrosion resistance), forgeability, stress corrosion cracking resistance, and mechanical strength. The fifth invention alloy is thus improved in corrosion resistance and other properties through the action of phosphorus and in machinability mainly by adding silicon. The addition of phosphorus in a very small quantity, that is, 0.02 or more percent by weight, could produce beneficial results. But the addition in more than 0.25 percent by weight would not be so effective as hoped from the quantity added. Rather, that would reduce the hot forgeability and extrudability.
[0032] As with phosphorus, antimony and arsenic in a very small quantity—0.02 or more percent by weight—are effective in improving the de-zinc-ification corrosion resistance and other properties. But their addition exceeding 0.15 percent by weight would not produce results in proportion to the excess quantity added. Rather, it would affect the hot forgeability and extrudability as does phosphorus applied in excessive amounts.
[0033] Those observations indicate that the fifth invention alloy is improved in machinability and also corrosion resistance and other properties by adding at least one element selected from among tin, phosphorus, antimony, and arsenic (which improve corrosion resistance) in quantities within the aforesaid limits in addition to the same quantities of copper and silicon as in the first invention copper alloy. In the fifth invention alloy, the additions of copper and silicon are set at 69 to 79 percent by weight and 2.0 to 4.0 percent by weight respectively—the same level as in the first invention alloy in which any other machinability improver than silicon and a small amount of lead is not added—because tin and phosphorus work mainly as corrosion resistance improvers like antimony and arsenic.
[0034] 6. A free-cutting copper alloy also with an excellent easy-to-cut feature and with a high corrosion resistance which is composed of 69 to 79 percent, by weight, of copper; 2.0 to 4.0 percent, by weight, of silicon; 0.02 to 0.4 percent, by weight, of lead; at least one element selected from among 0.3 to 3.5 percent, by weight, of tin, 0.02 to 0.25 percent, by weight, of phosphorus, 0.02 to 0.15 percent, by weight, of antimony, and 0.02 to 0.15 percent, by weight, of arsenic; one element selected from among 0.02 to 0.4 percent, by weight, of bismuth, 0.02 to 0.4 percent, by weight, of tellurium, and 0.02 to 0.4 percent, by weight, of selenium; and the remaining percent, by weight, of zinc. This sixth copper alloy will be herein after called the “sixth invention alloy.”
[0035] The sixth invention alloy has any one element selected from among 0.02 to 0.4 percent, by weight, of bismuth, 0.02 to 0.4 percent, by weight, of tellurium, and 0.02 to 0.4 percent, by weight, of selenium in addition to the components in the fifth invention alloy. The machinability is improved by adding, in addition to silicon and lead, any one element selected from among bismuth, tellurium and selenium as in the second invention alloy and the corrosion resistance and other properties are raised by adding at least one selected from among tin, phosphorus, antimony and arsenic as in the fifth invention alloy. Therefore, the additions of copper, silicon, bismuth, tellurium and selenium are set at the same levels as those in the second invention alloy, while the additions of tin, phosphorus, antimony, and arsenic are adjusted to those in the fifth invention alloy.
[0036] 7. A free-cutting copper alloy also with an excellent easy-to-cut feature and with an excellent high strength feature and high corrosion resistance which is composed of 62 to 78 percent, by weight, of copper; 2.5 to 4.5 percent, by weight, of silicon; 0.02 to 0.4 percent, by weight, of lead; at least one element selected from among 0.3 to 3.0 percent, by weight, of tin, 0.2 to 2.5 percent, by weight, of aluminum, and 0.02 to 0.25 percent, by weight, of phosphorus; and at least one element selected from among 0.7 to 3.5 percent, by weight, of manganese and 0.7 to 3.5 percent, by weight, of nickel; and the remaining percent, by weight, of zinc. The seventh copper alloy will be hereinafter called the “seventh invention alloy.”
[0037] Manganese and nickel combine with silicon to form intermetallic compounds represented by Mn x Si y or Ni x Si y , which are evenly precipitated in the matrix, thereby raising the wear resistance and strength. Therefore, the addition of manganese and nickel or either of the two would improve the high strength feature and wear resistance. Such effects will be exhibited if manganese and nickel are added in an amount not smaller than 0.7 percent by weight, respectively. But the saturation state is reached at 3.5 percent by weight, and even if the addition is increased beyond that, no proportional results will be obtained. The addition of silicon is set at 2.5 to 4.5 percent by weight to match the addition of manganese or nickel, taking into consideration the consumption to form intermetallic compounds with those elements.
[0038] It is also noted that tin, aluminum, and phosphorus help to reinforce the alpha phase in the matrix, thereby improving the machinability. Tin and phosphorus disperse the alpha and gamma phases, by which the strength, wear resistance, and also machinability are improved. Tin in an amount of 0.3 or more percent by weight is effective in improving the strength and machinability. But if the addition exceeds 3.0 percent by weight, the ductility will decrease. For this reason, the addition of tin is set at 0.3 to 3.0 percent by weight to raise the high strength feature and wear resistance in the seventh invention alloy, and also to enhance the machinability. Aluminum also contributes to improving the wear resistance and exhibits its effect of reinforcing the matrix when added in an amount of 0.2 or more percent by weight. But if the addition exceeds 2.5 percent by weight, there will be a decrease in ductility. Therefore, the addition of aluminum is set at 0.2 to 2.5 in consideration of improvement of machinability. Also, the addition of phosphorus disperses the gamma phase and at the same time pulverizes the crystal grains in the alpha phase in the matrix, thereby improving the hot workability and also the strength and wear resistance. Furthermore, it is very effective in improving the flow of molten metal in casting. Such results will be produced when phosphorus is added in an amount of 0.02 to 0.25 percent by weight. The content of copper is set at 62 to 78 percent by weight in the light of the addition of silicon and the property of manganese and nickel of combining with silicon.
[0039] 8. A free-cutting copper alloy also with an excellent easy-to-cut feature and with an excellent high-temperature oxidation resistance which comprises 69 to 79 percent, by weight, of copper, 2.0 to 4.0 percent, by weight, of silicon, 0.02 to 0.4 percent, by weight, of lead, 0.1 to 1.5 percent, by weight, of aluminum, and 0.02 to 0.25 percent, by weight, of phosphorus, and the remaining percent, by weight, of zinc. The eighth copper alloy will be hereinafter called the “eighth invention alloy.”
[0040] Aluminum is an element which improves strength, machinability, wear resistance, and also high-temperature oxidation resistance. Silicon, too, has a property of enhancing machinability, strength, wear resistance, resistance to stress corrosion cracking, and also high-temperature oxidation resistance. Aluminum works to raise the high-temperature oxidation resistance when it is used together with silicon in amounts not smaller than 0.1 percent by weight. But even if the addition of aluminum increases beyond 1.5 percent by weight, no proportional results can be expected. For this reason, the addition of aluminum is set at 0.1 to 1.5 percent by weight.
[0041] Phosphorus is added to enhance the flow of molten metal in casting. Phosphorus also works to improve the aforesaid machinability, de-zinc-ification corrosion resistance, and also high-temperature oxidation resistance, in addition to the flow of molten metal. Those effects are exhibited when phosphorus is added in amounts not smaller than 0.02 percent by weight. But even if phosphorus is used in amounts greater than 0.25 percent by weight, it will not result in a proportional increase in effect, rather weakening the alloy. Based upon this consideration, phosphorus is added to within a range of 0.02 to 0.25 percent by weight.
[0042] While silicon is added to improve machinability as mentioned above, it is also capable of improving the flow of molten metal like phosphorus. The effect of silicon in improving the flow of molten metal is exhibited when it is added in an amount not smaller than 2.0 percent by weight. The range of the addition for flow improvement overlaps that for improvement of the machinability. These taken into consideration, the addition of silicon is set to 2.0 to 4.0 percent by weight.
[0043] 9. A free-cutting copper alloy also with excellent easy-to-cut feature coupled with a good high-temperature oxidation resistance which is composed of 69 to 79 percent, by weight, of copper; 2.0 to 4.0 percent, by weight, of silicon; 0.02 to 0.4 percent, by weight, of lead; 0.1 to 1.5 percent, by weight, of aluminum; 0.02 to 0.25 percent, by weight, of phosphorus; one element selected from among 0.02 to 0.4 percent, by weight, of bismuth, 0.02 to 0.4 percent, by weight, of tellurium, and 0.02 to 0.4 percent, by weight, of selenium; and the remaining percent, by weight, of zinc. The ninth copper alloy will be hereinafter called the “ninth invention alloy.”
[0044] The ninth invention alloy contains one element selected from among 0.02 to 0.4 percent, by weight, of bismuth, 0.02 to 0.4 percent, by weight, of tellurium and 0.02 to 0.4 percent, by weight, of selenium in addition to the components of the eighth invention alloy. While a high-temperature oxidation resistance as good as in the eighth invention alloy is secured, the machinability is further improved by adding one element selected from among bismuth and other elements which are as effective as lead in raising the machinability,
[0045] 10. A free-cutting copper alloy also with excellent easy-to-cut feature and a good high-temperature oxidation resistance which is composed of 69 to 79 percent, by weight, of copper; 2.0 to 4.0 percent, by weight, of silicon; 0.02 to 0.4 percent, by weight, of lead; 0.1 to 1.5 percent, by weight, of aluminum; 0.02 to 0.25 percent, by weight, of phosphorus; at least one selected from among 0.02 to 0.4 percent, by weight, of chromium and 0.02 to 0.4 percent, by weight, of titanium; and the remaining percent, by weight, of zinc. The tenth copper alloy will be hereinafter called the “tenth invention alloy.”
[0046] Chromium and titanium are intended for improving the high-temperature oxidation resistance of the alloy. Good results can be expected especially when they are added together with aluminum to produce a synergistic effect. Those effects are exhibited when the addition is no less than 0.02 percent by weight, whether they are added alone or in combination. The saturation point is 0.4 percent by weight. For consideration of such observations, the tenth invention alloy has at least one element selected from among 0.02 to 0.4 percent by weight of chromium and 0.02 to 0.4 percent by weight of titanium in addition to the components of the eighth invention alloy and thus further improved over the eighth invention alloy with regard to high-temperature oxidation resistance.
[0047] 11. A free-cutting copper alloy also with excellent easy-to-cut feature and a good high-temperature oxidation resistance which is composed of 69 to 79 percent, by weight, of copper; 2.0 to 4.0 percent, by weight, of silicon; 0.02 to 0.4 percent, by weight, of lead; 0.1 to 1.5 percent, by weight, of aluminum; 0.02 to 0.25 percent, by weight, of phosphorus; at least one element selected from among 0.02 to 0.4 percent, by weight, of chromium and 0.02 to 0.4 percent, by weight, of titanium; one element selected from among 0.02 to 0.4 percent, by weight, of bismuth, 0.02 to 0.4 percent, by weight, of tellurium and 0.02 to 0.4 percent, by weight, of selenium; and the remaining percent, by weight, of zinc. The eleventh copper alloy will be hereinafter called the “eleventh invention alloy.”
[0048] The eleventh invention alloy contains any one element selected from among 0.02 to 0.4 percent, by weight, of bismuth, 0.02 to 0.4 percent, by weight, of tellurium, and 0.02 to 0.4 percent, by weight, of selenium, in addition to the components of the tenth invention alloy. While as high a high-temperature oxidation resistance as in the tenth invention alloy is secured, the eleventh invention alloy is further improved in machinability by adding one element selected from among bismuth and these other elements, which are as effective as lead in improving machinability.
[0049] 12. A free-cutting copper alloy with further improved easy-to-cut properties, obtained by subjecting any one of the preceding respective invention alloys to a heat treatment for 30 minutes to 5 hours at 400 to 600° C. The twelfth copper alloy will be hereinafter called the “twelfth invention alloy.”
[0050] The first to eleventh invention alloys contain machinability improving elements such as silicon and have an excellent machinability because of the addition of such elements. The effect of those machinability improving elements could be further enhanced by heat treatment. For example, the first to eleventh invention alloys which are high in copper content with gamma phase in small quantities and kappa phase in large quantities undergo a change in phase from the kappa phase to the gamma phase in a heat treatment. As a result, the gamma phase is finely dispersed and precipitated, and the machinability is improved. In the manufacturing process of castings, expanded metals and hot forgings in practice, the materials are often force-air-cooled or water cooled depending on the forging conditions, productivity after hot working (hot extrusion, hot forging, etc.), working environment, and other factors. In such cases, with the first to eleventh invention alloys, the alloys with a low content of copper in particular are rather low in the content of the gamma phase and contain beta phase. In a heat treatment, the beta phase changes into gamma phase, and the gamma phase is finely dispersed and precipitated, whereby the machinability is improved.
[0051] But a heat treatment temperature at less than 400° C. is not economical and practical in any case, because the aforesaid phase change will proceed slowly and much time will be needed. At temperatures over 600° C., on the other hand, the kappa phase will grow or the beta phase will appear, bringing about no improvement in machinability. From the practical viewpoint, therefore, it is desired to perform the heat treatment for 30 minutes to 5 hours at 400 to 600° C.
BRIEF DESCRIPTION OF THE DRAWING
[0052] FIG. 1 shows perspective views of cuttings formed in cutting a round bar of copper alloy by lathe.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
Example 1
[0053] As the first series of examples of the present invention, cylindrical ingots with compositions given in Tables 1 to 15, each 100 mm in outside diameter and 150 mm in length, were hot extruded into a round bar 15 mm in outside diameter at 750° C. to produce the following test pieces: first invention alloys Nos. 1001 to 1007, second invention alloys Nos. 2001 to 2006, third invention alloys Nos. 3001 to 3010, fourth invention alloys Nos. 4001 to 4021, fifth invention alloys Nos. 5001 to 5020, sixth invention alloys Nos. 6001 to 6045, seventh invention alloys Nos. 7001 to 7029, eight invention alloys Nos. 8001 to 8008, ninth invention alloys Nos. 9001 to 9006, tenth invention alloys Nos. 10001 to 10008, and eleventh invention alloys Nos. 11001 to 11011. Also, cylindrical ingots with the compositions given in Table 16, each 100 mm in outside diameter and 150 mm in length, were hot extruded into a round bar 15 mm in outside diameter at 750° C. to produce the following test pieces: twelfth invention alloys Nos. 12001 to 12004. That is, No. 12001 is an alloy test piece obtained by heat-treating an extruded test piece with the same composition as first invention alloy No. 1006 for 30 minutes at 580° C. No. 12002 is an alloy test piece obtained by heat-treating an extruded test piece with the same composition as No. 1006 for two hours at 450° C. No. 12003 is an alloy test piece obtained by heat-treating an extruded test piece with the same composition as first invention alloy No. 1007 under the same conditions as for No. 12001—for 30 minutes at 580° C. No. 12004 is an alloy test piece obtained by heat-treating an extruded test piece with the same composition as No. 1007 under the same conditions as for No. 12002—for two hours at 450° C.
[0054] As comparative examples, cylindrical ingots with the compositions as shown in Table 17, each 100 mm in outside diameter and 150 mm in length, were hot extruded into a round bar 15 mm in outside diameter at 750° C. to obtain the following round extruded test pieces: Nos. 13001 to 13006 (hereinafter referred to as the “conventional alloys”). No. 13001 corresponds to the alloy “JIS C 3604,” No. 13002 to the alloy “CDA C 36000,” No. 13003 to the alloy “JIS C 3771,” and No. 13004 to the alloy “CDA C 69800.” No. 13005 corresponds to the alloy “JIS C 6191.” This aluminum bronze is the most excellent of the expanded copper alloys under the JIS designations with regard to strength and wear resistance. No. 13006 corresponds to the navel brass alloy “JIS C 4622” and is the most excellent of the expanded copper alloys under the JIS designations with regard to corrosion resistance.
[0055] To study the machinability of the first to twelfth invention alloys in comparison with the conventional alloys, cutting tests were carried out. In the test, evaluations were made on the basis of cutting force, condition of chippings, and cut surface condition. The tests were conducted in this manner: The extruded test pieces thus obtained were cut on the circumferential surface by a lathe provided with a point noise straight tool at a rake angle of −8 degrees and at a cutting rate of 50 meters/minute, a cutting depth of 1.5 mm, and a feed of 0.11 mm/rev. Signals from a three-component dynamometer mounted on the tool were converted into electric voltage signals and recorded on a recorder. The signals were then converted into the cutting resistance. It is noted that while, to be perfectly exact, the amount of the cutting resistance should be judged by three component forces—cutting force, feed force, and thrust force, the judgement was made on the basis of the cutting force (N) of the three component forces in the present example. The results are shown in Table 18 to Table 33.
[0056] Furthermore, the chips from the cutting work were examined and classified into four forms (A) to (D) as shown in FIG. 1 . The results are enumerated in Table 18 to Table 33. In this regard, the chippings in the form of a spiral with three or more windings as (D) in FIG. 1 are difficult to process, that is, recover or recycle, and could cause trouble in cutting work as, for example, getting tangled with the tool and damaging the cut metal surface. Chippings in the form of a spiral arc from one with a half winding to one with two windings as shown in (C) in FIG. 1 do not cause such serous trouble as chippings in the form of a spiral with three or more windings, yet are not easy to remove and could get tangled with the tool or damage the cut metal surface. In contrast, chippings in the form of a fine needle as (A) in FIG. 1 or in the form of arc shaped pieces as (B) in FIG. 1 will not present such problems as mentioned above, are not as bulky as the chippings in (C) and (D), and are easy to process. But fine chipping as (A) still could creep in on the slide table of a machine tool such as a lathe and cause mechanical trouble, or could be dangerous because they could stick into the worker's finger, eye, or other body parts. Those factors taken into account, when judging machinability, the alloy with the chippings in (B) is the best, and the second best is that with the chippings in (A). Those with the chippings in (C) and (D) are not good. In Table 18 to Table 33, the alloys with the chippings shown in (B), (A), (C), and (D) are indicated by the symbols “⊚”, “∘”, “Δ”, and “x” respectively.
[0057] In addition, the surface condition of the cut metal surface was checked after cutting work. The results are depicted in Table 18 to Table 33. In this regard, the commonly used basis for indicating the surface roughness is the maximum roughness (Rmax). While requirements are different depending on the field of application of articles made from the brass, brass alloys with Rmax<10 microns are generally considered excellent in machinability. The alloys with 10 microns≦Rmax<15 microns are judged as industrially acceptable. Brass alloys with Rmax≧15 microns are taken as poor in machinability. In Table 18 through Table 33, the alloys with Rmax<10 microns are marked “∘”, those with 10 microns≦Rmax<15 microns are indicated by “Δ”, and those with Rmax≧15 microns are indicated by “x”.
[0058] As is evident from the results of the cutting tests shown in Table 18 to Table 33, the following invention alloys are all equal to the conventional lead-containing alloys Nos. 13001 to 13003 in machinability: first invention alloys Nos. 1001 to 1007, second invention alloys Nos. 2001 to 2006, third invention alloys Nos. 3001 to 3010, fourth invention alloys Nos. 4001 to 4021, fifth invention alloys Nos. 5001 to 5020, sixth invention alloys Nos. 6001 to 6045, seventh invention alloys Nos. 7001 to 7029, eighth invention alloys Nos. 8001 to 8008, ninth invention alloys Nos. 9001 to 9006, tenth invention alloys Nos. 10001 to 10008, eleventh invention alloys Nos. 11001 to 11011, and twelfth invention alloys Nos. 12001 to 12004. Especially with regard to the form of chippings, those invention alloys compare favorably not only with conventional alloys Nos. 13004 to 13006, which have a lead content of not higher than 0.1 percent by weight, but also Nos. 13001 to 13003, which contain large quantities of lead. Also to be remarked is that twelfth invention alloys Nos. 12001 to 12004, which are obtained by heat-treating first invention alloys Nos. 1006 and 1007, are improved over the first invention alloys in machinability. It is understood that a proper heat treatment could likewise further enhance machinability of the first to eleventh invention alloys, depending upon the compositions of the alloys and other conditions.
[0059] In another series of tests, the first to twelfth invention alloys were examined in comparison with conventional alloys in hot workability and mechanical properties. For the purpose, hot compression and tensile tests were conducted in the following manner.
[0060] First, two test pieces, the first and second test pieces, in the same shape, 15 mm in outside diameter and 25 mm in length, were cut out of each extruded test piece obtained as described above. In hot compression tests, the first test piece was held for 30 minutes at 700° C., and then compressed at the compression rate of 70 percent in the axial direction to reduce the length from 25 mm to 7.5 mm. The surface condition after the compression (700° C. deformability) was visually evaluated. The results are given in Table 18 to Table 33. The evaluation of deformability was made by visually checking for cracks on the side of the test piece. In Table 18 to Table 33, the test pieces with no cracks found are marked “∘”, those with small cracks are indicated by “Δ”, and those with large cracks are represented by the symbol “x”.
[0061] The tensile strength, N/mm 2 , and elongation, %, of the second test pieces was determined by the commonly practiced test method.
[0062] As the test results of the hot compression and tensile tests in Table 18 to Table 33 indicate, it was confirmed that the first to twelfth invention alloys are equal to or superior to the conventional alloys Nos. 13001 to 13004 and No. 13006 in hot workability and mechanical properties and are suitable for industrial use. The seventh invention alloys in particular have the same level of mechanical properties as the conventional alloy No. 13005, i.e. the aluminum bronze which is the most excellent in strength of the expanded copper alloys under the JIS designations, and thus clearly have a prominent high strength feature.
[0063] Furthermore, the first to six and eighth to twelfth invention alloys were put to de-zinc-ification corrosion and stress corrosion cracking tests in accordance with the test methods specified under “ISO 6509” and “JIS H 3250”, respectively, to examine the corrosion resistance and resistance to stress corrosion cracking in comparison with conventional alloys.
[0064] In the de-zinc-ing corrosion test by the “ISO 6509” method, the test piece taken from each extruded test piece was imbedded laid in a phenolic resin material in such a way that the exposed test piece surface is perpendicular to the extrusion direction of the extruded test piece. The surface of the test piece was polished with emery paper No. 1200, and then ultrasonic-washed in pure water and dried. The test piece thus prepared was dipped in a 12.7 g/l aqueous solution of cupric chloride dihydrate (CuCl 2 .2H 2 O) 1.0% and left standing for 24 hours at 75° C. The test piece was taken out of the aqueous solution and the maximum depth of de-zinc-ing corrosion was determined. The measurements of the maximum de-zinc-ification corrosion depth are given in Table 18 to Table 25 and Table 28 to Table 33.
[0065] As is clear from the results of de-zinc-ification corrosion tests shown in Table 18 to Table 25 and Table 28 to Table 33, the first to fourth invention alloys and the eighth to twelfth invention alloys are excellent in corrosion resistance in comparison with the conventional alloys Nos. 13001 to 13003 which contain large amounts of lead. And it was confirmed that especially the fifth and sixth invention alloys which whose improvement in both machinability and corrosion resistance has been intended are very high in corrosion resistance in comparison with the conventional alloy No. 13006, a naval brass which is the most resistant to corrosion of all the expanded alloys under the JIS designations.
[0066] In the stress corrosion cracking tests in accordance with the test method described in “JIS H 3250,” a 150-mm-long test piece was cut out from each extruded material. The test piece was bent with the center placed on an arc-shaped tester with a radius of 40 mm in such a way that one end forms an angle of 45 degrees with respect to the other end. The test piece thus subjected to a tensile residual stress was degreased and dried, and then placed in an ammonia environment in the desiccator with a 12.5% aqueous ammonia (ammonia diluted in the equivalent of pure water). To be exact, the test piece was held some 80 mm above the surface of aqueous ammonia in the desiccator. After the test piece was left standing in the ammonia environment for 2 hours, 8 hours, and 24 hours, the test piece was taken out from the desiccator, washed in sulfuric acid solution 10% and examined for cracks under 10× magnifications. The results are given in Table 18 to Table 25 and Table 28 to Table 33. In those tables, the alloys which developed clear cracks when held in the ammonia environment for two hours are marked “xx.” The test pieces which had no cracks at 2 hours but were found clearly cracked in 8 hours are indicated by “x.” The test pieces which had no cracks at 8 hours, but were found to clearly have cracks in 24 hours are identified by the symbol “Δ”. The test pieces which were found to have no cracks at all in 24 hours are indicated by the symbol “∘.”
[0067] As is indicated by the results of the stress corrosion cracking test given in Table 18 to Table 25 and Table 28 to Table 33, it was confirmed that not only the fifth and sixth invention alloys whose improvement in both machinability and corrosion resistance has been intended but also the first to fourth invention alloys and the eighth to twelfth alloys in which nothing particular was done to improve corrosion resistance were both equal to the conventional alloy No. 13005, an aluminum bronze containing no zinc, in stress corrosion cracking resistance. Those invention alloys were superior in stress corrosion cracking resistance to the conventional naval brass alloy No. 13006, the best in corrosion resistance of all the expanded copper alloys under the JIS designations.
[0068] In addition, oxidation tests were carried out to study the high-temperature oxidation resistance of the eighth to eleventh invention alloys in comparison with conventional alloys.
[0069] Test pieces in the shape of a round bar with the surface cut to a outside diameter of 14 mm and the length cut to 30 mm were prepared from each of the following extruded materials: No. 8001 to No. 8008, No. 9001 to No. 9006, No. 10001 to No. 10008, No. 11001 to No. 11011, and No. 13001 to No. 13006. Each test piece was then weighed to measure the weight before oxidation. After that, the test piece was placed in a porcelain crucible and held in an electric furnace maintained at 500° C. At the passage of 100 hours, the test piece was taken out of the electric furnace and was weighed to measure the weight after oxidation. From the measurements before and after oxidation was calculated the increase in weight by oxidation. It is understood that the increase by oxidation is the amount, mg, of increase in weight by oxidation per 10 cm 2 of the surface area of the test piece, and is calculated by the equation: increase in weight by oxidation, mg/10 cm 2 =(weight, mg, after oxidation−weight, mg, before oxidation)×(10 cm 2 /surface area, cm 2 , of test piece). The weight of each test piece increased after oxidation. The increase was brought about by high-temperature oxidation. Subjected to a high temperature, oxygen combines with copper, zinc, and silicon to form Cu 2 O, ZnO, SiO 2 , respectively. That is, oxygen adds to the weight. It can be said, therefore, that the alloys with a smaller weight increase due to oxidation are better in high-temperature oxidation resistance. The results obtained are shown in Table 28 to Table 31 and Table 33.
[0070] As is evident from the test results shown in Table 23 to Table 31 and Table 33, the eighth to eleventh invention alloys are equal, in regard to weight increase by oxidation, to the conventional alloy No. 13005, an aluminum bronze ranking high in resistance to high-temperature oxidation among the expanded copper alloys under the JIS designations, and are far smaller than any other conventional copper alloy. Thus, it was confirmed that the eighth to eleventh invention alloys are very excellent in machinability as well as resistance to high-temperature oxidation.
Example 2
[0071] As the second series of examples of the present invention, circular cylindrical ingots with compositions given in Tables 9 to 11, each 100 mm in outside diameter and 200 mm in length, were hot extruded into a round bar 35 mm in outside diameter at 700° C. to produce seventh invention alloys Nos. 7001a to 7029a. In parallel, circular cylindrical ingots with compositions given in Table 17, each 100 mm in outside diameter and 200 mm in length, were hot extruded into a round bar 35 mm in outside diameter at 700° C. to produce the following alloy test pieces: Nos. 13001a to 13006a as second comparative examples (hereinafter referred to as the “conventional alloys). It is noted that the alloys Nos. 7001a to 7029a and Nos. 13001a to 13006a are identical in composition with the aforesaid copper alloys Nos. 7001 to 7029 and Nos. 13001 to No. 13006, respectively.
[0072] Seventh invention alloys Nos. 7001a to 7029a were subjected to wear resistance tests in comparison with conventional alloys Nos. 13001a to 13006a.
[0073] The tests were carried out in this manner. Each extruded test piece thus obtained was cut on the circumferential surface, holed, and cut down into a ring-shaped test piece 32 mm in outside diameter and 10 mm in thickness (that is, the length in the axial direction). The test piece was then fitted and clamped on a rotatable shaft, and a roll 48 mm in diameter placed in parallel with the axis of the shaft was thrust against the test piece under a load of 50 kg. The roll was made of stainless steel having the JIS designation SUS 304. Then, the SUS 304 roll and the test piece put against the roll were rotated at the same number of revolutions/minute−209 r.p.m., with multipurpose gear oil being dropping on the circumferential surface of the test piece. When the number of revolutions reached 100,000, the SUS 304 roll and the test piece were stopped, and the weight difference between before rotation and after the end of rotation, that is, the loss of weight by wear, mg, was determined. It can be said that the alloys which are smaller in the loss of weight by wear are higher in wear resistance. The results are given in Tables 34 to 36.
[0074] As is clear from the wear resistance test results shown in Tables 34 to 36, the tests showed that those seventh invention alloys Nos. 7001a to 7029a were excellent in wear resistance as compared with not only the conventional alloys Nos. 13001a to 13004a and 13006a but also No. 13005a, which is an aluminum bronze most excellent in wear resistance among expanded copper designated in JIS. From comprehensive considerations of the test results including the tensile test results, it may safely be said the seventh invention alloys are excellent in machinability and also possess a high strength feature and wear resistance equal to or superior to the aluminum bronze which is the highest in wear resistance of all the expanded copper alloys under the JIS designations.
[0000]
TABLE 1
alloy composition (wt %)
No.
Cu
Si
Pb
Zn
1001
74.8
2.9
0.03
remainder
1002
74.1
2.7
0.21
remainder
1003
78.1
3.6
0.10
remainder
1004
70.6
2.1
0.36
remainder
1005
74.9
3.1
0.11
remainder
1006
69.3
2.3
0.05
remainder
1007
78.5
2.9
0.05
remainder
[0000]
TABLE 2
alloy composition (wt %)
No.
Cu
Si
Pb
Bi
Te
Se
Zn
2001
73.8
2.7
0.05
0.03
remainder
2002
69.9
2.0
0.33
0.27
remainder
2003
74.5
2.8
0.03
0.31
remainder
2004
78.0
3.6
0.12
0.05
remainder
2005
76.2
3.2
0.05
0.33
remainder
2006
72.9
2.6
0.24
0.06
remainder
[0000]
TABLE 3
alloy composition (wt %)
No.
Cu
Si
Pb
Sn
Al
P
Zn
3001
70.8
1.9
0.23
3.2
remainder
3002
74.5
3.0
0.05
0.4
remainder
3003
78.8
2.5
0.15
3.4
remainder
3004
74.9
2.7
0.09
1.2
remainder
3005
74.6
2.3
0.26
1.2
1.9
remainder
3006
74.8
2.8
0.18
0.03
remainder
3007
76.5
3.3
0.04
0.21
remainder
3008
73.5
2.5
0.05
1.6
0.05
remainder
3009
74.9
2.0
0.35
2.7
0.13
remainder
3010
75.2
2.9
0.23
0.8
1.4
0.04
remainder
[0000]
TABLE 4
alloy composition (wt %)
No.
Cu
Si
Pb
Sn
Al
P
Bi
Te
Se
Zn
4001
73.8
2.8
0.04
0.5
0.10
remain-
der
4002
74.5
2.6
0.11
1.5
0.04
remain-
der
4003
73.7
2.1
0.21
1.2
2.2
0.03
remain-
der
4004
76.8
3.2
0.05
0.03
0.31
remain-
der
4005
74.1
2.6
0.07
1.4
0.04
0.09
remain-
der
4006
75.5
1.9
0.32
3.2
0.15
0.16
remain-
der
4007
74.8
2.8
0.10
0.7
1.2
0.05
0.05
remain-
der
4008
70.5
1.9
0.22
3.4
0.03
remain-
der
4009
79.1
2.7
0.15
3.4
0.05
remain-
der
4010
74.5
2.8
0.10
0.05
0.05
remain-
der
4011
77.3
3.3
0.07
0.4
0.21
0.31
remain-
der
4012
76.8
2.8
0.05
2.0
0.03
0.13
remain-
der
4013
74.5
2.6
0.18
1.4
2.1
0.21
remain-
der
4014
74.0
2.5
0.20
2.1
1.1
0.10
0.07
remain-
der
4015
72.5
2.4
0.11
1.0
0.05
remain-
der
4016
76.1
2.5
0.07
2.3
0.10
remain-
der
4017
76.4
2.7
0.05
0.6
3.1
0.22
remain-
der
4018
74.0
2.5
0.23
0.22
0.03
remain-
der
4019
71.2
2.2
0.11
2.8
0.05
0.30
remain-
der
4020
75.3
2.7
0.22
1.4
0.03
0.05
remain-
der
4021
74.1
2.5
0.05
2.4
1.2
0.07
0.07
remain-
der
[0000]
TABLE 5
alloy composition (wt %)
No.
Cu
Si
Pb
Sn
P
Sb
As
Zn
5001
74.3
2.9
0.05
0.4
remainder
5002
69.8
2.1
0.31
3.1
remainder
5003
74.8
2.8
0.03
0.08
remainder
5004
78.2
3.4
0.16
0.21
remainder
5005
74.9
3.1
0.09
0.07
remainder
5006
72.2
2.4
0.25
0.13
remainder
5007
73.5
2.5
0.18
2.2
0.04
remainder
5008
77.0
3.3
0.06
0.7
0.15
remainder
5009
76.4
3.6
0.12
1.2
remainder
5010
71.4
2.3
0.26
2.6
0.03
remainder
5011
77.3
3.4
0.17
0.5
0.14
remainder
5012
74.8
2.8
0.07
1.4
0.03
remainder
5013
74.5
2.7
0.05
0.03
0.12
remainder
5014
76.1
3.1
0.14
0.18
0.03
remainder
5015
73.9
2.5
0.08
0.07
0.05
remainder
5016
74.5
2.8
0.07
0.08
0.04
remainder
5017
77.3
3.1
0.12
1.5
0.13
0.05
remainder
5018
72.8
2.4
0.18
0.7
0.03
0.09
remainder
5019
74.2
2.7
0.07
0.5
0.11
0.10
remainder
5020
74.6
2.8
0.05
0.9
0.07
0.05
0.03
remainder
[0000]
TABLE 6
alloy composition (wt %)
No.
Cu
Si
Pb
Bi
Te
Se
Sn
P
Sb
As
Zn
6001
70.7
2.3
0.17
0.05
2.8
remainder
6002
74.6
2.5
0.08
0.03
0.7
0.06
remainder
6003
78.0
3.7
0.05
0.34
0.4
0.05
remainder
6004
69.5
2.1
0.32
0.02
3.3
0.03
remainder
6005
76.8
2.8
0.03
0.07
0.8
0.21
0.02
remainder
6006
74.2
2.7
0.18
0.10
0.5
0.03
0.13
remainder
6007
76.1
3.2
0.12
0.05
1.7
0.12
0.02
remainder
6008
75.3
2.8
0.20
0.16
1.3
0.10
0.03
0.05
remainder
6009
77.0
3.1
0.14
0.06
0.21
remainder
6010
72.5
2.5
0.07
0.09
0.05
0.03
remainder
6011
74.7
2.9
0.10
0.32
0.14
0.10
remainder
6012
71.4
2.3
0.25
0.14
0.07
0.03
0.02
remainder
6013
74.7
3.0
0.13
0.05
0.12
remainder
6014
77.2
3.2
0.27
0.23
0.07
0.04
remainder
6015
74.0
2.8
0.07
0.03
0.03
remainder
6016
69.8
2.1
0.22
0.17
3.2
remainder
6017
73.8
2.9
0.15
0.03
1.6
0.07
remainder
6018
75.8
2.8
0.08
0.06
0.4
0.03
remainder
6019
71.2
2.3
0.15
0.07
2.5
0.07
remainder
6020
72.0
2.6
0.12
0.04
0.9
0.03
0.05
remainder
[0000]
TABLE 7
alloy composition (wt %)
No.
Cu
Si
Pb
Bi
Te
Se
Sn
P
Sb
As
Zn
6021
76.8
2.9
0.20
0.30
0.8
0.17
0.03
remainder
6022
78.3
3.2
0.15
0.36
0.4
0.06
0.14
remainder
6023
73.4
2.3
0.12
0.06
2.7
0.02
0.11
0.03
remainder
6024
74.6
2.8
0.05
0.08
0.19
remainder
6025
78.5
3.7
0.22
0.25
0.23
0.03
remainder
6026
74.9
2.9
0.16
0.05
0.05
0.10
remainder
6027
73.8
2.5
0.07
0.03
0.06
0.02
0.04
remainder
6028
74.8
2.6
0.12
0.02
0.12
remainder
6029
74.2
2.8
0.37
0.10
0.11
0.02
remainder
6030
76.3
3.2
0.08
0.05
0.07
remainder
6031
70.8
2.4
0.11
0.05
2.6
remainder
6032
74.6
3.0
0.25
0.32
0.6
0.06
remainder
6033
75.0
2.8
0.03
0.12
0.3
0.13
remainder
6034
73.5
2.8
0.12
0.07
1.0
0.11
remainder
6035
78.0
3.3
0.07
0.03
0.5
0.16
0.02
remainder
6036
72.4
2.5
0.13
0.05
3.1
0.03
0.05
remainder
6037
78.0
2.8
0.18
0.20
1.7
0.08
0.02
remainder
6038
76.5
3.1
0.10
0.11
1.7
0.03
0.03
0.04
remainder
6039
71.9
2.4
0.12
0.17
0.04
remainder
6040
77.0
3.5
0.03
0.35
0.23
0.03
remainder
[0000]
TABLE 8
alloy composition (wt %)
No.
Cu
Si
Pb
Bi
Te
Se
Sn
P
Sb
As
Zn
6041
74.7
2.9
0.07
0.12
0.06
0.03
remainder
6042
72.8
2.5
0.20
0.06
0.03
remainder
6043
78.0
3.7
0.33
0.15
0.02
0.10
remainder
6044
74.0
2.8
0.12
0.05
0.08
remainder
6045
76.1
3.1
0.05
0.07
0.03
0.09
0.03
remainder
[0000]
TABLE 9
alloy composition (wt %)
No.
Cu
Si
Pb
Sn
Al
P
Mn
Ni
Zn
7001
67.0
3.8
0.04
1.6
3.2
remainder
7001a
7002
69.3
4.2
0.15
0.4
2.2
remainder
7002a
7003
63.8
2.6
0.33
2.8
0.9
remainder
7003a
7004
66.5
3.4
0.07
1.5
2.0
remainder
7004a
7005
67.2
3.6
0.10
0.9
1.8
0.9
remainder
7005a
7006
63.0
2.7
0.27
2.7
1.2
2.1
remainder
7006a
7007
68.7
3.4
0.05
1.4
1.3
0.9
remainder
7007a
7008
70.6
4.1
0.03
0.5
1.6
3.4
remainder
7008a
7009
67.8
3.6
0.12
2.6
2.1
3.3
remainder
7009a
7010
68.4
3.5
0.06
0.4
0.3
1.8
remainder
7010a
[0000]
TABLE 10
alloy composition (wt %)
No.
Cu
Si
Pb
Sn
Al
P
Mn
Ni
Zn
7011
73.9
4.4
0.17
1.2
1.7
0.8
1.5
remainder
7011a
7012
65.5
2.9
0.20
1.5
1.0
0.12
2.3
remainder
7012a
7013
66.1
3.3
0.08
1.8
1.1
0.03
2.6
remainder
7013a
7014
70.3
3.9
0.15
1.0
1.4
0.21
1.8
1.2
remainder
7014a
7015
66.8
3.7
0.20
2.6
0.14
2.7
remainder
7015a
7016
69.0
4.0
0.07
0.5
0.20
3.2
remainder
7016a
7017
64.5
2.9
0.19
1.8
0.05
1.5
0.8
remainder
7017a
7018
72.4
3.5
0.08
1.5
1.1
remainder
7018a
7019
69.2
3.9
0.03
0.4
3.1
remainder
7019a
7020
76.6
4.3
0.14
2.3
1.9
remainder
7020a
[0000]
TABLE 11
alloy composition (wt %)
No.
Cu
Si
Pb
Sn
Al
P
Mn
Ni
Zn
7021
75.0
4.2
0.19
1.7
2.1
remainder
7021a
7022
72.3
3.7
0.05
1.4
1.1
0.8
remainder
7022a
7023
64.5
3.8
0.35
0.3
2.0
2.3
remainder
7023a
7024
75.8
3.9
0.05
2.7
0.04
1.0
remainder
7024a
7025
70.1
3.5
0.06
1.2
0.23
3.0
remainder
7025a
7026
67.2
2.8
0.22
1.8
0.14
2.2
0.9
remainder
7026a
7027
70.2
3.8
0.11
0.03
3.2
remainder
7027a
7028
75.9
4.4
0.03
0.20
1.1
remainder
7028a
7029
66.0
3.0
0.18
0.12
1.0
2.1
remainder
7029a
[0000]
TABLE 12
alloy composition (wt %)
No.
Cu
Si
Pb
Al
P
Zn
8001
74.5
2.9
0.16
0.2
0.05
remainder
8002
76.0
2.7
0.03
1.2
0.21
remainder
8003
76.3
3.0
0.35
0.6
0.12
remainder
8004
69.9
2.1
0.27
0.3
0.03
remainder
8005
71.5
2.3
0.12
0.8
0.10
remainder
8006
78.1
3.6
0.05
0.2
0.13
remainder
8007
77.7
3.4
0.18
1.4
0.06
remainder
8008
77.5
3.5
0.03
0.9
0.15
remainder
[0000]
TABLE 13
alloy composition (wt %)
No.
Cu
Si
Pb
Al
P
Bi
Te
Se
Zn
9001
74.8
2.8
0.05
0.6
0.07
0.03
remainder
9002
76.6
2.9
0.12
0.9
0.03
0.32
remainder
9003
72.3
2.2
0.32
0.5
0.12
0.25
remainder
9004
77.2
3.0
0.07
1.4
0.21
0.05
remainder
9005
78.1
3.6
0.16
0.3
0.15
0.29
remainder
9006
74.5
2.6
0.05
0.6
0.08
0.07
remainder
[0000]
TABLE 14
alloy composition (wt %)
No.
Cu
Si
Pb
Al
P
Cr
Ti
Zn
10001
76.0
2.8
0.12
0.7
0.13
0.21
remainder
10002
75.0
3.0
0.03
0.2
0.05
0.03
remainder
10003
78.3
3.4
0.06
1.3
0.20
0.34
remainder
10004
69.6
2.1
0.25
0.8
0.03
0.17
remainder
10005
77.5
3.6
0.12
0.7
0.15
0.23
remainder
10006
71.8
2.2
0.32
1.2
0.08
0.32
remainder
10007
74.7
2.7
0.1
0.6
0.10
0.03
remainder
10008
75.4
2.9
0.03
0.3
0.06
0.12
0.08
remainder
[0000]
TABLE 15
alloy composition (wt %)
No.
Cu
Si
Pb
Al
Bi
Te
Se
P
Cr
Ti
Zn
11001
76.5
2.9
0.08
0.9
0.03
0.12
0.03
remainder
11002
70.4
2.2
0.32
0.5
0.21
0.03
0.18
remainder
11003
78.2
3.5
0.16
1.3
0.35
0.20
0.34
remainder
11004
73.9
2.7
0.03
0.3
0.11
0.06
0.22
remainder
11005
75.8
3.0
0.06
0.6
0.08
0.11
0.10
0.07
remainder
11006
71.6
2.1
0.24
1.0
0.21
0.04
0.32
remainder
11007
73.8
2.4
0.10
1.1
0.04
0.07
0.03
remainder
11008
75.5
3.0
0.13
0.2
0.36
0.12
0.06
0.14
remainder
11009
77.7
3.2
0.03
1.4
0.17
0.23
0.23
remainder
11010
75.0
2.7
0.15
0.7
0.03
0.03
0.12
remainder
11011
72.9
2.4
0.20
0.8
0.31
0.06
0.09
0.05
remainder
[0000]
TABLE 16
alloy
composition (wt %)
heat treatment
No.
Cu
Si
Pb
Zn
temperature
time
12001
69.3
2.3
0.05
remainder
580° C.
30 min.
12002
69.3
2.3
0.05
remainder
450° C.
2 hr.
12003
78.5
2.9
0.05
remainder
580° C.
30 min.
12004
78.5
2.9
0.05
remainder
450° C.
2 hr.
[0000]
TABLE 17
alloy composition (wt %)
No.
Cu
Si
Pb
Sn
Al
Mn
Ni
Fe
Zn
13001
58.8
3.1
0.2
0.2
remainder
13001a
13002
61.4
3.0
0.2
0.2
remainder
13002a
13003
59.1
2.0
0.2
0.2
remainder
13003a
13004
69.2
1.2
0.1
remainder
13004a
13005
remainder
9.8
1.1
1.2
3.9
13005a
13006
61.8
0.1
1.0
remainder
13006a
[0000]
TABLE 18
corrosion
machinability
resistance
mechanical
stress
condition
maximum
properties
resistance
form
of
cutting
depth of
hot workability
tensile
corrosion
of
cut
force
corrosion
700° C.
strength
elongation
cracking
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
1001
⊚
◯
117
160
◯
533
35
◯
1002
⊚
◯
114
170
◯
520
32
◯
1003
⊚
◯
119
140
Δ
575
36
◯
1004
⊚
◯
118
220
Δ
490
30
Δ
1005
⊚
◯
114
170
◯
546
34
◯
1006
Δ
◯
126
230
◯
504
32
Δ
1007
⊚
Δ
127
170
Δ
515
44
◯
[0000]
TABLE 19
corrosion
machinability
resistance
mechanical
stress
condition
maximum
properties
resistance
form
of
cutting
depth of
hot workability
tensile
corrosion
of
cut
force
corrosion
700° C.
strength
elongation
cracking
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
2001
⊚
◯
116
180
◯
510
33
◯
2002
⊚
◯
115
230
Δ
475
28
Δ
2003
⊚
◯
115
160
Δ
540
32
◯
2004
⊚
◯
117
150
Δ
576
35
◯
2005
⊚
◯
116
140
Δ
543
37
◯
2006
⊚
◯
114
180
Δ
502
32
◯
[0000]
TABLE 20
corrosion
machinability
resistance
mechanical
stress
condition
maximum
properties
resistance
form
of
cutting
depth of
hot workability
tensile
corrosion
of
cut
force
corrosion
700° C.
strength
elongation
cracking
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
3001
⊚
◯
120
30
◯
542
23
◯
3002
⊚
◯
117
70
◯
550
30
◯
3003
⊚
◯
119
110
Δ
565
34
◯
3004
⊚
◯
118
140
◯
532
35
◯
3005
⊚
◯
119
50
Δ
547
27
◯
3006
⊚
◯
115
30
◯
538
34
◯
3007
⊚
◯
117
<5
Δ
562
36
◯
3008
⊚
◯
119
<5
◯
529
26
◯
3009
⊚
◯
118
<5
Δ
518
30
◯
3010
⊚
◯
116
<5
◯
555
28
◯
[0000]
TABLE 21
corrosion
machinability
resistance
mechanical
stress
condition
maximum
properties
resistance
form
of
cutting
depth of
hot workability
tensile
corrosion
of
cut
force
corrosion
700° C.
strength
elongation
cracking
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
4001
⊚
◯
119
70
◯
535
30
◯
4002
⊚
◯
116
120
◯
547
33
◯
4003
⊚
◯
118
60
Δ
539
26
◯
4004
◯
◯
113
30
Δ
550
31
◯
4005
⊚
◯
117
<5
◯
534
27
◯
4006
⊚
◯
118
<5
Δ
542
30
◯
4007
◯
◯
116
<5
◯
563
32
◯
4008
⊚
◯
120
40
Δ
507
25
◯
4009
⊚
◯
117
110
Δ
572
36
◯
4010
⊚
◯
115
10
◯
524
33
◯
4011
⊚
◯
116
<5
Δ
580
31
◯
4012
⊚
◯
114
20
◯
575
34
◯
4013
◯
◯
115
50
Δ
588
28
◯
4014
⊚
◯
117
<5
◯
543
26
◯
4015
⊚
◯
117
60
◯
501
27
◯
4016
⊚
◯
116
130
Δ
539
32
◯
4017
⊚
◯
118
50
◯
574
34
◯
4018
⊚
◯
115
<5
◯
506
30
◯
4019
⊚
◯
118
<5
◯
523
28
◯
4020
⊚
◯
115
20
Δ
548
32
◯
4021
⊚
◯
118
<5
◯
553
27
◯
[0000]
TABLE 22
corrosion
machinability
resistance
mechanical
stress
condition
maximum
properties
resistance
form
of
cutting
depth of
hot workability
tensile
corrosion
of
cut
force
corrosion
700° C.
strength
elongation
cracking
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
5001
⊚
◯
116
70
◯
525
34
◯
5002
⊚
◯
120
40
Δ
501
25
◯
5003
⊚
◯
117
<5
◯
510
33
◯
5004
⊚
◯
117
<5
Δ
547
42
◯
5005
⊚
◯
115
<5
◯
533
34
◯
5006
⊚
◯
116
<5
◯
470
30
Δ
5007
⊚
◯
118
<5
◯
512
28
◯
5008
⊚
◯
119
<5
Δ
558
36
◯
5009
⊚
◯
120
50
Δ
595
31
◯
5010
⊚
◯
121
<5
◯
516
27
◯
5011
⊚
◯
118
<5
Δ
569
34
◯
5012
◯
◯
117
<5
◯
523
30
◯
5013
⊚
◯
116
<5
◯
504
33
◯
5014
◯
◯
114
<5
◯
536
35
◯
5015
⊚
◯
117
<5
◯
488
31
◯
5016
⊚
◯
116
<5
◯
510
37
◯
5017
⊚
◯
118
<5
Δ
557
32
◯
5018
⊚
◯
117
<5
◯
480
30
◯
5019
⊚
◯
117
<5
◯
511
31
◯
5020
⊚
◯
115
<5
◯
528
30
◯
[0000]
TABLE 23
corrosion
machinability
resistance
mechanical
stress
condition
maximum
properties
resistance
form
of
cutting
depth of
hot workability
tensile
corrosion
of
cut
force
corrosion
700° C.
strength
elongation
cracking
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
6001
⊚
◯
119
40
◯
515
25
◯
6002
⊚
◯
117
<5
◯
496
35
◯
6003
⊚
◯
119
<5
Δ
570
34
◯
6004
⊚
◯
118
<5
Δ
503
26
◯
6005
⊚
◯
115
<5
◯
536
37
◯
6006
◯
◯
113
<5
◯
512
33
◯
6007
⊚
◯
117
<5
Δ
559
29
◯
6008
◯
◯
115
<5
Δ
527
31
◯
6009
⊚
◯
115
<5
Δ
546
40
◯
6010
⊚
◯
116
<5
◯
507
30
◯
6011
◯
◯
113
<5
Δ
520
30
◯
6012
⊚
◯
115
<5
Δ
488
29
Δ
6013
◯
◯
114
<5
◯
531
32
◯
6014
⊚
◯
114
<5
Δ
564
31
◯
6015
⊚
◯
115
20
◯
525
34
◯
6016
⊚
◯
121
30
◯
514
25
◯
6017
⊚
◯
119
<5
◯
510
27
◯
6018
⊚
◯
116
<5
◯
528
32
◯
6019
⊚
◯
119
<5
◯
526
28
◯
6020
⊚
◯
116
<5
◯
509
30
◯
[0000]
TABLE 24
corrosion
machinability
resistance
mechanical
stress
condition
maximum
properties
resistance
form
of
cutting
depth of
hot workability
tensile
corrosion
of
cut
force
corrosion
700° C.
strength
elongation
cracking
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
6021
⊚
◯
113
<5
◯
534
30
◯
6022
⊚
◯
117
<5
◯
562
34
◯
6023
⊚
◯
120
<5
◯
527
27
◯
6024
⊚
◯
116
<5
◯
515
33
◯
6025
⊚
◯
117
<5
Δ
575
35
◯
6026
⊚
◯
114
<5
◯
524
32
◯
6027
⊚
◯
119
<5
◯
503
34
◯
6028
⊚
◯
117
<5
◯
510
33
◯
6029
◯
◯
114
<5
Δ
522
30
◯
6030
⊚
◯
118
40
◯
546
37
◯
6031
⊚
◯
119
<5
◯
529
27
◯
6032
⊚
◯
115
<5
Δ
545
30
◯
6033
⊚
◯
116
<5
◯
521
34
◯
6034
⊚
◯
116
<5
◯
513
31
◯
6035
⊚
◯
118
<5
Δ
568
35
◯
6036
⊚
◯
118
<5
◯
536
26
◯
6037
◯
◯
116
<5
◯
530
29
◯
6038
⊚
◯
117
<5
Δ
555
30
◯
6039
⊚
◯
117
20
◯
497
31
◯
6040
⊚
◯
118
<5
Δ
574
35
◯
[0000]
TABLE 25
corrosion
machinability
resistance
mechanical
stress
condition
maximum
properties
resistance
form
of
cutting
depth of
hot workability
tensile
corrosion
of
cut
force
corrosion
700° C.
strength
elongation
cracking
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
6041
⊚
◯
115
<5
◯
520
34
◯
6042
⊚
◯
117
20
Δ
501
31
◯
6043
⊚
◯
118
<5
Δ
585
32
◯
6044
⊚
◯
116
<5
◯
516
32
◯
6045
⊚
◯
116
<5
◯
538
35
◯
[0000]
TABLE 26
machinability
hot work-
mechanical
condition
ability
properties
form
of
cutting
700° C.
tensile
elonga-
of
cut
force
deform-
strength
tion
No.
chippings
surface
(N)
ability
(N/mm 2 )
(%)
7001
⊚
◯
132
◯
755
17
7002
⊚
◯
127
◯
776
19
7003
⊚
Δ
135
◯
620
15
7004
⊚
◯
130
◯
714
18
7005
⊚
◯
128
◯
708
19
7006
⊚
◯
130
◯
685
16
7007
⊚
◯
132
◯
717
18
7008
⊚
◯
130
◯
811
18
7009
⊚
◯
130
◯
790
15
7010
⊚
◯
131
◯
708
18
7011
⊚
◯
128
◯
810
17
7012
⊚
◯
128
◯
694
17
7013
⊚
◯
132
◯
742
16
7014
⊚
◯
128
◯
809
17
7015
⊚
◯
129
◯
725
15
7016
⊚
◯
128
◯
765
18
7017
⊚
◯
130
◯
684
16
7018
⊚
◯
128
◯
710
21
7019
⊚
◯
128
◯
746
20
7020
⊚
◯
126
◯
802
19
[0000]
TABLE 27
machinability
hot work-
mechanical
condition
ability
properties
form
of
cutting
700° C.
tensile
elonga-
of
cut
force
deform-
strength
tion
No.
chippings
surface
(N)
ability
(N/mm 2 )
(%)
7021
⊚
◯
126
◯
792
19
7022
⊚
◯
128
◯
762
20
7023
⊚
◯
129
◯
725
17
7024
⊚
◯
128
◯
744
21
7025
⊚
◯
130
◯
750
20
7026
Δ
◯
132
◯
671
23
7027
⊚
◯
128
◯
740
23
7028
⊚
◯
133
◯
763
22
7029
Δ
◯
129
◯
647
24
[0000]
TABLE 28
corrosion
machinability
resistance
mechanical
stress
high-temperature
condition
maximum
properties
resistance
oxidation
form
of
cutting
depth of
hot workability
tensile
corrosion
increase in weight
of
cut
force
corrosion
700° C.
strength
elongation
cracking
by oxidation
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
(mg/10 cm 2 )
8001
⊚
◯
114
<5
◯
528
35
◯
0.5
8002
⊚
◯
116
<5
◯
545
37
◯
0.2
8003
◯
◯
113
<5
Δ
547
34
◯
0.4
8004
⊚
◯
116
40
◯
482
30
Δ
0.5
8005
⊚
◯
117
<5
◯
502
32
◯
0.3
8006
⊚
◯
117
<5
Δ
570
36
◯
0.4
8007
⊚
◯
117
<5
◯
575
33
◯
0.2
8008
⊚
◯
118
<5
◯
552
36
◯
0.3
[0000]
TABLE 29
corrosion
machinability
resistance
mechanical
stress
high-temperature
condition
maximum
properties
resistance
oxidation
form
of
cutting
depth of
hot workability
tensile
corrosion
increase in weight
of
cut
force
corrosion
700° C.
strength
elongation
cracking
by oxidation
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
(mg/10 cm 2 )
9001
⊚
◯
115
<5
◯
526
33
◯
0.4
9002
◯
◯
113
20
Δ
543
30
◯
0.3
9003
◯
◯
115
<5
Δ
508
28
◯
0.4
9004
⊚
◯
117
<5
◯
567
37
◯
0.2
9005
⊚
◯
115
<5
Δ
571
33
◯
0.4
9006
⊚
◯
116
<5
◯
513
35
◯
0.4
[0000]
TABLE 30
corrosion
machinability
resistance
mechanical
stress
high-temperature
condition
maximum
properties
resistance
oxidation
form
of
cutting
depth of
hot workability
tensile
corrosion
increase in weight
of
cut
force
corrosion
700° C.
strength
elongation
cracking
by oxidation
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
(mg/10 cm 2 )
10001
⊚
◯
115
<5
◯
534
38
◯
0.1
10002
⊚
◯
116
10
◯
538
36
◯
0.4
10003
⊚
◯
117
<5
◯
563
39
◯
<0.1
10004
⊚
◯
115
<5
◯
505
30
Δ
0.2
10005
⊚
◯
116
<5
Δ
572
38
◯
0.2
10006
⊚
◯
115
<5
◯
514
28
◯
0.1
10007
⊚
◯
114
<5
◯
525
34
◯
0.2
10008
⊚
◯
115
20
◯
530
36
◯
0.2
[0000]
TABLE 31
corrosion
machinability
resistance
mechanical
stress
high-temperature
condition
maximum
properties
resistance
oxidation
form
of
cutting
depth of
hot workability
tensile
corrosion
increase in weight
of
cut
force
corrosion
700° C.
strength
elongation
cracking
by oxidation
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
(mg/10 cm 2 )
11001
⊚
◯
115
<5
◯
552
35
◯
0.2
11002
⊚
◯
116
30
Δ
504
28
Δ
0.2
11003
⊚
◯
115
<5
Δ
598
34
◯
<0.1
11004
⊚
◯
116
<5
◯
515
32
◯
0.1
11005
◯
◯
113
<5
◯
540
35
◯
0.1
11006
⊚
◯
116
20
Δ
487
31
◯
0.1
11007
⊚
◯
117
<5
◯
524
32
◯
0.1
11008
◯
◯
114
<5
◯
537
30
◯
0.2
11009
⊚
◯
115
<5
Δ
569
35
◯
0.1
11010
⊚
◯
115
10
◯
531
32
◯
0.1
11011
⊚
◯
116
<5
◯
510
29
◯
0.1
[0000]
TABLE 32
corrosion
machinability
resistance
mechanical
stress
condition
maximum
properties
resistance
form
of
cutting
depth of
hot workability
tensile
corrosion
of
cut
force
corrosion
700° C.
strength
elongation
cracking
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
12001
⊚
◯
122
210
◯
486
36
◯
12002
⊚
◯
119
200
◯
490
35
◯
12003
⊚
◯
120
160
Δ
501
40
◯
12004
⊚
◯
119
160
Δ
505
41
◯
[0000]
TABLE 33
corrosion
machinability
resistance
mechanical
stress
high-temperature
condition
maximum
properties
resistance
oxidation
form
of
cutting
depth of
hot workability
tensile
corrosion
increase in weight
of
cut
force
corrosion
700° C.
strength
elongation
cracking
by oxidation
No.
chippings
surface
(N)
(μm)
deformability
(N/mm 2 )
(%)
resistance
(mg/10 cm 2 )
13001
◯
◯
103
1100
Δ
408
37
XX
1.8
13002
◯
◯
101
1000
X
387
39
XX
1.7
13003
◯
Δ
112
1050
◯
414
38
XX
1.7
13004
X
◯
223
900
◯
438
38
X
1.2
13005
X
◯
178
350
Δ
735
28
◯
0.2
13006
X
◯
217
600
◯
425
39
X
1.8
[0000]
TABLE 35
wear resistance
weight loss by wear
No.
(mg/100000rot.)
7021a
1.5
7022a
1.4
7023a
0.9
7024a
2.0
7025a
1.2
7026a
1.2
7027a
1.1
7028a
2.1
7029a
1.5
[0000]
TABLE 34
wear resistance
weight loss by wear
No.
(mg/100000rot.)
7001a
0.7
7002a
1.4
7003a
2.0
7004a
1.4
7005a
1.2
7006a
1.8
7007a
2.3
7008a
0.7
7009a
0.6
7010a
1.3
7011a
0.8
7012a
1.7
7013a
1.1
7014a
0.8
7015a
1.1
7016a
1.0
7017a
1.6
7018a
1.9
7019a
1.1
7020a
1.4
[0000]
TABLE 36
wear resistance
weight loss by wear
No.
(mg/100000rot.)
13001a
500
13002a
620
13003a
520
13004a
450
13005a
25
13006a
600
|
The free-cutting copper alloy according to the present invention contains a greatly reduced amount of lead in comparison with conventional free-cutting copper alloys, but provides industrially satisfactory machinability. The free-cutting alloys comprise 69 to 79 percent, by weight, of copper, 2.0 to 4.0 percent, by weight, of silicon, 0.02 to 0.4 percent, by weight, of lead, and the remaining percent, by weight, of zinc.
| 2
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FIELD OF THE INVENTION
The subject invention is generally directed to a technique of encoding data for serial transmission and the correlative technique of decoding the transmitted data. The invention has particular application to the transmission of data from a remote location to a central receiving station and the recording of data on a magnetic recording medium or the like and its subsequent extraction. In other words, the invention is not limited to a particular application since the technique according to the invention can be used to advantage in many digital transmission and storage applications.
BACKGROUND OF THE INVENTION
Serial data transmission typically involves the encoding of the data to be transmitted in an appropriate code for the transmission medium and the framing of the encoded data into blocks of serial data for transmission. The purpose of framing the data is to provide identification codes and timing signals that facilitate the detection of the beginning and end of data and the synchronism necessary to permit decoding of the received data. In those applications where the signal to noise ratio is low, special efforts must be undertaken to insure that the integrity of the transmitted data is maintained. To this end, sophisticated error detecting and correcting codes have been devised. These codes require the addition of bits to the framed data code that is to be transmitted. Thus, a large portion of the transmitted frame is composed of frame synchronising codes, clock timing pulses and error detection and correction bits. In other words, the overhead required to synchronously or asynchronously transmit serial data is a substantial portion of the frame that transmits the data. Even so, in particularly noisy environments, redundant transmission is often resorted to in order to minimize data errors. Whether the environment is especially noisy or is less hostile to the accurate transmission and/or recording of data, it is generally the goal of the communications engineer to decrease the overhead required to transmit data.
SUMMARY OF THE INVENTION
It is therefore the principle object of the subject invention to provide a technique for the encoding of serial data which minimizes the framing and clock recovery data necessary to assure the accurate transmission of data.
It is another object of the invention to provide a redundant transmission scheme that minimizes the bits required for framing.
Briefly stated, the foregoing and other objects of the invention are attained by redundantly encoding the data so that the second data string of a data string pair is the logical inverse or complement of the first data string of the pair. The two data strings are separated by at least two binary bits, and the first data string of the data string pair is preceded by at least two binary bits. Thus, both data strings of the data string pair are preceded by a short header, but these headers are different. The headers must have at least one bit the same and at least one bit different. Using this scheme, there is for example only one pair of bits in the headers which are both binary ones. Recognizing this provides an unambiguous indication of the beginning of a data string. This and the complemented data strings provide all that is necessary for correct frame synchronism. In a preferred embodiment, clock or bit synchronism is achieved by dividing each binary bit period into n clock periods, where n might typically be eight. Bit synchronism is achieved by making a decision based on a center weighting technique. Thus, the overhead required to transmit data is reduced to a minimum while still retaining the high reliablity of redundant encoding.
BRIEF DESCRIPTION OF THE DRAWINGS
The foregoing and other objects, aspects and advantages of the invention will be better understood from the following detailed description of the invention with reference to the drawings, in which:
FIG. 1 is a flow chart illustrating the algorithm for encoding the bit stream;
FIG. 2 is a flow chart illustrating the algorithm for decoding the bit stream; and
FIG. 3 is a flow chart illustrating the algorithm for bit extraction.
DETAILED DESCRIPTION OF THE INVENTION
The invention is perhaps best described by example. Assume the following conditions:
First Header=1 1
Second Header=1 0
Information=0 1 1 1 0 1 1 1
Then, according to the invention, the transmitted data is as follows:
1 1 0 1 1 1 0 1 1 1 1 0 1 0 0 0 1 0 0 0
If one examines pairs of bits separated by nine bits in between, they will be complements of each other except in the one case of the first bits of the headers. In general, if the length (number of bits) of each header is H and the length of the information is I, then two bits separated by H+I-1 bits are identical only if they are corresponding bits in the headers. This is how framing is accomplished. The last 2H +2I bits are stored. Pairs of bits the appropriate distance apart are examined and the data is extracted if a frame is detected. The bit(s) that is different in the two headers is used to distinguish the data from its complement. Without that bit, a repeated transmission of the same data would be undistinguishable from a repeated transmission of the complement of the data.
To better appreciate the advantages of the encoding technique according to the invention, consider a known telemetry scheme in which the basic asynchronous transmission is to send one start bit, usually a "0", the data, and finally some number of stop bits, say for example two "1's". Using the same information bytes as in the example given above, the transmission would be as follows:
______________________________________ ##STR1##
______________________________________
When no data is being sent, the transmitter continuously sends a "1". This system has been particularly useful because the data can be easily extracted by a mechanical device. A weakness of this system is that it relies on periods of inactivity (all "1's" transmitted) or distinct data being transmitted for correction of false frame synchronization. If no data is transmitted, a receiver can idle waiting for a start bit and properly synchronize. However, if the receiver is given a transmission with no inactive periods, it may not be able to properly synchronize. Consider the example above using one start "0" and two stop "1" bits and the following transmission:
______________________________________ ##STR2##
______________________________________
The transmission is ambiguous; it could be "correctly" decoded as either 1 1 0 1 1 1 1 1 or 1 1 1 1 1 1 1 0.
This problem can be circumvented by transmitting a number of stop bits nearly equal to or greater than the number of data bits, but this approach will lower the data rate significantly. For example, if eight stop bits are transmitted, there will be eight bits of data in seventeen bits transmitted.
The encoding technique according to the invention transmits according to the format 1 1 Data 1 0 Data. Thus, there will be, for example, eight bits of data in 20 bits transmitted, but all of the information will be transmitted twice thereby providing superior data integrity, error detection capability and no ambiguous sequences. If a parity bit is added to both systems, the prior system would then provide only single-bit error detection whereas the encoding technique according to the invention provides single bit error correction.
An additional advantage of the encoding technique according to the invention is that it synchronizes faster than the prior system even when the old system is restricted to unambiguous sequences. If an old system receiver is improperly synchronized, it will be looking for a start bit inside the data. Suppose the receiver has interpreted a zero in bit position three as the start bit, then the receiver expects bit position three in the next byte to be a zero. If it is not, then the receiver must wait until it finds a zero and interprets it as the next start bit. Correct synchronization will be achieved when the receiver expects the real start bit to be the start bit. The receiver can move one bit every byte, and has a 50% chance of doing so at each step, relying on distinct data in each frame. If the receiver synchronizes n bits away from the true frame, it takes at least n frames to resynchronize, and on average 3/2n frames. No data is recovered unless a good deal of intelligence and an arbitrary amount of storage space is available to the system. Framing errors will be flagged with probability (1-(1/2) s ), where s is the number of stop bits.
In contrast, the encoding technique according to the invention requires 2H+2I bits of storage and synchronizes immediately, recovering the first complete frame received. Each recovered bit is shifted into a 2H+2I shift register (or equivalent), and if the result is a valid frame, the data is extracted. By counting the number of bits shifted in, the device can know when to expect a valid frame, and flag an error if one is not detected.
Synchronous transmission has the advantage that all of the synchronization (framing) is transmitted first, followed by a comparitively large amount of data. Therefore, a larger percentage of the total transmission carries information than in the asynchronous case. Of course, if the synchronization information is lost, all the data that followed it is lost as well, so synchronous transmission is limited primarily to high quality signal lines. If it is desirable to send the data twice, the technique according to the invention offers framing information in just four bits, i.e. the two headers. The only constraint is that the length of the information must be known to the reciver.
By sending the data twice, much greater data integrity can be achieved than CRC polynomial, Hamming or BCH codes. Data integrity is defined as the probability that received data is valid, given that the decoder did not detect an error. By incorporating the framing information economically, the increased integrity is achieved with little or no increase in transmission length. These and other error detecting/correction techniques could still be employed within the encoding technique according to the invention to achieve any desired characteristics of data integrity. An encoder according to the invention may be implemented in either hardware or software. The preferred implementation and best mode for the practice of the invention is in software. Any of several commercially available microcomputers may be used in the software implementation. These include, for example, the MC 6805 microcomputer manufactured by Motorola, Inc., the 3870/F8 microcomputer manufactured by Mostek Corporation, the MCS-48 microcomputer manufactured by Intel Corporation. It should be understood, however, that the practice of the invention is not limited to the use of a particular microcomputer. FIG. 1 shows the flow chart of a software implementation of the encoding algorithm. In block 1, the data is obtained. In the example illustrated, the data is 11011110. In block 2, the headers are added to the data, and in block 3, the complement of the data is added to complete the data string. Finally, in block 4, the data is transmitted; alternatively, the data may be recorded.
A system decoder may be implemented in either hardware or software. FIG. 3 shows the flow chart of a software implementation. As with the encoding algorithm, the decoding algorithm can be implemented with any one of several commercially available microcomputers. To decode a transmission in this system, the receiver must process the information one bit at a time. Therefore, the procedure begins with decision block 10 in which it is determined if a new bit is available. If so, the bit is shifted into the buffer in block 12; otherwise, the process returns. In decision block 14, it is determined if the first header is present. If so, then a decison is made in block 16 as to whether the second header is present. If so, the data fields are checked in block 18 to make sure that they are complements. If any of these tests fail, then the process returns. But if all the tests are affirmative, block 20 indicates to the processor that data is available.
Extracting the bits one at a time is a simple matter if they are accompanied by a clock. If they are not, a more sophisticated method must be employed. The invention also contemplates a technique for bit extraction. A device to extract bits can also be implemented in either hardware or software. FIG. 2 is a flow chart of a software implementation which, again, can be implemented with any one of several commercially available microcomputers. The algorithm assumes knowledge of the baud rate of the transmission. If this is not a priori knowledge, then sequences of "0's" and "1's" can be sampled and recorded and an approximation of the greatest common divisor of the lengths taken. This result should equal the number of samples per bit period.
As a specific example, assume that sampling is done at eight times the data rate. The technique according to the invention arbitrarily "frames" sequences of eight samples as one bit each. This is indicated in blocks 22 and 24 of FIG. 2. Then, in block 26 using a center weighting technique, samples three, four, five, and six are examined to decide if the bit is a "1" or "0". This decision is made by majority vote. If there is a transition (ones followed by zeros or vice-versa) in the middle of a frame, then the frame is moved forward or backward in the sequence of samples so that the true iddle of a bit is in the middle of a frame. In block 28, the detected bit (one or zero) is sent to the decoder. Then, to fully synchronize the system, samples six and seven are checked in block 30 to determine if they differ from the detected bit. If they do, then in block 32, sample eight becomes sample one of the next bit, and the process returns to block 24. Otherwise, samples two and three are checked in block 34 to see if they differ from the detected bit. If they do, then in block 36, the process waits one sample time and then returns to block 22. Otherwise, the process returns directly to block 22. Thus, this process makes the correct decision as to whether the bit is a one or zero after only one transition and is completely synchronized in at most four transitions.
The process just described uses certain samples to vote and corrects when transitions are detected within a certain range of the middle of the frame. Variations are possible in the number of samples, which samples are used to vote, how the adjustment is determined necessary and how much adjustment is made each time. The implementation described allows only the samples two and three or six and seven to disagree with the middle four samples, completely ignoring samples one and eight except for timing purposes. This implementation works well when bit transitions may jitter forward or backward but not affect the overall bit rate. This is a situation frequently encountered in AFSK data links and magnetic tape recording. Another variation on this method is to let the sample rate run slightly faster than it would in perfect synchronization and allow the algorithm only to adjust the frame backwards. These systems do require transitions in order to operate properly, but the encoding technique according to the invention guarantees at least two transitions per frame with the headers 1 1 and 1 0. More transitions can be guaranteed by increasing the header length, as for example headers 1 1 and 0 0 1.
|
A technique for redundantly encoding data for synchronous or asynchronous serial transmission or recording and the correlative technique for decoding the serial bit stream are disclosed. The encoding technique involves making the second data string of a data string pair the complement of the first data string and formatting to the format H 1 Data H 2 Data where H 1 and H 2 are headers wherein at least one bit is the same in corresponding bit positions of the headers. Decoding involves first detecting the headers and then checking to confirm that the data fields are complements. Also disclosed is a technique for extracting bits from the data stream.
| 7
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a character processing apparatus and, in particular, to a character processing apparatus having a digit place alignment function to align and display an input numeral string.
2. Description or the Related Art
In a Japanese word processor which is a character processing apparatus, digit place alignment handling has been performed as in the following procedure. That is, first, the position of a numeral string to be aligned and input is specified by performing tab setting. When a numeral string is to be input, a digit place alignment key provided on a keyboard is pressed and as a result, a decimal point of the numeral string is aligned with a tab setting position as a reference and is input. In an English text word processor, a decimal tab key is pressed after tab setting and then a numeral string is input. Thus, the input numeral string is aligned around the decimal point in the same way as described above.
In the above-mentioned conventional word processor, however, since a special key for digit place alignment must be provided on a keyboard, such a word processor is complex in construction and expensive. During operation, an operator must press the special key (digit place alignment key or decimal tab key) for digit alignment prior to each time the operator aligns a numeral string and therefore a smooth input operation is hindered.
An arrangement is disclosed in Japanese Patent Laid-Open Publication No. 305454/1988, in which the number of digits after the decimal point are counted when numeric values and numeric values containing a decimal point are aligned at each tab position and input to find a maximum value, and vertical grid lines can be input automatically between the numeric values according to the maximum value determined.
SUMMARY OF THE INVENTION
The present invention is a character processing apparatus in which, when a numeral string containing a currency symbol is input, the apparatus is automatically switched to the digit place alignment mode so as to perform the digit place alignment of the numeral string. The character processing apparatus of the present invention comprises input means for inputting a numeral string containing a currency symbol and for specifying the position at which the numeral string is to be input on a screen, input position storage means for storing the position specified by the input means at which the numeral string is to be input, display means for displaying the currency symbol and/or the numeral string, storage means for storing a digit place alignment procedure, judgment means for judging whether or not the input position for the numeral string is stored in the input position storage means when the currency symbol is input form the input means, and digit place alignment means for aligning the numeral string in accordance with the digit place alignment procedure around the stored input position as a reference when it is judged that the input position for the numeral string is stored in the input position storage means and for outputting the aligned numeral string to the display means.
In the present invention, the currency symbol means a currency symbol consisting of one symbol such as $ and Y a currency symbol consisting of a plural character such as Fr and DM, or a currency symbol of a combination of these characters such as CAN$ and HK$. Digit place alignment is a process in which a numeral string is automatically aligned around a decimal point as a reference when it contains a decimal point and the last digit of the numeral at the rightmost character position when it does not contain a decimal point.
The fact has been noted that in table editing, during which numeric values are input in cells, an input numeral string is often preceded by a currency symbol, and thus the present invention is so designed that the currency symbol contains the digit place alignment function. It is desirable that an operator be able to select whether or not the currency symbol should be displayed on display means. The character processing apparatus of the present invention basically represents an apparatus consisting of input means, editing means, storage means, and display means. As typical apparatuses of this type, Japanese word processors, Western Alphabet word processors, Chinese word processors, and computers having a character editing function can be cited If apparatuses having a function equivalent to the tab setting function carried on apparatuses of this type, as the input position storage means, are to be included, portable electronic notebooks, computers having an information transfer function like a facsimile, and desk-top calculators with a programmable function can also be cited.
The digit place alignment process in the present invention is, in particular, useful for editing a table. Accordingly, it is preferable that the above-mentioned word processors or computers have the digit place alignment function of the present invention.
Also, in the arrangement in which a word processor or a computer has the digit place alignment function, if an input means can accept a currency symbol and a numeral string, then a keyboard and a pointing device, such as a tablet input device, a mouse, etc., may be used. However, a conventional keyboard having currency symbol keys and numeric keys should most preferably be used.
As the display means, a dot-matrix type display device connected or built in the above-mentioned apparatus such as a CRT, liquid crystal device (LCD), an electroluminescence (EL) display, or the like, may be used.
The input position storage means and the storage means can be formed by RAMs contained in the main body of a word processor or the like. A hard disk or a floppy disk as an external storage device can also be used. When a digit place alignment procedure (digit place alignment procedure program) is to be stored in the storage means, the digit place alignment procedure should merely be added without changing a Kana-Kanji conversion program. The program should be formed so that only when a numeral string containing a currency symbol is input, the operation will jump to the digit place alignment procedure process.
The judgment means and the digit place alignment means include a CPU, which at the present time operates in units of 8, 16, or 32 bits.
Further, according to the apparatus of the present invention, the judgment means judges whether or not the position at which a numeral string is to be input has been stored in the input position storage means when a currency symbol is input from the input means. When it is judged that it has been stored, the apparatus transfers the input numeral string, proceeded by the currency symbol, to the digit place alignment means. The digit place alignment means aligns the input currency symbol and the numeral string at the stored input position as a reference and displays it on the display means.
Therefore, according to the present invention, since the provision of a specialized key for digit place alignment is not needed, the cost of the apparatus can be lowered. In addition, when an apparatus in which the present invention is embodied is used, it is not necessary to press a digit place alignment key or a decimal tab key to switch to the digit place alignment mode each time a numeral string to be aligned is input, and ease of operation in the digit place alignment input is improved.
BRIEF DESCRIPTION OF THE DRAWINGS
An embodiment of the invention will now be described by way of example and with reference to the accompanying drawings, in which:
FIG. 1 is a block diagram illustrating the construction of a word processor according to an embodiment of the present invention:
FIG. 2 is a flowchart for explaining the operation according to the embodiment;
FIG. 3 is an explanatory view illustrating an example of a display for digit place alignment according to the embodiment;
FIG. 4 is an explanatory view illustrating an example of a display for digit place alignment according to the prior art.
DESCRIPTION OF THE PREFERRED EMBODIMENT
In FIG. 1, numeral 10 denotes a Japanese word processor main body mainly consisting of a CPU 11, a ROM 12, a RAM 13, and a digit alignment flag 14, which are connected to each other by a bus line 15. The contents of the ROM 12 consists of a control program 121 for controlling the CPU 11 and a digit place alignment procedure program 122 A work area for temporarily storing the intermediate results during execution of a program is allocated to the RAM 13. Further, when tab setting is made on a screen, the tab setting position is stored in the RAM 13. The ROM 12 and the RAM 13 constitute the main memory. The digit place alignment flag 14 stores the presence or absence of the setting of the digit place alignment mode. The CPU 11 performs the following processes in accordance with the digit place alignment procedure program. That is, when a currency symbol is input from a keyboard (described later), it is judged whether or not the input position for a numeral string has been stored in the RAM 13, namely, the input position has been specified by the pressing of the tab key. When it is judged the input position for the numeral string has been stored in the RAM 13, the numeral string is aligned at the input position stored in the RAM 13 as a reference and is output to an LCD (described later) on the basis of the digit place alignment procedure program 122.
A keyboard 16 is connected to the CPU 11 from the outside. This keyboard 16 mainly contains currency symbol keys of "Y" and "$", character input keys, numeric keys, a tab setting key, cursor movement keys (not shown), etc. Characters and numeral strings containing currency symbols are input from the keyboard 16. The position at which characters and numeral strings are to be input is specified by the keyboard 16, that is, tab setting is made. An LCD 17 is externally connected to the CPU 11 via an output control section (not shown). This LCD 17 displays various kinds of information containing currency symbols and numeral strings input from the keyboard 16.
In addition, a text memory 18 composed of RAMs is connected to the CPU 11 as an auxiliary storage device. In this text memory 18 text containing numeral strings which have been definitely input is stored.
Next, the operation of this embodiment will be explained with reference to the flowchart shown in FIG. 2 and the display example shown in FIG. 3. However, it is presupposed that the position at which a numeral string is to be input according to digit place alignment has been set beforehand on the screen by a conventional tab setting.
First, when the currency symbol "$" is input from the keyboard 16, the CPU 11 judges whether or not it is a currency symbol (steps 20 to 21), and further, whether or not a tab setting has been made (step 22). When the result of the judgment is yes, the digit place alignment mode is set and the digit alignment flag 14 is set to "on" (step 23). When a numeral string is input preceded by the currency symbol "$" (steps 24 to 25), it is right-justified at the input position set by the tab setting as a reference (step 26). When the inputting of the numeral string is terminated, the digit place alignment mode is released namely, the digit place alignment flag 14 is set to "off" (step 27). Where the numeral string preceded by the currency symbol contains, for example, a decimal point like "1234.5", it is judged to be yes in step 24 and decimal point editing is performed. That is, digit place alignment is performed in a state in which the input position at which tab setting has been made is fixed as the position of the decimal point Upon termination of the digit place alignment, the digit alignment mode is released. That is, the digit place alignment flag 14 is set to "off" (step 28). When a currency symbol is input a second time in a state in which the digit place alignment mode has been set in the digit place alignment flag 14, the setting of the digit place alignment mode is released (steps 22 to 23). In the case where tab setting has not been made in step 22, an entry will become a usual currency symbol input and a numeral string input for which digit place alignment is not performed.
FIG. 3 shows a display example according to this embodiment. When the currency symbol display "yes" mode is selected, the currency symbol "$" and the numeral string are both displayed When the currency symbol display "no" mode is selected, only the numeral string is displayed. The selection of the currency symbol "yes" or "no" mode may be made at initialization time or at digit place alignment input time. FIG. 4 shows an example of a digit place alignment display according to the prior art, in which a decimal tab symbol "D" indicating the state switched to the digit place alignment mode appears on the screen, since the decimal tab key is always pressed before a numeral string is input.
This embodiment is explained using the currency symbol "$". However, the currency symbol is not limited to this currency symbol. It may contain similar types of currency symbols, for example, yen "Y", pound " ", similar types of currency symbols consisting of a plural character, for example, Franc "Fr", Deutsche Mark "DM", Krone "Kr", and currency symbols derived from these currency symbols, for example, Canada collar "CAN$" and Hong Kong dollar "KH$". Many widely different embodiments of the present invention can be made without departing from the spirit and scope thereof, therefore, it is to be understood that this invention is not limited to the specific embodiments thereof except as defined in the appended claims.
|
A character processing apparatus having a judgment device which checks if a tab setting has been made when a currency symbol is input from an input device, and a digit place alignment device which aligns an input numeral string preceded by the currency symbol around the position at which the tab setting has been made as a reference when it is judged that the tab setting has been made and outputs the numeral string to a display device, and which outputs the numeral string as it is to the display device without aligning the currency symbol and the numeral string when tab setting has not been made.
| 6
|
CROSS REFERENCES RELATED TO THE APPLICATION
This application is a continuation-in-part of U.S. patent application Ser. No. 11/949,821, filed on Dec. 4, 2007 now abandoned.
BACKGROUND
1. Field of the Invention
This invention relates to thermally conductive materials, more particularly to a thermally conductive silicone composition.
2. Description of Related Art
Recently, removing heat from heat generating electronic appliances comes to be more and more important. Electronic appliances such as electronic instruments, computers, or mobile phones generate heat when they are used. The heat generated from the electronic appliances will affect their normal operation. Generally, heat dissipating sheets are applied in electronic appliances, for example, by being interposed between a heat generating electronic component and a radiator. The heat dissipating sheet which conducts heat from the electronic component to the radiator must have high thermal conductivity in order to efficiently cool the electronic appliances as described above. However, a clearance inevitably exists between the heat dissipating sheet and the electronic component. As such, a thermal impedance can be formed between the electronic component and the heat dissipating sheet, thereby greatly reduces the thermally conductive efficiency of the heat dissipating sheet. In order to reduce the thermal impedance between the electronic component and the heat dissipating sheet, thermally conductive silicone compositions are applied in the heat dissipating sheet. Thermally conductive silicone compositions can be used to fill the clearance between the heat dissipating sheet and the electronic component, thereby reducing the thermal impedance. Conventional thermally conductive silicone compositions have low heat conductivities (e.g., in a range from 0.1 W/mK to 0.3 W/mK). Therefore, heat conducting fillers are applied to thermally conductive silicone compositions to improving their heat conductivities. Presently, as heat dissipating manners, thermally conductive silicone compositions can be made into heat dissipating sheets as set forth above, heat dissipating greases or phase change materials to meet various requirements.
A thermally conductive composition is disclosed in U.S. Pat. No. 5,981,641. The thermally conductive composition includes a liquid silicone base, an aluminum nitride (AlN) filler and a zinc oxide (ZnO) filler dispersed into the liquid silicone base. A particle diameter of the aluminum nitride is equal to that of the zinc oxide, and is in a range from 0.1 micrometers to 5 micrometers. A content of the zinc oxide in the sum of the aluminum nitride and the zinc oxide is in a range from 0.05% to 0.5% by weight. A content of the sum of the aluminum nitride and the zinc oxide in the thermally conductive composition is in a range from 83% to 91% by weight. A heat conductivity of the thermally conductive composition is in a range from 2.5 W/mK to 3.7 W/mK. In this thermally conductive composition, zinc oxide can improve a lubricative property of the particles of the aluminum nitride.
U.S. Pat. Nos. 6,114,429 and 6,162,849 disclose a thermally conductive composition. In the conductive composition, a mixture of two types of liquid state silicon emulsion is used as a base, and three types of fillers are dispersed into the base. The three types of fillers respectively are aluminum oxide particles with a particle diameter of 40 micrometers to 80 micrometers, aluminum nitride particles with a particle diameter of 0.5 micrometers to 5 micrometers, boron nitride particles with a particle diameter of 1 micrometer to 10 micrometers, and silicon carbide particles with a particle diameter of 0.4 micrometers to 10 micrometers or zinc oxide particles with a particle diameter of 0.2 micrometers to 5 micrometers. Three types of above fillers with fine and coarse particles are mixed into the base to form a desired thermally conductive composition. A content of the sum of the three types of fillers in the thermally conductive composition is in a range from 50% to 90% by weight. A heat conductivity of the thermally conductive composition is in a range from 1.2 W/mK to 2.9 W/mK.
U.S. Pat. Nos. 6,174,841 and 6,255,257 disclose a thermally conductive composition. In the thermally conductive composition, two or more fillers with different diameters are dispersed into various silicone bases with different viscosity. The thermally conductive composition includes a main filler and a minor filler. The main filler is aluminum nitride. The minor filler is selected from a group consisting of aluminum oxide, boron nitride, silicon carbide and zinc oxide. A content of the main filler in the thermally conductive composition is in a range from 50% to 95% by weight. An average diameter of the particles of the main filler is in a range from 0.5 micrometers to 25 micrometers. A content of the minor filler in the thermally conductive composition is in a range from 0% to 50% by weight. These minor fillers can enable the filler dispersed in the silicone base having a highest density, thereby improving a heat conductivity of the thermally conductive composition. The heat conductivity of the thermally conductive composition is in a range from 1 W/mK to 3.5 W/mK.
U.S. Pat. No. 6,372,337 discloses a thermally conductive composition including fillers and a silicone base penetrating into clearances among the particles of the fillers. The silicone base is formed by mixing five or more liquid state silicones. The fillers include a main filler and a minor filler. The main filler can be aluminum particles, and an average diameter thereof is in a range from 0.5 micrometers to 50 micrometers. The minor filler can be boron nitride particles or zinc oxide particles. An average diameter of the boron nitride particles is in a range from 1 micrometer to 5 micrometers. An average diameter of the zinc oxide particles is in a range from 0.2 micrometers to 5 micrometers. A content of the sum of the main filler and the minor filler in the thermally conductive composition is in a range from 50% to 90% by weight. A heat conductivity of the thermally conductive composition is in a range from 3.3 W/mK to 4.2 W/mK.
U.S. Pat. No. 6,649,258 discloses a thermally conductive composition including fillers and a silicone base penetrating into clearances among the particles of the fillers. The silicone base is formed by mixing four or more liquid state silicones. The fillers include a main filler and a minor filler. The main filler can be aluminum particles, and an average diameter thereof is in a range from 0.1 micrometers to 50 micrometers. The minor filler can be zinc oxide particles. A ratio of the aluminum particles to the zinc oxide particles is in a range from 1/1 to 10/1. A content of the sum of the aluminum particles to the zinc oxide particles in the thermally conductive composition is in a range from 80% to 92% by weight. A heat conductivity of the thermally conductive composition is in a range from 1.7 W/mK to 3.8 W/mK.
U.S. Pat. No. 6,828,369 discloses a thermally conductive composition including an organic polymer, and spherical or non-spherical aluminum oxide particles dispersed into the organic polymer. As a heat conducting filler, the spherical or non-spherical aluminum oxide particles are sufficiently dispersed into the organic polymer. When a content of the heat conducting filler in the thermally conductive composition is higher than 70% by volume, a heat conductivity of the thermally conductive composition is larger than 5.5 W/mK.
However, regarding the above-described patents, a manufacturing cost of the main fillers is relatively high. In addition, the proportion and diameter of the main fillers render the thermally conductive composition having a low mechanical strength, low surface evenness or high surface roughness. As such, the thermally conductive silicone composition is difficult to be compressed, and a thermal impedance between the heat generating appliances and the thermally conductive silicone composition is relatively high.
Therefore, a thermally conductive silicone composition having low manufacturing cost, high mechanical strength, low thermal impedance, and is easily to be compressed is desired.
BRIEF SUMMARY
The present invention provides a thermally conductive silicone composition. The thermally conductive silicone composition is manufactured by adding three types of fillers with various ratios and different diameters into a silicone. Being manufactured by such method, the thermally conductive silicone composition has a low manufacturing cost, high mechanical strength, low thermal impedance, and is easily to be compressed. An embodiment of the thermally conductive silicone composition includes 25 to 50 volume % of a silicone, 30 to 60 volume % of a first heat conducting filler, and 15 to 40 volume % of a second heat conducting filler, and 1 to 2 volume % of a third heat conducting filler. That is to say, a proportion of the silicone to the thermally conductive silicone composition to be prepared is from about 25% to about 50% by volume. A proportion of the first heat conducting filler to the thermally conductive silicone composition is from about 30% to about 60% by volume. A proportion of the second heat conducting filler to the thermally conductive silicone composition is from about 15% to about 40% by volume. A proportion of the third heat conducting filler to the thermally conductive silicone composition is from about 1% to about 2% by volume. A proportion of the sum of the first heat conducting filler and the second heat conducting filler and the third heat conducting filler to the thermally conductive silicone composition is from about 50% to about 75% by volume.
The silicone can be high-temperature vulcanized silicone, or low-temperature vulcanized silicone. The silicone can be silicone rubber or silicone colloid. The silicone rubber has an excellent machanicality and high heat resistance. In addition, a physical feature of the silicone rubber can not be affected by temperature changes. Except having the above advantageous of the silicone rubber, the silicone colloid has excellent performance in adhesion, excellent fluidity, and low load. The silicone colloid is very soft, and can be obtained by curing a liquid silicone with low viscosity index.
The first heat conducting filler, the second heat conducting filler and the third heat conducting filler are mixed into the silicone. A proportion of the sum of the first heat conducting filler and the second heat conducting filler and the third heat conducting filler to the thermally conductive silicone composition is from about 50% to about 75% by volume. The first heat conducting filler may be comprised of particles with uniform or non-uniform size. When the first heat conducting filler is comprised of particles with uniform size, a diameter of the particle is in a range from about 15 micrometers to about 50 micrometers. When the first heat conducting filler is comprised of particles with non-uniform size, an average diameter of the particle is in a range from about 15 micrometers to about 50 micrometers. The first heat conducting filler can be selected from a group consisting of copper oxide, magnesium oxide, iron oxide, titanium oxide, silicon carbide and iron carbide. The second heat conducting filler may be comprised of particles with uniform or non-uniform size. When the second heat conducting filler is comprised of particles with uniform size, a diameter of the particle is in a range from about 1 micrometer to about 10 micrometers. When the second heat conducting filler is comprised of particles with non-uniform size, an average diameter of the particle is in a range from about 1 micrometer to about 10 micrometers. The second heat conducting filler can be selected from a group consisting of zinc oxide, magnesium oxide, titanium nitride, silicon carbide, iron carbide, iron oxide and copper oxide. When the third heat conducting filler is comprised of particles with nano size, a diameter of the particle is in a range from about 100 nanometer to about 200 nanometer. When the third heat conducting filler is comprised of particles with non-uniform size and uniform size, an average diameter of the particle is in a range from about 100 nanometer to about 200 nanometers. The third heat conducting filler can be selected from a group consisting of zinc oxide.
The thermally conductive silicone composition has a low manufacturing cost for employing the cheap first and second heat conducting fillers. In addition, The above first, second and third heat conducting fillers can be semi-conductors or insulators, therefore, the thermally conductive silicone composition containing these heat conducting fillers has an excellent electrical insulation. In detail, the silicon carbide and iron carbide are semi-conductors, and the copper oxide, magnesium oxide, iron oxide, zinc oxide, boron nitride are insulators. Because of containing these semi-conductors and/or insulators, the thermally conductive silicone composition can be safely arranged between the electronic component and the heat dissipating device. Furthermore, the first and second heat conducting fillers can be modified by silicon tetrachloride. Therefore, surfaces of the thermally conductive silicone composition containing the first, second and third heat conducting fillers can be modified by the silicon tetrachloride. As a result, the thermally conductive silicone composition can achieve a low surface roughness (i.e., a high surface evenness). As such, the thermally conductive silicone composition can be tightly combined with the electronic component and/or the heat dissipating device. Thus, the heat generated from the electronic component can be removed efficiently and timely.
The thermally conductive silicone composition has three heat conducting fillers with different sizes dispersed therein. The first heat conducting filler and the second heat conducting filler are cooperate to fill interstices formed by molecules of the silicone, thereby improving the heat conductivity of the thermally conductive silicone composition. Referring to FIG. 1 , a thermally conductive silicone composition includes a silicone 1 and a first heat conducting filler 2 dispersed therein. A number of interstices 3 are inevitably formed among molecules of silicone 1 or among particles of the first heat conducting filler 2 . Thus, the silicone 1 can be easily separated. In addition, the presence of the interstices 3 can form a thermal impedance, thereby reducing the heat conductivity of the thermally conductive silicone composition. Referring to FIG. 2 , a thermally conductive silicone composition includes a silicone 1 , a first heat conducting filler 2 and a second heat conducting filler 4 and a third heat conducting filler 5 . A particle diameter of the second heat conducting filler 4 is less than that of the first heat conducting filler 2 . Thus, the particles of the second heat conducting filler 4 and the third heat conducting filler 5 can disperse/fill into interstices 3 formed among molecules of silicone 1 or particles of the first heat conducting filler 2 . Therefore, the combination of the first, second and third heat conducting fillers 2 , 4 and 5 can efficiently reduce the thermal impedance, thereby improving the heat conductivity of the thermally conductive silicone composition.
On the one hand, when a ratio of the second heat conducting filler with small diameter is less than 20% by volume, because the interstices among the particles of the first heat conducting filler can not be filled, thus the heat conductivity of the thermally conductive silicone composition may be reduced. On the other hand, when a ratio of the second heat conducting filler with small diameter is larger than 40% by volume, a quantity of the second heat conducting filler may be larger than a desired quantity of the second heat conducting filler for filling the interstices formed among the first heat conducting filler, thus the heat conductivity of the thermally conductive silicone composition may also be reduced. Therefore, a ratio of the second heat conducting filler with small diameter to the thermally conductive silicone composition is, advantageously, in a range from 20% to 40% by volume.
The present invention additionally provides a heat dissipating sheet. The heat dissipating sheet is manufactured by curing the thermally conductive silicone composition with an appropriate hardener added therein.
The heat dissipating sheet can be a room-temperature heat dissipating sheet or a high-temperature heat dissipating sheet. The room-temperature heat dissipating sheet can be made by solidifying a mixture of the liquid thermally conductive silicone composition and a certain hardener at room temperature. Similarly, the high-temperature heat dissipating sheet can be made by solidifying a mixture of the liquid thermally conductive silicone composition and a certain hardener at a high temperature, e.g. at 175 degrees Celsius. A typical process for making heat dissipating sheet includes following steps. First, the silicone, the first heat conducting filler and the second heat conducting filler have been mixed and blended to form an uniform mixture. Second, the mixture can be molded using pressing, coating or laminating method. The process for manufacturing thermally conductive silicone composition can be freely selected according to the corresponding characteristic of the desired thermally conductive silicone composition.
Advantageously, a thickness of the heat dissipating sheet is in a range from about 0.1 millimeters to about 5 millimeters. When the thickness of the heat dissipating sheet is less than 0.5 millimeters, the heat dissipating sheet may have a low manufacturing efficiency. When the thickness of the heat dissipating sheet is larger than 5 millimeters, the thermal impedance the manufacturing cost may be inevitably increased.
Advantageous and novel features will become more apparent from the following detailed description when taken in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
These and other features and advantages of the various embodiments disclosed herein will be better understood with respect to the following description and drawings, in which like numbers refer to like parts throughout, and in which:
FIG. 1 is a schematic view of a thermally conductive silicone composition having a first heat conducting filler alone dispersed therein.
FIG. 2 is a schematic view of a thermally conductive silicone composition having a first heat conducting filler and a second heat conducting filler dispersed therein.
DETAILED DESCRIPTION
Embodiments will now be described below in detail. In the following Examples and Comparative Examples, the thermal conductivity of each thermally conductive silicone composition is measured at an identical circumstance (i.e. temperature: 23±1 degrees Celsius, humidity: 50%±10%), with a thermal conductivity meter (made by Hot Disk AB, Sweden), by the Center of EMO Materials and Nanotechnology, National Taipei University of Technology, Taiwan. The Center is a certificated laboratory by Taiwan Accreditation Foundation.
EXAMPLES 1 TO 8
A liquid room-temperature vulcanized silicone having a specific gravity of 0.98 and a consistency of 100 (trade name is SC412, made by Hsin Han Electronic Co. Ltd., Taiwan) is used as the silicone. In the Examples 1 to 8, a proportion of such silicone to the thermally conductive silicone composite to be prepared is 40% by volume. Silicon carbide (SiC) particles having an average diameter of 18 millimeters (MODEL GC8000, manufactured by Titanex Corp., Taiwan) is used as the first heat conducting filler. Zinc oxide (ZnO) particles having an average diameter of 1 millimeter to 5 millimeters (manufactured by Pan-Continental Chemical Co., Ltd., Taiwan) is used as the second heat conducting filler. At room temperature, the mixture of the silicone, the first and second heat conducting fillers is blended well to form a thermally conductive silicone composition. In such fashion, eight thermally conductive silicone compositions can be prepared. The thermal conductivity of each of the thermally conductive silicone compositions is measured. The proportion of the first and second heat conducting fillers, and the thermal conductivity of each of the thermally conductive silicone compositions to be prepared are shown in Table 1.
TABLE 1
Thermal
conductivity
Examples
SiC (18 μm)
ZnO (1~5 μm)
Cross-Link
(W/m · K)
1
55 vol %
5 vol %
—
X
2
50 vol %
10 vol %
—
2.4
3
45 vol %
15 vol %
—
2.6
4
40 vol %
20 vol %
—
2.4
5
35 vol %
25 vol %
—
2.5
6
30 vol %
30 vol %
—
2.4
7
20 vol %
40 vol %
—
2.1
8
10 vol %
50 vol %
—
1.6
According to the data shown in Table 1, the thermally conductive silicone compositions prepared in Examples 1 to 8 have their thermal conductivity in a range from 1.6 W/Mk to 2.4 W/Mk.
EXAMPLES 9 TO 13
The silicone and the first heat conducting filler of Examples 9 to 13 are similar to those of Examples 1 to 8, except that the second heat conducting filler and the proportion of the first and second heat conducting fillers. Copper oxide (CuO) particles having an average diameter of 5 millimeters (manufactured by Echo Chemical Co., Ltd., Taiwan) is used as the second heat conducting filler. The proportion of the first and second heat conducting fillers to the corresponding thermally conductive silicone composition to be prepared, and the thermal conductivity of each of the thermally conductive silicone compositions to be prepared are shown in Table 2.
TABLE 2
Thermal
conductivity
Examples
SiC (18 μm)
CuO (5 μm)
Cross-Link
(W/m · K)
9
50 vol %
10 vol %
—
1.9
10
40 vol %
20 vol %
—
1.9
11
30 vol %
30 vol %
—
2.0
12
20 vol %
40 vol %
—
1.7
13
10 vol %
50 vol %
—
1.5
As can be seen from the data shown in Table 2, the thermally conductive silicone compositions prepared in Examples 9 to 13 have their thermal conductivity in a range from 1.5 W/Mk to 2.0 W/Mk.
EXAMPLES 14 TO 18
The silicone and the first heat conducting filler of Examples 14 to 18 are similar to those of Examples 1 to 8, except that the second heat conducting filler and the proportion of the first and second heat conducting fillers. Iron oxide (Fe 2 O 3 ) particles having an average diameter of 1 millimeter (manufactured by Echo Chemical Co., Ltd., Taiwan) is used as the second heat conducting filler. The proportion of the first and second heat conducting fillers to the corresponding thermally conductive silicone composition to be prepared, and the thermal conductivity of each of the thermally conductive silicone compositions to be prepared are shown in Table 3.
TABLE 3
Thermal
conductivity
Examples
SiC(18 μm)
Fe 2 O 3 (1 μm)
Cross-Link
(W/m · K)
14
50 vol %
10 vol %
—
2.4
15
40 vol %
20 vol %
—
2.4
16
30 vol %
30 vol %
—
2.4
17
20 vol %
40 vol %
—
2.2
18
10 vol %
50 vol %
—
X
As can be seen from the data shown in Table 3, the thermally conductive silicone composition prepared in Examples 14 to 18 have their thermal conductivity in a range from 2.2 W/Mk to 2.4 W/Mk.
EXAMPLES 19 TO 23
The silicone and the first heat conducting filler of Examples 19 to 23 are similar to those of Examples 1 to 8, except that the second heat conducting filler and the proportion of the first and second heat conducting fillers. Aluminum oxide (Al 2 O 3 ) particles having an average diameter of 1 millmeter (manufactured by Unigue Enterprise Co., Ltd., Taiwan) is used as the second heat conducting filler. The proportion of the first and second heat conducting fillers to the corresponding thermally conductive silicone composition to be prepared, and the thermal conductivity of each of the thermally conductive silicone compositions to be prepared are shown in Table 4.
TABLE 4
Thermal
conductivity
Examples
SiC (18 μm)
Al2O3 (1 μm)
Cross-Link
(W/m · K)
19.
50 vol %
10 vol %
—
2.1
20.
40 vol %
20 vol %
—
2.3
21.
30 vol %
30 vol %
—
2.1
22.
20 vol %
40 vol %
—
2.2
23.
10 vol %
50 vol %
—
2.0
As can be seen from the data shown in Table 4, the thermally conductive silicone composition prepared in Examples 19 to 23 have their thermal conductivity in a range from 2.0 W/Mk to 2.3 W/Mk.
EXAMPLES 24 TO 27
A liquid room temperature vulcanized silicone having a specific gravity of 0.98 and a consistency of 100 (trade name is SC412, made by Hsin Han Electronic Co. Ltd., Taiwan) is used as the silicone. In the Examples 24 to 27, a proportion of such silicone to the thermally conductice silicone composite to be prepared is 35% by volume. The first and second heat conducting fillers of Examples 24 to 27 are similar to those of Examples 1 to 8, except that the ratios thereof. The proportion of the first and second heat conducting fillers to the corresponding thermally conductive silicone composition to be prepared, and the thermal conductivity of each of the thermally conductive silicone compositions to be prepared are shown in Table 5.
TABLE 5
Thermal
conductivity
Examples
SiC (18 μm)
ZnO (1~5 μm)
Cross-Link
(W/m · K)
24
55 vol %
10 vol %
—
—
25
45 vol %
20 vol %
—
3.0
26
35 vol %
30 vol %
—
3.1
27
40 vol %
25 vol %
—
3.0
28
35 vol %
30 vol %
◯
3.1
“◯” denoting using hardener
As can be seen from data shown in Table 5, the thermally conductive silicone composition prepared in Examples 24 to 27 have their thermal conductivity in a range from 3.0 W/Mk to 3.4 W/Mk.
EXAMPLE 28
Referring to Table 5, a proportion of the silicone to the thermally conductive silicone composite to be prepared is 35% by volume. A proportion of the first heat conducting filler to the thermally conductive silicone composite to be prepared is 35% by volume, and a proportion of the second heat conducting filler to the thermally conductive silicone composite to be prepared is 30% by volume. Such silicone, first and second heat conducting fillers, and an appropriate hardener (trade name is SC412, made by Hsin Han Electronic Co. Ltd., Taiwan) are mixed and blended well to obtain a thermally conductive silicone composition. Then at room temperature, the thermally conductive silicone composition is cured and made into a heat dissipating sheet having a thickness of 3 millimeters. Finally, the thermal conductivity of the heat dissipating sheet is measured. Referring to Table 5, the thermal conductivity of the heat dissipating sheet is 3.1 W/mK.
COMPARATIVE EXAMPLES 1 TO 4
A liquid room-temperature vulcanized silicone having a specific gravity of 0.98 and a consistency of 100 (trade name is SC412, made by Hsin Han Electronic Co. Ltd., Taiwan) is used as the silicone. In the Comparative Examples 1 to 4, a proportion of such silicone to the thermally conductice silicone composite to be prepared is 40% by volume. Four sorts of first heat conducting filler with identical ratio (i.e., 60% by volume) are separately mixed in the silicone to form four sorts of mixtures. The thermal conductivity of such four sorts of mixtures is shown in Table 6.
TABLE 6
Thermal
Comparative
SiC
ZnO
Fe 2 O 3
Al 2 O 3
Cross-
conductivity
Examples
(18 μm)
(1-5 μm)
(1 μm)
(1 μm)
Link
(W/m · K)
1
60 vol %
—
—
—
—
X
2
—
60 vol %
—
—
—
X
3
—
—
60 vol %
—
—
X
4
—
—
—
60 vol %
—
X
As can be seen from data shown in Table 6, the mixtures prepared in Comparative Examples 1 to 4 are not thermally conductive silicone compositions.
COMPARATIVE EXAMPLES 5 TO 6
A liquid room-temperature vulcanized silicone having a specific gravity of 0.98 and a consistency of 100 (trade name is SC412, made by Hsin Han Electronic Co. Ltd., Taiwan) is used as the silicone. In the Comparative Examples 5 to 6, a proportion of such silicone to the thermally conductive silicone composite is 35%. The proportion of the first and second heat conducting fillers to the corresponding thermally conductive silicone composition to be prepared, and the thermal conductivity of each of the thermally conductive silicone compositions to be prepared are shown in Table 7. According to Table 7, the thermally conductive silicone composite prepared in Comparative examples 5 to 6 have their thermal conductivity in a range from 3.0 W/Mk to 3.4 W/Mk.
TABLE 7
Thermal
Comparative
SiC
ZnO
SiC
Cross-
conductivity
Examples
(18 μm)
(1-5 μm)
(50 μm)
Link
(W/m · K)
5.
40 vol %
25 vol %
—
—
3.0
6.
—
25 vol %
40 vol %
—
3.4
7.
40 vol %
30 vol %
—
—
3.9
8.
—
30 vol %
40 vol %
—
4.4
9.
20 vol %
30 vol %
20 vol %
—
4.4
10.
20 vol %
21 vol %
31 vol %
—
4.4
11.
21 vol %
24 vol %
28 vol %
—
4.4
12.
20 vol %
23 vol %
29 vol %
—
4.8
13.
20 vol %
27 vol %
25 vol %
—
4.8
14.
20 vol %
25 vol %
27 vol %
—
4.9
15.
—
20 vol %
55 vol %
—
5.8
COMPARATIVE EXAMPLES 7 TO 8
A liquid room-temperature vulcanized silicone having a specific gravity of 0.98 and a consistency of 100 (trade name is SC412, made by Hsin Han Electronic Co. Ltd., Taiwan) is used as the silicone. In the Comparative Examples 7 to 8, a proportion of such silicone to the thermally conductive silicone composite to be prepared is 30%. The proportion of the first and second heat conducting fillers to the corresponding thermally conductive silicone composition to be prepared, and the thermal conductivity of each of the thermally conductive silicone composites are shown in Table 7. As shown in Table 7, the thermally conductive silicone composite prepared in Comparative examples 7 to 8 have their thermal conductivity in a range from 3.9 W/Mk to 4.4 W/Mk.
COMPARATIVE EXAMPLES 9 TO 14
A liquid room-temperature vulcanized silicone having a specific gravity of 0.98 and a consistency of 100 (trade name is SC412, made by Hsin Han Electronic Co. Ltd., Taiwan) is used as the silicone. In the Comparative Examples 9 to 14, a proportion of such silicon compound to the thermally conductive silicone composite to be prepared is 30%. The proportion of the first and second heat conducting fillers to the corresponding thermally conductive silicone composition to be prepared, and the thermal conductivity of each of the thermally conductive silicone composition are shown in Table 7. As shown in Table 7, the thermally conductive silicone composites prepared in Comparative examples 9 to 14 have their thermal conductivity in a range from 4.4 W/Mk to 4.9 W/Mk.
COMPARATIVE EXAMPLE 15
A liquid room-temperature vulcanized silicone having a specific gravity of 0.98 and a consistency of 100 (trade name is SC412, made by Hsin Han Electronic Co. Ltd., Taiwan) is used as the silicone. In the Comparative Example 15, a proportion of such silicone to the thermally conductive silicone composite to be prepared is 25%. The proportion of the first and second heat conducting fillers to the corresponding thermally conductive silicone composition to be prepared, and the thermal conductivity of the thermally conductive silicone composition are shown in Table 7. As shown in Table 7, the thermal conductivity of the thermally conductive silicone composite prepared in Comparative example 15 is 5.8 W/Mk.
EXAMPLE 29
A high-temperature vulcanized silicone having a specific gravity of 1.08 (trade name is TSE221-3U, made by General Silicones Co. Ltd., Taiwan) is used as the silicone. In the Example 29, a proportion of such silicone to the thermally conductive silicone composite to be prepared is 35% by volume. Silicon carbide (SiC) particles having an average diameter of 18 millimeters (MODEL GC8000, manufactured by Titanex Corp., Taiwan) is used as the first heat conducting filler. A proportion of such Silicon carbide to the thermally conductive silicone composite is 45% by volume. Zinc oxide (ZnO) particles having an average diameter of 1 millimeter to 5 millimeters (manufactured by Pan-Continental Chemical Co., Ltd., Taiwan) is used as the second heat conducting filler. An appropriate hardener (an accessional hardener of TSE221-3U, made by General Silicones Co. Ltd., Taiwan) is provided. At room temperature, the mixture of the silicone, the first and second heat conducting fillers, and the hardener is blended well to form a thermally conductive silicone composition. The thermally conductive silicone composition is cured at 175 degrees Celsius for 15 minutes, and is made into a heat dissipating sheet having a thickness of 3 micrometers. The thermal conductivity of such heat dissipating sheet is measured. Referring to Table 8, the thermal conductivity of the heat dissipating sheet in Example 29 is 3.0 W/mK.
TABLE 8
Thermal
conductivity
Examples
SiC (18 μm)
ZnO (1~5 μm)
Cross-Link
(W/m · K)
29.
45 vol %
20 vol %
◯
3.0
30.
45 vol %
20 vol %
—
2.5
EXAMPLE 30
The silicone, the first and second heat conducting fillers of Example 30 are similar to those of Example 29, except that their respective proportions. In addition, the thermally conductive silicone composition and its corresponding heat dissipating sheet are prepared in the same manner as in the aforementioned Example 29. Referring to Table 8, the thermal conductivity of the heat dissipating sheet in Example 30 is 2.5 W/mK.
COMPARATIVE EXAMPLES 30 TO 52
The silicone of Comparative Examples 30 to 52 is similar to that of Example 29. The proportion of the first and second heat conducting fillers to the corresponding thermally conductive silicone composition to be prepared, and the thermal conductivity of each of the thermally conductive silicone compositions are shown in Table 9. As shown in Table, the thermally conductice silicone composites prepared in Comparative Examples 30 to 52 have their thermal conductivity in a range from 0.39 W/Mk to 2.3 W/Mk.
TABLE 9
Thermal
Comparative
Silicone
SiC
AlN
Al 2 O 3
Al 2 O 3
Cross-
conductivity
Examples
Compound
(18 μm)
(2.5 μm)
(1 μm)
(50-100 μm)
Link
(W/m · K)
30.
90 vol %
10 vol %
—
—
—
—
0.39
31.
80 vol %
20 vol %
—
—
—
—
0.56
32.
70 vol %
30 vol %
—
—
—
—
0.77
33.
60 vol %
40 vol %
—
—
—
—
1.2
34.
50 vol %
50 vol %
—
—
—
—
1.7
35.
40 vol %
60 vol %
—
—
—
—
2.1
36.
90 vol %
—
10 vol %
—
—
—
0.49
37.
80 vol %
—
20 vol %
—
—
—
0.74
38.
70 vol %
—
30 vol %
—
—
—
0.92
39.
60 vol %
—
40 vol %
—
—
—
1.1
40.
50 vol %
—
50 vol %
—
—
—
1.8
41.
44 vol %
—
56 vol %
—
—
—
2.3
42.
90 vol %
—
—
10 vol %
—
—
0.51
43.
80 vol %
—
—
20 vol %
—
—
0.65
44.
70 vol %
—
—
30 vol %
—
—
0.78
45.
60 vol %
—
—
40 vol %
—
—
1.1
46.
50 vol %
—
—
50 vol %
—
—
X
47.
90 vol %
—
—
—
10 vol %
—
0.40
48.
80 vol %
—
—
—
20 vol %
—
0.48
49.
70 vol %
—
—
—
30 vol %
—
0.64
50.
65 vol %
—
—
—
35 vol %
—
0.87
51.
60 vol %
—
—
—
40 vol %
—
0.98
52.
55 vol %
—
—
—
45 vol %
—
X
COMPARATIVE EXAMPLES 53 TO 60
The proportion of the first, second and third heat conducting fillers to the corresponding thermally conductive silicone composition to be prepared, and the thermal conductivity of each of the thermally conductive silicone compositions are shown in Table 10. As shown in Table, the thermally conductice silicone composites prepared in Comparative Examples 53 to 56 have their thermal conductivity in a range from 3.2 W/Mk to 4.3 W/Mk.
TABLE 10
Thermal
Comparative
Silicone
SiC
ZnO
ZnO
Cross-
conductivity
Examples
Compound
(18 μm)
(1~5 μm)
(100 nm)
Link
(W/m · K)
53.
35 vol %
40 vol %
24 vol %
1 vol %
—
3.3
54.
35 vol %
40 vol %
23 vol %
2 vol %
—
3.2
55.
30 vol %
40 vol %
29 vol %
1 vol %
—
4.3
56.
30 vol %
40 vol %
28 vol %
2 vol %
—
4.3
The above description is given by way of example, and not limitation. Given the above disclosure, one skilled in the art could devise variations that are within the scope and spirit of the invention disclosed herein, including configurations ways of the recessed portions and materials and/or designs of the attaching structures. Further, the various features of the embodiments disclosed herein can be used alone, or in varying combinations with each other and are not intended to be limited to the specific combination described herein. Thus, the scope of the claims is not to be limited by the illustrated embodiments.
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A thermally conductive silicone composition includes 25 to 50 volume % of a silicone, 30 to 60 volume % of a first heat conducting filler, and 20 to 40 volume % of a second heat conducting filler, and 1 to 2 volume % of a third heat conducting filler. The thermally conductive silicone composition has two heat conducting fillers with different sizes dispersed therein, thus the thermal impedance can be efficiently reduced.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a digital radio communications receiver that predicts the structure of a received frame based on the phase and intervals of sync words picked up.
2. Description of the Related Art
In digital radio communications, correctly received information is extracted by detecting a received signal to extract received bit string and picking up a frame timing in the received bit string.
Typically, the detection of the frame timing and frame synchronization are performed by detecting a bit string that exhibits an outstanding autocorrelation in a predetermined position in frames, namely, by detecting a sync word.
A sync word is also referred to as a unique word, and the unique word is abbreviated UW in the drawings and the discussion that follows.
A unique word is detected by comparing a received bit string with the unique word bit string prepared at a receiver end. An unmatched bit count between both strings equal to or smaller than a predetermined threshold (hereinafter referred to as correlation threshold) determines that a unique word is detected.
On the other hand, an unmatched bit count at the timing of the unique word exceeds the correlation threshold determines that a unique word is missed.
When a frame synchronization is established, the receiver is capable of approximately predicting the position of the unique word. When the frame synchronization is established, a gate called an aperture is set up, and the probability of erroneous detection of the unique word is kept lowered by performing the valid detection of the unique word on or in the vicinity of the position of the unique word.
The frame synchronization is established by detecting the unique word at the predetermined positions for the specified number of consecutive frames. This operation is called backward guard and the specified number of frames is called the backward guard level. As the backward guard level is increased, the erroneous frame synchronization is less likely to take place, making higher the reliability of frame synchronization, but the time required to establish the frame synchronization gets longer. Conversely, as the guard level is decreased, the time required to establish the frame synchronization gets shorter but the erroneous frame synchronization is more likely to take place.
The detection of a frame missynchronzation is performed by verifying that the unique word is consecutively missed for the specified number of frames at the position where the unique word is supposed to appear. This operation is called forward guard, and the specified number of frames is called the forward guard level. As the forward guard level is increased, the probability of frame missynchronization due to degradation of channel quality or the like is reduced, but the time required to detect the frame missynchronization, when it actually takes place, is prolonged. Conversely, as the forward guard level is decreased, the time required to detect the frame missynchronization is shortened while the probability of the determination that a missynchronization is erroneously detected is heightened even in the situation where the frame synchronization needs to be maintained.
Some digital radio communications systems change the frame structure depending on communications conditions.
For example, in the system employing a voice activation technique, frames are transmitted only when voice remains significant, and no frames are in principle transmitted when no voice is recognized. In such a case, however, to maintain frame synchronization, a short burst containing a unique word is transmitted at regular intervals. Typically, this interval is different from the frame length.
When the frame structure changes depending on communications conditions as described above, a transmitter end is required to notify of the change in the frame structure. Available as methods of notifying of frame structure changes are one in which a predetermined bit string is set up for notifying of the frame structure in a frame and another method in which a bit string (hereinafter referred to as a frame structure flag) for notifying a change, when it takes place, is inserted.
FIG. 12 is a block diagram showing the configuration of a privately known but unpublished art digital radio communications receiver which performs frame synchronization and frame structure prediction.
Referring to FIG. 12, a unique word detector module 1 detects a unique word from a received bit string, based on the timing information from an aperture control module to be described later and the correlation threshold from a correlation threshold setting module to be described later. The radiowave received by a receiving antenna 100 is fed to a down-converter 101 which outputs a signal in an intermediate frequency bandwidth. A detector 102 detects the intermediate frequency signal and then outputs the received bit string to the unique word detector module 1. The aperture control module 2 outputs the timing information that controls the timing at which the unique word detector module 1 attempts to detect the unique word. In response to the aperture width from an aperture width setting module to be described later and the received timing information from a timing control module to be described later, the aperture control module 2 generates the timing information that is output to the unique word detector module 1.
There are further shown in FIG. 12 the timing control module 3 that outputs the receive timing information of the received signal in response to the unique word detection information from the unique word detector module 1, a frame synchronization guard level setting module 4 that sets frame synchronization determination conditions, namely, the backward guard level that is the number of consecutive detections of unique word and the forward guard level that is the number of consecutively misses of unique word (both levels are hereinafter collectively referred as the guard level), and a frame synchronization determining module 5 that results in the frame synchronization information, based on the unique word detection information from the unique word detector module 1 and the guard level from the frame synchronization guard level setting module 4.
There are yet further shown in FIG. 12 an aperture width setting module 6 that sets an aperture width as a time width within which the unique word detector module 1 attempts to detect a unique word, based on the unique word detection information from the unique word detector module 1 and the frame synchronization information from the frame synchronization determining module 5, a correlation threshold setting module 7 that sets the correlation threshold of unique word detection conditions, based on the unique word detection information from the unique word detector module 1 and the frame synchronization information from the frame synchronization determining module 5, a received signal extractor module 8 that extracts the received signal from the received bit string output by the detector 102 at the timing designated by the timing control module 3, and a frame structure determining module 9 for detecting the frame structure flag of the received signal to determine whether or not the frame structure changes.
The operation of the known digital radio communications receiver thus constructed is now discussed.
The radiowave received at the receiving antenna 100 is converted into an intermediate frequency signal, which is then fed, as a received signal by the down converter 101, to the detector 102. The detector 102 demodulates the received signal and outputs the received bit string.
The unique word detector module 1 receives the received bit string, correlates the received bit string with the unique word at the timing set by the aperture control module 2, detects the unique word and determines the phase of the unique word from the number of erratic bits and their correlation threshold, and then outputs the determination results as the unique word detection information.
The timing control module 3 controls the receive timing based on the unique word detection information.
The frame synchronization determining module 5 determines the frame synchronization state using the number of consecutive detections/misses of the unique word of the unique word detection information designated by the guard level setting module 4, and outputs the determination results as the frame synchronization information.
Referring to the unique word detection information and the frame synchronization information, the aperture width setting module 6 sets and outputs the aperture width that is used at the next attempt to detect the unique word.
Referring to the unique word detection information and the frame synchronization information, the correlation threshold setting module 7 sets and outputs the correlation threshold that is used at the next attempt to detect the unique word.
To determine whether the frame structure changes, the frame structure determining module 9 detects the frame structure flag indicative of the frame structure of the received signal that is extracted by the received signal extractor module 8 from the received bit string output by the detector 102 at the timing designated by the timing control module 3.
Discussed next is how the frame structure is recognized when the known art digital radio communications receiver performs frame synchronization control.
FIG. 13 shows an example of the change in the frame structure depending on communications conditions. Part of FIG. 13 herein shows a simplified version of FIG. 2 that is presented in a paper entitled "RADIO TRANSMISSION IN THE AMERICAN MOBILE SATELLITE SYSTEM" (A COLLECTION OF TECHNICAL PAPERS, AIAA-94-0945-CP, pp 280-294, 1994).
FIG. 13 shows a unique word 17, a frame structure flag 18-a indicative of a frame structure 1 and inserted at the change from a frame structure 2 to the frame structure 1, and a frame structure flag 18-b indicative of the frame structure 2 and inserted at the change from the frame structure 1 to the frame structure 2.
In the frame structure in FIG. 13, a unit or interval of the frame structure 1 delimited by unique words is called a subframe, and four subframes make up a frame. The interval between unique words in the frame structure 2 is identical to the frame length. In FIG. 13, in other words, the frame structure 1 has a unique word on a per subframe basis, and the frame structure 2 has a unique word on a per frame basis.
FIGS. 14 and 15 show examples of the recognition of the frame structure in which when the frame structure changes, a frame structure flag notifying of it is transmitted only once. FIG. 14 shows the example of the false detection of a frame structure flag, and FIG. 15 shows the example of a miss of a frame structure flag.
In FIG. 14, the frame structure determining module 9 suffers the false detection of a frame structure flag and thus erroneous determination of frame structure. The frame structure determining module 9 thus remains unable to receive a frame structure flag and thus unable to recognize correctly the frame structure until the frame structure is changed next.
In FIG. 15, the frame structure determining module 9 misses a frame structure flag and erroneously determines the frame structure. In this case, again, the frame structure determining module 9 remains unable to recognize correctly the frame structure until the next change in frame structure.
FIG. 16 shows an example of the effect of the above faulty determinations.
In the detection failure of the frame structure flag in FIG. 16, the frame synchronization forward guard level is 2.
As shown in FIG. 16, with the miss of the frame structure flag, the receiver attempts to receive the frame structure 1 though the frame is already changed from frame structure 1 to frame structure 2. Since the unique word interval is different between the frame structure 1 and the frame structure 2, the receiver suffers a detection failure of unique word in an attempt to detect the unique word with the unique word interval of the frame structure 1. Such a state continues until the frame is changed from frame structure 2 to frame structure 1, and it is highly likely that a missynchronization would take place in the course of repeated detection failures of the unique word.
In the known digital radio communication receiver thus constructed, when the flag notifying of the change in the frame structure is transmitted only once, followed by the failed or false detection of the flag, the receiver remains unable to correctly recognize the frame structure until the frame structure changes later again. Furthermore, the faulty recognition of the frame structure may cause the frame synchronization control to malfunction, possibly leading to a missynchronization.
SUMMARY OF THE INVENTION
The present invention has been developed to solve this problem, and it is therefore an object of the present invention to provide a digital radio communications receiver that predicts correctly a frame structure and assures correct frame synchronization.
To achieve the above object, the digital radio communications receiver of the present invention for use in a digital communications system having two or more frame structures on a single channel, comprises unique word detector means for detecting a unique word from a received bit string, receive timing control means for timing controlling a received frame timing based on the unique word detection information from the unique word detector means, frame structure determining means for determining a frame structure based on the unique word detection information from the unique word detector means and based on frame structure determining guard level, and a frame structure determining guard level setting means for setting the frame structure determining guard level that is the number of consecutive detections of the frame structure in frame structure determination conditions and outputting the resulting guard level to the frame structure determining means, whereby the probability of false detection of the frame structure is lowered by recognizing a change in the frame structure and by outputting the information about the new frame structure.
Receiving the unique word detection information from the unique word detector means, the frame structure determining means determines the frame structure. When the frame structure changes, frame structure information is output on condition that the new frame structure is detected consecutively by the guard level set by the frame structure determining guard level setting means and the frame structure is thus determined based on the state of the unique word characteristic of the frame structure, such as the detected intervals of the unique word (or phase of the unique word). The frame structure is recognized independently of the signal indicative of the switching of the frame structure. When the new frame structure is detected consecutively by the guard level set by the frame structure determining guard level setting module, the frame structure change is recognized, and new frame structure information is output. Thus, the probability of false detection of the frame structure is lowered and correct frame synchronization is assured.
The receiver further comprises frame synchronization determining means for determining the establishment of the synchronization of the received frame based on the unique word detection information from the unique word detector means and for outputting the determination results as frame synchronization information. The frame synchronization determining means achieves frame synchronization in synchronization procedure appropriate for the frame structure by selecting the procedure of the frame synchronization control based on the frame structure information from the frame structure determining means. A stable frame synchronization is thus assured.
The receiver further comprises frame synchronization control parameter setting means for setting frame synchronization parameters based on the frame structure information from the frame structure determining means, and feeding them back into synchronization control information of the received frame. Thus, frame synchronization control is performed by using the synchronization control parameters appropriate to the state of the frame structure, and a flexible and reliable frame synchronization is assured.
The receiver comprises, as the frame synchronization control parameter setting means, the frame synchronization guard level setting means for setting, as the frame synchronization control parameter, the frame synchronization guard level that is the number of consecutive detections or the number of consecutive misses of the unique word of frame synchronization determination conditions. The frame synchronization guard level is set according to the length of the frame, the length of the unique word and the switching of the bit pattern. Thus, a flexible and reliable frame synchronization is assured.
The receiver comprises, as the frame synchronization control parameter setting means, aperture width setting means for setting, as the frame synchronization control parameter, the aperture width that is a time width for the valid operation of unique word detection. The aperture width is set according to the frame length that is changed at the switching of the frame structure and variations in the transmission clock stability. A flexible and reliable frame synchronization is assured.
The receiver comprises, as the frame synchronization control parameter setting means, correlation threshold setting means for setting, as the frame synchronization control parameter, the correlation threshold as unique word detection conditions. The correlation threshold is set according to the frame length that is changed at the switching of the frame structure and variations in unique word length. A flexible and reliable frame synchronization is thus assured.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram showing the configuration of the digital radio communications receiver according to an embodiment 1 of the present invention.
FIG. 2 is a state transition chart of the digital radio communications receiver in the embodiment 1 of the present invention uses in the determination of the received frame structure.
FIG. 3 illustrates a miss of a frame structure flag in the embodiment 1.
FIG. 4 illustrates a false detection of a frame structure flag in the embodiment 1.
FIG. 5 illustrates an example of frame structure determination in the false detection of a unique word.
FIG. 6 is a block diagram showing the configuration of the digital radio communications receiver according to an embodiment 2 of the present invention.
FIG. 7 is a state transition chart of the digital radio communications receiver in the embodiment 2 of the present invention uses in frame synchronization.
FIG. 8 is a block diagram showing the configuration of the digital radio communications receiver according to an embodiment 3 of the present invention.
FIG. 9 is a block diagram showing the configuration of the digital radio communications receiver according to an embodiment 4 of the present invention.
FIG. 10 is a block diagram showing the configuration of the digital radio communications receiver according to an embodiment 5 of the present invention.
FIG. 11 is a block diagram showing the configuration of the digital radio communications receiver according to an embodiment 6 of the present invention.
FIG. 12 is the block diagram showing the configuration of the privately known but unpublished art digital radio communications receiver.
FIG. 13 illustrates the structure of frames and bursts used in the known digital radio communications receiver.
FIG. 14 illustrates the false detection of the frame structure flag in the known art.
FIG. 15 illustrates the miss of the frame structure flag in the known art.
FIG. 16 illustrates the effect of the miss of the frame structure flag.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Embodiment 1
FIG. 1 is the block diagram showing the configuration of the digital radio communications receiver according to an embodiment 1 of the present invention.
In FIG. 1, components identical to those in the known art in FIG. 12 are designated with the same reference numerals, and their description is not repeated herein. There are shown further a frame structure determining module 10 for determining the frame structure based on the unique word detection information from the unique word detector module 1 and the frame structure determining guard level and for outputting the determination results, and a frame structure determining guard level setting module 11 for setting the guard level that is the number of consecutive detections of the frame structure in frame structure determining conditions and for outputting the guard level to the frame structure determining module 10.
Receive timing control section for timing controlling of the received frame based on the unique word detection information from the unique word detector module 1 is constituted by the aperture control module 2, timing control module 3, frame synchronization guard level setting module 4, frame synchronization determining module 5, aperture width setting module 6 and correlation threshold setting module 7.
In the same way as in the known art in FIG. 12, in the digital communications receiver in FIG. 1, the received bit string fed to the unique word detector module 1 is derived by detecting, with the detector 102, the received signal in the intermediate frequency band that is output by the down-converter 101 in response to the radiowave received at the receiving antenna 100. The receiver also comprises the unshown received signal extractor module 8 for extracting the received signal from the received bit string output by the detector 102 at the timing designated by the timing control module 3.
The operation of the embodiment 1 is now discussed referring to FIG. 1.
As shown, the operation of the unique word detector module 1 for outputting the unique word detection information and the operation of the timing control module 3 are identical to those in the known art, and their description is not repeated herein.
The frame structure determining guard level setting module 11 sets the guard level to the frame structure determining module 10.
The frame structure determining module 10 predicts the frame structure from the detected intervals of the unique word based on the unique word detection information and the frame structure determining guard level.
The frame synchronization determining module 5, frame synchronization guard level setting module 4, aperture width setting module 6 and correlation threshold setting module 7 operate in the same way as in the known art, and their operations are not discussed herein again.
The embodiment 1 is different from the known art in that the frame structure determining module 10 determines the frame structure based on the detected intervals of the unique words derived from the unique word detection information and predicts the frame structure based on the guard level 23 for frame structure determination.
The prediction results are illustrated in the state transition chart in FIG. 2.
The transition from a frame structure 1 (S24) to a frame structure 2 (S26) is made only when the determination that the frame is at the frame structure 2 is consecutively repeated the specified number of times (referred to as the backward guard level for frame structure determination). When the number of the determinations is less than specified number of times, it is determined that the frame is at a tentative frame structure 2 (S27). Similarly, the transition from the frame structure 2 (S26) to the frame structure 1 (S24) is made only when the determination that the frame is at the frame structure 1 is consecutively repeated the specified number of times (referred to as the forward guard level for frame structure determination. Both the backward and forward guard levels are collectively called as guard level for frame structure determination.) When the number of determinations is less than the specified number of times, it is determined that the frame is at the tentative frame structure 2 (S27).
The method of determining the frame structure using the detected intervals of the unique word of the unique word detection information 3 is now discussed.
FIG. 3 illustrates the miss of a frame structure flag.
Referring to FIG. 3, part of the unique word detection information is a detected pulse 28 that is output when a unique word is detected. There are also shown intervals 29 at which each unique word is transmitted in the frame structure 1 and intervals 30 at which each unique word is transmitted in the frame structure 2.
When the frame is changed from frame structure 1 to frame structure 2 and if the frame structure flag goes undetected in the known art, the determination of the frame structure remains unchanged from the frame structure 1. In the embodiment 1, however, it is determined that the frame is at structure 2 based on the matter that the unique word is detected at intervals of T2.
FIG. 4 shows an example of the false detection of the frame structure flag.
Although the frame remains unchanged from structure 1, the known art may detect a false frame structure flag in the middle, leading to an erroneous determination that the frame is at frame structure 2. According to the embodiment 1, however, it is determined that the frame is at structure 2 based on the matter that the unique word is detected at intervals of T1.
FIG. 5 shows the example of frame structure determination in which a false detection of the unique word takes place though the frame remains unchanged. If the unique word detected at intervals T1 is immediately used to determine that the frame is at the frame structure 1, associated control modules using the erroneous determination results perform erroneous controlling.
In the embodiment 1, however, the frame is determined as the tentative frame structure 1 so that the associated control modules perform controlling that is compatible with the frame structure 1 and the frame structure 2, and thus erroneous controlling is avoided.
Since the detected intervals of the unique word are used to determine the frame structure in the embodiment 1 as described above, the result of the detection of the frame structure flag does not affect the determination of the frame structure. Thus, the determination of the frame structure is correctly performed regardless of whether the fame structure flag is falsely detected or missed.
Furthermore, the frame structure is determined referring to the guard level. Even when the unique word is falsely detected or missed, the frame is not determined as a conclusive frame structure unless false detection or miss of the unique word is consecutively repeated by the specified guard level. The frame structure determined becomes more reliable.
The embodiment 1 thus determines the frame structure without determining the frame structure flag, and the probability of erroneous determination of the frame structure is reduced.
Although in the embodiment 1, the intervals of the unique words are used to determine the frame structure, the frame structure flag or the frame structure and the intervals of the unique words in combination may be employed. In this case, however, the receiver has a total design that allows the frame structure flag to be consecutively issued a plurality of times.
In the embodiment 1, the detected intervals of the unique word are used to determine the frame structure. When the phase of the unique word differs between the frame structures, however, the detection of the phase of the unique word may be used. The above-described operation of the embodiment 1 remains the same.
Embodiment 2
FIG. 6 is the block diagram showing the configuration of the digital radio communications receiver according in the embodiment 2 of the present invention.
In the embodiment 1, the unique word and the guard level for frame synchronization are used to determine the frame synchronization. In the embodiment 2, the guard level for frame structure determination is additionally used to determine the frame synchronization.
In FIG. 6, components identical to those in the embodiment 1 in FIG. 1 are designated with the same reference numerals. As shown, the frame synchronization determining module 5 receives the frame structure information from the frame structure determining module 10, determines the frame synchronization state, and outputs the determination results as the frame synchronization information.
The operation of the embodiment 2 is now discussed referring to FIG. 6.
In FIG. 6, the unique word detector module 1 for outputting the unique word detection information, timing control module 3, aperture width setting module 6 and correlation threshold setting module 7 operate in the same way as in the embodiment 1, and thus the discussion of their operation is not repeated herein.
The frame structure determining module 10 determines the frame structure based on the unique word detection information, and outputs the results as the frame structure information.
The frame synchronization determining module 5 determines the frame synchronization state, based on the unique word detection information from the unique word detector module 1, the frame structure information from the frame structure determining module 10, and the consecutive detection/miss times of the unique word detection information specified by the guard level for frame synchronization coming from the frame synchronization guard level setting module 4. The frame synchronization determining module 5 outputs the determination results as the frame synchronization information.
The embodiment 2 is different from the embodiment 1 in that, to determine the frame synchronization, the frame synchronization determining module 5 uses not only the unique word detection information and the guard level for frame synchronization but also the frame structure information coming from the frame structure determining module 10.
It is obvious that the embodiment 2 offers the same advantage as the embodiment 1 when the embodiment 2 determines the frame structure based on the guard level.
As shown in the frame synchronization state transition chart in FIG. 7, depending on the determination of the frame structure, the synchronization control changes its mode from a state transition mode 40 to 41, 41 to 42, 42 to 43, and then 43 to 40. Thus, a flexible frame synchronization control is performed.
The embodiment 2 therefore determines the frame structure without determining the frame structure flag, the erroneous determination of the frame structure is less likely to take place, and a flexible synchronization control is performed.
All modifications and changes described in connection with the embodiment 1 also work in the embodiment 2.
Embodiment 3
FIG. 8 is the block diagram showing the configuration of the digital radio communications receiver in the embodiment 3 of the present invention.
The change in the frame structure is typically associated with the change in the frame length and the unique word length in many cases. When a signal is coming in from a different station, SNR (signal to noise ratio) suffers variations depending on the frame structure. To acquire stable frame synchronization, frame structure determination information is used to set the guard level for frame synchronization.
In FIG. 8, components identical to those in the embodiment 2 in FIG. 6 are designated with the same reference numerals. The frame synchronization guard level setting module 4, as the frame synchronization control parameter setting means, is designed to receive the frame structure information from the unique word detector module 1.
The embodiment 3 in FIG. 8 is now discussed.
In FIG. 8, the unique word detector module 1 for outputting the unique word detection information, timing control module 3, aperture width setting module 6 and correlation threshold setting module 7 operate in the same way as in the embodiment 2, and thus the discussion of their operation is not repeated herein.
The frame structure determining module 10 determines the frame structure based on the unique word detection information, and outputs the results as the frame structure information.
The frame synchronization guard level setting module 4 sets, as the frame synchronization control parameter, the guard level appropriate for each receive frame based on the frame structure information from the frame structure determining module 10. The guard level for frame synchronization is, for example, "4" for the tentative frame structure 1 during frame synchronization, and "3" for the conclusive frame structure 2 during frame synchronization.
The frame synchronization determining module 5 determines the frame synchronization state, based on the unique word detection information from the unique word detector module 1 and the consecutive detection times of the unique word detection information specified by the guard level for frame synchronization coming from the frame synchronization guard level setting module 4, and then outputs the determination results as the frame synchronization information.
The embodiment 3 is different from the embodiments 1 and 2 in that the frame synchronization guard level setting module 4 sets the guard level for frame synchronization based on not only the unique word detection information and the frame synchronization information but also the frame structure information coming in from the frame structure determining module 10.
It is obvious that the embodiment 3 offers the same advantage as the embodiment 1 when the embodiment 3 determines the frame structure based on the guard level.
Since the state transition modes for the frame synchronization control and the guard level for frame synchronization are modified based on the determination result of the frame structure, a flexible frame synchronization control is performed.
The embodiment 3 therefore determines the frame structure without determining the frame structure flag, the erroneous determination of the frame structure is less likely to take place, and a flexible synchronization control is performed.
All modifications and changes described in connection with the embodiment 1 also work in the embodiment 3.
Embodiment 4
FIG. 9 is the block diagram showing the configuration of the digital radio communications receiver in the embodiment 4 of the present invention.
The change in the frame structure is typically associated with the change in the frame length and the unique word length in many cases. As shown in the known art, the frame structure of continuous frames switches to the frame structure of burst form in some cases. In such a case, the quantity of drift of clocks varies depending on the frame structure, and the degree of shift in the timing of the unique word varies. To achieve a stable frame synchronization in such a case, the embodiment 4 sets the aperture width based on the frame structure determination information.
In FIG. 9, components identical to those in the embodiment 2 in FIG. 6 are designated with the same reference numerals. As shown, the aperture width setting module 6, as the frame synchronization control parameter setting means, is designed to receive the frame structure information 19.
The operation of the embodiment 4 is now discussed referring to FIG. 9.
In FIG. 9, the unique word detector module 1 for outputting the unique word detection information, timing control module 3, frame synchronization guard level setting module 4, frame synchronization determining module 5, correlation threshold setting module 7 and frame structure determining module 10 operate in the same way as in the embodiment 2, and thus the discussion of their operation is not repeated herein.
The aperture width setting module 6 sets, as the frame synchronization control parameter, the aperture width, based on the unique word detection information from the unique word detector module 1, the frame structure information from the frame structure determining module 10, and the frame synchronization information from the frame synchronization determining module 5. The aperture width set is, for example, "1" for the tentative frame structure 1 during synchronization, and "13" for the conclusive frame structure 2 during synchronization.
The embodiment 4 is different from the embodiment 2 in that the aperture setting module 6 sets the aperture based on not only the unique word detection information and the frame synchronization information but also the frame structure information coming in from the frame structure determining module 10.
It is obvious that the embodiment 4 offers the same advantage as the embodiment 2 when the embodiment 4 determines the frame structure based on the guard level.
Since the state transition modes for the frame synchronization control and the aperture width are modified based on the determination result of the frame structure, a flexible frame synchronization control is performed.
The embodiment 4 therefore determines the frame structure without determining the frame structure flag, the erroneous determination of the frame structure is less likely to take place, and a flexible synchronization control is performed.
All modifications and changes described in connection with the embodiment 1 also work in the embodiment 4.
Embodiment 5
FIG. 10 is the block diagram showing the configuration of the digital radio communications receiver in the embodiment 5 of the present invention.
When physical quantities that affect synchronization performance, such as the frame length, unique word length, SNR, and clock drift, vary in the preceding embodiments 3 and 4 as the frame structure changes, deterioration in synchronization performance is prevented by changing the correlation threshold. In the embodiment 5, the frame structure determination information is used in setting the correlation threshold so that a reliable frame synchronization is achieved.
In FIG. 10, components identical to those in the embodiment 2 are designated with the same reference numerals. The correlation threshold setting module 7, as the frame synchronization control parameter setting means, is designed to receive the frame structure information 19.
The operation of the embodiment 5 is now discussed referring to FIG. 10.
In FIG. 10, the unique word detector module 1 for outputting the unique word detection information, timing control module 3, frame synchronization guard level setting module 4, frame synchronization determining module 5, aperture width setting module 6 and frame structure determining module 10 operate in the same way as in the embodiment 2, and thus the discussion of their operation is not repeated herein.
The correlation threshold setting module 7 sets, as the frame synchronization control parameter, the correlation threshold, based on the unique word detection information from the unique word detector module 1, the frame structure information from the frame structure determining module 10, and the frame synchronization information from the frame synchronization determining module 5, and outputs the results as the correlation threshold. The correlation threshold set is, for example, "4" for the tentative frame structure 1 during frame synchronization and "6" for the frame structure 2 during frame synchronization.
The embodiment 5 is different from the embodiment 2 in that the correlation threshold setting module 7 sets the correlation threshold based on not only the unique word detection information and the frame synchronization information but also the frame structure information coming in from the frame structure determining module 10.
It is obvious that the embodiment 5 offers the same advantage as the embodiment 2 when the embodiment 5 determines the frame structure based on the guard level.
Since the state transition modes for the frame synchronization control and the correlation threshold are modified based on the determination result of the frame structure, a flexible frame synchronization control is performed.
The embodiment 5 therefore determines the frame structure without determining the frame structure flag, the erroneous determination of the frame structure is less likely to take place, and a flexible synchronization control is performed.
All modifications and changes described in connection with the embodiment 1 also work in the embodiment 5.
Embodiment 6
FIG. 11 is the block diagram showing the configuration of the digital radio communications receiver in the embodiment 6 of the present invention.
In the preceding embodiments 3 through 5, the frame structure information is used to set the guard level for frame synchronization, aperture width and correlation threshold on an individual basis. Alternatively, two or all of them may be concurrently set in combination. In the embodiment 6, all these synchronization control parameters are concurrently set.
In FIG. 11, components identical to those in the embodiment 2 in FIG. 6 are designated with the same reference numerals. The frame synchronization guard level setting module 4, aperture width setting module 6 and correlation threshold setting module 7 are designed to receive the frame structure information from the frame structure determining module 10.
The operation of the embodiment 6 is discussed referring to FIG. 11.
In FIG. 11, the unique word detector module 1 for outputting the unique word detection information, timing control module 3, frame synchronization determining module 5, and frame structure determining module 10 operate in the same way as in the embodiment 2, and thus the discussion of their operation is not repeated herein.
The frame synchronization guard level setting module 4 sets the guard level appropriate for each receive frame based on the frame structure information from the frame structure determining module 10.
The aperture width setting module 6 sets the aperture width, based on the unique word detection information from the unique word detector module 1, the frame structure information from the frame structure determining module 10, and the frame synchronization information from the frame synchronization determining module 5 and outputs the results as the aperture width.
The correlation threshold setting module 7 sets the correlation threshold, based on the unique word detection information from the unique word detector module 1, the frame structure information from the frame structure determining module 10, and the frame synchronization information from the frame synchronization determining module 5, and outputs the results as the correlation threshold.
The embodiment 6 is different from the embodiment 2 in that the frame synchronization guard level setting module 4, aperture width setting module 6 and correlation threshold setting module 7 perform their respective settings based on not only the unique word detection information and frame synchronization information but also the frame structure information from the frame structure determining module 10.
It is obvious that the embodiment 6 offers the same advantage as the embodiment 2 when the embodiment 6 determines the frame structure based on the guard level.
Since the state transition modes for the frame synchronization control, the guard level for frame synchronization, aperture width and correlation threshold are modified based on the determination result of the frame structure, a flexible frame synchronization control is performed.
The embodiment 6 therefore determines the frame structure without determining the frame structure flag, the erroneous determination of the frame structure is less likely to take place, and a flexible synchronization control is performed.
All modifications and changes described in connection with the embodiment 1 also work in the embodiment 6.
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A digital radio communications receiver for predicting correctly a frame structure and assuring correct synchronization. The digital radio communications receiver for use in a digital communications system having two or more frame structures on a single channel, comprises a unique word detector module for detecting a unique word from a received bit string, a receive timing controller for timing controlling a received frame based on the unique word detection information from the unique word detector module, a frame structure determining module for determining the frame structure based on the unique word detection information from the unique word detector module and the frame structure determining guard level, and a frame structure determining guard level setting module for setting the frame structure determining guard level that is the number of consecutive detections of the frame structure in frame structure determination conditions and outputting the resulting guard level to the frame structure determining module, whereby the probability of erroneous detection of the frame structure is lowered by recognizing a change in the frame structure and by outputting the information about the new frame structure.
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RELATED APPLICATIONS
[1] 1. This application is a divisional of prior application Ser. No. 09/093,520 filed Jun. 8, 1998.
BACKGROUND OF THE INVENTION
[2] 2. The present invention generally relates to a collector for collecting liquid samples from a source of liquid. More particularly, the present invention relates to a collector for collecting samples of liquid from at least one semiconductor wafer cleaning bath so that automated analytical instrumentation can analyze the samples for contamination.
[3] 3. Semiconductor wafers suitable for the fabrication of integrated circuits are produced by slicing thin wafers from a single crystal silicon ingot. After slicing, the wafers undergo a lapping process to give them a substantially uniform thickness. The wafers are then etched to remove damage and produce a smooth surface. The next step in a conventional wafer shaping process is a polishing step to produce a highly reflective and damage-free surface on at least one face of the wafer. It is upon this polished face that electrical device fabrication takes place.
[4] 4. The presence of contaminants on the surface of a semiconductor wafer can greatly diminish the quality and performance of integrated circuits fabricated from the wafer. Thus, semiconductor wafers are typically cleaned after some or all of the above wafer preparation steps to help reduce the amount of contamination present on the final wafer product. For example, organic and other particulate contaminants can be removed from the surfaces of a single crystal silicon wafer by immersing the wafer in each of a series of cleaning bath solutions.
[5] 5. Monitoring the concentration of contaminants in a semiconductor cleaning bath solution serves several useful purposes. First, the useful life of the cleaning bath solution can be maximized. As wafers are continuously processed through a particular cleaning bath, the concentration of contamination in the cleaning bath solution will generally rise. Ultimately, the cleaning bath solution becomes saturated with contamination, and will no longer adequately clean the wafer. By monitoring the concentration of contaminants present in a particular cleaning bath solution, the point at which the solution is spent can be more accurately determined.
[6] 6. The second advantage realized by monitoring the concentration of contaminants in a cleaning bath solution is that sources of contamination can be more accurately identified. The various reagents used to make up the cleaning bath solution may contain impurities that actually contaminate the wafer, as opposed to cleaning it. The preparation of purer cleaning bath solutions requires the identification and elimination of these sources of contamination, which are more easily accomplished by monitoring the concentration of contaminants in a cleaning bath.
[7] 7. The accuracy and reliability of the analytical data obtained by the monitoring of cleaning baths greatly impact both the identification of the source of a contaminant and the determination of the useful life of a cleaning bath. In addition, because even low levels of some impurities can result in wafer surface contamination, the sensitivity of the analytical method is also critical.
[8] 8. Traditionally, the type and concentration of a contaminant in a cleaning bath solution have been monitored through the use of a manual sampling technique, commonly referred to as an “off-line” method of sampling, wherein a human operator collects a sample of the cleaning bath solution. The sample is then transported to a laboratory for analysis.
[9] 9. One disadvantage of this off-line sampling method is that it is prone to the introduction of additional contaminants from outside sources. For example, human contact with the sample can lead to the introduction of contaminants such as aluminum, iron, calcium, and sodium. In addition, the vial or container which holds the sample, as well as the pipette or other sampling device, typically cannot be sufficiently cleaned to avoid the introduction of outside contaminants into the sample. Thus, this off-line sampling method lacks the accuracy and sensitivity needed to provide representative results of the actual condition of the cleaning bath solution being tested.
[10] 10. Also, it can take up to several hours for a laboratory to complete the analysis of the sample and provide the results to the operators responsible for wafer cleaning. In the interim period, if wafer cleaning continues, a bath containing highly contaminated solution can produce hundreds of unacceptable wafers. This necessitates the recall and re-cleaning of these wafers. Alternatively, use of the bath could be halted while operators wait for the results. In either case, the net effect is an increase in production cost and a decrease in overall efficiency of the cleaning process.
[11] 11. To avoid the time consuming and potentially costly process of laboratory analysis, it has become common practice to simply discard the cleaning solution after a predetermined period of time, such as every 12 hours. However, the many variables which dictate the useful life of a cleaning bath solution, including the quality of the chemical reagents, the quality of the process water, the cleanliness of the wafers immersed in the solution, and the precautions taken to prevent contamination by human operators, are not taken into account under such a method. Therefore, without the benefit of an analysis for contaminants, a portion of the useful life of the bath may be wasted.
[12] 12. To overcome the above disadvantages, the concentration of impurities in a cleaning bath solution can be determined by an “on-line” process which allows for the sampling and analysis of the cleaning solution in a single, integrated process. That is, a sample is mechanically removed from a cleaning bath solution and automatically analyzed by analytical instrumentation without being directly exposed to an environment in which a human operator is present. An example of such a process is the co-assigned U.S. application, Ser. No. 09/093,435, incorporated herein by reference, and entitled “Process for Monitoring the Concentration of Metallic Impurities in a Wafer Cleaning Solution.”
[13] 13. A mechanical sampling and automated analysis system should preferably be constructed to ensure that the sample obtained from the cleaning bath is representative of the cleaning bath as a whole. If the sample obtained is not representative of the cleaning bath, accurate and reliable contamination measurements may not be obtained. To help ensure that the sample obtained is representative of the cleaning bath as a whole, the on-line system must not be a source of contamination itself. For instance, if valves were used in the on-line system to intermittently collect a sample, they may ultimately wear and introduce contamination into the sample that is not present in the cleaning bath as a whole, causing inaccurate contamination measurements.
[14] 14. Further, when multiple baths are to be sampled, it may be impractical to mechanically remove a sample from the cleaning baths themselves because the baths are typically positioned a significant distance away from each other. In this instance, a collection device may be needed to facilitate automated analysis. The collection device can maintain a portion of the cleaning bath is solution from each bath in separate receptacles, all the receptacles being in close proximity to each other. If the collected portion of the cleaning solution is allowed to stagnate, however, the sample removed therefrom will not be representative of the cleaning bath as a whole and inaccurate contamination measurements will result.
SUMMARY OF THE INVENTION
[15] 15. Among the objects of the present invention, therefore, are the provision of a collector for collecting samples of liquid from a cleaning bath which allows for sample collection and analysis of the contaminants in the solution via an on-line process; the provision of such a collector which allows for analysis of the contaminants in a cleaning bath solution via an on-line process without delaying the wafer cleaning process; the provision of a collector which allows for reliable and reproducible analysis of the contaminants in a wafer cleaning bath solution via an on-line process; and the provision of such a collector which reduces the risk of contamination of the cleaning bath solution.
[16] 16. Briefly, therefore, the present invention is directed to a process for collecting and analyzing the content of a liquid from at least one source of liquid, the process comprising bleeding the liquid continuously from the source of liquid through a bleed line to a receptacle of a collector. The receptacle has an inlet at its bottom for receiving liquid into the receptacle and an open top. Next, the liquid is continuously delivered into the receptacle from the inlet to the open top of the receptacle, so that the liquid continuously flows from the bottom of the receptacle to the open top and continuously spills over the open top of the receptacle into a spillway of the collector. A sample of the liquid is drawn from the receptacle by an automated sample collecting device and then deposited from the sample collecting device into a liquid analysis device. Finally, the liquid is analyzed to determine its content.
[17] 17. Other objects and features of this invention will be in part apparent and in part pointed out hereinafter.
BRIEF DESCRIPTION OF THE DRAWINGS
[18] 18.FIG. 1 is a schematic view of an on-line wafer cleaning system incorporating a collector of the present invention;
[19] 19.FIG. 2 is a perspective view of the collector of FIG. 1;
[20] 20.FIG. 3 is a sectional view taken along the plane of line 3 — 3 of FIG. 2; and
[21] 21.FIG. 4 is a sectional view taken along the plane of line 4 — 4 of FIG. 2.
[22] 22. Corresponding reference characters indicate corresponding parts throughout the drawings.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[23] 23. With reference to FIG. 1, a collector of the present invention for use in collecting samples of liquid from a cleaning bath is generally indicated at 1 . The collector is preferably part of an “on-line” device (including the collector 1 and automatic analytical instrumentation 4 ) for sampling and analyzing a liquid, such as a cleaning bath solution, contained in a cleaning bath 8 for cleaning semiconductor wafers. The construction and operation of such on-line sampling and analysis device, with the exception of the collector described herein, is well known to those of ordinary skill in the art, and will not be further described in detail herein.
[24] 24. The collector 1 is connected to a recirculation line 6 of the cleaning bath 8 by a suitable bleed line 12 . As recirculation pump 10 continuously circulates cleaning solution through the cleaning bath, a small portion of the cleaning solution in the cleaning bath is bled off into the bleed line 12 for delivery to the collector 1 . Since the solution diverted through the feed line is typically not returned to the cleaning bath 8 , the diameter of the feed line is preferably minimized to prevent excessive depletion of the cleaning solution from the bath. For example, the bleed line 12 of the illustrated embodiment is less than about ¼″ in diameter, more preferably about ⅛″ in diameter, and most preferably about {fraction (1/16)}″ in diameter. The automated analytical instrumentation 4 is positioned in close proximity to the collector 1 to facilitate access by the analytical instrumentation to the samples collected by the collector.
[25] 25. Referring now to FIGS. 2-4, the collector 1 comprises a generally rectangular block 25 constructed from a material which, after thorough cleaning, will not leach metallic impurities into the solution. For example, the block 25 of the illustrated embodiment is constructed from Teflon.
[26] 26. The block 25 has a central waste trough 11 extending longitudinally within the upper surface of the block and multiple overflow spillways 7 extending laterally within the upper surface of the block in communication with the central waste trough. The waste trough 11 and spillways 7 are designated generally by their reference numbers. The receptacle troughs 7 each have a floor 27 , an outer end 29 disposed generally adjacent a lateral edge margin of the upper surface of the block and an inner end 31 opening into the central waste trough 11 . The floor 27 of each receptacle trough 7 slopes downward from the outer end 29 to the inner end 31 of the receptacle trough for delivering liquid in the receptacle trough to the central waste trough 11 (FIG. 3).
[27] 27. Vertically oriented receptacles 3 are formed in the block at the laterally outer end 29 of each spillway 7 . The receptacles 3 open at their upper ends into the spillways 7 to allow overflow liquid from the receptacles to drain to the central waste trough 11 . The diameter of each receptacle is sized to permit a sample collector 41 of the automated analytical instrumentation 4 (FIG. 1) to be dipped down into the receptacle 3 for collecting a sample to be analyzed. Each receptacle 3 also has an inlet 17 generally adjacent the bottom of the receptacle for receiving fluid into the receptacle (FIG. 3). The inlet 17 communicates with a respective inlet port 9 in a side wall of the block. The diameter of the inlet 17 is substantially reduced at an inner portion adjacent the receptacle for controlling the flow rate of liquid into the receptacle. The inlet port 9 communicates with the cleaning bath 8 (FIG. 1) by the bleed line 12 for receiving the liquid into the collector 1 to analyze the liquid.
[28] 28. With particular reference to FIG. 4, the central waste trough 11 slopes downward from a rear end of the block 25 toward a front end of the block to direct liquid in the waste trough 11 to a waste drain 13 . The waste drain 13 has an outlet 23 generally adjacent the bottom of the waste drain for discharging liquid from the waste drain. The outlet 23 extends to an outlet port 15 in the front end of the block 25 for discharging liquid from the collector 1 to a suitable drainage system (not shown) or sewer (not shown) of the type well known to those of ordinary skill in the art.
[29] 29. The automated analytical instrumentation 4 (FIG. 1) is preferably a conventional instrumentation capable of detecting trace amounts of impurities in a liquid sample (e.g., Hewlett Packard 4500 ICP/MS machine). Such instrumentation includes atomic absorption, inductively-coupled plasma mass spectrometry (ICP/MS), capillary electrophoresis, and ion chromatography instrumentation.
[30] 30. The sample collection device 40 (FIG. 1) is preferably an autosampler designed for ICP/MS instrumentation (e.g., Cetac 500, commercially available from Cetac of Omaha; Gilson 222, commercially available from Gilson of England). Typically, these devices comprise a syringe or other suitable sampling device 41 which is inserted into the receptacle 3 through its opening 5 by a robotic arm or similar automated mechanism. Again through automation, the syringe extracts a sample of the cleaning solution from the receptacle 3 . The syringe is then withdrawn from the receptacle and the contents of the syringe are analyzed.
[31] 31. In a preferred embodiment, the collector 1 comprises more than one receptacle so that a plurality of cleaning baths can be connected to the collector at the same time. As shown in FIG. 2, the collector 1 has two sets of ten receptacles 3 , one set being on each side of the central waste trough 11 . The receptacles 3 of each set are arranged in series, which in the illustrated embodiment is a line of equally spaced receptacles, to permit the instrumentation 4 to progressively dip into the receptacles one after another in a predetermined order. However, it is understood that the arrangement and number of receptacles 3 in the collector 1 may vary without departing from the scope of this invention. Each receptacle 3 would be connected to its own bleed line (not shown) to receive liquid from a different cleaning bath (not shown).
[32] 32. In operation, the recirculation pump 10 draws cleaning bath solution from the cleaning bath 8 and pumps the solution through the recirculation line 6 . The recirculation pump 10 creates sufficient pressure in the recirculation line 6 such that a small portion of the cleaning solution is continuously diverted from the recirculation line, through the feed line 12 for delivery to the collector 1 . The solution then flows through the inlet port 9 of the block 25 into the inlet 17 . The inlet 17 meters the solution into the receptacle 3 . Since the solution diverted through the inlet 17 is typically not returned to the cleaning bath 8 , the diameter of the inlet is preferably minimized to prevent excessive depletion of the cleaning solution from the bath. For example, the inlet 17 of the illustrated embodiment is less than about ¼″ in diameter, and more preferably about ⅛″ in diameter.
[33] 33. The receptacle inlet 17 delivers liquid to the receptacle 3 at the bottom of the receptacle so that the liquid flows upward from the bottom of the receptacle. Filling the receptacle 3 from the bottom prevents stagnation of the solution in the receptacle 3 . Further, by eliminating stagnation of the cleaning solution, the solution within the receptacle 3 at all times remains representative of the cleaning solution contained within the cleaning bath 8 . Moreover, any contaminants which might be introduced from the syringe 41 of the sample collector device 40 do not enter the cleaning bath 8 .
[34] 34. A continuing flow of solution into the receptacle 3 causes the solution to overflow to the receptacle into the spillway 7 . The sloped floor 27 of the spillway 7 directs the overflow solution downward, away from the receptacle 3 and into the waste trough 11 . The waste trough 11 receives the overflow liquid and directs the waste solution to the waste drain 13 . The overflow solution exits the waste drain through the outlet 23 , and is ultimately discharged from the block 25 to a suitable drainage system or sewer via the outlet port 15 . No valves are used to shut off the flow of solution from the cleaning bath 8 , thereby eliminating a source of contamination.
[35] 35. The syringe 41 or other sampling means of the automated analytical instrumentation is selectively inserted into the upper end of one of the receptacles 3 by a robotic arm 40 or the like. The syringe 41 automatically extracts a sample of the cleaning solution from the receptacle 3 and is withdrawn from the receptacle. The contents of the syringe 41 are then deposited in the ICP-MS machine of the automated analytical instrumentation 4 .
[36] 36. In view of the foregoing, it will be seen that the several objects of the invention are achieved. The present invention is instrumental in obtaining more accurate and reliable sampling results by reducing the potential for contamination of the sample to be analyzed, such as through direct human contact or through the use of sampling devices or containers which are contaminated. Further, by providing a collector having receptacles adapted for directing overflow solution into respective spillways that run off into a waste trough for exhaustion from the collector, a representative sample of the cleaning bath can be maintained in the collector. In this way, an accurate reading of the level of contaminants in the cleaning solution entering the cleaning bath at a given moment can be obtained. The continuous feed system also reduces the complexity and risk of mechanical failure of the collector. The present invention also eliminates the need for valves or other similar devices, thereby reducing the risk of additional contamination of the sample being tested.
[37] 37. This collector also helps reduce the time required to sample and analyze a cleaning bath solution, as compared to existing “off-line” methods wherein the sample is collected and transported to a remote location for conducting the analysis. By utilizing the collector of the present invention, analytical instrumentation can be incorporated as an integral part of an “on-line” bath analysis system.
[38] 38. As various changes could be made in the above-described collector without departing from the scope of the invention, it is intended that all matter contained in the above description be interpreted as illustrative and not in a limiting sense.
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A collector and method for collecting samples of liquid from at least one source of liquid for automated analysis of the samples. The collector has at least one receptacle for receiving liquid from the source of liquid and holding a quantity of the liquid for obtaining a sample. Each receptacle has an inlet for delivery of liquid from the respective source of liquid and an open top sized to admit the sample collection device into the receptacle. The collector also has a spillway in fluid communication with the open top of the receptacle for receiving excess liquid spilling over the open top of the receptacle. The collector is constructed so that liquid continuously flows through the collector. A drain of the collector receives liquid from the spillway for draining the liquid from the collector.
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RELATED APPLICATIONS
This application claims priority to U.S. Provisional Patent Application No. 60/651,436, filed Feb. 10, 2005, and entitled “Magnetic Finger Glove,” which is herein incorporated by reference.
FIELD OF THE INVENTION
This invention relates to gloves, and more particularly, to gloves designed to facilitate the gripping or holding of objects.
BACKGROUND OF THE INVENTION
While working in a tight space such as under the hood of a car, people routinely encounter difficulties in positioning nuts, screws, and bolts in hard-to-reach places for fastening. Often times, a nut must be started at an angle and/or in a position obstructed from view. Unable to position the nut by sight, the person must position it by feel. During this process, it is common to drop or lose the nut. Countless mechanics working on cars and other assemblies have experienced the frustration of dropping and losing the fastener in some crook, cranny, or crevice.
In many hard-to-reach places, a magnetized screwdriver or other common tool is generally unsuitable for positioning a nut. A magnetized screwdriver may also be unsuitable for positioning and starting a screw when the target position is obstructed from view or when the screw is most easily started by hand. Furthermore, a telescoping magnetic pick-up tool is not always suitable for picking up dropped metallic objects.
SUMMARY OF THE INVENTION
Therefore, there is a need for a tool that prevents or minimizes droppage of nuts, screws, and other small metallic fasteners and objects, without getting in the way of direct finger manipulation of the fastener. There is also a need for alternative ways to retrieve dropped metallic objects.
The present invention meets this need with a magnetic finger glove. The finger glove is made from an assembly of fabric pieces with size, shape, and material characteristics designed to stay on and comfortably conform to an adult human index finger. The magnetic finger glove comprises, preferably, a single small round disc neodymium magnet, rated with a maximum energy product of between 35 and 54 megagauss-oersteds, affixed to a fabric assembly in the region corresponding to the distal segment (i.e., fingertip) of the index finger. The magnet weighs less than 0.002 pounds and is small enough to be confined within an area on the fabric assembly of less than 0.5 square inches. Yet, the magnet has a holding force of at least 1 pound. A person wearing the finger glove can magnetically grasp small metal objects with his fingertip. Other embodiments may include multiple magnets of different powers, sizes, and types.
The finger glove fabric assembly comprises an upper panel with an elastic region corresponding to at least the proximal and middle segments of the dorsal (i.e., back) side of the finger and a substantially non-elastic bottom panel with an surface area corresponding to the palmar side of the finger. In one embodiment, the magnet is affixed to the bottom panel in a region corresponding to the distal segment of the finger. In another embodiment, the magnet is affixed to the bottom panel in a sub-region proximate to the ventral side of the distal phalanx head of the finger, whereby the finger glove facilitates tactile sensation by the person wearing the glove of the attachment of a small metallic object to the finger glove. In a third embodiment, the magnet is affixed to the top upper panel in the region corresponding to the fingernail of the finger.
The present invention also provides a full-hand glove embodiment sized to conform to a human hand, with a small magnet affixed to the forefinger in the region corresponding to the distal segment of the index finger. Preferably, the magnet is affixed to the part of the forefinger corresponding to the top of the fingernail.
A more detailed appreciation of the invention is provided in the following detailed description and the annexed sheets of drawings, which illustrate the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is an outside view of the dorsal (top) side of one embodiment of a finger glove.
FIG. 2 is an inside view of the dorsal (top) side of the finger glove of FIG. 1 .
FIG. 3 is an outside view of the palmar (bottom) side of the finger glove of FIG. 1 .
FIG. 4 is an inside view of the palmar (bottom) side of the finger glove of FIG. 1 .
FIG. 5 is a side view of the finger glove of FIG. 1 .
FIG. 6 depicts an embodiment of a finger glove with a disc magnet located proximate the ventral side of the distal phalanx head of a human index finger wearing the glove.
FIG. 7 depicts another embodiment of a finger glove with a disc magnet located proximate to the midpoint of the palmar side of the fingertip of a human index finger wearing the glove.
FIG. 8 depicts yet another embodiment of a finger glove with a disc magnet located proximate to the nail plate of a human index finger wearing the glove.
FIG. 9 depicts a further embodiment of a finger glove with a first disc magnet located proximate to the ventral side of the distal phalanx head and a second disc magnet proximate to the nail plate of a human index finger wearing the glove.
FIG. 10 is a top or dorsal view of a human hand wearing the finger glove of FIG. 1 .
FIG. 11 is a palmar view of a human hand wearing the finger glove of FIG. 1 .
FIG. 12 is a dorsal view of one embodiment of a full-hand glove with a disc magnet sewn into the forefinger of the glove.
FIG. 13 is a palmar view of the full-hand glove of FIG. 12 .
DETAILED DESCRIPTION
Before the subject invention is described further, it is to be understood that the invention is not limited to the particular embodiments of the invention described below or depicted in the drawings. Many modifications may be made to adapt or modify a depicted embodiment without departing from the objective, spirit and scope of the present invention Therefore, it should be understood that, unless otherwise specified, this invention is not to be limited to the specific details shown and described herein, and all such modifications are intended to be within the scope of the claims made herein.
FIGS. 1-5 show various views of one embodiment of a finger glove (or cot or fingerstall) 100 according to the present invention. Use of the terms “dorsal” and “palmar” are used herein to refer to those portions of the glove 100 in contact with the dorsal (back-of-the-hand) and palmar surfaces, respectively, of a human hand 70 wearing the finger glove 100 , as shown in FIGS. 10 and 11 .
The finger glove 100 is formed of a cooperative assembly of fabric pieces, including a top side fabric piece 120 sized and dimensioned to fit at least over the dorsal region of the proximal and middle segments of the finger, a bottom side fabric piece 130 sized and dimensioned to fit over the palmar region of the finger, and a bridging fabric piece 140 that joins the top side fabric piece 120 to the bottom side fabric piece 130 . The finger glove 100 is preferably manufactured to two sizes—a small/medium size approximately 3 inches long by 1.125 inches wide and a large/extra large size approximately 3.25 inches long by 1.25 inches wide.
Both the top side fabric piece 120 and the bridging fabric piece 140 are formed of one or more elastic materials to help secure the finger glove 100 to the finger. The material should be both comfortable and of sufficient elasticity so that the top side fabric piece conforms to the ventral region of the finger in both the straightened and articulated positions. Most preferably, the top side fabric piece 120 is made of a four-way stretch synthetic fabric such as spandex, which is marketed by Invista Corp. of Wichita, Kans. under the trademark LYCRA®. A two-way stretch fabric is sufficient for the bridging fabric piece 140 . A fingertip cap 110 made of a comfortable, protective, leathery-feeling and substantially non-elastic fabric (such as the synthetic leather fabric frequently marketed under the trademark AMARA® which is a registered trademark of Kuraray Co. of Japan), may be affixed to the distal portion of the top side fabric piece 120 corresponding to the fingernail of the wearer. The bottom side fabric piece 130 is also made of a comfortable, protective, leathery-feeling and substantially non-elastic fabric such as AMARA® brand synthetic leather. Although not shown in the drawings, additional lining may be placed on the inside to provide additional comfort to the wearer.
A disc magnet 200 is placed on the inside surface 136 of the distal portion of bottom-side fabric piece 130 , corresponding to the distal segment of the index finger. A disc pouch fabric piece 210 large enough to cover the magnet 200 is placed over the magnet 200 and affixed to the inside surface 136 of the bottom-side fabric piece 130 using glue, a weld, or one, two or more circles of stitches 220 . The closer the magnet 200 is to the very tip of the finger, the easier it will be for the thumb and middle finger to manipulate a metallic object (e.g., turn a nut) magnetically suspended from the index fingertip. For this reason, the magnet is placed as close to the tip of the bottom-side fabric piece 130 (preferably less than 1 cm from the tip) as practicable.
In order to inform the wearer of the location of the magnet, the stitches 220 are preferably made of a thread whose color contrasts highly with the color of the bottom side fabric piece 130 . For example, forming the stitches using a red thread creates the appearance of a bulls-eye target location on the finger glove 100 . Alternatively, a circle, dot, or bulls-eye decoration can be dyed or imprinted on the outside surface 134 of the bottom side fabric piece 130 pinpointing the location of the magnet 200 .
The top side fabric piece 120 is joined at its periphery to the bridging fabric piece 140 with stitches 121 . The bottom side fabric piece 130 is also joined at its periphery to the bridging piece 140 with stitches 131 . As shown in FIG. 5 , the bridging piece 140 is wider near the opening of the finger glove 100 than at the finger tip, giving the finger glove 100 a pinch style tip.
FIGS. 1-5 also depicts other features of the finger glove 100 . Silicone ovals 170 may be affixed to the outside surface 134 of the bottom side fabric piece 130 to facilitate gripping, and also to enhance the visual appearance of the finger glove 100 . The bottom side fabric piece 130 may include an integral pull tab 180 to assist the user with putting it on. The integral pull tab 180 also facilitates attachment of the finger glove 100 to a header card for displaying the finger glove on a merchandise hook. A tag 190 affixed to the proximal portion of the inside surface 126 of the top side fabric piece 120 identifies the size and place of manufacture, or manufacturing company, of the finger glove 100 . Finally, a logo 160 for trademark identification can be conveniently welded or silkscreened onto the outside surface 124 of the top side fabric piece 120 .
The magnet 200 is preferably small enough to minimize interference with normal handling, powerful enough to hold small lightweight metal objects like nuts, but not so powerful that it accelerate metallic objects to the user's finger so quickly that it hurts, stuns, or irritates the user's finger. Consequently, it is preferred that the magnet 200 have a holding force of between about eight ounces and two pounds, more preferably, about one pound.
In one embodiment, a round disc magnet is used having an approximately 0.375-inch (0.95-cm) diameter and an approximately 0.06-inch (0.15-cm) thickness. This equates to a volume of about 0.0066 cubic inches or 0.11 cubic centimeters. Smaller or larger sizes may be utilized in the alternative depending on the application and the size of the objects one needs the magnet to carry.
The online encyclopedia WIKIPEDIA reports that neodymium magnets are made of a combination of mostly neodymium, iron, and boron, according to the chemical formula Nd 2 Fe 14 B. This website also reports that neodymium magnets have about 18 times as much strength, per unit volume, as ceramic magnetic material, and can lift several hundred times their own mass. Other websites report that neodymium magnets have about 10 times the strength of a comparable ceramic magnet. Neodymium magnets are graded in strength from N24 to N54, with the number following the N representing the magnetic energy product (more commonly referred to as “maximum energy product”), in megagauss-oersteds (MGOe) (1 MG·Oe=7,957 T·A/m=7,957 J/m 3 ). Thus, a N35 neodymium magnet would have a maximum energy product of 35 MGOe, and a N40 neodymium magnet would have a maximum energy product of 40 MGOe. More information concerning rare earth magnets can be found in U.S. Pat. Nos. 4,802,931 to Croat and 4,496,395 to Croat, which are herein incorporated by reference.
The website www.wikipedia.org reports that neodymium magnets are made of a combination of mostly neodymium, iron, and boron, according to the chemical formula Nd 2 Fe 14 B. This website also reports that neodymium magnets have about 18 times as much strength, per unit volume, as ceramic magnetic material, and can lift several hundred times their own mass. Other websites report that neodymium magnets have about 10 times the strength of a comparable ceramic magnet. Neodymium magnets are graded in strength from N24 to N54, with the number following the N representing the magnetic energy product (more commonly referred to as “maximum energy product”), in megagauss-oersteds (MGOe) (1 MG·Oe=7,957 T·A/m=7,957 J/m 3 ). Thus, a N35 neodymium magnet would have a maximum energy product of 35 MGOe, and a N40 neodymium magnet would have a maximum energy product of 40 MGOe. More information concerning rare earth magnets can be found in U.S. Pat. Nos. 4,802,931 to Croat and 4,496,395 to Croat, which are herein incorporated by reference.
Neodymium-iron-boron magnets have a density of approximately 0.27 pounds per cubic inch or 7.5 g per cubic centimeter. Thus, a small 0.0066 cubic inch or 0.11 cubic centimeter magnet would have a weight of about 0.0018 pounds or 0.825 grams. Such a small magnet should hold more than 600 times its mass, or at least one pound.
FIGS. 6-9 depict four different finger glove embodiments, each one mounting one or more magnets in different places in the region of the finger glove corresponding to the fingertip 40 . In one embodiment of the finger glove 300 ( FIG. 6 ), the magnet 305 is placed on the very end of the fingertip of the glove 300 . In another embodiment of the finger glove 310 ( FIG. 7 ), the magnet 315 is placed about a tenth of an inch back from the very tip. When a finger is inserted into the glove 310 , the magnet 305 will be proximate to the ventral side of the distal phalanx head 55 of the finger 40 , a region of acute tactile sensation.
In yet another embodiment of the finger glove 320 ( FIG. 8 ), the magnet 325 is affixed to the top side fabric piece 120 or fingertip cap 110 ( FIG. 1 ). When a finger 40 is inserted into glove 320 , the magnet 325 will be proximate to the tip of the nail plate 60 of the finger 40 . With this embodiment, a person can hold a small metallic fastener (such as a screw or nut) on the back of the dorsal side of the finger glove 320 while using the fingertip to feel around for the opening or shaft in which to insert or attach the fastener. Once located, the person can use his thumb and middle finger to retrieve the fastener and place it in its proper location. FIG. 9 depicts a finger glove 330 embodiment comprising two disc magnets 340 and 345 placed on the dorsal side of the finger glove, one at the very tip of the finger, and the other backed off about ¼ inch. Other embodiments, not shown, may include one disc magnet placed on the dorsal side of the finger glove, in the region of the fingernail, and another on the ventral or palmar side of the finger glove.
FIGS. 12 and 13 depict dorsal and palmar views of one an embodiment of a full-hand magnetic finger glove 500 incorporating the fabric materials and magnetic disc features of the above-noted finger glove embodiments. The finger glove 500 comprises a combination of elastic material 510 and substantially non-elastic fabric material 520 and includes a hook and fastener strap 550 . A disc magnet 510 is attached to the inside surface of the dorsal side of the forefinger 530 of the glove 500 corresponding to the region of the finger nail. The gloves are preferably sold in pairs (left hand and right hand). In one embodiment, the gloves 500 are sold with a single magnet placed in only one of the gloves (right or left hand), or in both of the gloves. In another embodiment, the gloves 500 are sold with one or more magnets 510 affixed to the palmar side of the forefinger 530 of the glove 500 corresponding to the region of the fingertip. In yet another embodiment, the gloves 500 are sold with one or more magnets 510 affixed to the both the palmar and dorsal sides of the forefinger 530 of the glove 500 corresponding to the region of the fingertip. In yet other embodiments, the gloves 500 are sold with one or more magnets 510 affixed to one or more other fingers of the gloves, such as the middle finger 540 .
Although the foregoing specific details describe various embodiments of the invention, persons reasonably skilled in the art will recognize that various changes may be made in the details of the apparatus of this invention without departing from the spirit and scope of the invention as defined in the appended claims.
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A magnetic finger glove helps persons hold, install, and retrieve small metallic objects, such as nuts or screws, in hard-to-reach places. The finger glove is sized and shaped to sheathe and conform to an adult human index finger. A small round disc neodymium magnet is affixed to a fabric assembly in the region corresponding to the fingertip. The magnet weighs less than 0.002 pounds and is small enough to be confined within an area on the fabric assembly of less than 0.5 square inches. Yet, the magnet has a holding force of at least 1 pound.
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BACKGROUND OF THE INVENTION
[0001] (1) Field of the Invention
[0002] The invention relates to the preparation of a bituminous composition, such as asphalt, which is prepared, cooled and packaged for subsequent transport and use at a work cite, such as a road or highway. The invention relates to the preparation of a bituminous composition, such as asphalt, modified asphalt, or engineering asphalts, which is prepared, cooled and packaged for subsequent transport and blending or reaction and use at a work cite, such as a road or highway, roofing manufacturing unit, cable manufacturing unit and other types of manufacturing and processing units.
[0003] (2) Brief Description of the Prior Art
[0004] As used herein, bitumen, bitumen composition and asphalt are synonymous. Bitumen is completely soluble in carbon disulfide, and composed primarily of a mixture of highly condensed polycyclic aromatic hydrocarbons. Asphalt is most commonly modeled as a colloid, with asphaltenes as the dispersed phase and maltenesmateria as the continuous phase (though there is some disagreement amongst chemists regarding its structure). Although a considerable amount of work has been done on the two to discover the chemical composition of asphalt, it is exceedingly difficult to separate individual hydrocarbon in pure form and it is almost impossible to separate and identify all the different molecules of asphalt, because the number of molecules with different chemical structure is extremely large
[0005] Most natural bitumens contain sulfur and several heavy metals, such as nickel, vanadium, lead, chromium, mercury, arsenic, selenium, and other toxic elements Bitumens can provide good preservation of plants and animal fossils.
[0006] Asphalt/bitumen can sometimes be confused with “tar”, which is a similar black, thermoplastic material produced by the destructive distillation of coal. During the early and mid-20th century when town gas was produced, tar was a readily available product and extensively used as the binder for road aggregates. The addition of tar to macadam roads led to the word tarmac, which is now used in common parlance to refer to road-making materials. However, since the 1970s, when natural gas succeeded town gas, asphalt/bitumen has completely overtaken the use of tar in these applications. Other examples of this confusion include the La Brea Tar Pits and the Canadian tar sands. Pitch is another term mistakenly used at times to refer to asphalt/bitumen, as in Pitch Lake.
[0007] Natural deposits of asphalt/bitumen include lakes such as the Pitch Lake in Trinidad and Tobago and Lake Bermudez in Venezuela, Gilsonite, the Dead Sea, asphalt/bitumen-impregnated sandstones known as bituminous rock and the similar “tar sands”. Asphalt/bitumen was mined at Ritchie Mines in Macfarlan in Ritchie County, West Virginia in the United States from 1852 to 1873. Bituminous rock was mined at many locations in the United States for use as a paving material, primarily during the late 1800s.
[0008] Asphalt/bitumen can be separated from the other components in crude oil (such as naphtha, gasoline and diesel) by the process of fractional distillation, usually under vacuum conditions. A better separation can be achieved by further processing of the heavier fractions of the crude oil in a de-asphalting unit, which uses either propane or butane in a supercritical phase to dissolve the lighter molecules which are then separated. Further processing is possible by “blowing” the product: namely reacting it with oxygen. This makes the product harder and more viscous.
[0009] Asphalt/bitumen is typically stored and transported at temperatures around 150° C. (300° F.). Sometimes diesel oil or kerosene are mixed in before shipping to retain liquidity; upon delivery, these lighter materials are separated out of the mixture. This mixture is often called “bitumen feedstock”, or BFS, or bitumen or asphalt compositions. Some dump trucks route the hot engine exhaust through pipes in the dump body to keep the material warm. The backs of tippers carrying asphalt/bitumen, as well as some handling equipment, are also commonly sprayed with an agent before filling to aid release. Diesel oil is no longer used as a release agent due to environmental concerns.
[0010] Heretofore, the manufacture of bitumen compositions has required heating of the additives and the maintaining of the produced composition at elevated temperatures even as the resultant composition is being transported to a job cite, such as an area near the building of a road or highway, or airport runway, or roofing products manufacturing unit, or bituminous products process plants or the like. This becomes extremely problematic where the work cite is in a location far away from the manufacturing facility, requiring considerable time for transporting the bitumen composition by truck, barge or ship. The bitumen composition must be heated continuously during the transport step and storage. Where the job cite is overseas, the problem is compounded, oftentimes requiring the building and operation of a substantial manufacturing facility far from readily available sources of bitumen or additives for the formation of the ultimately desired composition.
[0011] Asphalt or bitumen is a thermoplastic material, a consistency of peanut butter or harder at ambient temperatures. It is a brittle solid at cold temperatures and liquid at high temperatures. It is easier and more cost effective to process most asphalts/bitumens in the liquid form.
[0012] The present invention addresses problems associated with the manufacture, storage and delivery of bituminous compositions such that the necessity for continued heating during transportation and delivery to the work cite is eliminated.
[0013] The present invention provides for the preparation of a carefully defined cold blend/mixture of bitumen compositions that, when subsequently heated and mixed and/or blended at a hot mix plant yield a composition that meets the project, job and/or agency binder specifications. Some of the benefits of such a process are:
(1) elimination of qualifying, ordering and logistically processing multiple materials; (2) elimination of metering, blending and/or mixing ingredients in proper ratios; (3) minimization of the storage areas, or tankage necessary to support multiple ingredients; (4) minimization of operational and staff personnel, as well as the need for the presence at the job cite of an advanced knowledgeable technical staff; (5) the elimination of unused, excess raw material inventories at the completion of the project; (6) the elimination of an expensive process system (capital and operating costs) to produce polymer modified bitumen (PMB); (7) the ability/flexibility to make large or small quantities of PMB's as demand dictates; (8) the minimization of wastes, packaging containers of ingredients, off-spec products, etc.; (9) increasing the distance the product may travel; making competition and market reach more economic and viable; (10) reducing the risks of gelling and loss of quality at time of re-use and after re-heating; and (11) eliminating technical risks of loss of quality and reduction of properties of materials used in the production of the PMB's.
[0025] In accordance with the present invention, the majority of the work and complex formula development is done using the teachings herein, and the end user simply heats blends/mixes and uses the resultant product to make hot mix pavement, or in other uses.
[0026] In the present invention, bulk cold packed containerized pre-blended modified asphalt/bitumen is prepared for subsequent use in asphalt, cold patches and/or but not limited to roofing products. Bulk cold packed containers in the form and various sizes of polyolefin bags, big bags, jumbo bags, polybags, bitumen transportation containers (commonly referred to as Bitutainers or ISO Containers) or steel drums, as commonly used in the industry, provides a means to transport and use modified bitumen, PMB's, into areas not equipped for common bulk transportation by truck, rail or ship or simply as a preferred form by the user.
[0027] The cold packaged containerized bitumen is formulated to contain non-reacted or prepared mixtures of bitumen, additives, polymers, modifiers, extenders, and associated ingredients that at the use site are melted and blended or added to host bitumen and blended in proportions yielding bitumen meeting project specifications or requirements. The bulk cold packed containerized pre-blended bitumen is prepared using a process involving and combining a specially designed steel belt process conveyor system which combines selected ingredients into a non-reacted mixture which in turn is feed into an extruder forming the mixture into morphology suitable for filling the type of bulk container used.
[0028] The containers, ‘Bitutainers’ are available in various sizes from 50 gals to 5,000+ gals and capabilities. Larger ISO type containers with capacities up to 30 MT are reusable and equipped for various types heating and pouring/pumping capabilities. Smaller drums, in the 150-250 Kg capacity range typically non-usable, require a heating and pouring system such as a decanter. Polybags in the 25-2,000 Kg capacity are constructed from materials which permit the entire bag to be added to hot bitumen, the entire package with contents are used, there is no waste.
[0029] The pre-blended modified asphalt may be specifically formulated to meet specifications or project requirements and be suitable for direct use through heating and mixing or may be in a concentrate form for addition and letdown in a host hot bitumen for mixing.
Markman Constructions
[0030] I intend for the following words and phrases to have the following meanings, as used in the claims and all other parts of the specification:
(1) Bitumen composition: As described in the section entitled “Brief Description Of The Prior Art”. (2) Cold blending: a step in which the additives are mixed, blended and/or reacted without application of an external heat source. This may involve liquids at ambient temperatures and/or particulate solid materials, such a powdered or pelletized polymers such as SBS, PE, terpolymers, ground tire rubber. Related additives, such as cross-linking agents such a powdered or pelletized sulfur of value added C-L agents which may contain multiple ingredients again in powder or pellet form may also be used. It also includes use of additives such as hard asphalts (PDA's, asphaltenes, solvent precipitated asphaltenes, TLA, Gilsonite, or carbon black) (3) Receptacle: a body, such as a housing, a tank, or a reactor. (4) Additive(s): Any chemicals known to those skilled in the art of formulating or manufacturing final asphalt compositions for ultimate use in roads, highways, roofs, and the like. Additives may include: natural and synthetic polymers; ground tire rubber; lubricants; Naphtanic oils; cross-linking agents, such as sulfur; emulsifiers; thinners (to be distinguished from modifiers, which are the essentially polymeric chemicals). (5) Mixing: to combine into one mass. (6) Heating: a step in which the additives are mixed, blended and/or reacted with application of an external heat source. (7) Exposing: a step in which the additives or the composition are directly or indirectly caused to be contacted by a known thermal reduction variant within a receptacle. (8) Means for reducing the temperature: a device(s) for causing the temperature of additives during mixing or the composition to be lowered to a pre-determined temperature before the step of packaging. (9) Pre-determined temperature: the temperature at which the additives or the composition are caused to be lowered by the temperature reducing means (10) Packaging: the step of introducing the additives or the composition into a container for subsequent transport to a work cite. (11) Cooled bitumen composition: the resulting product of the step of exposing. (12) Container: any device for the transport of a given amount of a plurality of additives or a composition, re-usable or non-reusable. (13) Heat exchanger: a device used to transfer heat from a fluid on one side of a barrier to a fluid on the other side without bringing the fluids into direct contact with one another. (14) Pre-cooled temperature reducing fluid: air or other gas, or a liquid. (15) Elongated continuously rotatable belt: a device driven by an energy source and having first and second opposing surfaces, upon one surface is deposited one or more additives and/or bituminous composition(s). (16) Incrementally deposited: the deposition of additives or the composition onto a surface for the purpose of reducing the temperature of the additives or the composition to a pre-determined temperature. (17) Second receptacle: a housing or full or partial enclosure for a continuously rotatable belt. (18) Means for introducing said composition into said second receptacle and onto said belt: a device for transporting the additives or the composition between a receptacle where additives are mixed or reacted to form a composition, and thence to an area for exposure of the additives or the composition to means for reducing the temperature. (19) Cutting means: a device for separating a composition or additives into portions of a given dimension. (20) Extruding means: a device for producing various geometric profiles of additives or composition that may thereafter be separated into given lengths and/or configuration. (21) Composition: the combination of additives using the method of the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0052] FIG. 1 is a graphical flow illustration of a device incorporating the present invention wherein additives are reacted or blended in a receptacle prior to being cooled and packaged.
[0053] FIG. 2 is a view similar to FIG. 1 illustrating the flow of the resultant composition subsequent to the procedures shown in FIG. 1 .
[0054] FIG. 3 is an illustration of an extruder system incorporated into the invention.
[0055] FIG. 4 is a graphical illustration combining to procedures or steps illustrated in FIGS. 1 through 3 , but showing an alternative step of providing extrusion of the composition subsequent to the cooling procedure.
[0056] FIG. 5 is a graphical flow diagram of a process using the invention.
SUMMARY OF THE INVENTION
[0057] A cold blending and containerizing method and apparatus are disclosed and claimed for preparing a bitumen composition for subsequent transport to a selected work cite and final preparation. Into a first receptacle is introduced a pre-selected quantity of one or more additives for the formation of the composition. The additives are then mixed and/or heated within the receptacle to form the bitumen composition. The bitumen composition is exposed to means for reducing the temperature of the composition to cool the composition to a pre-determined temperature, such as by use of one or more fluids, preferably delivered onto at least one side of a rotating belt, and thereafter packaging the cooled bitumen composition into at least one container for transport to a selected work cite.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Description of a Theoretical Apparatus and Method
[0058] As an illustration of an asphalt composition preparation, cooling and packaging which would use the present apparatus and method, the following composition formulas may be prepared using the additives as described below:
[0000]
Prototype Formulas, #
1
2
3
4
Additives
Base Asphalt,
Base
Pre-
Base
Pre-
Base Asphalt, 250-300° F.
250-300° F.
Asphalt
blended
Asphalt
blended;
Cross-linking
Extender
250-300° F.
Extender
250-300° F.
Cross-linking
agent, 60-80° F.,
Oil
Oil
agent, 60-80° F.,
ambient
ambient
Dry SBS
Cross-linking agent
Cross-linking agent
Dry SBS polymer
polymer
Powder, ambient,
Powder,
60-80° F.
ambient, 60-80° F.
Dry SBS Polymer
Polymer 1: Dry SBS
Base Asphalt, 150-225° F.
Powder
Powder
Polymer 2:
Polyethylene
1. A. Asphalt layer deposited on belt (described above) in predefined layer (quantity), 250-300° F., approximately 85-98% by volume of final composition.
B. Cross-linking agent is sulfur, deposited on top of molten asphalt, ambient powder, 60-80° F., approximately 0.05-2.0% by volume of final composition. C. SBS powder deposited uniformly on top of molten asphalt, ambient powder, 60-80° F., approximately 0.5-20% by volume of total composition. Cooling starts immediately when the hot liquid additives contact the cooler belt. As the cooling continues, the particulate additives become embedded in the asphalt deposited on the belt during the cooling step. D. Resultant composition from belt feed is placed into extruder to further cool the composition to between about 30-60° F., and 100% of the resultant asphalt composition is fed into an extruder (described above). E. Extruded, cooled asphalt composition is cut to desired form and fed into container/packages, at a temperature of about 50-70° F.
2. A. Base asphalt and extender oil additives are heated and mixed in a receptacle.
B. Additive “A” is fed to a belt and deposited in a uniform predefined layer (quantity). C. A sulfur cross-linking agent, is deposited on the belt top of the heated asphalt. D. SBS powder is deposited uniformly on the belt on top of the asphalt to complete the preparation of the asphalt composition. E. The asphalt/bitumen composition on the belt is fed into an extruder. F. The composition is cut to desired form and fed into container/packages.
3. A. Base asphalt and extender oil additives are heated and pre-blended/mixed.
B. The additives are fed to a continuous, looped belt and deposited in a uniform predefined layer. C. A sulfur cross-linking agent, is then deposited on top of the additives and on the belt. D. Polymer 1: SBS powder is deposited uniformly on top of the additives. E. Polymer 2: polyethylene pellets are deposited uniformly on top of the additives and the SBS powder additive to form the final bitumen/asphalt composition. F. The composition on the belt is fed into the extruder. G. The extruded composition is cut to desired form and feed into container/packages.
4. A. A heated (250-300 F) asphalt/bitumen additive is deposited on a continuous looped belt to form a layer deposited on the belt, in a predefined layer (quantity), to provide approximately 85-98% by volume of the entire composition.
B. A sulfur cross-linking agent, in the form of an ambient powder (60-80 F) is deposited on top of the heated asphalt additives, to provide approximately 0.05-2.0% by weight of the entire composition. C. SBS powder is deposited uniformly on top of the heated bitumen/asphalt SBS powder additives, at approximately 0.5-20% by weight of the entire bitumen/asphalt composition. D. A thin layer of base asphalt/bitumen additive is deposited over the additives of “A”, “B” and “C” at a temperature of about 150-225 F to seal the additives and form the final asphalt/bitumen composition. The temperature of this step for the composition is reduced by exposing the surface of the composition to means for reducing the temperature, such as cool air or inert gas jets or water misters or foggers directed onto a surface of the belt while cold water, streams jets or similar liquid or gaseous material is sprayed onto another, i.e., the underside, of the belt not containing the additives. The temperatures required for appropriate cooling of the additives is determined by the minimum temperature required to flow into an extruder or similar device for packaging, per requirements. E. The bitumen/asphalt composition is fed from the belt at between about 30-60 F into an extruder. F. The extruded composition is cut to desired form and feed into container/packages, 50-70° F., 100% of cold mixed materials.
[0083] Now with reference to the Figs., there is shown in FIGS. 1 and 4 the apparatus for the mixing of the additives used to make a bitumen/asphalt composition. Raw materials 1 , 2 , and 3 , such as those described in the theoretical example described herein, are separately introduced into a receptacle 4 , which, as shown, is a three-sided vat or reactor. The receptacle 4 includes an electrically driven agitator, of known construction, for mixing and agitating the additives as they are blended or reacted in the receptacle 4 . Although not shown, the receptacle 4 may also include a heat exchanger or other heating means for heating the additives during the mixing step. The lower portion of the receptacle 4 contains a flow line 4 A leading to a pump 6 for circulating the additives back into the receptacle 4 as the mixing or reaction is continued. The heat exchanger may be placed within the receptacle 4 or, alternatively, exterior of the receptacle 4 , such as within the flow line upstream or downstream of the pump 6 . A valve 6 A is placed in the flow line 4 A for selective directing of the flow either back into the receptacle 4 or, when closed, to a connecting portion of flow line 4 A which may contain auxiliary equipment for a number of procedures, such as strainers and/or filters 7 .
[0084] FIG. 2 illustrates the continuous, loop belt system and cooling procedure used in the invention. The conduit line 4 A transmits the additives which have been mixed in the receptacle 4 as in FIG. 1 to provide the bitumen composition, from the components shown in FIG. 1 to a second receptacle or housing 20 . The receptacle 20 has a continuously moving elongated belt made of known construction, such as steel, aluminum or elastomer members, or the like, forming the belt 8 . In lieu of depositing the bitumen composition onto the belt 8 , additives for the formation of the bitumen composition may be introduced separately into the receptacle 20 and on to the belt 8 by use of one or more containers 9 and 10 , placed just over the belt 8 . The additives, pre-heated, are thus introduced onto the belt 8 incrementally or continuously as the belt 8 travels horizontally within the receptacle or housing 20 . An exhaust system 11 is provided through the top of the receptacle 20 to vent fumes and the like as the bitumen composition is deposited and cooled along the belt 8 . As the belt 8 continues to be moved along a horizontal path within the receptacle 20 , a chilling system 13 below the belt 8 sprays or otherwise injects water or other cooling fluid either directly onto the lower face 8 A of the belt 8 such that the fluid does not directly contact the bitumen composition on the belt 8 , but provides cooling of the composition by indirectly cooling it through the belt 8 . A troth 13 below the belt 8 collects the cooling fluid, if in liquid form, and transmits it through recirculation lines 21 into a cooler device, such as refrigeration device 22 , thence back through recirculation conduit 21 A and onto the lower face 8 A of the belt 8 .
[0085] FIG. 3 illustrates the steps and means used to extrude and package the cooled bitumen composition. A mechanical extruder 14 is placed in communication with one end of the rotating belt 8 such that after the composition is cooled to the pre-selected temperature, the composition may be delivered to the extruder and processed therein in a known manner. Thereafter, the extruded composition is transferred into drums 15 , barrels 16 and/or bags 17 , for subsequent delivery to a work cite.
[0086] Optionally, all additives may be pre-blended (as opposed to reacted) and deposited onto the belt as a homogenous mixture of bitumen. If polymers are used, they have not been dissolved nor have they been cross-linked.
[0087] Typically, the asphalt initially will be hot, such as 200-350° F. The polymers and related additives may be dry, particulate solids at ambient conditions. Any cross-linking agents may be powder sulfur, or oil extender or pelletized sulfur. The base asphalt may be a combination of asphalts and may include extender oils, and other additives such a PPA, polyphosphoric acid or other materials known to change the base asphalt properties and/or chemical composition.
[0088] It is assumed that at the work site, there are tanks or vessels to melt and mix the packaged blend of materials in a fashion suitable to yield the desired PMB. The melters, typically referred to as decanters, are packaged units sold for the purpose of melting and transferring the hot liquid bitumen to tanks for subsequent mixing, storage and delivery to the hot mix plant for combination with the aggregates.
[0089] FIG. 4 is an illustration of the method and apparatus combined as in FIGS. 1 through 3 as well as including an extruder 14 for extruding the composition subsequent to processing on the belt 8 and before packaging into containers 15 , 16 and/or 17 .
[0090] Now, with reference to FIG. 5 , there is shown a general process flow diagram for the invention. Bitumen/asphalt and/or additives 50 through 55 are delivered into a first housing 56 or 57 for proportionate blending or reaction. Additives 55 include other performance enhancing additives, carbon black, hard asphalts (PDA's, Gilsonite, Asphaltenes, etc.) chemicals and sustainable materials beneficial to performance and specification compliance of the composition. The resultant composition is placed onto a chilled steel belt process system 58 for cooling. The composition is then extruded by extruder 59 and then delivered to one or more polybags 60 , drums 61 and/or bitutainers 62 for transport to a work cite.
[0091] The belt assembly 8 and cooling system may be as described in PS-452 ENG 10.2004, “Sandvik bitumen-asphalt packaging” system, the total disclosure of which is hereby incorporated herein, and which device is available from Sandvik Mining, World Trade Center, Tower C, 15 th Floor, Strawinsky 1545, 107 XX Amsterdam, Netherlands. This system must be reconfigured in accordance with the present invention to accommodate the bitumen/asphalt and additives for the formation of the composition as disclosed herein.
[0092] Although the invention has been described herein, it should be understood that this is by illustration only, and that changes and modifications may be made to the apparatus and method which are well within the abilities of one having ordinary skill in the art but still remain within the scope, spirit and intent of the invention, and that scope of the invention is as defined in the claims, below.
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A cold blending and containerizing method and apparatus for preparing a bitumen composition for subsequent transport to a selected work cite. A pre-selected quantity each of a plurality of additives is introduced into a receptacle. The additives may or may not be heated and then mixed within a receptacle to form a bitumen composition, and exposed to temperature reduction device to a pre-determined cooled point. The cooled bitumen composition may then be cut into profiled pieces or configurations and then packaged into a container for transport to a selected work cite.
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CROSS REFERENCE TO RELATED APPLICATIONS
This is a continuation-in-part of U.S. application Ser. No. 10/771,031, filed Feb. 3, 2004, entitled “IMAGE SIGNAL PROCESSING METHOD AND DEVICE,” which is cooperated by reference herein.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to analog front-end (AFE) circuits, and more particularly, to analog front-end circuits for digital displaying apparatus and control methods thereof.
2. Description of the Prior Art
In various digital displaying apparatuses, such as the liquid crystal display (LCD) and the plasma display panel (PDP), an analog front-end (AFE) circuit is typically employed to convert the analog RGB signals into digital signals.
Please refer to FIG. 1 , which shows a block diagram of a conventional analog front-end (AFE) circuit 100 of a digital display. As shown, the AFE 100 comprises a clock generator 110 , a bandgap voltage reference 120 , and three color processing modules 130 , 140 , and 150 for processing the three analog signals R, G, and B, respectively. Each color-processing module comprises a clamp circuit, a gain and offset adjusting circuit, and an analog-to-digital converter (ADC). The operations of the above components are well known in the art and further details are therefore omitted for brevity.
The performance of the analog-to-digital converters of the AFE 100 influences the image quality of the digital display. For example, in a 15-inch LCD monitor, the ADC must operate at 94.5 MHz when the displaying mode is configured to 1024*768*85 Hz (i.e., the XGA mode). In a 17-inch LCD monitor, the ADC must operate at 157.5 MHz when the displaying mode is configured to 1280*1024*85 Hz (i.e., the SXGA mode). Thus, it can be seen that the ADC must operate at higher speeds for higher resolution displaying modes.
In the conventional art, a time-interleaved ADC architecture is typically employed in the AFE circuit. FIG. 2 illustrates a simplified block diagram of an AFE circuit 200 adopting the interleaved ADC architecture according to the prior art. In the AFE circuit 200 , however, the mismatch between analog-to-digital converters 220 and 230 easily results in problems such as: offset error, gain error, and phase difference. In some displaying modes or pictures, these problems become more obvious and may be detectable by human eyes. For example, an offset between the ADCs 220 and 230 may cause the presence of stripes or saw tooth artifacts in the screen image thereby negatively affecting the image quality of the digital display.
SUMMARY OF THE INVENTION
It is therefore an objective of the claimed invention to provide analog front-end circuits of a digital display to solve the above-mentioned problems.
According to an exemplary embodiment of the claimed invention, analog front-end (AFE) circuits of a digital display and related controlling methods are disclosed. One proposed AFE circuit comprises: a first circuit to intermittently invert a working clock to generate a control signal and to generate a sampling signal, wherein the sampling signal is corresponding to the working clock; a first analog-to-digital converter (ADC) coupled to the first circuit for converting an analog video signal into a first digital video signal according to the sampling signal; a second analog-to-digital converter coupled to the first circuit for converting the analog video signal into a second digital video signal according to the sampling signal; and a first multiplexer for selectively outputting the first digital video signal or the second digital video signal according to the control signal.
These and other objectives of the present invention will no doubt become obvious to those of ordinary skill in the art after reading the following detailed description of the preferred embodiment that is illustrated in the various figures and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a block diagram of an analog front-end (AFE) circuit of a digital display according to the prior art.
FIG. 2 is a simplified block diagram of an AFE circuit with interleaved analog-to-digital converters according to the prior art.
FIG. 3 is a simplified block diagram of an AFE circuit according to one embodiment of the present invention.
FIG. 4 is a block diagram of a control unit of FIG. 3 according to a first embodiment of the present invention.
FIG. 5 is a block diagram of the control unit of FIG. 3 according to a second embodiment of the present invention.
DETAILED DESCRIPTION
The operations for processing each of the RGB signals are substantially the same as one other. For convenience and simplification of the descriptions, the operations of processing only a single RGB signals is utilized as an example hereinafter.
Please refer to FIG. 3 , which shows a simplified block diagram of an AFE circuit 300 according to one embodiment of the present invention. The AFE circuit 300 adopts the interleaved ADC architecture. As shown, the AFE circuit 300 comprises a first analog-to-digital converter (ADC) 320 , a second ADC 330 , and a clock control circuit 360 ; the first and second ADC construct a time-interleaved ADC. In FIG. 3 , the analog video signal V_analog corresponds to one of the three primary colors R, G, or B.
The clock control circuit 360 is arranged for intermittently or alternatively inverting a working clock to generate a control signal. The clock control circuit 360 is also employed to generate a sampling signal according to the control signal or the working clock. In one embodiment, the clock control circuit 360 comprises a first frequency divider 310 and a control unit 350 . In this embodiment, the first frequency divider 310 is arranged for dividing the frequency of a working clock WCLK by two to generate the sampling signal. In other words, the frequency of the sampling signal is half of the working clock WCLK. The first ADC 320 converts the even pixels of the analog video signal V_analog into a first digital video signal V_even according to the sampling signal. The second ADC 330 converts the odd pixels of the analog video signal V_analog into a second digital video signal V_odd according to the sampling signal.
In practice, the first frequency divider 310 of the clock control circuit 360 can be designed to generate the sampling signal by dividing the frequency of the control signal or an inverted signal of the working clock WCLK.
In this embodiment, the control unit 350 of the clock control circuit 360 is arranged for intermittently inverting the working clock WCLK to generate a control signal C_clk. The control signal C_clk is employed to control the first multiplexer 340 to selectively output the first digital video signal V_even or the second digital video signal V_odd.
In practice, the control unit 350 can be implemented utilizing other design choices. For example, FIG. 4 shows a block diagram of the control unit 350 according to a first embodiment of the present invention. In this embodiment, a second frequency divider 410 is employed in the control unit 350 to divide the frequency of a vertical sync signal Vs by two to produce a selection signal SEL. A second multiplexer 420 is then utilized to selectively output the working clock WCLK or an inverted clock WCLK of the working clock WCLK to be the control signal C_clk under the control of the selection signal SEL.
As is well known in the art, each pulse of the vertical sync signal Vs corresponds to an individual frame. In another aspect, the interval between two successive pulses corresponds to the data length of an entire frame. Accordingly, the logical level of the selection signal SEL generated from the second frequency divider 410 will be alternated between two successive frames. For example, in one embodiment, the selection signal SEL is at logic 1 during the period of each odd frame and then goes to logic 0 during the period of each even frame. If the second multiplexer 420 outputs the working clock WCLK as the control signal C_clk when the selection signal SEL is at logic 1 (i.e., during the period of each odd frame), then it will output the inverted clock WCLK as the control signal C_clk when the selection signal SEL goes to logic 0 (i.e., during the period of each even frame).
Therefore, the timing of outputting the first digital video signal V_even and the second digital video signal V_odd from the first multiplexer 340 during the period of the odd frame is opposite to that during the period of the even frame. As a result, the light stripes and shade stripes on the odd picture caused by the mismatch between the ADC 320 and ADC 330 will be swapped or alternated on the even frame. Specifically, the light stripes on the odd frame will become shade stripes on the even frame and the shade stripes on the odd frame will become light stripes on the even frame. The human eye averages the visual effects of successive frames. Therefore, the human eye will not be able to detect the above-described image defects caused by the mismatch between ADC 320 and ADC 330 .
FIG. 5 shows a block diagram of the control unit 350 according to a second embodiment of the present invention. In this embodiment, a third frequency divider 510 is employed in the control unit 350 to divide the frequency of the vertical sync signal Vs by two to generate a selection signal SEL. Then, an XOR gate 520 is utilized for receiving the selection signal SEL and the working clock WCLK to produce the control signal C_clk. By utilizing the XOR gate 520 , the polarity of the control signal C_clk will alternate between two successive frames, i.e. the polarity of the control signal C_clk during the period of the odd frame will be opposite to the polarity of the control single C_clk during the period of the even frame. This renders the timing of outputting the first digital video signal V_even and the second digital video signal V_odd from the first multiplexer 340 during the period of the odd frame as opposite of that during the period of the even frame.
In practice, the divisor of the frequency dividers 410 and 510 can be set to another value other than 2. For example, the divisor of the frequency dividers 410 and 510 can be set to 4. When a divisor is set to a value of 4 the timing of outputting the first digital video signal V_even and the second digital video signal V_odd from the first multiplexer 340 changes every other frame.
In addition, the clock control circuit 360 can be designed to invert the working clock WCLK every other predetermined time period. Thereto, in another embodiment, the frequency divider 410 or 510 of the clock control circuit 360 is replaced with a counter (not shown). The counter is utilized for generating a count value by counting pulses of the working clock WCLK or by counting pulses of the vertical sync signal Vs. In this embodiment, each time the count value reaches a predetermined value; the clock control circuit 360 utilizes the second multiplexer 420 or the XOR gate 520 , mentioned above, to invert the working clock WCLK.
Note that, other means exist that allows the first multiplexer 340 to periodically swap the output timing of the digital video signals V_even and V_odd. These other means should also be included in the embodiment of the present invention.
Additionally, in the AFE circuit 300 , the number of ADCs employed to process each color signal can be extended beyond two. In this situation, the divisor of the first frequency divider 310 should be correspondingly adjusted according to the number of ADCs employed. For example, when three ADCs are employed to process a single color signal, the divisor of the first frequency divider 310 should be configured to three. In practical implementations, since the control signal C_clk generated from the control unit 350 has the same frequency as the working clock WCLK, the first frequency divider 310 can also divide the frequency of the control signal C_clk to generate the sampling signal.
Those skilled in the art will readily observe that numerous modifications and alterations of the device and method may be made while retaining the teachings of the invention. Accordingly, the above disclosure should be construed as limited only by the metes and bounds of the appended claims.
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An analog front-end (AFE) circuit of a digital display is disclosed including: a first circuit to intermittently invert a working clock to generate a control signal and to generate a sampling signal, wherein the sampling signal is corresponding to the working clock; a first analog-to-digital converter (ADC) coupled to the first circuit for converting an analog video signal into a first digital video signal according to the sampling signal; a second analog-to-digital converter coupled to the first circuit for converting the analog video signal into a second digital video signal according to the sampling signal; and a first multiplexer for selectively outputting the first digital video signal or the second digital video signal according to the control signal.
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RELATED APPLICATION
The present application is a continuation of U.S. patent application Ser. No. 10/173,990, filed Jun. 18, 2002, which is hereby incorporated by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to a fuel recovery system for recovery leaks that occur in fuel supply piping in a retail fueling environment.
BACKGROUND OF THE INVENTION
Managing fuel leaks in fueling environments has become more and more important in recent years as both state and federal agencies impose strict regulations requiring fueling systems to be monitored for leaks. Initially, the regulations required double walled tanks for storing fuel accompanied by leak detection for the tanks. Subsequently, the regulatory agencies have become concerned with the piping between the underground storage tank and the fuel dispensers and are requiring double walled piping throughout the fueling environment as well.
Typically, the double walled piping that extends between fuel handling elements within the fueling environment terminates at each end with a sump that is open to the atmosphere. In the event of a leak, the outer pipe fills and spills into the sump. The sump likewise catches other debris, such as water and contaminants that contaminate the fuel caught by the sump, thereby making this contaminated fuel unusable. Thus, the sump is isolated from the underground storage tank, and fuel captured by the sump is effectively lost.
Coupled with the regulatory changes in the requirements for the fluid containment vessels are requirements for leak monitoring such that the chances of fuel escaping to the environment are minimized. Typical leak detection devices are positioned in the sumps. These leak detection devices may be probes or the like and may be connected to a control system for the fueling environment such that the fuel dispensing is shut down when a leak is detected.
Until now, fueling environments have been equipped with elements from a myriad of suppliers. Fuel dispensers might be supplied by one company, the underground storage tanks by a second company, the fuel supply piping by a third company, and the tank monitoring equipment by yet a fourth company. This makes the job of the designer and installer of the fueling environment harder as compatibility issues and the like come into play. Further, it is difficult for one company to require a specific leak detection program with its products. Interoperability of components in a fueling environment may provide economic synergies to the company able to effectuate such, and provide better, more integrated leak detection opportunities.
Any fuel piping system that is installed for use in a fueling environment should advantageously reduce the risk of environmental contamination when a leak occurs and attempt to recapture fuel that leaks for reuse and to reduce excavation costs, further reducing the likelihood of environmental contamination. Still further, such a system should include redundancy features and help reduce the costs of clean up.
SUMMARY OF THE INVENTION
The present invention capitalizes on the synergies created between the tank monitoring equipment, the submersible turbine pump (STP), and the fuel dispenser in a fueling environment. A fluid connection that carries a fuel supply for eventual delivery to a vehicle is made between the underground storage tank and the fuel dispensers via double walled piping. Rather than use the conventional sumps and low point drains, the present invention drains any fuel that has leaked from the main conduit of the double walled piping back to the underground storage tank. This addresses the need to recapture the fuel for reuse and to reduce fuel that is stored in sumps which must later be retrieved and excavated by costly service personnel.
The fluid in the outer conduit may drain to the underground storage tank by gravity coupled with the appropriately sloping piping arrangements, or a vacuum may be applied to the outer conduit from the vacuum in the underground storage tank. The vacuum will drain the outer conduit. Further, the return path may be fluidly isolated from the sumps, thus protecting the fuel from contamination.
In an exemplary embodiment, the fuel dispensers are connected to one another via a daisy chain fuel piping arrangement rather than by a known main and branch conduit arrangement. Fuel supplied to a first fuel dispenser by the STP and conduit is carried forward to other fuel dispensers coupled to the first fuel dispenser via the daisy chain fuel piping arrangement. The daisy chain is achieved by a T-intersection contained within a manifold in each fuel dispenser. Fuel leaking in the double walled piping is returned through the piping network through each downstream fuel dispenser before being returned to the underground storage tank.
The daisy chain arrangement allows for leak detection probes to be placed within each fuel dispenser so that leaks between the fuel dispensers may be detected. The multiplicity of probes causes leak detection redundancy and helps pinpoint where the leak is occurring. Further, the multiple probes help detect fuel leaks in the outer conduit of the double walled piping. This is accomplished by verifying that fuel dispensers downstream of a detected leak also detect a leak. If they do not, a sensor has failed or the outer conduit has failed. A failure in the outer piping is cause for serious concern as fuel may be escaping to the environment and a corresponding alarm may be generated.
Another possibility with the present invention is to isolate sumps, if still present within the fuel dispenser, from this return path of captured leaking fuel such that contaminants are precluded from entering the leaked fuel before being returned to the underground storage tank. In this manner, fuel may potentially be reused since it is not contaminated by other contaminants, such as water, and reclamation efforts are easier. Since the fuel is returned to the underground storage tank, there is less danger that a sump overflows and allows the fuel to escape into the environment.
Those skilled in the art will appreciate the scope of the present invention and realize additional aspects thereof after reading the following detailed description of the preferred embodiments in association with the accompanying drawing figures.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
The accompanying drawing figures incorporated in and forming a part of this specification illustrate several aspects of the invention, and together with the description serve to explain the principles of the invention.
FIG. 1 illustrates a conventional communication system within a fueling environment in the prior art;
FIG. 2 illustrates a conventional fueling path layout in a fueling environment in the prior art;
FIG. 3 illustrates, according to an exemplary embodiment of the present invention, a daisy chain configuration for a fueling path in a fueling environment;
FIG. 4 illustrates, according to an exemplary embodiment of the present invention, a fuel dispenser;
FIG. 5 illustrates a first embodiment of a fuel return to underground storage tank arrangement;
FIG. 6 illustrates a second embodiment of a fuel return to underground storage tank arrangement; and
FIG. 7 illustrates a flow chart showing the leak detection functionality of the present invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The embodiments set forth below represent the necessary information to enable those skilled in the art to practice the invention and illustrate the best mode of practicing the invention. Upon reading the following description in light of the accompanying drawing figures, those skilled in the art will understand the concepts of the invention and will recognize applications of these concepts not particularly addressed herein. It should be understood that these concepts and applications fall within the scope of the disclosure and the accompanying claims.
Fueling environments come in many different designs. Before describing the particular aspects of the present invention (which begins at the description of FIG. 3 ), a brief description of a fueling environment follows. A conventional exemplary fueling environment 10 is illustrated in FIGS. 1 and 2 . Such a fueling environment 10 may comprise a central building 12 , a car wash 14 , and a plurality of fueling islands 16 .
The central building 12 need not be centrally located within the fueling environment 10 , but rather is the focus of the fueling environment 10 , and may house a convenience store 18 and/or a quick serve restaurant 20 therein. Both the convenience store 18 and the quick serve restaurant 20 may include a point of sale 22 , 24 , respectively. The central building 12 may further house a site controller (SC) 26 , which in an exemplary embodiment may be the G-SITE® sold by Gilbarco Inc. of Greensboro, N.C. The site controller 26 may control the authorization of fueling transactions and other conventional activities as is well understood. The site controller 26 may be incorporated into a point of sale, such as point of sale 22 if needed or desired. Further, the site controller 26 may have an off-site communication link 28 allowing communication with a remote location for credit/debit card authorization, content provision, reporting purposes or the like, as needed or desired. The off-site communication link 28 may be routed through the Public Switched Telephone Network (PSTN), the Internet, both, or the like, as needed or desired.
The car wash 14 may have a point of sale 30 associated therewith that communicates with the site controller 26 for inventory and/or sales purposes. The car wash 14 alternatively may be a stand alone unit. Note that the car wash 14 , the convenience store 18 , and the quick serve restaurant 18 are all optional and need not be present in a given fueling environment.
The fueling islands 16 may have one or more fuel dispensers 32 positioned thereon. The fuel dispensers 32 may be, for example, the ECLIPSE® or ENCORE® sold by Gilbarco Inc. of Greensboro, N.C. The fuel dispensers 32 are in electronic communication with the site controller 26 through a LAN or the like.
The fueling environment 10 also has one or more underground storage tanks 34 adapted to hold fuel therein. As such the underground storage tank 34 may be a double walled tank. Further, each underground storage tank 34 may include a tank monitor (TM) 36 associated therewith. The tank monitors 36 may communicate with the fuel dispensers 32 (either through the site controller 26 or directly, as needed or desired) to determine amounts of fuel dispensed and compare fuel dispensed to current levels of fuel within the underground storage tanks 34 to determine if the underground storage tanks 34 are leaking.
The tank monitor 36 may communicate with the site controller 26 and further may have an off-site communication link 38 for leak detection reporting, inventory reporting, or the like. Much like the off-site communication link 28 , off-site communication link 38 may be through the PSTN, the Internet, both, or the like. If the off-site communication link 28 is present, the off-site communication link 38 need not be present and vice versa, although both links may be present if needed or desired. As used herein, the tank monitor 36 and the site controller 26 are site communicators to the extent that they allow off site communication and report site data to a remote location.
For further information on how elements of a fueling environment 10 may interact, reference is made to U.S. Pat. No. 5,956,259, which is hereby incorporated by reference in its entirety. Information about fuel dispensers may be found in commonly owned U.S. Pat. Nos. 5,734,851 and 6,052,629, which are hereby incorporated by reference in their entirety. Information about car washes may be found in commonly owned U.S. patent application Ser. No. 60/380,111, filed 6 May 2002, entitled SERVICE STATION CAR WASH, which is hereby incorporated by reference in its entirety. An exemplary tank monitor 36 is the TLS-350R manufactured and sold by Veeder-Root. For more information about tank monitors 36 and their operation, reference is made to U.S. Pat. Nos. 5,423,457; 5,400,253; 5,319,545; and 4,977,528, which are hereby incorporated by reference in their entireties.
In addition to the various conventional communication links between the elements of the fueling environment 10 , there are conventional fluid connections to distribute fuel about the fueling environment as illustrated in FIG. 2 . Underground storage tanks 34 may each be associated with a vent 40 that allows over-pressurized tanks to relieve pressure thereby. A pressure valve (not shown) is placed on the outlet side of each vent 40 to open to atmosphere when the underground storage tank 34 reaches a predetermined pressure threshold. Additionally, under-pressurized tanks may draw air in through the vents 40 . In an exemplary embodiment, two underground storage tanks 34 exist—one a low octane tank ( 87 ) and one a high octane tank ( 93 ). Blending may be performed within the fuel dispensers 32 as is well understood to achieve an intermediate grade of fuel. Alternatively, additional underground storage tanks 34 may be provided for diesel and/or an intermediate grade of fuel (not shown).
Pipes 42 connect the underground storage tanks 34 to the fuel dispensers 32 . Pipes 42 may be arranged in a main conduit 44 and branch conduit 46 configuration, where the main conduit 44 carries the fuel to the branch conduits 46 , and the branch conduits 46 connect to the fuel dispensers 32 . Typically, pipes 42 are double walled pipes comprising an inner conduit and an outer conduit. Fuel flows in the inner conduit to the fuel dispensers, and the outer conduit insulates the environment from leaks in the inner conduit. For a better explanation of such pipes and concerns about how they are connected, reference is made to Chapter B13 of PIPING HANDBOOK, 7 th edition, copyright 2000, published by McGraw-Hill, which is hereby incorporated by reference.
In a typical service station installation, leak detection may be performed by a variety of techniques, including probes and leak detection cables. More information about such devices can be found in the previously incorporated PIPING HANDBOOK. Conventional installations do not return to the underground storage tank 34 fuel that leaks from the inner conduit to the outer conduit, but rather allow the fuel to be captured in low point sumps, trenches, or the like, where the fuel mixes with contaminants such as dirt, water and the like, thereby ruining the fuel for future use without processing.
While not shown, vapor recovery systems may also be integrated into the fueling environment 10 with vapor recovered from fueling operations being returned to the underground storage tanks 34 via separate vapor recovery lines (not shown). For more information on vapor recovery systems, the interested reader is directed to U.S. Pat. Nos. 5,040,577; 6,170,539; and Re. 35,238, and U.S. patent application Ser. No. 09/783,178 filed 14 Feb. 2001, all of which are hereby incorporated by reference in their entireties.
Now turning to the present invention, the main and branch supply conduit arrangement of FIG. 2 is replaced by a daisy chain fuel supply arrangement as illustrated in FIG. 3 . The underground storage tank 34 provides a fuel delivery path to a first fuel dispenser 32 1 via a double walled pipe 48 . The first fuel dispenser 32 1 is configured to allow the fuel delivery path to continue onto a second fuel dispenser 32 2 via a daisy chaining double walled pipe 50 . The process repeats until an nth fuel dispenser 32 n is reached. Each fuel dispenser 32 has a manifold 52 with an inlet aperture and an outlet aperture as will be better explained below. In the nth fuel dispenser 32 n , the outlet aperture is terminated conventionally as described in the previously incorporated PIPING HANDBOOK.
As better illustrated in FIG. 4 , each fuel dispenser 32 comprises a manifold 52 with a T-intersection housed therein. The T-intersection 54 allows the fuel line conduit 56 to be stubbed out of the daisy chaining double walled pipe 50 and particularly to extend through the outer wall 58 of the daisy chaining double walled pipe 50 . This T-intersection 54 may be a conventional T-intersection such as is found in the previously incorporated PIPING HANDBOOK. The manifold 52 comprises the aforementioned inlt aperture 60 and outlet aperture 62 . While shown on the sides of the manifold 52 's housing, they could equivalently be on the bottom side of the manifold 52 , if desired. Please note that the present invention is not limited to a manifold 52 with a T-joint, and that any other suitable configuration may be used that allows fuel to be supplied to a fuel dispenser 32 and allows to continue on as well to the next fuel dispenser 32 until the last fuel dispenser 32 is reached.
A leak detection probe 64 may also be positioned within the manifold 52 . This leak detection probe 64 may be any appropriate liquid detection sensor as needed or desired. The fuel dispenser 32 has conventional fuel handling components 66 therein, such as fuel pump 68 , a vapor recovery system 70 , a fueling hose 72 , a blender 74 , a flow meter 76 , and a fueling nozzle 78 . Other fuel handling components 66 may also be present as is well understood in the art.
With this arrangement, the fuel may flow into the fuel dispenser 32 in the fuel line conduit 56 , passing through the inlet aperture 60 of the manifold 52 . A check valve 80 may be used if needed or desired as is well understood to prevent fuel from flowing backwards. The fuel handling components 66 draw fuel through the check valve 80 and into the handling area of the fuel dispenser 32 . Fuel that is not needed for that fuel dispenser 32 is passed through the manifold 52 upstream to the other fuel dispensers 32 within the daisy chain. A sump (not shown) may still be associated with the fuel dispenser 32 , but it is fluidly isolated from the daisy chaining double walled pipe 50 .
A first embodiment of the connection of the daisy chaining double walled pipe 50 to the underground storage tank 34 is illustrated in FIG. 5 . The daisy chaining double walled pipe 50 connects to a casing construction 82 , which in turn connects to the double walled pipe 48 . A submersible turbine pump 84 is positioned within the underground storage tank 34 , preferably below the level of the fuel 86 within the underground storage tank 34 . For a more complete exploration of the casing construction 82 and the submersible turbine pump 84 , reference is made to U.S. Pat. No. 6,223,765 assigned to Marley Pump Company, which is incorporated herein by reference in its entirety and the product exemplifying the teachings of the patent explained in Quantum Submersible Pump Manual: Installation and Operation , also produced by the Marley Pump Company, also incorporated by reference in its entirety. In this embodiment, fuel captured by the outer wall 58 is returned to the casing construction 82 such as through a vacuum or by gravity feeds. A valve (not shown) may allow the fuel to pass into the casing construction 82 and thereby be connected to the double walled pipe 48 for return to the underground storage tank 34 . The structure of the casing construction in the '765 patent is well suited for this purpose having multiple paths by which fuel may be returned to the outer wall of the double walled pipe that connects the casing construction 82 to the submersible turbine pump 84 .
A second embodiment of the connection of the daisy chaining double walled pipe 50 to the underground storage tank 34 is illustrated in FIG. 6 . The casing construction 82 is substantially identical to the previously incorporated U.S. Pat. No. 6,223,765. The daisy chaining double walled pipe 50 however comprises a fluid connection 88 to the double walled pipe 48 . This allows the fuel in the outer wall 58 to drain directly to the underground storage tank 34 , instead of having to provide a return path through the casing construction 82 . Further, the continuous fluid connection from the underground storage tank 34 to the outer wall 58 causes any vacuum present in the underground storage tank 34 to also be existent in the outer wall 58 of the daisy chaining double walled pipe 50 . This vacuum may help drain the fuel back to the underground storage tank 34 . In an exemplary embodiment, the fluid connection 88 may also be double walled so as to comply with any appropriate regulations.
FIG. 7 illustrates the methodology of the present invention. During new construction of the fueling environment 10 , or perhaps when adding the present invention to an existing fueling environment 10 , the daisy chained piping system according to the present invention is installed (block 100 ). The pipe connection between the first fuel dispenser 32 1 and the underground storage tank 34 may, in an exemplary embodiment, be sloped such that gravity assists the drainage from the fuel dispenser 32 to the underground storage tank 34 . The leak detection system, and particularly, the leak detection probes 64 , are installed in the manifolds 52 of the fuel dispensers 32 (block 102 ). Note that the leak detection probes 64 may be installed during construction of the fuel dispensers 32 or retrofit as needed. In any event, the leak detection probes 64 may communicate with the site communicators such as the site controller 26 or the tank monitor 36 as needed or desired. This communication may be for alarm purposes, calibration purposes, testing purposes or the like as needed or desired. Additionally, this communication may pass through the site communicator to a remote location if needed. Further, note that additional leak detectors (not shown) may be installed for redundancies and/or positioned in the sumps of the fuel dispensers 32 . Still further, leak detection programs may be existent to determine if the underground storage tank 34 is leaking. These additional leak detection devices may likewise communicate with the site communicator as needed or desired.
The fueling environment 10 operates as is conventional, with fuel being dispensed to vehicles, vapor recovered, consumers interacting with the points of sale, and the operator generating revenue (block 104 ). At some point a leak occurs between two fuel dispensers 32 x and 32 x+1 . Alternatively, the leak may occur at a fuel dispenser 32 x+1 (block 106 ). The leaking fuel flows towards the underground storage tank 34 (block 108 ), as a function of the vacuum existent in the outer wall 58 , via gravity or the like. The leak is detected at the first downstream leak detection probe 64 (block 110 ). Thus, in the two examples, the leak would be detected by the leak detection probe 64 positioned within the fuel dispenser 32 x . This helps in pinpointing the leak. An alarm may be generated (block 112 ). This alarm may be reported to the site controller 26 , the tank monitor 36 or other location as needed or desired.
A second leak detection probe 64 , positioned downstream of the first leak detection probe 64 in the fuel dispenser 32 x−1 , will then detect the leaking fuel as it flows past the second leak detection probe 64 (block 114 ). This continues, with the leak detection probe 64 in each fuel dispenser 32 downstream of the leak detecting the leak until fuel dispenser 32 1 detects the leak. The fuel is then returned to the underground storage tank 34 (block 116 ).
If all downstream leak detection probes 64 detect the leak at query block 118 , that is indicative that the system works (block 120 ). If a downstream leak detection probe 64 fails to detect the leak during the query of block 118 , then there is potentially a failure in the outer wall 58 and an alarm may be generated (block 122 ). Further, if the leak detection probes 64 associated with fuel dispensers 32 x+1 and 32 x−1 both detect the leak, but the leak detection probe 64 associated with the fuel dispenser 32 x does not detect a leak, that is indicative of a sensor failure and a second type of alarm may be generated.
Additionally, once a leak is detected and the alarm is generated, the fueling environment 10 may shut down so that clean up and repair can begin. However, if the double walled piping system works the way it should, the only repair will be to the leaking section of inner pipe within the daisy chaining double walled pipe 50 or the leaking fuel dispenser 32 . Any fuel may caught by the outer wall 58 is returned for reuse, thus saving on clean up.
Those skilled in the art will recognize improvements and modifications to the preferred embodiments of the present invention. All such improvements and modifications are considered within the scope of the concepts disclosed herein and the claims that follow.
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A fueling environment that distributes fuel from a fuel supply to fuel dispensers in a daisy chain arrangement with a double walled piping system. Fuel leaks that occur within the double walled piping system are returned to the underground storage tank by the outer wall of the double walled piping. This preserves the fuel for later use and helps reduce the risk of environmental contamination. Leak detectors may also be positioned in fuel dispensers detect leaks and provide alarms for the operator and help pinpoint leak detection that has occurred in the piping system proximate to a particular fuel dispenser or in between two consecutive fuel dispensers.
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This application is based on Provisional Patent Application Serial No. 60/157,625, which was filed on Oct. 4, 1999, and priority is claimed thereto.
BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to the manufacture of window systems. More specifically, this invention relates to the manufacture of window systems using polymer based or metallurgy based component parts.
2. Description of Related Art
A variety of methods and process for the construction of window system assemblies have been proposed. Typically, these prior methods and processes require costly, complex, inconsistent, error and waste prone, susceptible to defects manufacturing steps. Generally, these prior methods and processes require a large number of pieces of equipment and skilled craftsmen. For general background, the reader is directed to the following United States Patent Nos., each of which is hereby incorporated by reference in its entirety for the material contained therein: U.S. Pat. Nos. 4,327,142, 4,407,100, 4,460,737, 5,155,956, 5,491,940, 5,540,019, 5,555,684, 5,585,155, 5,603,585, 5,620,648, 5,622,017, and 5,799,453. The reference to this related U.S. Patent documents is not an admission of prior art, as the inventor's date of invention may predate the date of filing and/or publication of these references.
SUMMARY OF THE INVENTION
It is desirable to provide a method and process of the manufacture window systems, which makes use of singular advanced components of a polymer based or metallurgy based window system, that minimizes complexity, cost, product inconsistencies, defects, while producing a universal window system using largely automated procedures and advanced materials.
Therefore, it is a general object of this invention to provide a method and process for the construction of universal window systems, using advanced components of a polymer based or a metallurgy based product.
It is a further object of this invention to provide a method and process for the construction of universal window systems that reduces labor costs.
It is a still further object of this invention to provide a method and process for the construction of universal window systems that reduces the defects of the window system products.
Another object of this invention is to provide a method and process for the construction of universal window systems that makes use of automation techniques to improve product quality.
A further object of this invention is to provide a method and process for the construction of universal window systems that produces window components in a singular form.
A still further object of this invention is to provide a method and process for the construction of universal window systems that works with extruded, injected, or other composite derived materials.
These and other objects of this invention will be readily apparent to those or ordinary skill in the art upon review of the following drawings, detailed description and claims. In the preferred embodiment of this invention, the method and process of this invention are described as follows.
BRIEF DESCRIPTION OF THE DRAWINGS
In order to show the manner that the above recited and other advantages and objects of the invention are obtained, a more particular description of the preferred embodiment of this invention, which is illustrated in the appended drawings, is described as follows. The reader should understand that the drawings depict only a present preferred and best mode embodiment of this invention, and are not to be considered as limiting in scope. A brief description of the drawings is as follows:
FIG. 1 a is a window component profile, manufactured using the process of this invention.
FIG. 1 b is an alternative window component profile, manufactured using the process of this invention.
FIG. 2 a is a window component profile in the rotational stage of the process of this invention.
FIG. 2 b is an alternative window component profile in the rotational stage of the process of this invention.
FIG. 3 a is a completed window component in the final stage ready for installation.
FIG. 3 b is an alternative completed window component in the final stage ready for installation.
FIG. 4 is a process flow diagram of the preferred method of this invention.
Reference will now be made in detail to the present preferred embodiment of the invention, examples of which are illustrated in the accompanying drawings.
DETAILED DESCRIPTION OF THE INVENTION
FIG. 1 a shows a window component profile, manufactured using the process of this invention. This preferred embodiment of the window component has three generally elongate sections 101 a , 101 b , 101 c and two half sections 102 a , 102 b , each connected 113 a , 113 b , 113 c , 113 d to an adjacent section. In alternative embodiments, when it is desired to have windows with non-rectangular shapes, the number of sections can be increased or reduced. For example, a triangular shaped window may have only two long sections and two half sections. In another example, an octagonal shaped window may have seven long sections and two half sections. The connections 113 a , 113 b , 113 c , 113 d are flexible permitting a bend at the connection 113 a , 113 b , 113 c , 113 d . The preferred elongate sections 101 a , 101 b , 101 c and half sections 102 a , 102 b are preferably made of a composite material, molded, cut, milled, routed or otherwise shaped in to the desired generally decorative shape. While the sections 101 a , 101 b , 101 c are shown, in this embodiment, as being of generally the same length, in alternative embodiments, the sections 101 a , 101 b , 101 c may have different lengths as appropriate to the desired window shape. Each section 101 a , 101 b , 101 c is provided with two diagonal cut sloped portions (respectively 105 , 106 ; 107 , 108 ; and 109 , 110 ). These diagonal cut sloped portions 105 , 106 , 107 , 108 , 109 , 110 are shown having an angle of 45 degrees, however, in alternative embodiments this angle may be either increased or decreased as necessary in order to facilitate the joining of two adjacent diagonal sloped portions, to thereby produce a window component having the desired shape. The ends 103 and 112 are, in this embodiment, at approximately 90 degrees from the base 100 of the window portions, thereby facilitating the joining of the ends 103 , 112 , as shown in FIG. 3 a.
FIG. 1 b shows an alternative window component profile, manufactured using the process of this invention. This second preferred embodiment of the window component has four generally elongate sections 114 a , 114 b , 114 c , 114 d each connected 116 a , 116 b , 116 c to an adjacent section. In alternative embodiments, when it is desired to have windows with non-rectangular shapes, the number of sections can be increased or reduced. For example, a triangular shaped window may have only three long sections. In another example, an octagonal shaped window may have eight long sections. The connections 116 a , 116 b , 116 c are flexible permitting a bend at the connection 116 a , 116 b , 116 c . The preferred elongate sections 114 a , 114 b , 114 c , 114 d are preferably made of a composite material, molded, cut, milled, routed or otherwise shaped in to the desired generally decorative shape. While the sections 114 a , 114 b , 114 c , 114 d are shown, in this embodiment, as being of generally the same length, in alternative embodiments the sections 114 a , 114 b , 114 c , 114 d may have different lengths, as appropriate for the desired window shape. Each section 114 a , 114 b , 114 c , 114 d is provided with two diagonal cut sloped portions (respectively 115 a , 115 b ; 115 c , 115 d ; 115 e , 115 f ; 115 g , 115 h ). These diagonal cut sloped portions 115 a , 115 b , 115 c , 115 d , 115 e , 115 f , 115 g , 115 h are shown having an angle of 45 degrees, however, in alternative embodiments this angle may be either increased or decreased as necessary in order to facilitate the joining of two adjacent diagonal sloped portions, to thereby produce a window component having the desired shape. The joining of the ends 117 , 118 are as shown in FIG. 3 b to form the complete window component.
FIG. 2 a shows a window component profile in the rotational stage of the process of this invention. This view shows the window component of FIG. 1 a , with the diagonal sloped portions 106 , 107 and 108 , 109 brought into contact and joined to form corners 201 , 202 and thereby the bottom 205 of the window component.
FIG. 2 b shows an alternative window component profile in the rotational stage of the process of this invention. This view shows the window component of FIG. 1 b , with the diagonal sloped portions 15 b , 115 c and 115 d , 115 e brought into contact and joined to form corners 203 , 204 and thereby the bottom 206 of the window component.
FIG. 3 a shows a completed window component in the final stage ready for installation of the window component of FIG. 1 a . Ends 103 and 112 are connected forming a joint 301 at the top 309 of the window component. Diagonal sloped portions 104 , 105 and 110 , 111 are brought into contact and joined to form corners 302 and 303 and to define an interior 307 suitable for holding and retaining glass or other similar transparent or semi-transparent material. The joints 301 , 311 , 312 , 313 , 314 are typically and preferably made using adhesive, although alternatives such as bolts, screws, pins, clips and the like can be substituted without departing from the concept of this invention.
FIG. 3 b shows a completed window component in the final stage ready for installation of the window component of FIG. 1 b . Ends 117 and 118 are connected forming a joint 315 of the diagonal sloped portions 115 a , 115 h , thereby forming a corner 304 . Diagonal sloped portions 115 f , 115 g are brought into contact and joined to form corner 305 and to define an interior 308 suitable for holding and retaining glass or other similar transparent or semi-transparent material. The joints 315 , 316 , 317 , 318 are typically and preferably made using adhesive, although alternatives such as bolts, screws, pins, clips and the like can be substituted without departing from the concept of this invention.
FIG. 4 shows a process flow diagram of the preferred method of this invention. Initially, the material is fed 400 into the assembly process. Next, the material is straight cut 401 preferably by a saw or mill machine. The cut material is set 402 for Lifter or Balance Holding punch, preferably on a drill or router machine. The material is then punched 403 for the lifter clip, also preferably on a drill or router machine. Weep punching 404 is next performed on the material, again typically using a punch, drill or router machine. These punching steps are used to provide ventilation and drainage points in the window component. Miscellaneous processing 405 is performed to remove loose material and/or rough edges. A first three-way cut 405 is made, to produce diagonal portions, preferably using a cutter, grinder, or corner set. A second three-way cut 406 is made, to produce additional diagonal portions, also preferably using a cutter, grinder or corner set. A second weep punch 408 is made to further provide additional drainage and ventilation, preferably using a drill or router machine. A polymer compound is applied 409 to the joint regions thereby providing durable, flexible corners. Identification markings are applied 410 to permit control and tracking of window components. The assembly or window component is rotated with the corner and/or end portions joined together using adhesive, screws, bolts, clips, pins or the like forming the complete window component ready for the insertion of the transparent medium and for installation in the building structure.
The described embodiments of this invention are to be considered in all respects only as illustrative and not as restrictive. Although specific steps and window system components are illustrated and described, the invention is not to be limited thereto. The scope of this invention is, therefore, indicated by the claims. All changes, which come within the meaning and range of equivalency of, the claims are to be embraced as being within their scope.
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A method for producing window components using polymer based, metallurgy based, extruded, injection molded, or wood material is provided. This invention provides a low cost, highly reliable, low defect method of producing window components by machining from a singular piece of material, providing bendable portions, with angled portions adapted to fit together to define a wide range of window shapes and sizes.
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RELATED APPLICATIONS
[0001] This application claims the benefit of Korean Patent Application No. 10-2013-0074203, filed on Jun. 27, 2013, which is hereby incorporated by reference as if fully set forth herein.
FIELD OF THE INVENTION
[0002] The invention relates to a voltage clamp step-up boost converter, and more specifically, to a voltage clamp step-up boost converter that removes the configuration of a dissipative snubber using a resonant clamp capacitor.
[0003] This work was supported by the MSIP (Ministry of Science, ICT and Future Planning) and NIPA (National IT Industry Promotion Agency) in Korea under Project 2013-H0301-13-2007 [Technology Research for Energy-IT Convergence].
BACKGROUND OF THE INVENTION
[0004] Recently, various power supply units used to boost a low DC voltage are being developed for electronic devices based on a fuel cell or battery. In particular, a boost converter using a tapped inductor is launched in the market in order to satisfy a high boost ratio, high power conversion efficiency, and low manufacturing cost.
[0005] The boost converter using the tapped inductor is manufactured by adding the tapped inductor serving as a transformer to the boost converter. In connection with the boost converter using the tapped inductor, Korean Patent Publication No. 2010-0082084 A (laid-open published on Jul. 16, 2010) discloses a method of embodying a zero-voltage turn-on and zero-current turn-off function by using a tapped inductor of the boost converter.
[0006] In the boost converter using tapped inductor, it is possible to obtain a high boost ratio, but an inductor and a capacitor of a switch causes an occurrence of resonance when the switch is turned off. As a result, a surge voltage is generated across the switch, which incurs an excessive stress on the switch. Hence, the boost converter using tapped inductor needs to use a high withstand voltage diode and a dissipative snubber.
SUMMARY OF THE INVENTION
[0007] In view of the above, the present invention provides a voltage clamp step-up boost converter that is capable of reducing voltage stress on a switch and a diode of the boost converter without using a dissipative snubber and that is capable of reducing a switching loss while maintaining a high input-to-output boost ratio. However, the technical subject of the embodiment of the present invention is not limited to the foregoing technical subject, and there may be other technical subjects.
[0008] In accordance with an aspect of the embodiment, there is provided an apparatus for a voltage clamp step-up boost converter comprising: a leakage inductor having a first end connected to a power supply unit; a tapped inductor having a first end connected to a second end of the leakage inductor; a magnetizing inductor having a first end connected to the second end of the leakage inductor and a second end connected to a second end of the tapped inductor; a switch having a first end connected to the second end of the tapped inductor and a second end connected to a second end of the power supply unit; a first diode having a first end connected to the second end of the tapped inductor; a second diode having a first end connected to a second end of the first diode and a second end connected to a third end of the tapped inductor; a resonant clamp capacitor having a second end connected between the second end of the first diode and the first end of the second diode and a first end connected between the first end of the power supply unit and the first end of the leakage inductor, the resonant clamp capacitor being configured to perform the clamping of the voltage across the switch and zero-voltage switching thereof when the switch is turned-off; an output capacitor having a first end connected to the second end of the second diode and a second end connected to the second end of the switch; an output load resistor having a first end connected to the first end of the second end of the output capacitor and a second end connected to the output capacitor; and a blocking capacitor having a first end connected to the third end of the tapped inductor and a second end connected to the second end of the second diode, wherein when the switch is turned-on, the voltage clamp step-up boost converter is configured to form a conductive path through the power supply unit, the resonant clamp capacitor, the blocking capacitor, the tapped inductor, and the switch and cause resonance through the resonant clamp capacitor and the leakage inductor with each other to decrease the voltage applied to the resonant clamp capacitor to a negative (−) voltage, thereby making the switch to be zero-current turned-on; and wherein when the switch is turned-off, the voltage clamp step-up boost converter is configured to form a conductive path through the leakage inductor, the tapped inductor, the first diode, and the resonant clamp capacitor to increase the voltage applied to the resonant clamp capacitor to a positive (+) voltage, thereby making the switch to be zero-voltage turned-off.
[0009] In accordance with any one of solutions to the aforementioned subject of the present invention, it is possible to reduce the voltage stress on a switch and a diode of the boost converter without using a dissipative snubber and to reduce a switching loss while maintaining a high input-output boost ratio.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] The above and other objects and features of the present invention will become apparent from the following description of the embodiments given in conjunction with the accompanying drawings, in which:
[0011] FIG. 1 is a circuit diagram of a voltage clamp step-up boost converter in accordance with an embodiment of the present invention;
[0012] FIGS. 2A to 2C are circuit diagrams illustrating other embodiments of a voltage clamp step-up boost converter shown in FIG. 1 ;
[0013] FIGS. 3A to 3N are circuit diagrams and timing diagrams of waveforms explaining the operation of the voltage clamp step-up boost converter shown in FIG. 1 ; and
[0014] FIGS. 4A and 4B illustrates experimental waveforms of the voltage clamp step-up boost converter of FIG. 1 and a prior art for the comparison between them.
DETAILED DESCRIPTION OF THE INVENTION
[0015] Hereinafter, embodiments of the present invention will be described in detail with reference to the accompanying drawings so that they can be readily implemented by those skilled in the art. However, the present invention may be embodied in different forms, but it is not limited thereto. In drawings, further, portions unrelated to the description of the present invention will be omitted for clarity of the description, and like reference numerals and like components refer to like elements throughout the detailed description.
[0016] In the entire specification, when a portion is “connected” to another portion, it means that the portions are not only “connected directly” with each other but they are electrically connected” with each other by way of another device between them. Further, when a portion “comprises” a component, it means that the portion does not exclude another component but further comprises other component unless otherwise described. Furthermore, it should be understood that one or more other features or numerals, steps, operations, components, parts or their combinations can be or are not excluded beforehand.
[0017] Hereinafter, the embodiments of the present invention will be described in detail with reference to the accompanying drawings.
[0018] FIG. 1 is a circuit diagram of a voltage clamp step-up boost converter in accordance with an embodiment of the present invention, and FIGS. 2A to 2C are circuit diagrams illustrating other embodiments of the voltage clamp step-up boost converter shown in FIG. 1 .
[0019] Before describing the embodiment of the present invention, a voltage clamp step-up boost converter 1 shown in FIG. 1 is defined functionally as follows.
[0020] The voltage clamp step-up boost converter 1 may include a boost converter, a tapped inductor, a resonant clamp capacitor, a blocking capacitor, and an output load resistor. Herein, reference numerals would not be assigned to the respective components of the voltage clamp step-up boost converter 1 because of a mere functional definition of them.
[0021] The boost converter serves to store current applied from a power supply unit in at least one inductor, add energy stored in the at least one inductor to the energy of the power supply voltage to deliver the added energy to an output end in accordance with on/off operations of a switch, and then output a boosted voltage through the output end.
[0022] The tapped inductor outputs an increased voltage based on a conversion factor, and the blocking capacitor is charged with the voltage in accordance with the on/off operations of the switch. In addition, the boosted voltage is applied to the output load resistor in accordance with the outputs from the boost converter, the tapped inductor, and the blocking capacitor. In the aforementioned configuration, the output load resistor may be incorporated into the boost converter, however, for the sake of convenience of explanation, the description thereof will be made separately.
[0023] Accordingly, the voltage clamp step-up boost converter 1 of the embodiment may have a high boost ratio by totaling all of the boost ratio of the boost converter itself, the boost ratio based on the turn ratio of the tapped inductor and the voltage charged in the blocking capacitor.
[0024] Hereinafter, the connection of the components in the voltage clamp step-up boost converter will be described in detail.
[0025] Referring to FIG. 1 , the voltage clamp step-up boost converter 1 may include a power supply unit 100 , a leakage inductor 210 , a magnetizing inductor 230 , a tapped inductor 300 , a switch 400 , a first diode 510 , a second diode 520 , a resonant clamp capacitor 600 , an output capacitor 710 , an output load resistor 730 , a DC blocking capacitor 800 , and an output diode 900 .
[0026] The leakage inductor 210 has a first end connected to the power supply unit 100 and a second end connected to the tapped inductor 300 and the magnetizing inductor 230 . The magnetizing inductor 230 has a first end connected to a second end of the leakage inductor 210 and a second end connected to a second end of the tapped inductor 300 .
[0027] The tapped inductor 300 has a first end connected to the second end of the leakage inductor 210 , a second end connected to a first end of the switch 400 , and a third end connected to a first end of the blocking capacitor 800 . The tapped inductor 300 may have a conversion factor of 1:N, where the first end of the tapped inductor becomes the primary side and the third end thereof becomes the secondary side. Like a transformer, the input-to-output conversion ratio of the tapped inductor 300 may be determined based on a coupling coefficient.
[0028] The switch 400 has the first end connected to the second end of the tapped inductor 300 and a second end connected to the second end of the power supply unit 100 . The switch 400 may be, for example, any one of a BJT (Bipolar Junction Transistor), a JFET (Junction Field-Effect Transistor), a MOSFET (Metal-Oxide Semiconductor Field-Effect Transistor), and a GaAs MESFET (Metal Semiconductor FET).
[0029] The first diode 510 has a first end that is connected to the second end of the tapped inductor 300 and a second end that is connected to a second end of the resonant clamp capacitor 600 and a first end of the second diode 520 . Further, the second diode 520 has the first end connected to the second end of the first diode 510 and a second end connected to the third end of the tapped inductor 300 .
[0030] The resonant clamp capacitor 600 has a second end connected between the second end of the first diode 510 and the first end of the second diode 520 . The resonant clamp capacitor 600 may be interposed for the voltage clamping across the switch 400 and the zero-voltage switching when the switch 400 is turned off. In this case, the first end of the resonant clamp capacitor 600 may be connected to a node to ensure that a constant voltage level is maintained. That is, the first end of the resonant clamp capacitor 600 is used as a clamp node, which may be connected to any node at which the constant voltage level is maintained. This will be explained with reference to FIGS. 2A to 2C .
[0031] Referring now to FIG. 2A , a resonant clamp capacitor 600 has a second end that is fixed between a first diode 510 and a second diode 520 . The resonant clamp capacitor 600 also has a first end that is freely connected to any one of points A, B, and C. The embodiment shown in FIG. 1 is defined as a case where the first end of the resonant clamp capacitor 600 is connected to a point A; an embodiment shown in FIG. 2A is defined as a case where the first end of the resonant clamp capacitor 600 is connected to a point B; and an embodiment shown in FIG. 2C is defined as a case where the first end of the resonant clamp capacitor 600 is connected to a point C.
[0032] When the first end of the resonant clamp capacitor 600 is connected to the point A, the arrangement corresponds to that illustrated in FIG. 1 . In this case, the first end of the resonant clamp capacitor 600 is connected between the first end of the power supply unit 100 and the first end of the leakage inductor 210 . When the first end of the resonant clamp capacitor 600 is connected to the point B, the arrangement corresponds to that illustrated in FIG. 2B . In this case, the first end of a resonant clamp capacitor 600 is connected between the second end of a power supply unit 100 and the second end of a switch 400 . When the first end of the resonant clamp capacitor 600 is connected to the point C, the arrangement corresponds to that illustrated in FIG. 2C . In this case, the first end of the resonant clamp capacitor 600 is connected between the second end of an output diode 900 and the first end of an output capacitor 710 .
[0033] The overall operations of the voltage clamp step-up boost converters illustrated in FIGS. 2A to 2C are substantially same one other, except the difference in the offset voltages applied to the resonant clamp capacitor 600 . Specifically, the offset voltage applied to the resonant clamp capacitor 600 of FIG. 2A may be lower than that of the resonant clamp capacitor 600 of FIGS. 2B and 2C . Therefore, the voltage clamp step-up boost converter 1 of the embodiment illustrated in FIG. 2A may exhibit the lowest withstand voltage property.
[0034] Referring back to FIG. 1 , the output capacitor 710 has a first end connected to the second end of the second diode 520 and a second end connected to the second end of the switch 400 . In addition, the output load resistor 730 has a first end connected to the first end of the output capacitor 710 and a second end connected to the second end of the output capacitor 710 .
[0035] The DC blocking capacitor 800 has a first end connected to the third end of the tapped inductor 300 and a second end connected to the second end of the second diode 520 . The output diode 900 has a first end connected to the second ends of the blocking capacitor 800 and the second diode 520 and a second end connected to the first end of the output capacitor 710 .
[0036] FIGS. 3A to 3N illustrate circuit diagrams and timing diagrams of waveforms explaining the operation of the voltage clamp step-up boost converter shown in FIG. 1 . Hereinafter, the operation of the voltage clamp step-up boost converter 1 having the foregoing configuration will be explained in detail with reference to FIG. 1 and FIGS. 3A to 3N .
[0037] Before explaining the operation, it is assumed for the convenience of the interpretation of the operation modes as follows:
[0038] i) the magnetizing inductor 230 has inductance as large as to ignore a current ripple caused by the magnetizing inductor 230 ; ii) the components of the voltage clamp step-up boost converter 1 of the embodiments are ideal; iii) the output capacitor 710 has capacitance as large as to ignore the voltage ripple of an output voltage Vo; iv) the blocking capacitor 800 has capacitance as large as to ignore the voltage ripple of a voltage V C applied to the blocking capacitor 800 ; and V) all operations are in steady-states.
[0039] Hereinafter, two terms in pairs will be designated as the same component such as the power supply unit 100 and V in ; the leakage inductor 210 and L Lk ; the magnetizing inductor 230 and L m ; the switch 400 and M; the first diode 510 and D 1 ; the second diode 520 and D 2 ; the resonant clamp capacitor 600 and C S ; the output capacitor 710 and C O ; the output load resistor 730 and R O ; the blocking capacitor 800 and C C ; and the output diode 900 and D 3 . Moreover, i pri means the primary side current of the tapped inductor 300 ; V LK means the voltage applied to the leakage inductor 210 ; V Lm means the voltage applied to the magnetizing inductor 230 ; i ds means current flowing to a drain and source of the switch 400 ; V sec means the secondary side voltage of the tapped inductor 300 ; V C means the voltage applied to the blocking capacitor 800 ; i sec means the secondary side current of the tapped inductor 300 (the waveform of i sec will be represented in an inverted form throughout FIGS. 3A to 3N for the sake of convenience); V D1 the voltage applied to the first diode 510 ; in means the current flowing to the first diode 510 ; V S means the voltage applied to the resonant clamp capacitor 600 ; i CS means the current flowing to the resonant clamp capacitor 600 ; V D2 means the voltage applied to the second diode 520 ; i D2 means the current flowing to the second diode 520 ; V D3 means the voltage applied to the output diode 900 ; and i D3 means the current flowing to the output diode 900 .
[0040] FIG. 3A represents a conductive path in accordance with the operation of the voltage clamp step-up boost converter at t 0 ˜t 1 . Referring to FIG. 3B , the switch 400 is in a turned-off state prior to t 0 , and the energy stored in the magnetizing inductor 230 is passed to the output end through the output diode 900 . At t 0 ˜t 1 , the switch 400 become a turned-on state, a conductive path of the voltage clamp step-up boost converter is illustrated as in FIG. 3A .
[0041] As illustrated in the FIG. 3B , the voltage V ds across the switch 400 rapidly decreases from V O /(1+N) to 0V and at the same time the primary side current i pri of the tapped inductor 300 increases and the secondary side current i sec decreases (in view of its inverted waveform). Specifically, the secondary side current i sec slowly decreases to 0 A by the leakage inductor 210 (in view of its inverted waveform) and the magnetizing inductor 230 and the primary side current i pri slowly increases.
[0042] Therefore, because the current i pri −i sec which flows through the switch 400 gradually increases, when the switch 400 is turned on, the voltage V ds and the current i ds have a phase reversal relation enough not to overlap with each other in their waveforms, thereby reducing the switching loss.
[0043] FIG. 3C represents a conductive path in accordance with the operation of the voltage clamp step-up boost converter at t 1 ˜t 2 . Referring to FIG. 3D , the operation of the voltage clamp step-up boost converter at t 1 ˜t 2 is started when the primary side current i pri gradually increases to become equal to the current i Lm of the magnetizing inductor 230 and the secondary side current i sec of the magnetizing inductor 230 becomes equal to 0 A. At this time, the output diode 900 is turned off and the second diode 520 is turned on, thereby forming the conductive path illustrated in FIG. 3C . Accordingly, the voltage applied to the blocking capacitor 800 becomes to reduce to −V in due to the resonance of the resonant clamp capacitor 600 and the leakage inductor 210 .
[0044] FIG. 3E represents a conductive path in accordance with the operation of the voltage clamp step-up boost converter at t 2 ˜t 3 . Referring to FIG. 3F , the operation of the voltage clamp step-up boost converter at t 2 ˜t 3 is started when the voltage applied to the resonant clamp capacitor 600 reaches −V in . At this time, the first diode 510 is conducted, thereby forming the conductive path illustrated in FIG. 3E . In this case, because the switch 400 is in a turned-on state, the input voltage V in is applied to both of the leakage inductor 210 and the magnetizing inductor 230 . Accordingly, energy is stored in the magnetizing inductor 230 and simultaneously, NV in is charged in the blocking capacitor 800 with the turn ratio of the tapped inductor 300 .
[0045] FIG. 3G represents a conductive path in accordance with the operation of the voltage clamp step-up boost converter at t 3 ˜t 4 . Referring to FIG. 3H , when the blocking capacitor 800 is fully charged, the first diode 510 and the second diode 520 are turned off as illustrated in FIG. 3G . Since the switch 400 is still turned on, the input voltage V in is applied to the leakage inductor 210 and the magnetizing inductor 230 as similar to FIG. 3C and thus energy is stored in the magnetizing inductor 230 .
[0046] FIG. 3I represents a conductive path in accordance with the operation of the voltage clamp step-up boost converter at t 4 ˜t 5 . Referring to FIG. 3I , when the switch 400 is turned off, the conductive path is formed as illustrated in FIG. 3I and the current i Lm of the switch 400 is rapidly reduced to 0 A as illustrated in FIG. 3J . At the same time, the energy stored in the leakage inductor 210 and the magnetizing inductor 230 is charged in the resonant clamp capacitor 600 through the first diode 510 . Therefore, the voltage applied to the resonant clamp capacitor 600 begins to gradually increase from −V in . Further, the voltage across the switch 400 , which is represented as V in +V CS , gradually begins to increase from 0V. Accordingly, when the switch 400 is turned-off, the voltage V ds and the current i ds have a phase reversal relationship enough not to overlap with each other in their waveforms, whereby it is possible to reduce the switching loss.
[0047] FIG. 3K represents a conductive path in accordance with the operation of the voltage clamp step-up boost converter at t 5 ˜t 6 . Referring to FIG. 3L , when the voltage V ds across the switch 400 reaches V O /(1+N), the output diode 900 is conducted and the resonant clamp capacitor 600 and the leakage inductor 210 cause resonance together. Therefore, the voltage V S of the resonant clamp capacitor 600 and the voltage V ds of the switch 400 increase as illustrated in Fig. L, and the current i D1 of the first diode 510 becomes 0 after ¼ resonance cycle. Simultaneously, when the secondary side current i sec reaches i Lm /(N+1), the operation at the t 5 ˜t 6 is finished.
[0048] FIG. 3M represents a conductive path in accordance with the operation of the voltage clamp step-up boost converter at t 6 ˜t 7 . Referring to FIG. 3N , when the secondary side current i sec reaches the i Lm /(N+1), the conductive path is formed as illustrated in FIG. 3M and the energy stored in the leakage inductor 210 and the magnetizing inductor 230 is passed to the output end. Thereafter, when the switch 400 is again turned on, the operation at t 6 ˜t 7 is finished.
[0049] The voltage relational expressions are derived in accordance with the aforementioned operations as follows.
[0050] First, let the operations at t 0 ˜t 2 and t 4 ˜t 6 be ignored for the convenience of deriving the voltage relational expressions related to the respective components off the voltage clamp step-up boost converter in accordance with the embodiment of the present invention.
[0051] The voltage V C is applied to the secondary side of the tapped inductor 300 for the duration DT S where the switch 400 is in a turned-on state whereas the voltage −(V O −V C −V in )N/(N+1) is applied to the secondary side of the tapped inductor 300 for the duration (1−D)T S where the switch 400 is in a turned-off state. Therefore, the following Equation can be derived by applying a voltage-time balanced condition to the secondary side of the tapped inductor 300 .
[0000]
DT
S
V
C
=
(
1
-
D
)
T
S
N
N
+
1
(
Vo
-
V
C
-
V
in
)
[
EQUATION
1
]
[0052] By rearranging the Equation 1, V C can be expressed as the following Equation 2.
[0000] V C NV in [EQUATION 2]
[0053] In the meantime, the voltage V in is applied to an voltage V LM of the primary side of the magnetizing inductor 230 for the duration DT S where the switch 400 is in a turned-on state whereas the voltage −(V O −V in −V C )/(1+N) is applied to the voltage V LM of the primary side of the magnetizing inductor 230 for the duration (1-D)T S where the switch 400 is in a turned-off state. Therefore, the following Equation can be derived by applying voltage-time balanced condition to the primary side of the tapped inductor 300 .
[0000] DT S V in =(1− D ) T S ( V O −V in −V C )/(1+ N ) [EQUATION 3]
[0054] By substituting the Equation 3 with the Equation 2, the following Equation 4 can be derived.
[0000]
V
O
=
N
+
1
1
-
D
V
in
[
EQUATION
4
]
[0000] where V O represents an output voltage, V in represents an input voltage, N represents the conversion factor (or, turn ratio) of the tapped inductor, and D represents a duty ratio.
[0055] FIGS. 4A and 4B shows experimental waveforms of the voltage clamp step-up boost converter of FIG. 1 and a prior art for the comparison between them. Specifically, FIG. 4A shows an experimental result on the voltage clamp step-up boost converter of the present invention using a simulation tool.
[0056] The specification used in the simulation is as follows: the input voltage is 24V; the output voltage and electricity are 250V and 100 W, respectively; the inductance of the leakage inductor 210 is 10 μl; the inductance of the magnetizing inductor 230 is 100 μH; the turn ratio of the inductors is 1:4; and the capacitance of the resonant clamp capacitor 600 is 47 nF.
[0057] Referring to FIG. 4A , it can be known that regardless of the resonance caused by the inductor component of the tapped inductor and the parasitic capacitor, the voltage of each component is clamped by the input and output voltages. Further, the current of the switch 400 increases with a slow inclination when the switch 400 is turned on. Therefore, the waveforms of the voltage V ds across the switch 400 and the current i ds of the switch 400 are not overlap with each other. Meanwhile, the voltage of the switch 400 also increases with a slow inclination when the switch 400 is turned off. Therefore, the waveforms of the voltage V ds across the switch 400 and the current I ds of the switch 400 are also not overlap. Consequently, a very low switching loss is achieved in the actual implementation.
[0058] On the other hand, FIG. 4B shows an experimental result on the voltage clamp step-up boost converter of the prior art under the same condition. It can be seen from FIG. 4B that the diode and switch have high voltage stress with the resonance of the inductor component of the transformer and the parasitic capacitor. Particularly, it is observed that the magnitude of current of the magnetizing inductor in the tapped inductor is 7.5 A which is higher than the embodiment of the present invention with respect to the same output load. In addition, the prior art requires the winding number more than usual and a magnetic core having a large air gap and large size in order to prevent the saturation of the tapped inductor.
[0059] As set forth above, the voltage clamp step-up boost converter in accordance with the embodiments can be ensured to get the input-to-output boost ratio which is higher than the conventional tapped inductor boost converter by combining all of the turn ratio of the transformer, the voltage of the blocking capacitor, and the boost ratio of the boost converter itself. Especially, the voltage clamp step-up boost converter enables to make the zero current switching by means of the leakage inductance when switch is in a turned-on state and to make the zero-voltage switching by means of the resonant clamp capacitor when the switch is in a turned-off state, thereby significantly reducing the switching loss. Accordingly, the voltage clamp step-up boost converter of the embodiments enables to improve the system efficiency and heat generation.
[0060] Description of the present invention as mentioned above is intended for illustrative purposes, and it will be understood to those having ordinary skill in the art that this invention can be easily modified into other specific forms without changing the technical idea and the essential characteristics of the present invention. Accordingly, it should be understood that the embodiments described above are exemplary in all respects and not limited thereto. For example, respective components described to be one body may be implemented separately from one another, and likewise components described separately from one another may be implemented in an integrated type.
[0061] The scope of the present invention is represented by the claims described below rather than the foregoing detailed description, and it should be construed that all modifications or changes derived from the meaning and scope of the claims and their equivalent concepts are intended to be fallen within the scope of the present invention.
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A apparatus provides a voltage clamp step-up boost converter that is capable of reducing voltage stress on a switch and a diode of the boost converter without using a dissipative snubber and that is capable of reducing a switching loss while maintaining a high input-to-output boost ratio.
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BACKGROUND OF THE INVENTION
The advent of structural thermoplastic materials having good heat and electrical resistive properties has resulted in the use of such materials as circuit breaker and power bus support saddles hereafter referred to as "saddles". Such plastic molded saddles having means integrally formed for supporting the circuit breakers as well as the main bus conductors and neutral bus connectors are already known. It is also known to interconnect several individual modular saddles to accomplish circuit breaker load centers and panel boards of adjustable length. The molded thermoplastic support saddles currently available require angular mounting of the neutral bus connectors within integrally formed supports. The angular loading requirement has heretofore deterred completely automated production because of the difficulties involved with robotic assembly when such neutral bus conductors must be angularly mounted.
A further hindrance to automated circuit breaker load center and panel board manufacture is the requirement that the modular auxiliary plastic saddles used for extending the length of such load centers and panel boards be interconnected with the main plastic saddle by means of a horizontal sliding procedure that is likewise difficult to automate. One example of an automatable lighting panel board assembly is shown in U.S. patent application Ser. No. 705,454, filed Feb. 25, 1985 and entitled "Lighting Circuit Breaker Panel Board Modular Assembly". This Application is incorporated herein for reference purposes and should be reviewed for its description of the materials used to form the molded plastic saddle. One purpose of the instant invention therefore is to provide an automated circuit breaker load center and panel board assembly wherein the main bus conductors and neutral bus conductors are "down-loaded" onto the plastic saddle in the vertical plane for ease in robotic assembly. A further purpose is to provide modular auxiliary circuit breaker and power bus supports that can be interconnected by means of a down-loaded operation for robotic assembly.
SUMMARY OF THE INVENTION
The invention comprises a molded thermoplastic circuit breaker and power bus support saddle having means integrally formed therein for receiving the main bus and neutral bus conductors in a down-loaded process. Means are provided on the support for accepting one or more auxiliary thermoplastic extension modules to provide such circuit breaker and power bus support saddles of varying length without interferring with the speed of automated assembly.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a plan view of the molded plastic support saddle according to the invention;
FIG. 2 is a side view of the support saddle of FIG. 1;
FIG. 3 is a plan view of a modular auxiliary support saddle for connecting with the bus support saddle of FIGS. 1 and 2; and
FIG. 4 is a side view of the modular auxiliary support saddle depicted in FIG. 3.
DESCRIPTION OF THE PREFERRED EMBODIMENT
A circuit breaker and power bus support saddle 10 hereafter "saddle", is shown in FIG. 1 to consist of a thermoplastic support 11 having a plurality of posts 12 integrally formed therein for supporting the main power busses on the inner planar parallel surfaces 16 and 17. A plurality of circular recesses 13 are integrally formed within the bottom of the support for providing insulation between the bottom of the screws used to attach the circuit breaker contact stabs to the main power bus. A plurality of circuit breaker branch strap support platforms 34 having circuit breaker stab support posts 36, 37 and a stop 35 integrally formed therein extend upward from the support platform. A plurality of circuit breaker support hooks 15 are formed next to each inner planar parallel surface 16, 17 to support the circuit breakers when loaded on to the plastic saddle. Planar surfaces 19 and 20 outboard the inner planar parallel surfaces 16, 17 provide support to the neutral bus connector terminals when supported thereon by means of support posts 22 and pedestals 21 integrally formed at one end of the outboard planar parallel surfaces. A raised end barrier 40 is formed upright from these surfaces to electrically insulate the neutral conductor terminals from other electrical components within the circuit breaker load center or panel board enclosure. Tubular extension members 30, 31 are formed at one end of the circuit breaker support hooks to electrically shield the support screws which are used to hold the saddle to the load center or panel board support pan (not shown). A pair of split posts 32, 33 are integrally formed next to the tubular extensions for receiving a main circuit breaker modular adapter which may optionally be connected to the main saddle for use within some electrical installations. The relative height of the raised insulating barriers 28, 29 formed on opposite sides of the support with respect to the circuit breaker hooks 15 and the raised end barriers 40 can be seen by referring now to FIG. 2. The outer planar parallel surfaces 20 provide support for the neutral terminal connectors when arranged thereon and supported at their ends by means of the pedestal 21 and post 22 formed at one end and by means of support posts 25, 26 formed at an opposite end. Reinforcing ribs 41 extend across the bottom of the saddle to provide additional structural support and the circular recesses 13 extend from the bottom to provide electrical isolation between the screws used to hold the circuit breaker stabs to the power busses as well as to provide spacing between the saddle and the load center or panel board enclosure, or a metal mounting pan used therein. The saddle is attached to the enclosure by means of screws inserted through the slots 9 and through the holes in the tubular extension members 30 and 31. A projection 42 on one side of each of the two inverted U-shaped rails 43 which extend from one end of the support tightly engages a complimentary slot 65,66 formed on a modular extension saddle 44 hereafter "extension module" best seen by referring now to FIG. 3 to further increase the length of the saddle.
The extension module is similar to the plastic saddle 10, described earlier in that both are formed from a thermoplastic material within an injection molding process. A plastic module support 45 contains an integrally molded step 46 at one end for mating with a recessed area 68 of a similar extension module when more than one extension module is required. The two inverted U-shaped rails 49 which extend from the end 46 of the support 45 proximate the end of the circuit breaker support hooks 69 receive similar inverted U-shaped rails 70 which are part of the opposite end 68. When an additional extension module is attached by placement of a complimentary additional end 68 (not shown) over step 46 in a downward motion defined as the vertical plane in FIG. 3, the inverted U-shaped rails 70 overlap the inverted U-shaped rails 49 and the projections 63, 64 formed on the sides of the rails snappingly engage complimentary slots 65, 66 formed in the sides of the rails 70. The plastic saddle expansion facility by the use of slots 65, 66 and projections 63, 64 at opposite ends of the module can be seen by referring now to FIG. 4 wherein a similar module support 45A is shown positioned above step 46 at one end for down-loading rail 70A over rail 49 such that the slot 65A in rail 70A snappingly engages projection 64 formed in rail 49. Connection is made at the opposite end by engagement of rail 70 over step 46B on a similar module support 45B. Rail 70 fits over rail 49B and slot 65 snappingly engages projection 64B on module support 45B. Although only one such projection and slot are shown, it is understood that projections and slots on the opposite side of each end, although not visible, also become engaged in the assembly process.
Referring back to FIG. 3, the modular extension 44 is shown similar to the plastic saddle of FIGS. 1 and 2 in that similar planar surfaces 54, 55 are formed within the module support 45 for receiving the power busses when positioned over the integrally formed support posts 57 and to which the circuit breaker mounting stabs (not shown) are attached by insertion of screws down within the circular recesses 58 formed within the support. A bus support platform 59 containing the circuit breaker stab support posts 60-62 cooperate to maintain and support the circuit breaker stabs in a manner similar to that described earlier with reference to FIGS. 1 and 2. A pair of extensions 51 and 52 are integrally formed on either side of the module support and contain slots 53 for the insertion of screws for attachment to the load center or panel board bottom pan or enclosure.
It is thus shown that an inexpensive thermoplastic saddle having integral circuit breaker, power bus and neutral terminal support means formed thereon can be utilized within a completely automated assembly process in view of the down-loaded assembly of components. A large number of circuit breakers for any size load center or panel board design can be provided by means of auxiliary extension modules having double-ended facility for attachment to a main circuit breaker saddle or to another extension module in a down-loaded serial arrangement.
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A modular molded plastic circuit breaker and power bus support carries a plurality of integrally formed circuit breaker support hooks and power bus support posts on a common thermoplastic saddle for automated assembly. Means are formed at one end of the saddle for receiving modular extension saddles to accommodate circuit breaker load centers and panel boards of varying length during the automated assembly process.
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BACKGROUND OF THE INVENTION
It is desirable to have telescopically length variable steering columns in motor vehicles for adapting the length of the steering column to the body size of the respective driver.
STATEMENT OF THE PRIOR ART
In the German Patent Application P 39 02 882.8 (published after Sept. 12, 1989), it was suggested to provide a hydraulically blockable gas spring as a positioning device for the length adjustment of a steering column in a motor vehicle.
OBJECT OF THE INVENTION
It is an object of the present invention to provide a length variable steering column with hydraulic locking means such that these hydraulic locking means are integrated into the steering column and that no lateral parts project beyond the steering column.
A further object of the present invention is to provide a steering column of adjustable length which can be easily manufactured with a minimum of costs.
A further object of the present invention is to provide a steering column which is adapted to transmit even high steering torques.
SUMMARY OF THE INVENTION
A telescopically length variable steering column arrangement for a motor vehicle has an axis and comprises at least two telescopically and torque transmittingly interengaging steering column elements. These steering column elements are rotatably mounted in a bearing system of the body work of the motor vehicle. A steering wheel is allocated to a first one of said steering column elements for common rotation therewith, and connection means are allocated to a second one of said steering column element for being connected with steering gear means. The steering gear means are provided for effecting the steering movement of the vehicle wheels. A fluid operated locking system is provided within at least one of said at least two steering column elements for locking the steering column elements in a plurality of selectable relative axial positions. The locking means comprise locking valve means and a locking control element operatively connected with the locking valve means.
With a steering column arrangement of the present invention, the majority of parts of the fluid operated locking system are housed within the steering column. There are no laterally projecting parts. The column has therefore a good appearance. No housing means are necessary for accommodating laterally projecting parts. There is no danger of injury in the event of an accident.
The steering column arrangement has a first end portion adjacent the steering wheel and a second end portion adjacent the steering gear means. The locking control element may be preferably located adjacent the first end of the steering column arrangement, and this means that the locking control element may be located in the central area of the steering wheel. If an actuating device of a signal horn is located in this central area of the steering wheel, it is easy to provide a transmission means extending from the central area of the steering wheel to an excentrically located control element.
According to a preferred embodiment, the fluid operated locking system comprises a cylinder having an axis and two ends and defining a cavity therein. A piston rod unit extends through at least one of the two ends. A piston unit is connected with the piston rod unit within the cavity and separates two working chambers within the cavity from each other. Passage means are provided for interconnecting the working chambers, and locking valve means are allocated to the passage means. Such a fluid operated locking system is readily available in the market, e.g. in form of gas spring and hydraulic locking units or hydropneumatic locking units.
When the fluid operated locking system is in the form of a cylinder piston device, the cylinder member may act as one of the steering column elements, and a tube member may be non-rotatably guided on the cylinder member and act as the other one of the steering column elements. In this case, the piston rod unit may be operatively connected with this tube member.
Due to the fact that the cylinder member fulfills the function of one of the telescopic steering column elements, a very compact steering column is obtained with a minimum of components.
The tube member may be operatively connected with the steering wheel, whereas the cylinder member is operatively connected with the steering gear means. In this case, the locking control element may be provided adjacent an end portion of the piston rod unit and adjacent the steering wheel. E.g., the piston rod unit may be provided with a hollow piston rod, and the locking control element may be provided at the outer end of this piston rod. Such, the movement of the locking control element on actuation thereof may be transmitted through the bore of the piston rod to the locking valve means which may be provided adjacent the piston unit.
Alternatively, the cylinder member may be operatively connected adjacent a bottom end thereof with a steering wheel. In this case, the tube member will be operatively connected with the steering gear means, and the locking control element may be provided adjacent the bottom end of the cylinder member.
When the cylinder member acts as one of the steering column elements, this cylinder member is provided with torque transmission means engaging complementary torque transmission means of the tube member. These torque transmission means may be shaped in the cylinder member itself. Alternatively, it is possible also that the cylinder member is surrounded by a torque transmitting sleeve non-rotatably connected with the cylinder member and that this torque transmitting sleeve is provided with torque transmission means engageable with complementary torque transmission means of the tube member.
The torque transmission means and the complementary torque transmission means may be provided by axially extending spline means which provide a low resistance against telescoping of the cylinder member and the tube member with respect to each other.
The complementary torque transmission means of the tube member may be provided by a torque transmission ring member fixed to an end portion of the tube member. This facilitates the manufacturing of the complementary torque transmission means and helps to lower the manufacturing costs.
Besides the possibility of using the cylinder member as one of the steering column elements, there exists also the possibility that the steering column elements are provided by two steering column tubes providing a hollow space therein. In this case, the cylinder member and the piston rod unit of the cylinder piston device may be housed within this hollow space and one of the steering column tubes may be operatively connected with the piston rod unit, whereas the other one of the steering column tubes is operatively connected with the cylinder member. In this case, the steering column tubes are provided with respective torque transmission means, and these torque transmission means may again be spline means.
The steering column elements may be rotatably mounted within an external bearing tube. Such an external bearing tube is of particular interest, if it is desired also to selectively vary the inclination of the steering column with respect to the body work of the motor vehicle.
Irrespective of the existence or non-existence of an external bearing tube, the first steering column element may be slidingly and rotatably mounted within a first bearing unit, whereas the second steering column element may be rotatably mounted and axially supported by a second bearing unit.
It is desirable that a telescopically length variable steering column is unlocked for a reduction of its axial length in case of an accident. This may be achieved in that the fluid operated locking system is provided with securing means unlocking the steering column elements in a respective position in response to a predetermined axial load. If the fluid operated locking system comprises at least two working chambers the respective volumes of which are variable in response to relative axial movement of the steering column elements, at least one of the working chambers may be provided with an escape opening. This escape opening may be provided with emergency closure means. These emergency closure means may be provided for opening under a predetermined axial load on the steering column elements.
The fluid operated locking means may be combined with biasing means biasing the steering column elements towards a terminal relative position such that the steering column elements move towards said terminal relative position in response to opening the locking valve means. E.g., it is possible that the steering column is under prestress such that on opening the locking valve means, the steering column is automatically adjusted to its maximum length. In this case, the driver who wants to lengthen the steering column must only actuate the locking control element and wait for the automatic increase of length, until the desired length value is obtained. In this moment, the driver has to stop actuation of the locking control element. Alternatively, it is also possible to integrate the biasing means such that on releasing the locking system, the length of the steering column is automatically shortened.
The biasing means may comprise a volume of pressurized gas, such as it is known from gas springs and hydropneumatic locking elements.
The fluid operated locking system may comprise a volume of locking liquid in at least two working chambers separated from each other by said locking valve means.
The fluid operated locking system may also be used for a damping movement of the steering column in case of an accident.
The various features of novelty which characterize the invention are pointed out with particularity in the claims annexed to and forming a part of the disclosure. For a better understanding of the invention, its operating advantages and specific objects attained by its use, reference should be had to the accompanying drawings and descriptive methods, in which there are illustrated and described preferred embodiments of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention will be explained in greater detail hereinafter with reference to embodiments shown in the accompanying drawings in which
FIG. 1 shows a longitudinal section through a first embodiment of a steering column arrangement according to the present invention;
FIG. 2 shows a section according to line II--II of FIG. 1;
FIG. 3 shows a hydropneumatic cylinder piston device to be used as a fluid operated locking system for a steering column of the present invention;
FIG. 4 shows a diagrammatic sectional view of a second embodiment of a steering column arrangement and
FIG. 5 shows a diagrammatic sectional view of a third embodiment of a steering column arrangement of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The steering column 2 shown in FIG. 1 comprises a tube member 3, which at its upper end is rigidly connected with a steering wheel 1. The steering column 2 further comprises a cylinder 6 of a hydropneumatic adjusting element 4. A piston rod 5 of this hydropneumatic adjusting element 4 is connected with the upper end of the tube member 3 in the area of the steering wheel 1. The cylinder 6 of the hydropneumatic adjusting element 4 is in telescopic engagement with the tube member 3 so that the tube member 3 is axially slidable with respect to the cylinder 6, and a steering torque can be transmitted from the steering wheel 1 through the tube member 3 to the cylinder 6. The length of the steering column 2 is variable by axially sliding the tube member 2 with respect to the cylinder member 6. A torque transmitting ring 16 is fixed to the lower end of the tube member 3. This torque transmitting ring 16 is provided with axially extending groove means 18 interengaging with complementary axially extending spline means 17 of the cylinder member 6. The spline means of the cylinder member 6 may either be directly shaped into the wall of the cylinder member or may be provided on a sleeve surrounding the cylinder 6 and fixed with respect to the cylinder both in axial and circumferential direction.
To accommodate the steering column 2, which consists of the tube member 3 and the cylinder member 6, an external tube 7 is provided which is fixed on parts 8 and 9 which are rigid with the body work of the motor vehicle. Alternatively, the external tube 7 may also be tiltable and fixable in various tilting positions with respect to the body work. A bearing bush 10 is fixed in the external tube 7 near the upper end thereof. In this bearing bush 10, the tube member 3 is axially slidable and rotatable. A further bearing 11 is provided at the lower end of the external tube 7 and is fixed in this external tube. A stud-like connection part 12 is connected with a bottom plate of the cylinder 6. This stud-like connection part is rotatably mounted and axially fixed by the lower bearing 11 within the stationary external tube 7. The axial fixation is obtained by a locking ring 14 engaging a groove 13 of the stud-like connection part 12. Thus, axial forces from the cylinder 6 are transmitted to the external tube 7 via the bearing 11.
The assembling of the steering column arrangement is very simple. One can enter the cylinder 6 together with the tube member 3 into the external tube 7 from the upper end thereof and thereafter fix the cylinder 6 within the bearing 11 by providing the locking ring 14. A push member 15 serves as a locking control element. This push member 15 is provided at the upper end of the hollow piston rod 5 and is located in the centre of the bearing wheel 1. This push member 15 serves to actuate a valve disposed within the hydropneumatic adjusting element 4. The push member 15 can e.g. be actuated via an actuating lever not shown in the drawings, since usually the actuating device for the signal horn is provided in the centre of the driving wheel 1.
In FIG. 1, the external tube 7 is supported by rigid parts 8 and 9 of the body work of the motor vehicle. It is easily understandable, however, that the external tube 7 could also be tiltably mounted within the body work of the motor vehicle so that the inclination of the steering column 2 could be adjusted according to the wishes of the driver.
FIG. 3 shows the adjusting element 4. The cylinder 6 is provided with longitudinal grooves or is surrounded by a sleeve which is axially and circumferentially fixed with respect to the cylinder 6, and in this case the sleeve could be provided with longitudinal grooves. At the upper end of the cylinder 6, there is provided a guiding and sealing unit for the piston rod 5. The cavity within the cylinder 6 comprises a liquid filled space, which is subdivided into two working chambers 20 and 21 by a piston 19. The piston 19 is connected to the piston rod 5. A passage 22 opens into the upper working chamber 20. This passage is provided within the piston 19. A further passage 23 is allocated to the lower working chamber 21. By means of a valve member 24 which can be actuated by the push member 15, the two passages 22 and 23 can be interconnected, such as to provide a connection between the working chambers 20 and 21. In the position of the valve member 24 shown in the drawing of FIG. 3, the adjusting element 4 is hydraulically locked, since the closed valve does not permit any communication between the passage 22 and 23. Furthermore, there is at the bottom end of the piston 19 a piston rod extension 25 which passes through a partition defining a lower chamber 29. The piston rod extension 25 enters into the pressure chamber 29 below the partition. The piston rod extension 25 is provided with a longitudinal bore 26 at the end of which a rupture disc 27 is secured by means of a fixing nut 28. The chamber 29 is filled with a pressurized gas.
As the cross-sectional area of the piston rod 5 and the cross-sectional area of the piston rod extension 25 are equal to each other, the volume within the chambers 20 and 21 is independent of the axial position of the piston rod 5 with respect to the cylinder 6. The pressurized gas within the chamber 29 exerts a biasing force onto the piston rod extension 25 and the piston rod 5 in upward direction. This means that the steering wheel is biased towards the driver body and can be pushed inwards against the biasing force, when the valve member 24 has been brought into opening position.
The pressurized gas within the chamber 29 can be avoided. E.g., one can provide an opening from the chamber 29 to atmosphere. In this case, no biasing force is acting onto the extension 25 and the piston rod 5. The opening could be made, however, with a very small cross-sectional area so that on inward movement of the piston rod 5 with respect to the cylinder 6 a damping effect is obtained.
The rupture disc 27 mounted at the lower end of the bore 26 is so designed that with effect from a predetermined pressure difference between the working chamber 21 and the chamber 29 this disc breaks so overcoming the locking effect of the adjusting element. This means that under high axial forces, the steering column collapses axially and helps to absorb energy in the case of an accident.
Normal adjustment takes place in that via an actuating lever the push member 15 is pushed downwards, and thus the valve member 24 is also pushed downwards. Thus, a connection is made between the upper working chamber 20 and the lower working chamber 21. Then the steering column 2 can be varied in its length, until the desired position of the steering wheel is reached. When the actuating lever is released, the spring force of a spring causes the valve member 24 to be pushed backwards into the position shown in the drawings so that the adjusted position of the steering wheel is fixed. Due to the axial fixing of the cylinder 6 within the external tube 7 by means of the bearing 11 and the ring member 14, the axial position of the cylinder 6 and the connecting part 12 fastened thereto are in variable position. During adjustment, there is only a relative movement between the tube member 3 and the cylinder 6 of the hydropneumatic adjusting element 4, and the steering torque can always be transmitted because the tube member 3 is in torque transmitting engagement with the cylinder 6. The connecting part 12 is in connection with a steering gear driving the wheels for steering movement.
In FIG. 4, there is again shown an external tube 107, which is fixed on parts 108 and 109 of the body work. A steering column 102 is accommodated within the external tube 107.
The steering column 102 comprises a gas spring 104. The gas spring 104 comprises a cylinder 106 and a piston rod 105. The piston rod 105 is combined with a piston 119. The piston 119 divides the cavity within the cylinder 106 into two working chambers 120 and 121. The working chambers 120 and 121 are housed within an inner casing 106a. The working chambers 120 and 121 are interconnectable by a passage 106b, 106c, 106d. This passage is provided with a locking valve member 124. The locking valve member 124 is biased towards the closing position as shown in FIG. 4 by the pressurized gas contained within the working chambers 120 and 121. The locking valve member 124 can be shifted into an open position by axial pressure exerted onto a push member 115. The steering wheel 101 is fastened to the upper portion or bottom portion of the cylinder 106. The cylinder 106 is rotatably and axially movably mounted by a bearing unit 110 within the external tube 107. The cylinder 106 is combined with a tube member 103. The tube member 103 is in telescopic engagement with the cylinder 106, and further the tube member 103 is in torque transmitting engagement with the cylinder 106 by spline means (not shown).
The tube member 103 is provided with a bottom part 103a. This bottom part 103a is provided with a stud-like connecting part 112 which is rotatably mounted within the external tube 107 by a lower bearing unit 111. The lower bearing unit 111 is fixed with respect to the external tube 107 by axial abutments 107a and 107b. The stud-like connecting part 112 is axially fixed with respect to the bearing unit 111 by the bottom wall 103a on the one hand and a releasable fastening ring 114 on the other hand. The piston rod 105 is axially supported by the stud-like connecting part 112 in the support socket 112a. The lower end of the stud-like connecting part 112 is connected by connection means 112b with a steering gear 130. The working chambers 120 and 121 are filled with pressurized gas. The pressurized gas biases the cylinder 106 upwards with respect to the piston rod 105. When the locking valve member 124 is brought to the opened position by actuating the push member 115, the cylinder 106 moves upwards together with the steering wheel 101. Rotation of the steering wheel 101 is transmitted to the tube member 103 and from the tube member 103 to the stud-like connecting part 112.
Alternatively, the working chambers 121 and 122 could also be filled with a liquid. In this case, it would be necessary to provide a piston rod extension extending through the upper end of the cylinder 106 as shown in FIG. 3. The valve member 124 could in such case be shifted to an excentric position.
The steering column is in the embodiment of FIG. 4 established by the cylinder 106 and by the tube member 103 which form telescopically and torque transmittingly engaging steering column elements.
In the embodiment of FIG. 5, the gas spring 204 is substantially identic with the gas spring 104 of the embodiment of FIG. 4. Analogous parts are designated by the same reference numberal as in FIG. 4 increased by 100.
In the embodiment of FIG. 5, the steering column 202 is established by a lower tube member 203 and an upper tube member 231. The upper tube member 231 is telescopically and torque transmittingly engaged with the lower tube member 203 by axially extending spline means 232. The upper end of the upper tube member 231 is provided with an end wall 233. The upper end wall 206e of the cylinder member 206 engages the upper end wall 233 of the upper tube member 231. An adapter member 234 centres the upper end of the cylinder member 206 within the upper tube member 231. The push member 215 extends through an opening 235 of the upper end wall 233. The steering wheel 201 is fastened to the upper tube member 231. An actuating lever 236 is pivotally mounted on the steering wheel 201 and acts onto the push member 215. The steering column 202 is established in this embodiment by the telescopically and torque transmittingly engaging tube members 203 and 231.
While specific embodiments of the invention have been shown and described in detail to illustrate the application of the inventive principles, it will be understood that the invention will be embodied otherwise without departing from such principles.
The reference numerals in the claims are only used for facilitating the understanding and are by no means restrictive.
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A steering column of a motor vehicle is composed of two telescopically and torque transmittingly interengaging steering column tubes. These tubes are mounted in bearings. A steering wheel is allocated to a first steering column tube. The other steering column tube is connected with a steering gear box. A cylinder piston device is provided within at least one of the two steering column tubes. This cylinder piston device can be locked in a plurality of positions, such as to define a plurality of variable lengths of the steering column.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a ferromagnetic resonator formed of ferromagnetic thin film and suitable for use in microwave devices, and particularly, to a ferromagnetic resonator designed for use in suppressing spurious response.
2. Description of Prior Art
By use of the liquid phase epitaxial growth technology for growing a garnet magnetic film on the gadolinium-gallium garnet (GGG) substrate that has become popular recently through the development of magnetic bubble memory devices, it is possible to make an yttrium-iron garnet (YIG) thin film with satisfactory crystallinity. By forming the YIG thin film into disk or rectangular shape through the selective etching process, and utilizing its ferromagnetic resonance property, microwave devices can be constructed. Application of usual photolithography facilitates the manufacturing process, and yet a high productivity is promised, since a sheet of GGG substrate yields a large number of devices. Moreover, because of it being a thin film material, microwave integrated circuits (MICs) can easily be realized using microstrip lines for transmission lines.
As has been known in the art, microwave devices utilizing ferromagnetic resonance are advantageous in compactness and sharpness of response, and YIG single crystalline spheres have been used in practice to make such microwave devices. The YIG single crystalline sphere is advantageous in that it is hardly excited in magnetostatic modes and a unique resonance mode can be obtained by a uniform precession mode. However, the YIG single crystalline sphere has shortcomings in manufacturing and productivity, and therefore, formation of ferromagnetic resonator using the YIG thin film has been desired.
The YIG thin film has had a problem of being apt to excite in many magnetostatic modes even if it is placed in a uniform RF magnetic field, due to its nonuniform internal DC magnetic field. Magnetostatic modes of a disk-shaped ferrimagnetic specimen with a DC magnetic field applied perpendicularly to the specimen surface is analyzed in an article in Journal of Applied Physics, Vol. 48, July 1977, pp. 3001-3007. Each mode is expressed by (n,N) m , i.e., the node has n modes in the circumferential direction, N nodes in the radial direction, and m-1 nodes in the thickness direction. When the high-frequency magnetic field is applied uniformly to the whole area of specimen, the (1,N) 1 series becomes the major magnetostatic mode. FIG. 1 shows, the measured result of ferromagnetic resonance in a disk shaped thin film specimen measured in the 9 GHz cavity, indicating the excitation in many magnetostatic modes of (1, N) 1 series. When this specimen is used to form a microwave device such as a band-pass filter, its major resonance mode, i.e., mode (1,1) 1 is used, and in this case all other magnetostatic modes cause spurious response.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a ferromagnetic resonator using ferrimagnetic thin film.
Another object of the invention is to provide a ferromagnetic resonator using ferrimagnetic thin film and capable of suppressing spurious response.
Still another object of the invention is to provide a thin film ferromagnetic resonator capable of being readily formed into a microwave integrated circuit.
Still another object of the invention is to provide a ferromagnetic resonator using ferrimagnetic thin film and operable to suppress excitation in magnetostatic modes causing spurious response without impairing the major resonance mode.
According to one aspect of the present invention, there is provided a ferromagnetic resonator comprising a ferrimagnetic layer, means for applying a DC magnetic field perpendicularly to the layer, and means for applying an RF magnetic field to the layer so as to cause ferromagnetic resonance, the ferrimagnetic layer being processed so that spurious response caused by magnetostatic modes other than the uniform mode is suppressed.
According to another aspect of the invention, there is provided a ferromagnetic resonator as mentioned above, wherein the ferrimagnetic layer is processed to have a groove at a predetermined position on one surface of the layer so that spurious response caused by magnetostatic modes other than the uniform mode is suppressed.
According to still another aspect of the invention, there is provided a ferrimagnetic resonator as mentioned above, wherein the ferrimagnetic layer is processed to have a predetermined area in a central portion thereof with a thickness smaller than that of peripheral portions of the layer so that the internal D.C. magnetic field in the thinner area is made uniform.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a graph showing the occurrence of magnetostatic modes in the conventional disk shaped ferrimagnetic thin film;
FIG. 2 is a graph showing the distribution of internal DC magnetic field in the disk shaped ferrimagnetic thin film;
FIGS. 3A and 3B are graphs showing the relation between the distribution of internal DC magnetic field and the distribution of RF magnetization in the magnetostatic modes for the disk shaped ferrimagnetic thin film;
FIGS. 4A and 4B are graphs showing the distribution of demagnetizing field in the disk shaped ferrimagnetic thin film;
FIG. 5 is a perspective view of the ferrimagnetic thin film used in the ferromagnetic resonator embodying the present invention;
FIG. 6 is a perspective view of the ferrimagnetic thin film used in another embodiment of the ferromagnetic resonator of the present invention;
FIG. 7 is a cross-sectional view of the ferromagnetic thin film used in still another embodiment of the ferromagnetic resonator of the present invention;
FIGS. 8 and 9 are graphs showing the measured result of insertion loss in the ferromagnetic resonators of the present invention;
FIG. 10 is a graph showing an example of insertion loss useful to compare with the measured result shown in FIGS. 8 and 9;
FIGS. 11A to 11F, 12 and 13 are illustrations used to explain the method of fabricating the ferromagnetic resonator of the present invention; and
FIGS. 14A to 14C are diagrams showing the filter device constructed by application of the ferromagnetic resonator of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENT
The inventors of the present invention have pursued studies in order to achieve the foregoing objectives, and became to pay attention to the fact that the RF magnetization components distribute in the specimen differently depending on the magnetostatic mode. This affair will first be discussed in connection with FIGS. 2 and 3. FIG. 2 shows the distribution of internal DC magnetic field Hi when the DC magnetic field is applied perpendicularly to the surface of a YIG disk with a thickness of t and diameter of D (or radius of R). Here, the aspect ratio t/D of the specimen is assumed to be small enough, so that the distribution of magnetic field in the thickness direction can be ignored. Since the demagnetizing field is large in the inner portion of the disk and falls sharply as the measuring point moves toward the periphery, the internal DC magnetic field is small in the central section and increases sharply at the peripheral section. According to the analysis of the above-mentioned publication, magnetostatic modes reside in a region of 0≦r/R≦ξ, where ξ is the value of r/R at the position of Hi=ω/γ, ω is the resonant angular frequency in magnetostatic modes, and γ is gyromagnetic ratio. Under the fixed magnetic field, the resonance frequency increases as the mode number N increases, and the magnetostatic mode region expands outward as shown in FIG. 3A. FIG. 3B shows the distribution of RF magnetization in the specimen in low-order three modes of (1,N) 1 , where the absolute value indicates the relative magnitude of RF magnetization where the polarity indicates the phase relation of RF magnetization and each of the magnitudes is normalized at the center. As can be seen from FIGS. 3A and 3B, RF magnetization components have different forms depending on the magnetostatic mode, and by utilizing this property, excitation in magnetostatic modes causing spurious response can be suppressed without a significant effect on the major resonance mode.
The inventors also have become to pay attention to the fact that the internal DC magnetic field becomes substantially constant across a wide range when the inner area of the ferrimagnetic thin film is made thinner than the outer area.
This affair will be discussed in connection with FIGS. 4A and 4B. The internal DC magnetic field Hi when the DC magnetic field Ho is applied perpendicularly to the major plane of a YIG disk with a thickness of t and diameter of D (or radius of R) will be Hi=Ho-Hd(r/R)-Ha, where Hd is the demagnetizing field and Ha is the anisotropic magnetic field. Here, the aspect ratio t/D is assumed to be small enough, so that the distribution of magnetic field in the thickness direction of the specimen can be ignored. FIG. 4A is a plot, based on calculation of the demagnetizing field Hd for a YIG disk with a thickness of 20 μm and radius of 1 mm.
The demagnetizing field is large in the inner section and falls sharply at the peripheral section, and in consequence, the internal DC magnetic field is small in the center and rises sharply at the peripheral section. FIG. 4B is a plot of the distribution of demagnetizing field based on the calculation for the YIG disk with a thickness of 20 μm and radius of 1 mm, but made thinner by 1 μm for the inner area within 0.8 mm in radius. The plot indicates that by making the inner section of film a bit thinner, the demagnetizing field in the portion immediately outside the thinner portion is lifted, so that the flat region of demagnetizing field expands outward.
Accordingly, the present invention contemplates to suppress only excitation in magnetostatic modes causing spurious response as mentioned above through the physical treatment for the shape of the ferrimagnetic thin film. Namely, according to this invention, a groove is formed in a certain position of the ferrimagnetic thin film so that the magnetostatic modes other than the major mode causing spurious response are suppressed, or alternatively, a certain extent of inner area of the ferrimagnetic thin film is made thinner than the remaining outer area so as to expand the flat region of internal magnetic field, thereby suppressing the magnetostatic modes causing spurious response.
The invention will now be described in detail. On a major surface 1a of a substrate 1, there is formed a ferrimagnetic layer 2 in a certain shape as shown in FIG. 5. An annular groove 2a is formed in the ferrimagnetic layer 2. A magnetic field (not shown) is applied perpendicularly to the substrate 1.
The substrate 1 may be, for example, of a GGG material, and, in this case, a YIG thin film is formed by liquid phase epitaxial growth, and thereafter, the ferrimagnetic layer 2 is formed by the photolithographic technology. The ferrimagnetic layer 2 may of course be formed by processing a bulk material. Possible shapes of the ferrimagnetic layer 2 are disk, square, rectangle, etc. The ferrimagnetic layer 2 is made thin enough (small aspect ratio) so that the magnetic field distributes uniformly in the thickness direction of the layer 2. In this case, the exciting magnetostatic mode is (1,N) 1 .
The groove 2a is formed concentrically in a certain distance from the center so that RF magnetization in mode (1,1) 1 is nullified. The groove 2a may either be continuous or interruptive.
In such a ferromagnetic resonator, magnetization is determined by the presence of the groove 2a. Since the groove 2a is located at the position where RF magnetization is nullified for mode (1,1) 1 , excitation in mode (1,1) 1 is not affected. On the other hand, the groove 2a is located at a position where RF magnetization for other magnetostatic modes are not zero, and therefore, excitation in these modes is weakened. Consequently, spurious response can be suppressed without impairing the major resonance mode.
The distribution of RF magnetization in the ferrimagnetic layer 2 (see FIG. 3B) is entirely independent of the magnitude of the saturation magnetization of the specimen, and does not largely depend on the aspect ratio. Accordingly, this invention is advantageous in that the position of the groove 2a does not need to change depending on the possible variation in the saturation magnetization or thickness of the ferrimagnetic layer 2, and this is practically beneficial in the lithographic process.
An alternative formation of the inventive ferromagnetic resonator is as follows. On a major surface 1a of a substrate 1, there is formed a ferrimagnetic layer 2 in a certain shape as shown in FIG. 6. A recess 2a is formed in the upper surface of the layer 2 so that the inner area becomes thinner than the outer area. A magnetic field (not shown) is applied perpendicularly to the substrate 1.
The substrate 1 may be, for example, of a GGG material, and, in this case, a YIG thin film is formed by liquid phase epitaxial growth, and thereafter, the ferrimagnetic layer 2 is formed by the photolithographic technology. The ferrimagnetic layer 2 may of course by formed by processing a bulk material. Possible shapes of the ferrimagnetic layer 2 are disk, square, rectangle, etc. The layer 2 is made thin enough (small aspect ratio) so that the magnetic field distributes uniformly in the thickness direction of the layer 2. In this case, the magnetostatic mode is (1,N) 1 .
The recess 2a is extended to the position so that excitation of magnetostatic modes causing spurious response can be supressed sufficiently. Preferably, the recess 2 is extended to the position at which the amplitude of mode (1,1) 1 is nullified, e.g., to the distance 0.75-0.85 time the diameter of the layer 2 when it is a disk.
Such a ferromagnetic resonator provides a substantially uniform demagnetization across the entire area of the recess 2a, as has been mentioned previously in connection with FIG. 4B. In consequence, the internal DC magnetic field can be made uniform in a wide range, whereby magnetostatic modes causing spurious response can be suppressed.
The area enclosed by the groove 2a may be made thinner than the outer area as shown in FIG. 7. In this case, demagnetization is lifted at the inner portion in proximity to the groove 2a, and a substantially uniform demagnetization is obtained up to this range. In other words, the internal DC magnetic field becomes substantially constant in a wide range along the radial direction as shown by the dot-and-dash line in FIG. 3A. This allows further effective suppression against excitation in magnetostatic modes other than the major resonance mode.
In the above-mentioned photolithographic process, polyimide can be used for the protection film. Namely, as shown in FIG. 11A, a polyimide precursor is applied over the material to be processed (garnet thin film and substrate) 13 and, thereafter, hardened by heating to form a polyimide film 14. Then, a photoresist pattern 15 is formed on the polyimide film 14 (FIG. 11B) and, thereafter, the polyimide film 14 is etched off using the polyimide etchant, e.g., hydrazine hydrate, to form a pattern of polyimide film 14 (FIG. 11C). After that, the photoresist 15 is removed (FIG. 11D). Etching is carried out in the heated phosphoric acid (FIG. 11E). The etching speed is, for example, about 0.5 μm/min in phosphoric acid at 160° C., or about 1 μm/min in phosphoric acid at 180° C. Finally, the polyimide film 14 is removed using the polyimide etchant (FIG. 11F).
Conventionally, the SiO 2 film formed by CVD method or sputtering method have been used as a protection film for chemical etching for the garnet thin film or garnet substrate. However, this has needed a large facility for coating the SiO 2 film, and the occurrence of cracks and pinholes has also been a problem. In addition, it has been difficult to make a coating of SiO 2 film 16 over the entire surface as shown in FIG. 12 when the surface is offset for the purpose of recess 2a as in the inventive structure (see FIG. 6).
The polyimide protection film allows the use of small facility, and the occurrence of pinholes and cracks can mostly be avoided. The flow ability of polyimide precursor ensure the coating of polyimide protection film to the offset portions, as shown in FIG. 13.
In order to further enhance the heat resistivity of the protection film, polyimide resin having the iso-indroquinazolinedione structure is included. Moreover, a polyimide film formed of the photosensitive polyimide precursor which is a copolymer of photosensitive polymer and polyimide precursor is included. In this case, the polyimide pattern can be formed in the similar process to that of the usual photoresist, and the foregoing steps of forming a resist pattern and etching the polyimide film for making the polyimide pattern are eliminated, whereby the fabricating process can be simplified considerably.
For the etching process, reactive sputtering or ion milling may be employed in addition to the foregoing chemical etching, but at a cost of larger facility.
The invention will be described in more detail by way of embodiment.
Embodiment 1
A YIG disk with a thickness of 20 μm and radius of 1 mm cut out from a YIG thin film was processed to form an annular groove wih a depth of 2 μm and width of 10 μm at a distance of 0.8 mm from the disk center, and the ferromagnetic resonance was measured by introducing an electromagnetic wave using microstrip lines, while the external magnetic field being applied perpendicularly to the disk surface. FIG. 8 shows the measured result of insertion loss. The value of unloaded Q was 775. Note: RF magnetization of mode (1,1) 1 falls to zero at the position of r/R=0.8 on the YIG disk.
Embodiment 2
A YIG disk with a thickness of 20 μm and radius of 1 mm cut out from a YIG thin film was processed to form a circular recess with a depth of 1.7 μm and radius of 0.75 mm concentrically on the disk, and the ferromagnetic resonance was measured using microstrip lines. FIG. 9 shows the measurement result of insertion loss. The value of unloaded Q was 865.
Comparison Sample
A YIG disk with a thickness of 20 μm and radius of 1 mm cut out from the same YIG thin film as used in the foregoing embodiments was prepared, but without making any groove nor recess in this case, and the ferromagnetic resonance was measured using microstrip lines. FIG. 10 shows the measurement result of insertion loss. The value of unloaded Q was 660.
As will be appreciated by comparing the embodiments with the comparison sample, the inventive structure is effective in suppressing excitation of magnetostatic modes other than mode (1,1) 1 , whereby spurious response can be suppressed. In addition, the major resonance mode is not sacrificed, and thus the unloaded Q is not impaired.
The inventive ferromagnetic resonator can be applied to band-pass filters and band-stop filters. As an example, FIGS. 14A to 14C show a MIC band-pass filter made from YIG thin film. FIG. 14A is a perspective view of the device, FIG. 14B is a plan view, and FIG. 14C is a cross-sectional view taken along the line A-A' of FIG. 14B. Reference number 21 denotes an alumina substrate, on the rear surface of which is formed a ground conductor 22, while the remaining surface being provided with a formation of input and output transmission lines (microstrip lines) 23 and 24 aligned in parallel to each other. Each end of the transmission lines 23 and 24 is connected to the ground conductor 22.
On the top surface of the alumina substrate 21, there is placed a GGG substrate 27 having two circular YIG thin films 25 and 26. The GGG substrate 27 is provided thereon with a formation of an interconnection line (microstrip line) for linking the YIG thin films 25 and 26 disposed to intersect the input and output transmission lines 23 and 24, with both ends of the line 28 being connected to the ground conductor 22. The first YIG thin film 25 is placed at the position where the input transmission line 23 and interconnection line 28 intersect, and the second YIG thin film 26 is placed at the position where the output transmission line 24 and interconnection line 28 intersect. The distance between the two YIG thin films 25 and 26 is set equal to a quarter of wavelength (λ/4) of the center frequency of the transmission band so that the insertion loss increases sharply outside the transmission band.
Although not shown in the figures, the first and second YIG thin films are provided with yokes of permanent magnet which apply the external DC magnetic field perpendicularly to their major surfaces.
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A ferromagnetic resonator employing a disk of ferrimagnetic material is disclosed. The ferromagnetic resonator comprises a disk of ferrimagnetic material such as yttrium iron garnet (YIG) and a magnet applying D.C. magnetic field perpendicularly to a surface of the disk, and microstrip line applying RF magnetic field to the disk. The disk of ferrimagnetic material is processed to have a groove at a predetermined position on one surface of the disk, or to have a predetermined area in a central portion of the disk with a thickness smaller than that of peripheral portion of the disk, so that spurious response caused by magnetostatic mode other than the uniform mode is suppressed.
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GOVERNMENTAL RIGHTS
The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms as provided by the terms of F33615-01-C-1602 awarded by the Air Force Research Laboratory.
BACKGROUND OF INVENTION
1. Field of the Invention
The present invention relates to methods of making semiconductor devices and in particular to methods of providing ohmic contacts to compound semiconductor layers utilized in semiconductor devices.
2. Description of the Related Art
The fabrication and operation of basic transistor devices is well known. New technologies have developed needs for higher speed and power transistors capable of withstanding extreme operating conditions such as high temperatures, current, and radiation. Silicon carbide devices have the potential to fulfill these needs but have yet to achieve commercial success. One obstacle to using silicon carbide in electronic devices is the difficulty in providing electrical contacts to the device.
Electrical contacts to silicon carbide may be formed by reacting a contact metal with silicon carbide. One such method involves melting an alloy on the surface of silicon carbide. When the alloy melts, it dissolves and reacts with a small portion of the silicon carbide to form a contact. A second method of creating a contact involves laminating the surface of the silicon carbide with a contact metal. When annealed, this metal reacts with the silicon carbide to form an ohmic contact. The first method results in a contact that is too large for use in miniature devices. Annealing temperatures in the second method would be destructive to insulating layers. Both methods are incompatible with semiconductor devices having thin silicon carbide layers because of problems with metal spiking.
In order to prevent metal spiking, barrier layers between the contact metal and silicon carbide may be used. In one method a portion of doped silicon carbide is bombarded with ions to produce a heavily doped barrier region to which contact is made. Alternatively, a silicide barrier layer may be formed during annealing. Both of these methods are impractical for forming contacts to thin silicon carbide layers. Ion bombardment is not feasible for thin silicon carbide layers because the highly doped region is likely to extend through the entire layer and into an underlying layer. Similarly, the formation of a silicide barrier layer may electrically short a thin silicon carbide layer to an underlying layer because the reaction can consume the entire thickness of the thin silicon carbide layer and a portion of the underlying layer.
SUMMARY OF INVENTION
In embodiments described below, the process overcomes the problems above to enable the creation of microscopic contacts and is thus compatible with modern, miniature devices. Another benefit of the described embodiments is that insulating layers created during the process are preserved because of lower process temperatures. Finally, the embodiments described may be used with thin silicon carbide layers without causing electrical shorts through the layer.
In one set of embodiments, a process for forming a contact to a compound semiconductor layer can comprise forming a first compound semiconductor layer over a substrate. The first compound semiconductor layer may have a first conductivity type. The process can also comprise forming a second compound semiconductor layer. The second compound semiconductor layer may have a second conductivity type that is opposite the first conductivity type. The process can further comprise forming a third compound semiconductor layer. The third compound semiconductor layer may have the first conductivity type. The process can still further comprise patterning the third compound semiconductor layer to define an opening with a wall. The process can also comprise forming an insulating material along the wall, and forming a fourth compound semiconductor layer at least partially within the opening. The fourth compound semiconductor layer may have the second conductivity type and a dopant concentration that is higher than a dopant concentration of the second compound semiconductor layer. The fourth compound semiconductor layer may also be electrically connected to the second compound semiconductor layer and may be insulated from the third compound semiconductor layer.
In another set of embodiments, a semiconductor device can comprise a first active layer including a first compound semiconductor material and having a first conductivity type. The semiconductor device may also comprise a second active layer including a second compound semiconductor material and having a second conductivity type opposite the first conductivity type. The second active layer can contact the first active layer. The semiconductor device may further comprise a third active layer that includes a third compound semiconductor material having the first conductivity type. The third active layer can contact the second active layer, and a combination of the first, second, and third active layers can be at least part of a transistor. An opening may extend through the third active layer and contact the second active layer. The semiconductor device can still further comprise a fourth compound semiconductor material at least partially within the opening. The fourth compound semiconductor material may have the second conductivity type and a dopant concentration higher than a dopant concentration of the second active layer and may be electrically connected to the second active layer. The semiconductor device can also comprise a first insulating layer at least partially within opening. The first insulating layer may lie between the third active layer and the fourth compound semiconductor layer.
The foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention, as claimed.
BRIEF DESCRIPTION OF DRAWINGS
The present invention is illustrated by way of example and not limitation in the accompanying figures.
FIG. 1 includes an illustration of a cross-sectional view of a portion of a substrate after forming first, second, and third active layers.
FIG. 2 includes an illustration of a cross-sectional view of the substrate of FIG. 1 after patterning the third active layer to define openings.
FIG. 3 includes an illustration of a cross-sectional view of the substrate of FIG. 2 after forming an insulating layer over the third active layer and within the openings.
FIG. 4 includes an illustration of a cross-sectional view of the substrate of FIG. 3 after planarizing and etching the insulating layer to expose the second active layer at the bottom of the trenches.
FIG. 5 includes an illustration of a cross-sectional view of the substrate of FIG. 4 after forming a layer of heavily doped silicon carbide deposited in the trenches.
FIG. 6 included an illustration of a cross-sectional view of the substrate of FIG. 5 after removing portions of the heavily doped silicon carbide layer lying outside the openings.
FIG. 7 includes an illustration of a cross-sectional view of the substrate of FIG. 6 after forming metal contacts to the second and third active layers.
FIG. 8 includes an illustration of a cross-sectional view of the substrate of FIG. 7 after forming an insulating layer over the third active layer and metal contacts.
FIG. 9 includes an illustration of a cross-sectional view of the substrate of FIG. 8 after removing a portion of the insulating layer to expose surfaces of the metal contacts.
Skilled artisans appreciate that elements in the figures are illustrated for simplicity and clarity and have not necessarily been drawn to scale. For example, the dimensions of some of the elements in the figures may be exaggerated relative to other elements to help to improve understanding of embodiments of the present invention.
DETAILED DESCRIPTION
Reference is now made in detail to the exemplary embodiments of the invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts (elements).
Described generally below is a process for fabricating an electrical connection between a metal contact and a thin layer of silicon carbide while reducing the likelihood of spiking of the silicon carbide layer. The contact process is described in the context of fabricating a planar, multi-layered silicon carbide device, but as one skilled in the art may surmise, it may be used for forming connections between any applicable metal and silicon carbide layer.
FIG. 1 includes an illustration of a portion of a substrate 10 . The substrate 10 may include silicon carbide, gallium nitride, aluminum nitride, or other wide bandgap semiconductors. A wide bandgap material will have a bandgap of about 3 eV or greater. Active layers 12 , 14 , and 16 are sequentially formed over the substrate 10 . Each of the active layers 12 , 14 , and 16 may be formed using conventional epitaxial growing techniques and comprise one or more compound semiconductor materials. A compound semiconductor includes at least two dissimilar elements that form a semiconductor material. In one specific example, at least two dissimilar Group IVA elements such as carbon, silicon, or germanium can be part of the semiconductor material. Silicon carbide (SiC) is an example of a compound semiconductor material having Group IVA elements. In this particular embodiment, layers 12 , 14 , and 16 can comprise SiC. SiC polytype 4H may be used as well as 6H, 3C, or other similarly reactive polytypes.
Layer 12 can have a thickness in a range of approximately 2–20 microns, can be n-type doped with nitrogen, phosphorus, or the like, and can have a dopant concentration in a range of approximately 1E15 to 1E18 atoms per cubic centimeter. Layer 14 can have a thickness in a range of approximately 0.1–2.0 microns, can be p-type doped with aluminum, boron, or the like, and have a dopant concentration in a range of approximately 1E15 to 1E17 atoms per cubic centimeters. Layer 16 can have a thickness in a range of approximately 0.5–2.0 microns, can be n-type doped with nitrogen, phosphorus, or the like, and have a dopant concentration in a range of approximately 1E17 to 1E19 per cubic centimeters. Layer 12 may be a collector, layer 14 may be a base, and layer 16 may be an emitter of a transistor.
Next, openings 20 can be formed by masking layer 16 with aluminum, nickel, or the like (not shown) and etching layer 16 . The openings 20 extend through layer 16 and expose a portion of layer 14 . A reactive ion etch (RIE) in an ionized CF 4 /O 2 /H 2 atmosphere may be used.
An insulating layer 30 , capable of being anisotropically etched, is then deposited on the exposed surfaces of layer 16 and at least partially within the openings 20 as shown in FIG. 3 . An insulator such as silicon dioxide, silicon nitride, silicon oxynitride, or the like may be used for insulating layer 30 . The insulating layer 30 can serve to passivate the walls of the opening 20 and insulate layer 16 from a subsequently formed material that may be electrically connected to layer 14 . Portions of insulating layer 30 may be mechanically or chemically removed to expose layer 16 . Then insulating layer 30 is masked and the insulating material in the openings 20 is anisotropically etched to expose a portion of layer 14 as illustrated in FIG. 4 . A typical anisotropic etch may be a CF 4 /O 2 -based reactive ion etch.
As shown in FIG. 5 , a heavily doped SiC layer 50 is then sputtered on to layer 14 . The layer 50 may be RF sputtered at a power in the range of approximately 100–200 watts using a SiC target. Sputtering may be done at low pressure in the range of approximately 50–200 mTorr, in the presence of a non-reactive gas such as argon. During sputtering, the substrate may be held at a temperature in a range of approximately 800° C. 1100° C., which is below the melting temperature of the insulating layer 30 , which is roughly 1100° C.
The desired dopant concentration for the SiC layer 50 is in the range of approximately 1E19–1E20 atoms per cubic centimeter. Dopants can be incorporated by simultaneously co-sputtering, DC sputtering, or by sputtering in the presence of a gas. For example, aluminum may be incorporated by simultaneously co-sputtering, DC sputtering from an aluminum target, or by sputtering in the presence of gaseous trimethyl aluminum (Al(CH 3 ) 3 ). Aluminum may be sputtered with a power in the range of approximately 10–50 watts of DC power. An alternative p-dopant may be boron, which can be added as gaseous diborane (B 2 H 6 ). Alternatively, the dopants can be alloyed with the silicon carbide target.
Portions of SiC layer 50 overlying the third active layer 16 may be mechanically or chemically removed to expose portions of layer 16 , leaving SiC material 50 at least partially within openings 20 , as illustrated in FIG. 6 .
Illustrated in FIG. 7 , a metal layer 70 may be deposited on the heavily doped silicon carbide 50 . The metal layer 70 may be aluminum or any other metal that can form an ohmic contact to p-doped silicon carbide. A metal layer 72 may be deposited on n-doped silicon carbide layer 16 . The metal layer 72 on layer 16 can be nickel or any other metal that can form an ohmic contact to n-doped silicon carbide. The metal layers 70 and 72 can be deposited by any of a number of methods, including DC sputtering, RF sputtering, thermal evaporation, e-beam evaporation and chemical vapor deposition. The metal layers 70 and 72 may be patterned by photolithography and wet or dry chemical etching.
The metal layers 70 and 72 can be annealed to form an ohmic electrical connection or contact with the underlying silicon carbide. Depending upon the metal, the annealing temperature may be in a range of approximately 600° C. 1100° C., which is below the melting temperature of the insulating layer 30 . Due to the thickness of the heavily doped silicon carbide layer 50 , the reaction region 74 between the metal contact 70 and the heavily doped silicon carbide 50 that occurs when the metal is annealed should not extend through the thin layer 14 . In this particular embodiment, region 74 does not physically contact layer 14 .
Insulating layer 80 can be deposited on layer 16 and metal layers 70 and 72 as shown in FIG. 8 . Layer 80 may be an insulator such as silicon dioxide, silicon nitride, silicon oxynitride, or the like. The insulating layer 80 may then be mechanically or chemically removed to expose surfaces of metal layers 70 and 72 as illustrated in FIG. 9 . Wire leads (not shown) may be soldered, bonded, or otherwise electrically connected to the metal layer 70 and 72 contacts. For basic a transistor operation, an additional wire lead can be attached to layer 12 to form a substantially completed semiconductor device.
Additional compound semiconductor layers having appropriate contacts and conductivity types may be incorporated to create devices such as thyristors.
Accordingly, devices produced can exhibit faster performance because the active layer 14 can be thin and not exhibit high contact resistance or junction spiking. Further, high temperature anneals are not required at stages where insulating material may be damaged, thus processing is simplified and reduced. Also, as shown in FIG. 9 , the device has an exposed surface that is substantially planar, making the semiconductor device easier to integrate and make external connections to than conventional multi-leveled devices. Because of the higher band-gap and chemical stability of silicon carbide, devices described herein may be used in higher power applications and at higher temperature or radiation levels than traditional silicon devices. The increased power handling capability and temperature resistance of silicon carbide devices also allows for the manufacture of smaller devices than with conventional silicon devices.
Because of these benefits, transistors produced according to the process described herein may operate in any standard transistor application and are particularly suited for wireless communication base amplifiers or high power switching devices where these devices may be smaller and faster than existing devices. In RF applications such as amplification, the devices may handle approximately 120 volts and up to approximately 5 watts per millimeter perimeter at roughly 3 gigahertz. Power switching devices may handle approximately 2000 volts and may have a switching frequency around 1 megahertz. Devices can be scalable so that greater power levels may be utilized.
In the foregoing specification, the invention has been described with reference to specific embodiments. However, one of ordinary skill in the art appreciates that various modifications and changes can be made without departing from the scope of the present invention as set forth in the claims below. Accordingly, the specification and figures are to be regarded in an illustrative rather than a restrictive sense, and all such modifications are intended to be included within the scope of present invention.
Benefits, other advantages, and solutions to problems have been described above with regard to specific embodiments. However, the benefits, advantages, solutions to problems, and any element(s) that may cause any benefit, advantage, or solution to occur or become more pronounced are not to be construed as a critical, required, or essential feature or element of any or all the claims. As used herein, the terms “comprises,” “comprising,” or any other variation thereof, are intended to cover a non-exclusive inclusion, such that a process, method, article, or apparatus that comprises a list of elements does not include only those elements but may include other elements not expressly listed or inherent to such process, method, article, or apparatus.
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Provided is a process for forming a contact for a compound semiconductor device without electrically shorting the device. In one embodiment, a highly doped compound semiconductor material is electrically connected to a compound semiconductor material of the same conductivity type through an opening in a compound semiconductor material of the opposite conductivity type. Another embodiment discloses a transistor including multiple compound semiconductor layers where a highly doped compound semiconductor material is electrically connected to a compound semiconductor layer of the same conductivity type through an opening in a compound semiconductor layer of the opposite conductivity type. Embodiments further include metal contacts electrically connected to the highly doped compound semiconductor material. A substantially planar semiconductor device is disclosed. In embodiments, the compound semiconductor material may be silicon carbide.
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BACKGROUND
[0001] 1. Field of the Invention
[0002] The present invention relates generally to the field of telephone switching equipment. More specifically, the present invention relates to verifying subscriber information stored in various components of a cellular telephone system to ensure that subscribers are correctly billed for the services they use.
[0003] 2. Background of the Invention
[0004] A critical issue facing cellular telephone companies is ensuring appropriate subscriber billing. For example, it is important to ensure that subscribers are billed for services they use, and not billed for services they do not use. Billing errors result in upset customers, and costly allocation of cellular telephone company resources to locate and fix problems leading to billing errors.
[0005] Data regarding particular subscribers and the services that they subscribe to are usually located in several places in a telephone system. A home location register (HLR) stores subscriber data that can be used by a switch in a cellular telephone network to determine the services that a subscriber subscribes to. The HLR is generally located on a service control point (SCP) of the subscriber's provider of record. The HLR contains data that is used to identify and verify subscribers, as well as data indicating what services subscribers can use and data used to provide these services.
[0006] The data in the HLR is also used when a subscriber is roaming. A subscriber is roaming when he or she is outside the coverage area of the service provider of record. When roaming, the visited telephone system obtains a copy of the subscriber's data record from the roaming subscriber's HLR and stores it as a temporary record in a visitor location register (VLR). The VLR is maintained during the duration of the subscriber's roaming. It is used by the visited telephone company to provide services in accordance with the services identified by the temporary record stored in the VLR, as well as to provide billing identification information so the visited system can appropriately bill the roaming subscriber.
[0007] Cellular telephone networks also contain a billing system that calculates and distributes bills to subscribers for the services they use. Like the HLR, the billing system comprises information regarding each subscriber in the system. The billing data for each subscriber provides information on the services accessible by the subscriber.
[0008] The subscriber data located in both the HLR and billing systems includes data regarding the services to which each subscriber has subscribed. The services can be individual services or bundled in service plans. A service plan generally offers a combination of services and service features at a reduced billing rate. Services include local telephone service, long distance telephone service, cellular telephone service, paging service, Internet service and other services. Services for purposes of the present disclosure also include features such as caller ID, call waiting, three-way calling, call return, special ring and other features.
[0009] Services are provided to subscribers based on the subscriber data stored in the HLR. Thus, if subscriber data in the HLR indicates a particular subscriber has caller ID, that subscriber is provided caller ID whether the subscriber is billed for it or not. Also, billing is generated based on the subscriber data stored in the billing system. Thus, if the subscriber data in the billing system indicates a particular subscriber has caller ID, that subscriber is billed for caller ID, whether or not the subscriber is actually authorized to use caller ID by the subscriber database.
[0010] As a result, it is apparent that significant problems can arise if the subscriber data stored in the HLR and/or the billing system is inconsistent. Such inconsistency can arise if, for example, there are duplicate subscriber records for a particular subscriber that indicate the subscriber subscribes to different and inconsistent services.
[0011] In addition, billing problems can occur if the data stored in the HLR differs from the subscriber data stored in the billing system for a particular subscriber. For example, if subscriber data in the HLR indicates that a subscriber can use a particular service, but the subscriber data in the billing system indicates the subscriber does not have access to that service, the subscriber will be able to use the service but will not be billed for that use. Such use represents a lost revenue opportunity for the service provider. In addition, this use by the non-paying subscriber represents a drain on resources that could be used by other subscribers.
[0012] Similarly, if subscriber data in the HLR for a particular subscriber indicates that the subscriber does not have access to a particular service, but the billing system subscriber data indicates that the subscriber does have access to the service, the subscriber will be charged for the service even though the subscriber cannot actually use the service. This situation leads to complaints from subscribers who are billed for services they do not use. In addition, expensive telephone company resources are required to track, locate and solve the problem.
[0013] A significant problem existing in current cellular telephone systems is that there is no convenient way to compare HLR subscriber data with billing data for consistency. As a result, problems often go undetected unless a customer complains to the telephone company due to the improper billing (which many not happen, for example if the customer is being under-billed).
SUMMARY OF THE INVENTION
[0014] The present invention provides a solution to the foregoing problems with conventional cellular telephone systems by providing a consistency verification tool that performs a consistency check on subscriber data records stored in the cellular telephone system. For example, in one embodiment of the present invention, the consistency verification tool analyzes subscriber data records in a home location register (HLR) and in a billing system to determine the presence of duplicate records. Preferably, duplicate records are stored in a duplicate record file for later analysis.
[0015] During the duplicate record consistency analysis, the consistency verification tool creates a record list. In one embodiment of the present invention, the record list stores subscriber data records and any duplicate subscriber duplicate records in an array structure that facilitates identifying the duplicate records. In this embodiment, a sorting algorithm can be applied to the array such that after sorting the array, duplicate records appear adjacent to one another. In another embodiment of the present invention, the record list stores main records and duplicate records in a linked-list structure that facilitates identifying families of duplicate records.
[0016] The consistency verification tool can also perform inter-device consistency checks. For example, the subscriber data stored on the HLR can be compared to the subscriber data stored in the billing system to ensure that the two systems have consistent subscriber data.
[0017] Performing the consistency checks is important to prevent portions of the cellular telephone system from processing subscriber information in different ways. For example, determination of inconsistent billing records between the HLR and the billing system can avoid the cellular telephone company billing for services that are not provided or not billing for services that are provided.
[0018] In one embodiment, the present invention is a method for verifying consistency of subscriber data record stored on a device in a cellular telephone network. Such devices include, for example, a billing system and an HLR. The method begins with the step of reading a new record of subscriber data from the device. The new record of subscriber data is compared to each record of subscriber data stored in a record list. In one embodiment, the record list is an array of records. After sorting the array, duplicate records are adjacent to one another in the array.
[0019] In another embodiment, the present invention is a system for verifying consistency of subscriber records stored on a device of a cellular telephone system. The system includes a device on which subscriber records are stored. A consistency verification tool coupled to the device reads subscriber records from the device and stores them in memory. Subscriber records are then read from the billing system. Each record is compared to the subscriber data records that are in memory. The consistency verification tool determines whether the new subscriber data record matches a record in the record list, and stores the new subscriber data record in the record list or on disk in accordance with this determination.
[0020] In another embodiment, the present invention is a method for verifying subscriber data stored on a source device and target device in a cellular telephone system. The method begins with the step of reading a new subscriber record from the source device. The new subscriber record is compared to each subscriber record in the target device, or until a matching record in the target device is found. The new subscriber record is stored in a non-matching file if the new subscriber record matches no record in the target device. The method continues for each record in the source device until there are no more records in the source device.
[0021] In another embodiment, the present invention is a system for verifying subscriber data stored on a source device with subscriber data stored on a target device. The system includes a source device containing a plurality of subscriber data records and a target device containing a plurality of subscriber data records. The subscriber data records on the source device are compared to the subscriber data records on the target device. The system also include a consistency verification tool that reads each subscriber record from the source device and compares it to subscriber data records in the target device until a match is found. If no match is found, the non-matching subscriber data record from the source file is stored in a non-match file.
BRIEF DESCRIPTION OF THE DRAWINGS
[0022] [0022]FIG. 1 is a schematic diagram of a system for verifying subscriber data records in a cellular telephone system according to an embodiment of the present invention. The terms “subscriber data record” and “subscriber record” are used herein interchangeably.
[0023] [0023]FIG. 2 is a flow chart of a method for performing a duplicate consistency check according to an embodiment of the present invention.
[0024] [0024]FIG. 3 illustrates reordering of a record list using a sorting algorithm according to an embodiment of the present invention.
[0025] [0025]FIG. 4 is a flow chart of a method for performing a duplicate consistency check according to another embodiment of the present invention.
[0026] [0026]FIG. 5 is an exemplary record list according to an embodiment of the present invention using a linked list.
[0027] [0027]FIG. 5A is an exemplary main record structure for a record list according to an embodiment of the present invention using a linked list.
[0028] [0028]FIG. 5B is an exemplary duplicate record structure for a record list according to an embodiment of the present invention using a linked list.
[0029] [0029]FIG. 6 is a flow chart for a method of comparing subscriber records stored on a source and target device according to an embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0030] [0030]FIG. 1 is a schematic diagram illustrating a system for verifying subscriber data records in a cellular telephone system according to an embodiment of the present invention. A switch 102 is coupled to an HLR 103 . HLR 103 comprises a disk 104 . Disk 104 stores subscriber data. Preferably, disk 104 stores the subscriber data in a plurality of subscriber records. Disk 104 can be any data storage medium including, for example, disk, tape, CD-ROM or any other data storage medium. The subscriber records include data related to services available to each subscriber that is homed on switch 102 . Examples of services include local telephone service, long distance service, cellular service, paging service, and Internet service and other services, as well as features such as caller ID, call waiting, three-way calling, call forwarding and other features.
[0031] A billing system 106 generates billing for all of or for a portion of the cellular telephone system. Billing system 106 includes a disk 109 . Disk 109 stores subscriber data. Preferably, disk 109 stores the subscriber data in a plurality of subscriber records. Disk 109 can be any data storage medium including, for example, disk, tape, CD-ROM or any other data storage medium. Like the subscriber data stored on disk 104 in HLR 103 , the subscriber data stored on disk 109 includes data related to the services that a subscriber billed by billing system 106 has access to. Exemplary services are described above.
[0032] A computer 107 is coupled to both HLR 103 and billing system 106 . Computer 107 executes a consistency verification tool 108 . Consistency verification tool 108 can perform a number of verification functions. In one verification function, consistency verification tool 108 analyzes the HLR subscriber data and/or billing subscriber data to determine the presence of duplicate records. Consistency verification tool 108 reports any duplicate records it discovers during its analysis.
[0033] There are several reasons why duplicate records might be found in the subscriber data stored in HLR 103 and/or in subscriber data stored in billing system 106 . For example, a subscriber may be homed on several HLRs; a subscriber may be assigned multiple phone numbers for a single cellular telephone serial number (which could indicate a nonsensical situation); or a subscriber may have a single telephone number assigned to multiple cellular telephone serial numbers. Consistency verification tool 108 can also store duplicate records in a duplicate record file 116 . These records can be analyzed later to determine why there are duplicate records.
[0034] Duplicate records need not be identical in their entirety. Rather, duplicate records are those records that have inconsistent information regarding the services subscribed to by a particular subscriber. For example, suppose there are two records for a particular subscriber that indicate the subscriber subscribes to a different set of services. How a particular subscriber is treated in such a case depends on how service provision is implemented in the cellular telephone system. For example, the subscriber may have access to all of the services in the multiple records. Alternatively, the subscriber may have access to the services identified in only one of the multiple records. Alternatively, the subscriber may be given an error condition indicating that the call cannot be completed. In the latter case, the subscriber is not allowed access to the cellular telephone system until the problem is resolved.
[0035] A method for performing a duplicate consistency check according to an embodiment of the present invention is illustrated in the flow chart of FIG. 2. The method begins in step 202 with the step of creating a record list. Creation of the record list can be a declaration of a structure into which record-matching criteria related to records can be stored. In one embodiment of the present invention, the record list structure is an array. In an alternative embodiment of the present invention, described below, the record list structure is a linked list. The record list can be any data structure into which whole or partial subscriber data records can be stored.
[0036] In step 204 , the method continues with the step of reading a new subscriber data record from a subscriber data source file. In the present invention, the subscriber data source file is preferably a file comprising subscriber data from HLR 103 or billing system 106 . In step 206 , the method continues with the step of comparing the new subscriber data record to record-matching criteria for records in the record list. Records that match are termed duplicate records. If there is no match, the method continues in step 210 with the step of creating a new entry in the record list. The method continues in step 212 by determining if there are more records to check. If there are more records, the method continues in step 204 . If there are no more records, the method ends in step 214 .
[0037] If a duplicate record is found in step 208 , the duplicate record is preferably stored as a duplicate in the record list. This can be stored in a separate list or as part of the record list itself as described below. Duplicate records can be stored in file 116 .
[0038] As described above, the record list according to one embodiment of the present invention is an array structure comprising record list elements. The record list elements correspond to specific records in the subscriber data records. The record list elements can comprise some or all of the record data stored in their corresponding subscriber data records.
[0039] [0039]FIG. 2 is a flow chart for a method for performing a duplicate consistency check according to an embodiment of the present invention. The embodiment illustrated in the flow chart of FIG. 2 uses a record list having an array structure. The method begins in step 202 . In step 204 , the subscriber data records are read into a record list. Preferably, all of the subscriber data records from the HLR or billing system are read into the record list.
[0040] For example, FIG. 3 illustrates a record list 302 having an array structure into which five exemplary records are stored. As shown in FIG. 3, record list 302 comprises five records: record 1 , record 2 , record 3 , record 4 and record 5 . Record 1 comprises serial number 1 and telephone number 1 . Record 2 comprises serial number 2 and telephone number 2 . Record number 3 comprises serial number 1 and telephone number 1 . Record number 4 comprises serial number 4 and telephone number 1 . Finally, record number 5 comprises serial number 2 and telephone number 2 . Record 3 is a duplicate of record land record 5 is a duplicate of record 2 .
[0041] The method continues in step 206 with the step of sorting the record elements in the record list according to one or more match criteria. The match criteria can be any desired data that can be stored in the record elements of the record list. For example, in one embodiment of the present invention, the match criteria are the telephone number and serial number associated with the mobile telephone. The sorting algorithm can be any of a number of well-known sorting algorithms for sorting the data in the record list according to the match criteria. One such sorting algorithm for sorting the record elements in the record list according to the match criteria, for example, is the well-known quick sort algorithm.
[0042] In step 208 any duplicate records are identified. The present invention facilitates this identification because, after sorting, any duplicate records appear in consecutive record elements. FIG. 3 also illustrates a record list 304 that results sorting the records in record list 302 according to the match criteria of telephone number and serial number. After sorting, the order of the record elements in record list 304 is record 1 , record 3 , record 2 , record 5 and record 4 . As can be seen record 1 and record 3 are duplicates. As such record 1 and record 3 appear in consecutive record elements as a result of sorting. Likewise, record 2 and record 5 are duplicate records. As such, they too appear in consecutive records as a result of sorting.
[0043] Returning to the description of the method of FIG. 2, the record data in the record list can be analyzed at this point. For example, the record list can be stored in a file in a viewable format. Preferably however, in step 210 , the duplicate records are stored in a duplicate record file that can be later analyzed. The method then ends in step 212 .
[0044] A method for performing a duplicate consistency check according to another embodiment of the present invention is illustrated in the flow chart of FIG. 4. The method illustrated by the flow chart of FIG. 4 can be used for other record list structures in addition to arrays. For example, the method illustrated by the flow chart of FIG. 4 can be used for a record list structure that is a linked list. The method begins in step 401 . In step 402 , the method continues with the step of creating a record list. Creation of the record list can be a declaration of a structure into which record-matching criteria related to records can be stored. In step 404 , the method continues with the step of reading a new subscriber data record from a subscriber data source file. In the present invention, the subscriber data source is preferably a file comprising subscriber data from HLR 103 or billing system 106 . In step 406 , the method continues with the step of comparing the new subscriber data record to record-matching criteria for records in the record list. As described above, the record matching criteria can be some or all of a subscriber data record. Records that match are termed duplicate records.
[0045] If there is no match, the method continues in step 410 with the step of creating a new entry in the record list, and storing information corresponding to the non-matching record in the record list. This information can be the non-matching record itself, the match criteria or some other subset of the non-matching record. If the entire non-matching record is not stored, the information also includes an identification of the non-matching record corresponding to the match criteria.
[0046] If a duplicate record is found in step 208 , the information corresponding to the duplicate record is stored in step 411 . In one embodiment of the present invention, the information corresponding to the duplicate record is stored in a separate duplicate records list in step 411 . In an alternative embodiment of the present invention, the information corresponding to the duplicate record is stored in the record list itself in step 411 . This information can be the duplicate record itself, the match criteria or some other subset of the duplicate record. If the entire duplicate record is not stored, the information also includes an identification of the duplicate record corresponding to the match criteria. Duplicate records can also be stored in duplicate records file 116 for later analysis.
[0047] The method continues in step 412 by determining if there are more records to check. If there are more records, the method continues in step 404 . If there are no more records, the method ends in step 414 .
[0048] In an embodiment of the present invention, the record list is a linked list structure as shown, for example, by record list 501 in FIG. 5. Record list 501 has elements 502 , 504 , 506 , 508 , 510 , 512 and 514 . These record list elements represent specific records in the linked list.
[0049] Record elements 502 , 508 , 512 and 514 have a similar structure, and are termed main records. A main record does not match any other main record in record list 501 . A record becomes a main record, if when tested, the record does not match any other main record in record list 501 .
[0050] The structure of a main record according to an embodiment of the present invention is described using exemplary main record 520 shown in FIG. 5A. Main record 520 preferably has four elements. A match criteria structure 522 includes any portion of the data in a subscriber data record. Alternatively, the match criteria structure includes the entire subscriber data record. The match criteria are the criteria used to match records to determine the presence of duplicate records. For example, match criteria can be the subscriber name and telephone number. In this case, if a record is found to have the same subscriber name and telephone number, the record is considered a match, otherwise there is no match.
[0051] A record ID 524 identifies the actual subscriber data record in the HLR or billing system that record 520 corresponds to. A duplicate pointer 526 points to the address of the next matching record if one exists. Otherwise duplicate pointer 526 is assigned the value NULL. A NULL value for duplicate pointer 526 indicates that record has no further duplicate records in its chain. A next pointer 528 points to the address of the next main record in record list 501 if one exists. If there are no additional main records, next pointer 528 us assigned the value NULL. A NULL value for next pointer 528 indicates that record is the last main record in the chain of main records in record list 501 .
[0052] Record list 501 elements 504 , 506 and 510 have the same structure. The records corresponding to elements 504 , 506 and 510 matched one of the main records during the consistency check. Such records are called duplicate records. The structure of these duplicate record elements is shown in FIG. 5B by a duplicate record structure 530 .
[0053] A record ID 532 identifies the actual subscriber data record in the HLR or billing system corresponding to matching record 530 . A duplicate pointer 534 points to the address of the next duplicate record if any exists. If there are no more matching records, duplicate pointer 534 points to NULL. A NULL value for duplicate pointer 534 indicates the last record in that family of duplicate records.
[0054] It should be noted that any subscriber data record can correspond to a main record or a duplicate record. A main record simply indicates that there was no match for the record at the time the record is compared to records in record list 501 .
[0055] Consistency verification tool 108 can also be used to compare the subscriber data records in HLR 103 with subscriber data records in billing system 106 . In an embodiment of the present invention, matching records are stored in a matched record file 110 , and unmatched records are stored in an unmatched records file 112 .
[0056] Comparing the subscriber data in billing system 106 with subscriber data in HLR 103 can be used to assure that switch 102 provides correct call detail records to billing system 106 . For example, if subscriber data for a particular subscriber in HLR 103 indicates that a subscriber is a postpaid customer, whereas the subscriber data in billing system 106 indicates that the subscriber is a prepaid subscriber, all CDRs related to the subscriber's telephone calls are forwarded by switch 102 to billing system 106 . Billing system 106 looks at the CDRs and discards them because it treats the subscriber as a prepaid subscriber. Consequently, billing system 106 does not process the CDRs, because it is programmed to treat prepaid CDRs as if they have already been paid and recorded in a prepaid platform.
[0057] To prevent such errors, consistency verification tool 108 compares the subscriber data in billing system 106 to the subscriber data in HLR 103 . To perform this compare function, consistency verification tool 108 compares each subscriber record in HLR 103 with each subscriber record in billing system 106 , and vice versa.
[0058] The comparison is a comparison of subscriber services as they are stored on HLR 103 and billing system 106 . In some instances, bundles of services are classified by a single name. In these cases, the individual service for each service that a subscriber subscribes to are unbundled so they can be compared on an individual rather than bundled basis. This ensures that all subscriber data is compared.
[0059] In one embodiment, consistency verification tool 108 performs the compare function according to the method shown by the flow chart of FIG. 6. The method begins in step 601 . In step 602 , consistency verification tool 108 reads the subscriber records from a target device. The target device is the device on which the presence of a subscriber record matching the subscriber record read from the source device is being determined. For example, according to an embodiment of the present invention, the target device is preferably disk 104 or disk 109 , whichever is not the source device.
[0060] In step 604 , the subscriber records read from the target device are sorted. The sorting is performed using predetermined criteria. For example, in an embodiment of the present invention, the subscriber records from the target device are sorted according to the serial number and telephone number stored in the subscriber record. Any sorting algorithm can be used to perform the sorting of step 604 . For example, the well-known quick sort algorithm can be used.
[0061] Preferably all subscriber records are read from the target device in step 602 . Alternatively, a portion of subscriber records from the target device is read into a computer memory. If only a portion of the subscriber records is read, then steps 602 and 604 are repeated with additional portions of memory read in from the target device. The repetition is performed until a matching record is found or all subscriber records stored on the target device have been processed.
[0062] In step 606 , consistency verification tool 108 reads a subscriber record from a source device. According to an embodiment of the present invention, the source device is either disk 104 , which stores subscriber data on HLR 103 , or disk 109 , which stores subscriber data on billing system 106 .
[0063] Consistency verification tool 108 can use any of the data in the source device subscriber data record as the basis of the search. For example, in an embodiment of the present invention, the search is performed using the serial number and telephone number associated with the source device subscriber record. Any search algorithm can be used to search the sorted target device subscriber records in step 608 . Preferably, the well-known binary search algorithm is used.
[0064] In step 610 , consistency verification tool 108 determines if there is a record in the target device that matches the source device subscriber data record. If there is no such matching record, then there is an error condition. Consistency verification tool 108 continues the method by reporting the error condition in step 612 . In addition, consistency verification tool 108 can store and/or print the non-matching source device.
[0065] The error condition depends on the specific search comparison being performed. For example, where HLR 103 is the source device and billing system 106 is the target device, the lack of a matching record in the target device means that there is a record in HLR 103 for which there is no corresponding record in billing system 106 . As a result, a customer would have access to service, but billing system 106 would not know how to bill them. This situation could result in the customer receiving service free of charge and lost revenues to the cellular telephone company. Similarly, where billing system 106 is the source device and HLR 103 is the target device, the lack of a matching record in the target device means that there is a record in billing system 106 for which there is no corresponding record in billing system 103 . As a result, a customer would be billed for service that the customer does not receive.
[0066] If consistency verification tool 108 detects a matching record in step 610 , it continues in step 614 by determining if the source device subscriber record fully matches the matching record in the target device. If the match is not complete there is a potential error condition, which consistency verification tool 108 reports in step 616 . In addition, consistency verification tool 108 can store and/or print the source device and partially matching target device subscriber records.
[0067] The consequence of partially matching records depends on the kind of error. For example, one error condition involves incorrectly classifying a customer. The customer may be classified as being a pre-paid customer, when the customer is actually a post-paid customer or vice verse. As described above, this condition often leads to improper billing and/or lost revenues. Another possibility is that a customer may be listed as active by the source device record but inactive or suspended by the target device record. Again, this condition likely leads to improper billing and/or lost revenues. Another possible consequence of partial matching records is that the customer may be getting services he or she is not paying for or paying for services he or she is not getting. Other potential error conditions would be known to those skilled in the art.
[0068] If there is a complete match determined in step 614 , consistency verification tool 108 continues the method in step 618 by reporting that the source device subscriber record successfully matched a target device subscriber data record.
[0069] Consistency verification tool 108 continues the method in step 619 with the step of determining whether there is are more source device subscriber records to process. If there are more source device subscriber records to process, the method continues in step 606 with the step of reading the next source device subscriber record. Thus, the method of FIG. 6 can be executed to compare one or more source device subscriber records with the target device subscriber records. If consistency verification tool 108 determines that there are no more source device subscriber records to process in step 619 , the method ends in step 620 .
[0070] The foregoing disclosure of the preferred embodiments of the present invention has been presented for purposes of illustration and description. It is not intended to be exhaustive or to limit the invention to the precise forms disclosed. Many variations and modifications of the embodiments described herein will be apparent to one of ordinary skill in the art in light of the above disclosure. The scope of the invention is to be defined only by the claims appended hereto, and by their equivalents.
[0071] Further, in describing representative embodiments of the present invention, the specification may have presented the method and/or process of the present invention as a particular sequence of steps. However, to the extent that the method or process does not rely on the particular order of steps set forth herein, the method or process should not be limited to the particular sequence of steps described. As one of ordinary skill in the art would appreciate, other sequences of steps may be possible. Therefore, the particular order of the steps set forth in the specification should not be construed as limitations on the claims. In addition, the claims directed to the method and/or process of the present invention should not be limited to the performance of their steps in the order written, and one skilled in the art can readily appreciate that the sequences may be varied and still remain within the spirit and scope of the present invention.
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A consistency verification tool performs a consistency check on subscriber data records stored in the cellular telephone system. One such consistency check analyzes subscriber data records in a home location register (HLR) and a billing system to determine the presence of duplicate records. Duplicate records can be stored in a duplicate record file for later analysis. During the duplicate record consistency analysis, the consistency verification tool creates a record list. The record list can be a linked list structure for storing main records and duplicate records in a manner that facilitates identifying families of duplicate records. The consistency verification tool can also perform inter-device consistency checks. For example, the subscriber data stored on the HLR can be compared to the subscriber data stored in the billing system to ensure that the two systems have consistent subscriber data.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent application Ser. No. 10/431,270, filed on May 6, 2003, titled “Emission Control System”, which claims priority from U.S. Provisional Application Ser. No. 60/378,861, filed May 7, 2002, titled “Emission Control System,” the contents of which are incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
[0002] The present invention generally relates to emission control systems. More particularly, the invention concerns a method and apparatus to decrease the emissions of compression and spark ignition engines.
BACKGROUND OF THE INVENTION
[0003] Nitrogen oxide (NOx) emissions contribute significantly to photochemical smog and also to acid rain. NOx includes both nitrogen oxide (NO) and nitrogen dioxide (NO.sub. 2 ), both of which will be referred to as NOx. NOx is generated during the combustion of fossil fuels and a major generator of NOx is the diesel engine. Currently, new emissions standards for diesel engines are being proposed. For example, the European Euro-5 and the proposed US-2007 standards require a significant reduction in both NOx and particulate matter (PM) emissions.
[0004] In addition, diesel emissions have been classified as Toxic Air Contaminants (TACs) in the State of California. Under the Federal Clean Air Act, California must meet certain clear air requirements established by the Federal Government in order to qualify for federal highway funding. It is unlikely that those guidelines can be met without reducing emissions from mobile sources. Diesel mobile sources produce a disproportionate percentage of all emissions due to the inherent nature of the fuel and the engine.
[0005] In response, diesel engine manufacturers are developing systems to treat the exhaust stream of their diesel engines. Most of these solutions, however, make a clear trade off between emissions and fuel consumption. Some proposed systems are even associated with a distinct fuel penalty. Of course, fuel efficiency is extremely important, as the engine operator incurs an increased operational cost.
[0006] Another problem is that diesel engines typically last longer than other types of engines, and older engines produce more toxic emissions than newer engines.
[0007] Therefore, there exists a need for an emission control system that can reduce both NOx and PM emissions without incurring a fuel penalty, and that can be retrofitted to existing diesel engines.
SUMMARY OF THE INVENTION
[0008] The present invention reduces emissions generated by a diesel engine by injecting ammonia into the exhaust stream. The present invention efficiently injects ammonia, and can be incorporated into new engine designs or retrofitted to existing engines.
[0009] One feature of the present invention relates to a method and an apparatus for metering a reagent into a flowing medium, for instance for introducing ammonia into an exhaust stream containing NOx. The present invention can adjust a concentration of the reagent, such as ammonia, even when an abrupt change occurs in the concentration of NOx in the exhaust stream.
[0010] Therefore, even if the discharge amount and the concentration of NOx change abruptly, an optimum amount of ammonia can be supplied, and the NOx in the exhaust stream can be substantially eliminated.
[0011] These and other features and advantages of the present invention will be appreciated from review of the following detailed description of the invention, along with the accompanying figures in which like reference numerals refer to like parts throughout.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] FIG. 1 is a schematic illustration of a first embodiment of an emission control system constructed according to the present invention;
[0013] FIG. 2 is a schematic illustration of a second embodiment of an emission control system constructed according to the present invention;
[0014] FIG. 3 is a schematic illustration of a third embodiment of an emission control system constructed according to the present invention;
[0015] FIG. 4 is a schematic illustration of a fourth embodiment of an emission control system constructed according to the present invention;
[0016] FIG. 5 is a side elevation view of one embodiment of an ammonia diffuser nozzle located in an exhaust pipe;
[0017] FIG. 6 is a side elevation view of another embodiment of an ammonia diffuser nozzle located in an exhaust pipe;
[0018] FIG. 7 is a side elevation view of yet another embodiment of an ammonia diffuser nozzle located in an exhaust pipe; and
[0019] FIG. 8 is a side elevation view of a final embodiment of an ammonia diffuser nozzle located in an exhaust pipe.
[0020] It will be recognized that some or all of the Figures are schematic representations for purposes of illustration and do not necessarily depict the actual relative sizes or locations of the elements shown.
DETAILED DESCRIPTION
[0021] In the following paragraphs, the present invention will be described in detail by way of example with reference to the attached drawings. Throughout this description, the preferred embodiment and examples shown should be considered as exemplars, rather than as limitations on the present invention. As used herein, “the present invention” refers to any one of the embodiments of the invention, or equivalents thereof.
[0022] The present invention provides a method of reducing NOx emitted from an engine, by employing a controller that communicates with a plurality of sensors that provide information to the controller. The controller then regulates an amount of ammonia that is introduced into the engine's exhaust gas stream by analyzing the information provided by the plurality of sensors.
[0023] The present invention can be retrofitted to existing engines, or installed as original equipment. One embodiment of the present invention comprises a diesel engine NOx and PM emission reduction retrofit system. By incorporating a “retrofit” system, the engine owner will achieve immediate and significant reductions in NOx and PM emissions on most diesel, natural gas, and “lean-burn” vehicles, ships, generators, and other equipment that emit NOx. Another embodiment of the present invention may be incorporated into a new engine design.
[0024] The present invention may use any form of ammonia, such as urea, aqueous ammonia, or gaseous ammonia, or liquid ammonia. The ammonia is introduced into the exhaust stream to reduce NOx and combines an electronic controlled diffusion system together with a Selective Catalytic Reduction (“SCR”) component. A noticeable reduction in the NOx emission of a diesel motor can be achieved by applying SCR. In the SCR method, ammonia (NH.sub.3) is injected into the exhaust stream as a reduction agent. The present invention has already demonstrated its ability on diesel engines to reduce NOx by 75% or more and PM by 40% or more, and CO and HC by 70% or more over most engine operating parameters. In addition, the present invention may also reduce ammonia slip, which is the unintentional emission of ammonia in the exhaust stream. Moreover, simultaneous with the NOx reduction, hydrocarbons (HC), Carbon monoxide (CO) and particulate matter (PM) are reduced.
[0025] The ability of ammonia as a reductant to achieve significant reductions of NOx has been well established for over 35 years in stationary power generator applications. The uniqueness of the present invention is its safe and cost effective ability to create substantial reductions of mobile, as well as fixed source NOx emissions.
[0026] One embodiment of the present invention includes a controller that directs an ammonia injector to emit precise amounts of ammonia into an engine's exhaust stream. This embodiment also comprises a combination of a selective non-catalytic reduction (SNCR), and the above-mentioned selective catalytic reduction (SCR) to create a NOx reduction system that increases the reactive temperature range between the NOx and ammonia from anywhere between 275.degree.Fahrenheit (F.) to about 1200.degree. F.
[0027] This embodiment injects ammonia into the exhaust system between an engine exhaust manifold and a SCR (selective catalytic reaction) converter, and employs a mixer element to mix the ammonia with the exhaust gases. Preferably, the mixer element comprises a group of blades, fins, tabs, or other suitable components to mix the ammonia with the exhaust gases.
[0028] In a preferred embodiment, ammonia injection occurs at a location where the exhaust gases do not exceed the auto ignition temperature of ammonia, which is about 1200.degree. F., but at a high enough temperature to cause reaction of the ammonia with NO and NO2 (NOx) in the exhaust system prior to the exhaust gases reaching the SCR catalyst.
[0029] By being able to precisely control the amount and timing of ammonia injected necessary to reduce NOx, without any waste or slippage, that is without excess ammonia exiting the exhaust system, the size and weight of the on-board ammonia storage tank can be greatly reduced—in other words, many tank size options are available depending on user requirements. Thus, the safety concern of carrying very large ammonia storage tanks has been virtually eliminated.
[0030] One feature of the present invention is a computer control unit, or controller 1 that varies the amount of ammonia injected into the exhaust stream in proportion to the amount of NOx being produced at any given time. The control unit 1 , is designated as a “controller box” in FIGS. 1-2 , and as a “Extengine ADEC” in FIG. 3 , and as a “control unit” in FIG. 4 .
[0031] The present invention has a very high rate of reduction of NOx without the introduction of unneeded amounts of ammonia, with little or no slippage. “Slippage” refers to ammonia that is not fully utilized in the process of reducing NOx, and is then released into the atmosphere. Slippage is mostly a problem in systems in which a steady quantity of ammonia is injected into an exhaust system. With stationary, steady state heavy-duty engines, it is possible to inject a known steady quantity of ammonia without much slippage. But with mobile sources, or non-steady-state sources, the state of the engine is constantly changing, along with the amount of NOx and particulates being produced. If a steady quantity of ammonia is injected, the possibility of slippage is greater: any time very little NOx is being produced, too much ammonia could be injected into the system, with the inevitable result of significant slippage.
[0032] Another feature of the present invention is its ability to act as a combination SCR/SNCR emission control system. For example, one embodiment of the present invention may include an ammonia nozzle 10 that is placed into the exhaust pipe 31 at the exhaust manifold 30 . The higher temperature exhaust will react with the ammonia, even without a catalyst (the SNCR component). As the exhaust emissions continue through the exhaust pipe a secondary reaction occurs within the oxidation and reduction catalyst (the SCR element 19 ). Because of this dual reactive function as both a SNCR and SCR system, the present invention is capable of reducing NOx emissions over the entire range of temperatures (from 1200.degree. F. to 250.degree. F.) at which a typical mobile engine will operate. Therefore, all NOx emissions produced, regardless of operating temperature, will be reduced by the present invention.
[0033] The present invention can achieve large reductions of NOx emissions from vehicles powered by diesel engines, however, other embodiments of the invention will work equally well with vehicles powered by gasoline and natural gas.
[0034] The present invention can also be incorporated into new engine designs with additional benefits. For example, incorporation of the present invention may result in reduced consumption of petroleum through the use of revised injection/compression timing. Where appropriate, particularly on new OEM diesel engines, the elimination of the exhaust gas recycle (EGR) component on a new engine can increase operating performance, thereby reducing fuel consumption.
[0035] In addition, the installation of the present invention will permit an engine to be adjusted to run leaner, should the owner, distributor, or OEM so desire, thereby saving fuel, without unduly increasing NOx or other emissions. It is estimated that a reduction in fuel consumption of about 8% may be achieved. Also, the engine compression ratio may be increased, resulting in greater power, again without unduly increasing emissions of NOx or PM. This could result in a savings in fuel operating costs of about 8%.
[0036] In a preferred embodiment, the present invention utilizes the injection of ammonia that will be supplied to the system from a replaceable and/or refillable DOT approved tank similar to those used to contain propane, which is released into the exhaust stream by a pressure regulator, or ammonia injection nozzle 10 . As NOx is being created, fuel flow, and other sensors send signals to the controller box that directs the NH.sub.3 solenoid valve to open, thereby dispersing the ammonia, in a proportion necessary to effectively eliminate the NOx being created. Various embodiments of the present invention are illustrated in FIGS. 1-4 .
[0037] One embodiment of the present invention consumes approximately between ¼ and ½ pound of ammonia for each pound of NOx reduced. The present invention may use ordinary, readily-available liquid ammonia in order to achieve the projected and anticipated levels of reduction of NOx and other harmful emissions. Alternative embodiments may use other forms of ammonia such as urea or aqueous ammonia.
[0038] The present invention can work equally well on engines powered by gasoline, natural gas or diesel, and does not require any change or modification in the fuel.
[0039] The present invention should be attractive to the target market sector of owners of fleets of heavy-duty diesel vehicles for the following reasons: 1) the technology will be easy to add-on, as a retrofit kit; 2) the technology will not reduce engine efficiency or power, and will not increase operating fuel costs; 3) fleet owners may be able to realize savings of 5-8% in fuel costs; 4) the technology will allow fleet owners to comply with federal clean air regulations; 5) fleet owners may become eligible for trading credits, which they can sell on the open market; 6) and because of the extremely cost-effective nature of the present invention (approximately $3,283 per ton of NOx reduced compared to $15,000+ per ton average price during 2000), the cost to the fleet owner of installing the proposed technology will be minimized.
[0040] The present invention utilizes a computerized unit, or controller 10 that controls the amount of ammonia being injected into the system. The present invention measures the amount of NOx being produced by the engine at any given moment. The controller 10 then injects an amount of ammonia needed to reduce the amount of NOx being produced. Under most engine load conditions, the actual amount of ammonia that is injected is very small.
[0041] Illustrated in FIG. 3 , one embodiment of the present invention is comprised of sensors for exhaust gas temperature 7 , 8 , intake air temperature 3 , engine load information, turbo boost 26 , throttle position 4 , engine rpm 5 , exhaust back-pressure 6 , NH.sub.3 temperature 17 , a NOx sensor 9 , ammonia bottle, or tank heater 15 , the electronic controller (designated as the “Extengine ADEC 1 ”), the SCR catalysts 19 , a pre-catalyst 18 and a slip-catalyst 20 . The controller 1 is responsible for controlling the amount of ammonia being injected for NOx reduction, while minimizing any ammonia slip, and may also include circuitry for a redundant fail-safe and OBD (On Board Diagnostic) system that may include a warning light 27 , and a data port 25 .
[0042] The controller 1 calculates the correct amount of ammonia needed, by analyzing the information supplied by the various sensors, together with the engine speed information, and compares these values with the appropriate point of the injection map that is contained in the vehicle's original engine control system. The amount of ammonia being injected is controlled by an ammonia metering solenoid, or other suitable valve 11 that introduces the ammonia into the exhaust system at a location before the SCR converters 19 , but after the pre-converter 18 (see FIG. 3 ).
[0043] The controller 1 , includes at least one general purpose digital computer with associated computer code, or logic for analyzing the data received from the sensors, and instructing the various components communicating with the controller 1 .
[0044] Referring to FIGS. 5-8 , several arrangements for introducing ammonia into the exhaust stream are illustrated. The ammonia nozzle 10 may comprise any of the following embodiments.
[0045] Specifically, in FIG. 5 , an ammonia nozzle 15 is located within an exhaust pipe 10 . The ammonia nozzle 15 includes at least two ports 17 that introduce ammonia into the exhaust stream. The ports 17 are inset below the contour of the nozzle 15 , thereby minimizing any disruption in the flow of the exhaust stream and reducing the build-up of any particulate matter over the ports 17 . Similarly, FIG. 6 illustrates an alternative nozzle 15 configuration. The ports are located on projections that extend from the nozzle 15 . Because the ports 17 are facing downstream of the exhaust stream, particulate matter does not accumulate on the ports 17 .
[0046] FIG. 7 illustrates an alternative nozzle 15 configuration. The nozzle 15 has a “teardrop” shape that minimizes drag in the exhaust stream and also minimizes particulate buildup over the ports 17 .
[0047] Finally, FIG. 8 illustrates another embodiment of a nozzle 15 . The nozzle 15 is substantially U-shaped and protects the port 17 from accumulation of particulates in the exhaust stream. It will be appreciated that other nozzle 15 configurations can be incorporated into the present invention to introduce ammonia into the exhaust stream of an exhaust pipe 10 .
[0048] Any one of the above-described nozzle 15 configurations may also be designed to mix the ammonia with the exhaust stream so that the exhaust gases and ammonia are mixed together before reaching the various catalysts. This mixing may be facilitated by orienting the ports 17 in different directions, or the mixing may be accomplished by the insertion of a vortex generator or other type of device into the exhaust pipe. In addition, the present invention may include a device to direct the flow of the exhaust stream over the catalyst so the exhaust is disbursed evenly over the catalyst's surface. This device may include directing elements located in the exhaust pipe to direct the flow of the exhaust gases.
[0049] In addition, the present invention, may for example, includes a fail-safe system that detects any ammonia leaks. In a preferred embodiment, electromagnetic valves will assure shutoff of the ammonia supply in case of accidents or system malfunctions. Replacing or refilling of the ammonia tank 14 may be performed without any release of ammonia by employing of a quick-connect system.
[0050] As discussed above, the present invention employs multiple sensors operating with the controller 1 . The controller 1 , designated as “controller box” in FIGS. 1 and 2 , and as “Extengine ADEC” in FIG. 3 , and as “control unit” in FIG. 4 , may obtain signals from some of, or all of the following sensors:
[0051] 1 Crankshaft Sensor: Supplies information about engine speed and injection pulses. Throttle Position Sensor: Supplies information about fuel flow (throttle position) and together with engine speed represents engine load. Turbo Boost Sensor: Supplies information about engine load. Exhaust gas temperature sensors: At Manifold: Supplies information about Exhaust Temperature right at the exhaust manifold. This information can be used to “predict” the creation of NOx. During heavy acceleration the exhaust temperature at the manifold changes more rapidly than at the converter. This information about “temperature-spread” can be used to adjust NH.sub.3 flow during acceleration and deceleration. At the Converter: Supplies information about Catalytic Converter Temperature and is used to compensate NH.sub.3 flow depending on converter temperature (cold—no NH.sub. 3 , hot—extra NH.sub.3). This added feature results in greater NOx reduction and less chance for ammonia slip. Exhaust Backpressure Supplies information about Exhaust Sensor: Backpressure. Excessive exhaust backpressure may be caused by a non-regenerating PM trap, or a clogged SCR catalyst or a clogged Pre-catalyst. (The vehicle operator may be warned by an audible and/or visual signal, or by an engine shut-down). Intake Air Temperature Since intake are temperature is Sensor: directly affected by the production of NOx, this sensor supplies information about Intake Air Temperature and is used to compensate NH.sub.3 flow. NH.sub.3 Line Temperature This information is needed to enable Sensor: reliable operation in all climate conditions. Since the mass of the ammonia changes with temperature, this sensor provides the NH.sub.3 temperature. NOx Sensor: The NOx sensor allows the system to operate in a closed-loop mode. This gives added controllability of the amount of ammonia being injected. This assures a short system reaction time during transient conditions and maximum emissions reduction. NH.sub.3 Tank Temperature This information is needed to enable Sensor: reliable operation in all climate conditions. This information is used to control the ammonia tank heating element. NH.sub.3 Tank Pressure Sensor: This sensor, in combination with the pulse-width information of the injector, determines if the system is being used and if ammonia is being consumed. In case the system is not being used, or the ammonia tank is empty, the use of the vehicle can be prohibited. (A vehicle operator warning may include: an audible and/or visual signal, or engine shutdown after 3 restarts). This sensor is also used for ammonia leak detection in a catastrophic event and system shutdown. The controller 1 , designated as “controller box” in FIGS. 1 and 2 , and as “Extengine ADEC” in FIG. 3 , and as “control unit” in FIG. 4 , may send signals to the following units: NH.sub.3 Injector: Receives pulse-width signals from the controller for accurate NH.sub.3 delivery. NH.sub.3 Shut-Off Valve: Isolates the high-pressure NH.sub.3 in the tank from the rest of the system. The Shut-off valve is only open when the engine is running. Also controls system shutdown in case of Ammonia leak detection (rapid drop in pressure). Diagnostic Light and The controller is equipped with self-Error Codes: diagnostic logic. The system will inform the operator or technician which sensor is malfunctioning by flashing a light in the dashboard. The vehicle must go to an authorized service center where the problem can be repaired and the Diagnostic Light reset. The present invention may also include the following components: Pressure Regulator: Accurately regulates NH.sub.3 pressure. NH.sub.3 Tank Heater: Works with the NH.sub.3 Tank Temperature Sensor and regulates NH.sub.3 temperature under cold climate conditions. Pre-Catalytic Converter: Removes substantial amounts of HC and CO and encourages the formation of NO.sub.2. The presence of up to 50% NO.sub.2 in the exhaust stream increases the efficiency of the SCR catalysts. SCR Converter: The formulation of the “wash coat”, as well as the Catalytic Converter sizing, is an important feature of the present invention. Ammonia Slip Converter: The Ammonia Slip Conveter can be considered a cleanup-catalyst and reduces any ammonia from the exhaust stream unused by the SCR. Catalyzed Diesel Removes soot particles from the Particulate Trap: exhaust stream and when used in place of the Pre-Catalytic Converter, removes substantial amounts of HC and CO and encourages the formation of NO.sub.2. The presence of up to 50% NO.sub.2 in the exhaust stream increases the efficiency of the SCR catalysts. Fast response NOx/NH.sub.3 fast response NOx or NH.sub.3 Sensors: sensors may be used as feedback sensors, with the data sent to the controller 1 to optimize NOx reduction.
[0052] As shown in FIG. 4 , the present invention may also include some of the following components for an emission control system using urea or aqueous ammonia: an air fan or pump to help vaporize the ammonia; a liquid pump to pressurize the urea or aqueous ammonia; and a heater to heat the urea or aqueous ammonia. The heater may comprise an ammonia-carrying tube that is wound about the inner diameter of the exhaust pipe 31 , or it may comprise a heating element that heats the urea or aqueous ammonia.
[0053] In the embodiment illustrated in FIG. 4 , the urea or aqueous ammonia (NH.sub.3.H.sub.2O) is stored in a pressurized tank. From there it is piped through the pump to the ammonia metering solenoid. From there the ammonia, which in this embodiment uses ammonia in a water solution at about 27% to about 32% ammonia. To liberate the ammonia from the water/ammonia solution, at least two options are available: The water/ammonia solution is routed through the heater, schematically illustrated in FIG. 4 . The heater may comprise a heating mechanism where the temperature is hot enough to turn the water into steam and liberate the ammonia as ammonia gas. This can be achieved by routing the water/ammonia mixture through a coiled metal tube, which is placed inside the exhaust pipe 31 as discussed above. The length of the coiled pipe can be increased or decreased and the location of the pipe can be optimized to liberate the ammonia from the water/ammonia mixture. Alternatively, the water/ammonia solution is routed through a tubular electric (or other shape) heater where the temperature is hot enough to turn the water into steam and liberate the ammonia as a gas. The length of the tubular electric (or other shape) heater (heating element) can be increased or decreased and the heating power can be increased or decreased so that the temperature is optimum to liberate the ammonia from the water/ammonia mixture.
[0054] The ammonia and water vapor is next routed into the exhaust pipe 31 where it mixes with the exhaust gas stream at a location upstream of the SCR catalyst. A mixer may be placed in the exhaust pipe 31 to aid in the mixing of the exhaust gases with the ammonia.
[0055] Generally, once routed through the heater element the urea undergoes hydrolysis and thermal decomposition producing ammonia. This hydrolysis continues when the urea/aqueous ammonia mixes with the hot exhaust gas. The mixture of exhaust gases and ammonia (decomposed urea/aqueous ammonia) enters the SCR catalyst where nitrogen oxides are reduced to nitrogen.
[0056] One feature of the present invention is that the controller 1 also monitors the exhaust gas temperature. When the temperature drops below a predetermined value, somewhere between about 150.degree. C. to about 250.degree. C., depending on the catalyst type and configuration, the controller 1 closes the urea supply to prevent catalyst deactivation and secondary emissions (ammonia slip) that may occur at low temperatures.
[0057] In a preferred embodiment of the present invention, the controller 1 calculates the correct amount of ammonia needed, by “reading” the information supplied by the various sensors, together with the engine speed information, and compares these values with the appropriate point of the factory-programmed Injection-Map. A fail-safe system assures that possible ammonia leaks do not go undetected and the on-board-diagnostic (OBD) system alarms the vehicle operator of any problems. Electromagnetic valves, or a shut-off solenoid 22 assures the auto-shutoff of the ammonia supply in case of accidents or system malfunctions. Replacing or refilling of the ammonia tank 14 is performed entirely without any accidental release of the reducing agent by using quick-release connectors.
[0058] Another embodiment of the present invention may account for changes to the ambient temperature. Generally, a change in ammonia storage pressure, caused by changes to ambient temperature, will change the amount of ammonia being delivered. In addition, the vapor pressure of ammonia changes with the increase or decrease of the ammonia temperature and therefore, in cold climates, a heater for the ammonia tank 14 may be necessary. For example, a blanket-type heater, which may be controlled by the controller 1 , could maintain the ammonia at a temperature of about 80 to about 110 degrees F. at all times.
[0059] One embodiment of the present invention may employ an open-loop configuration where a pre-programmed map of engine NO.sub.x emissions is used to control the ammonia/urea/aqueous injection rate as a function of engine speed, load, exhaust temp, intake air temp, an other parameters. This open-loop configuration is generally capable of about 80% NO.sub.x reduction. However, an alternative embodiment, employing a closed-loop system may be employed for more demanding applications requiring 90%+ NO.sub.x reduction targets. The closed-loop system may require NO.sub.x sensors of 40-20 ppm NO.sub.x sensitivity having low cross-sensitivity to NH.sub.3 for closed-loop operation. The use of a closed loop system may also minimize the amount of engine calibration work that is generally required in the development of open-loop systems.
[0060] The above-described invention includes several features including: monitoring if the system is being used and how much ammonia is being consumed; a self-diagnostic logic; ammonia leak detection; exhaust backpressure monitoring; data storage and system monitoring; and a Diagnostic Port for Runtime Data and System Information that can be accessed with a portable computer. All the system perimeters of the present invention are adjustable, and the present invention also incorporates easy and safe removal and replacement of ammonia containers.
[0061] In addition to the above-described controller and associated sensors, the present invention also employs several catalysts. Referring to FIG. 3 , one embodiment of the present invention may employ three different catalysts in series: a diesel oxidation catalyst, or pre-catalyst 18 , a SCR catalyst 19 and a guard oxidation catalyst or ammonia slip converter 20 . The ammonia is introduced into the exhaust pipe between the pre-catalyst 18 and the SCR 19 . The ammonia then reacts on the SCR catalyst with the NOx present in the exhaust gas to form nitrogen (N.sub.2) Finally, the ammonia slip converter 20 eliminates any secondary emissions of ammonia during dynamic operation.
[0062] In the SCR catalyst, ammonia reacts with NOx according to the following reactions:
4NH.sub.3+4NO+O.sub.2.fwdarw.4N.sub.2+6H.sub.2O (3)
2NH.sub.3+NO+NO.sub.2.fwdarw.2N.sub.2+3H.sub.2O (4)
4NH.sub.3+2NO.sub.2+O.sub.2.fwdarw.3N.sub.2+6H.sub.2O (5)
[0063] Of these three reactions, reaction (4) is appreciably more facile than either reaction (3) or (5), occurring at a significant rate at much lower reaction temperatures. Thus, if an appreciable proportion of the NOx in the exhaust consists of NO.sub.2 (ideally 50%) the SCR catalyst will perform much more efficiently. For this reason, the present invention may include a pre-catalyst 18 , shown in FIG. 3 . The pre-catalyst 18 enables a significant improvement in the low temperature NOx removal performance of the present invention. This technology enables simultaneous NOx conversions of 75-90% and PM conversions of 75-90% to be obtained on existing engines.
[0064] In the ammonia slip converter catalyst 20 , ammonia reacts with NOx according to the following reactions:
4NH.sub.3+3O.sub.2.fwdarw.2N.sub.2+6H.sub.2O
4HC+5O.sub.2.fwdarw.4CO.sub.2+2H.sub.2O
2CO+O.sub.2.fwdarw.2CO.sub.2
[0065] Generally, a SCR catalyst is a homogenous, extruded base metal catalyst (TiO.sub.2—V.sub.2O.sub.5—WO.sub.3). In a preferred embodiment of the present invention, the SCR catalyst may use a 100 to 400 cpsi/6.5 mil ceramic substrate coated with a V.sub.2O.sub.5/WO.sub.3/TiO.sub.2 mixture.
[0066] In summary, the present invention reliably and instantaneously introduces the correct amount of ammonia to the exhaust gas stream in order to efficiently reduce the amount of noxious NOx. In addition, the present invention synergistically arranges several catalytic converters and particulate traps to achieve a significant reduction in NOx, CO and particulate matter emissions.
[0067] Thus, it is seen that an apparatus and method for control of emissions is provided. One skilled in the art will appreciate that the present invention can be practiced by other than the preferred embodiments, which are presented in this description for purposes of illustration and not of limitation, and the present invention is limited only by the claims that follow. It is noted that various equivalents for the particular embodiments discussed in this description may practice the invention as well.
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A method and apparatus to reduce the emissions of an exhaust stream is provided. One feature of the present invention includes a control unit for metering a reagent into the exhaust strean. The control unit adjusts a quantity of the reagent to be metered into the exhaust stream. One embodiment of the present invention concerns a method of removing nitrogen oxides in exhaust gases from a diesel engine by introducing ammonia into the exhaust stream. This Abstract is provided for the sole purpose of complying with the Abstract requirement rules that allow a reader to quickly ascertain the subject matter of the disclosure contained herein. This Abstract is submitted with the explicit understanding that it will not be used to interpret or to limit the scope or the meaning of the claims.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a divisional application of U.S. Ser. No. 08/262,813, filed Jun. 21, 1994, which is a divisional of U.S. Ser. No. 07/513,282, filed Apr. 20, 1990 U.S. Pat. No. 5,352,575; which was a continuation-in-part of U.S. Ser. No. 07/100,817 filed Jun. 29, 1987, abandoned; which was a continuation of International Patent Application No. PCT/US86/01761, filed Aug. 28, 1986; which was a continuation-in-part of U.S. Ser. No. 06/886,260, filed Jul. 16, 1986, abandoned; which was a continuation-in-part of U.S. Ser. No. 06/844,113, filed Mar. 26, 1986, now abandoned and of U.S. Ser. No. 06/801,799, filed Nov. 26, 1985, all abandoned.
FIELD OF INVENTION
This invention relates to DNA sequences encoding pseudorabies virus glycoproteins and polypeptides related thereto. These DNA sequences are useful for screening animals to determine whether they are infected with PRV and also for expressing the glycoproteins encoded thereby.
BACKGROUND OF THE INVENTION
Pseudorabies virus (PRV) is a disease which infects many species of animals worldwide. PRV infections are variously called infectious Bulbar paralysis, Aujeszky's disease, and mad itch. Infections are known in important domestic animals such as swine, cattle, dogs, cats, sheep, rats and mink. The host range is very broad and includes most mammals and, experimentally at least, many kinds of birds (for a detailed list of hosts, see D. P. Gustafson, “Pseudorabies”, in Diseases of Swine, 5th ed., A. D. Leman et al., eds., (1981)). For most infected animals the disease is fatal. Adult swine and possibly rats, however, are not killed by the disease and are therefore carriers.
Populations of swine are particularly susceptible to PRV. Although the adult swine rarely show symptoms or die from the disease, piglets become acutely ill when infected and death usually ensues in 24 to 48 hours often without specific clinical signs (T. C. Jones and R. D. Hunt, Veterinary Pathology, 5th ed., Lea & Febiger (1983)).
PRV vaccines have been produced by a variety of techniques and vaccination in endemic areas of Europe has been practiced for more than 15 years. Losses have been reduced by vaccination, but vaccination has maintained the virus in the environment. No vaccine has been produced that will prevent infection. Vaccinated animals that are exposed to virulent virus survive the infection and then shed more virulent virus. Vaccinated animals may therefore harbor a latent infection that can flare up again. (See, D. P. Gustafson, supra).
Live attenuated and inactivated vaccines for PRV are available commercially in the United States and have been approved by the USDA (See, C. E. Aronson, ed., Veterinary Pharmaceuticals & Biologicals, (1983)).
Because adult swine are carriers of PRV, many states have instituted screening programs to detect infected animals. DNA/DNA hybridization can be used to diagnose actively infected animals utilizing the DNA sequence of the instant invention. Some of the PRV glycoproteins of the present invention are also useful in producing diagnostics for PRV infections and also to produce vaccines against PRV.
PRV is a herpesvirus. The herpesviruses generally are among the most complex of animal viruses. Their genomes encode at least 50 virus specific proteins and contain upwards of 150,000 nucleotides. Among the most immunologically reactive proteins of herpesviruses are the glycoproteins found, among other places, in virion membranes and the membranes of infected cells. The literature on PRV glycoproteins refers to at least four viral glycoproteins (T. Ben-Porat and A. S. Kaplan, Virology, 41, pp. 265-73 (1970); A. S. Kaplan and T. Ben-Porat, Proc. Natl. Acad. Sci. USA, 66, pp. 799-806 (1970)).
INFORMATION DISCLOSURE
M. W. Wathen and L. K. Wathen, J. Virol., 51, pp. 57-62 (1984) refer to a PRV containing a mutation in a viral glycoprotein (gp50) and a method for selecting the mutant utilizing neutralizing monoclonal antibody directed against gp50. Wathen and Wathen also indicate that a monoclonal antibody directed against gp50 is a strong neutralizer of PRV, with or without the aid of complement, and that polyvalent immune serum is highly reactive against gp50, therefore concluding that gp50 may be one of the important PRV immunogens. On the other hand, it has been reported that monoclonal antibodies that react with the 98,000 MW envelope glycoprotein neutralize PRV infectivity but that monoclonal antibodies directed against some of the other membrane glycoproteins have very little neutralizing activity (H. Hampl, et al., J. Virol., 52, pp. 583-90 (1984); and T. Ben-Porat and A. S. Kaplan, “Molecular Biology of Pseudorabies Virus”, in B. Roizman ed., The Herpesviruses, 3, pp. 105-73 (1984)).
L. M. K. Wathen, et al., Virus Research, 4, pp. 19-29 (1985) refer to the production and characterization of monoclonal antibodies directed against PRV glycoproteins identified as gp50 and gp83 and their use for passively immunizing mice against PRV infection.
A. K. Robbins, et al., “Localization of a Pseudorabies Virus Glycoprotein Gene Using an E. coli Expression Plasmid Library”, in Herpesvirus, pp. 551-61 (1984), refer to the construction of a library of E. coli plasmids containing PRV DNA. They also refer to the identification of a PRV gene that encodes glycoproteins of 74,000 and 92,000 MW. They do not refer to the glycoproteins of the instant invention.
A. K. Robbins, et al., European patent application No. 85400704.4 (publication No. 0 162 738) refers to the isolation, cloning and expression of PRV glycoproteins identified as gII and gIII. They do not refer to the PRV glycoproteins of the instant invention.
T. C. Mettenleiter, et al., “Mapping of the Structural Gene of Pseudorabies Virus Glycoprotein A and Identification of Two Non-Glycosylated Precursor Polypeptides”, J. Virol., 53, pp. 52-57 (1985), refer to the mapping of the coding region of glycoprotein gA (which they equate with gI) to the BamHI 7 fragment of PRV DNA. They also state that the BamHI 7 fragment codes for at least three other viral proteins of 65K, 60K, and 40K MW. They do not disclose or suggest the DNA sequence encoding the glycoproteins of the instant invention or the production of such polypeptides by recombinant DNA methods.
B. Lomniczi, et al., “Deletions in the Genomes of Pseudorabies Virus Vaccine Strains and Existence of Four Isomers of the Genomes”, J. Virol., 49, pp. 970-79 (1984), refer to PRV vaccine strains that have deletions in the unique short sequence between 0.855 and 0.882 map units. This is in the vicinity of the gI gene. T. C. Mettenleiter, et al., “Pseudorabies Virus Avirulent Strains Fail to Express a Major Glycoprotein”, J. Virol., 56, pp. 307-11 (1985), demonstrated that three commercial PRV vaccine strains lack glycoprotein gI. We have also found recently that the Bartha vaccine strain contains a deletion for most of the gp63 gene.
T. J. Rea et al., J. Virol., 54, pp. 21-29 (1985), refers to the mapping and the sequencing of the gene for the PRV glycoprotein that accumulates in the medium of infected cells (gX). Included among the flanking sequences of the gX gene shown therein is a small portion of the gp50 sequence, specifically beginning at base 1682 of FIG. 6 therein. However, this sequence was not identified as the gp50 sequence. Furthermore, there are errors in the sequence published by Rea et al. Bases 1586 and 1603 should be deleted. Bases should be inserted between bases 1708 and 1709, bases 1737 and 1738, bases 1743 and 1744 and bases 1753 and 1754. The consequence of these errors in the published partial sequence for gp50 is a frameshift. Translation of the open reading frame beginning at the AUG start site would give an incorrect amino acid sequence for the gp50 glycoprotein.
European published patent application 0 133 200 refers to a diagnostic antigenic factor to be used together with certain lectin-bound PRV glycoprotein subunit vaccines to distinguish carriers and noncarriers of PRV.
SUMMARY OF INVENTION
The present invention provides recombinant DNA molecules comprising DNA sequences encoding polypeptides displaying PRV glycoprotein antigenicity.
More particularly, the present invention provides host cells transformed with recombinant DNA molecules comprising the DNA sequences set forth in Charts A, B, and C, and fragments thereof.
The present invention also provides polypeptides expressed by hosts transformed with recombinant DNA molecules comprising DNA sequences of the formulas set forth in Charts A, B, and C, and immunologically functional equivalents and immunogenic fragments and derivatives of the polypeptides.
More particularly, the present invention provides polypeptides having the formulas set forth in Charts A, B, and C, immunogenic fragments thereof and immunologically functional equivalents thereof.
The present invention also provides recombinant DNA molecules comprising the DNA sequences encoding pseudorabies virus glycoproteins gp50, gp63, gI or immunogenic fragments thereof operatively linked to an expression control sequence.
The present invention also provides vaccines comprising gp50 and gp63 and methods of protecting animals from PRV infection by vaccinating them with these polypeptides.
DETAILED DESCRIPTION OF INVENTION
The existence and location of the gene encoding glycoprotein gp50 of PRV was demonstrated by M. W. Wathen and L. M. Wathen, supra.
The glycoprotein encoded by the gene was defined as a glycoprotein that reacted with a particular monoclonal antibody. This glycoprotein did not correspond to any of the previously known PRV glycoproteins. Wathen and Wathen mapped a mutation resistant to the monoclonal antibody, which, based on precedent in herpes simplex virus (e.g., T. C. Holland et al., J. Virol., 52, pp. 566-74 (1984)), maps the location of the structural gene for gp50. Wathen and Wathen mapped the gp50 gene to the smaller SalI/BamHI fragment from within the BamHI 7 fragment of PRV. Rea et al, supra, have mapped the PRV glycoprotein gX gene to the same region.
The PRV gp63 and gI genes were isolated by screening PRV DNA libraries constructed in the bacteriophage expression vector λgt11 (J. G. Timmins, et al., “A method for Efficient Gene Isolation from Phage λgt11 Libraries: Use of Antisera to Denatured, Acetone-Precipitated Proteins”, Gene, 39, pp. 89-93 (1985); R. A. Young and R. W. Davis, Proc. Natl.Acad. Sci. USA, 80, pp. 1194-98 (1983); R. A. Young and R. W. Davis, Science, 222, pp. 778-82 (1983)).
PRV genomic DNA derived from PRV Rice strain originally obtained from D. P. Gustafson at Purdue University was isolated from the cytoplasm of PRV-infected Vero cells (ATCC CCL 81). The genomic DNA was fragmented by sonication and then cloned into λgt11 to produce a λ/PRV recombinant (λPRV) DNA library.
Antisera for screening the λPRV library were produced by inoculating mice with proteins isolated from cells infected with PRV (infected cell proteins or ICP's) that had been segregated according to size on SDS gels, and then isolating the antibodies. The λPRV phages to be screened were plated on a lawn of E. coli. λgt11 contains a unique cloning site in the 3′ end of the lacZ gene. Foreign DNA's inserted in this unique site in the proper orientation and reading frame produce, on expression, polypeptides fused to β-galactosidase. A nitrocellulose filter containing an inducer of lacZ transcription to enhance expression of the PRV DNA was laid on top of the lawn. After the fusion polypeptides expressed by λPRV's had sufficient time to bind to the nitrocellulose filters, the filters were removed from the lawns and probed with the mouse antisera. Plaques producing antigen that bound the mice antisera were identified by probing with a labeled antibody for the mouse antisera.
Plaques that gave a positive signal were used to transform an E. coli host (Y1090, available from the ATCC, Rockville, Md. 20852). The cultures were then incubated overnight to produce the λPRV phage stocks. These phage stocks were used to infect E. coli K95 (D. Friedman, in The Bacteriophage Lambda, pp. 733-38, A. D. Hershey, ed. (1971)). Polypeptides produced by the transformed E. coli K95 were purified by preparative gel electrophoresis. Polypeptides that were overproduced (due to induction of transcription of the lacZ gene), having molecular weights greater than 116,000 daltons, and which were also absent from λgt11 control cultures were β-galactosidase-PRV fusion proteins. Each individual fusion protein was then injected into a different mouse to produce antisera.
Labeled PRV ICP's were produced by infecting Vero cells growing in a medium containing, for example, 14 C-glucosamine (T. J. Rea, et al., supra.). The fusion protein antisera from above were used to immunoprecipitate these labeled ICP's. The polypeptides so precipitated were analyzed by gel electrophoresis. One of them was a 110 kd MW glycoprotein (gI) and another a 63 kd MW glycoprotein (gp63). The genes cloned in the phages that produced the hybrid proteins raising anti-gI and anti-gp63 serum were thus shown to be the gI and gp63 genes. These genes were found to map within the BamHI 7 fragment of the PRV genome (T. J. Rea, et al., supra.) as does the gp50 sequence (see Chart D). The gI location is in general agreement with the area where Mettenleiter, et al., supra, had mapped the gI gene. However, Mettenleiter, et al. implied that the gI gene extends into the BamHI 12 fragment which it does not.
This λPRV gene isolation method is rapid and efficient when compared to DNA hybridization and to in vitro translation of selected mRNAs. Because purified glycoproteins were unavailable, we could not construct, rapidly, oligonucleotide probes from amino acid sequence data, nor could we raise highly specific polyclonal antisera. Therefore we used the method set forth above.
As mentioned above, the genes encoding gp50, gp63, and gI mapped to the BamHI 7 fragment of the PRV DNA. The BamHI 7 fragment from PRV can be derived from plasmid pPRXh1 (also known as pUC1129) and fragments convenient for DNA sequence analysis can be derived by standard subcloning procedures. Plasmid pUC1129 is available from E. coli HB101, NRRL B-15772. This culture is available from the permanent collection of the Northern Regional Research Center Fermentation Laboratory (NRRL), U.S. Department of Agriculture, in Peoria, Ill., U.S.A.
E. coli HB101 containing pUC1129 can be grown up in L-broth by well known procedures. Typically the culture is grown to an optical density of 0.6 after which chloramphenicol is added and the culture is left to shake overnight. The culture is then lysed by, e.g., using high salt SDS and the supernatant is subjected to a cesium chloride/ethidium bromide equilibrium density gradient centrifugation to yield the plasmids.
The availability of these gene sequences permits direct manipulation of the genes and gene sequences which allows modifications of the regulation of expression and/or the structure of the protein encoded by the gene or a fragment thereof. Knowledge of these gene sequences also allows one to clone the corresponding gene, or fragment thereof, from any strain of PRV using the known sequence as a hybridization probe, and to express the entire protein or fragment thereof by recombinant techniques generally known in the art.
Knowledge of these gene sequences enabled us to deduce the amino acid sequence of the corresponding polypeptides (Charts A-C). As a result, fragments of these polypeptides having PRV immunogenicity can be produced by standard methods of protein synthesis or recombinant DNA techniques. As used herein, immunogenicity and antigenicity are used interchangeably to refer to the ability to stimulate any type of adaptive immune response, i.e., antigen and antigenicity are not limited in meaning to substances that stimulate the production of antibodies.
The primary structures (sequences) of the genes coding for gp50, gp63, and gI also are set forth in Charts A-C.
The genes or fragments thereof can be extracted from pUC1129 by digesting the plasmid DNA from a culture of NRRL B-15772 with appropriate endonuclease restriction enzymes. For example, the BamHI 7 fragment may be isolated by digestion of a preparation of pUC1129 with BamHI, and isolation by gel electrophoresis.
All restriction endonucleases referred to herein are commercially available and their use is well known in the art. Directions for use generally are provided by commercial suppliers of the restriction enzymes.
The excised gene or fragments thereof can be ligated to various cloning vehicles or vectors for use in transforming a host cell. The vectors preferably contains DNA sequences to initiate, control and terminate transcription and translation (which together comprise expression) of the PRV glycoprotein genes and are, therefore, operatively linked thereto. These “expression control sequences” are preferably compatible with the host cell to be transformed. When the host cell is a higher animal cell, e.g., a mammalian cell, the naturally occurring expression control sequences of the glycoprotein genes can be employed alone or together with heterologous expression control sequences. Heterologous sequences may also be employed alone. The vectors additionally preferably contain a marker gene (e.g., antibiotic resistance) to provide a phenotypic trait for selection of transformed host cells. Additionally a replicating vector will contain a replicon.
Typical vectors are plasmids, phages, and viruses that infect animal cells. In essence, one can use any DNA sequence that is capable of transforming a host cell.
The term host cell as used herein means a cell capable of being transformed with the DNA sequence coding for a polypeptide displaying PRV glycoprotein antigenicity. Preferably, the host cell is capable of expressing the PRV polypeptide or fragments thereof. The host cell can be procaryotic or eucaryotic. Illustrative procaryotic cells are bacteria such as E. coli, B. subtilis, Pseudomonas, and B. stearothermophilus. Illustrative eucaryotic cells are yeast or higher animal cells such as cells of insect, plant or mammalian origin. Mammalian cell systems often will be in the form of monolayers of cells although mammalian cell suspensions may also be used. Mammalian cell lines include, for example, VERO and HeLa cells, Chinese hamster ovary (CHO) cell lines, WI38, BHK, COS-7 or MDCK cell lines. Insect cell lines include the Sf9 line of Spodoptera frugiperda (ATCC CRL1711). A summary of some available eucaryotic plasmids, host cells and methods for employing them for cloning and expressing PRV glycoproteins can be found in K. Esser, et al., Plasmids of Eukaryotes (Fundamentals and Applications), Springer-Verlag (1986) which is incorporated herein by reference.
As indicated above, the vector, e.g., a plasmid, which is used to transform the host cell preferably contains compatible expression control sequences for expression of the PRV glycoprotein gene or fragments thereof. The expression control sequences are, therefore, operatively linked to the gene or fragment. When the host cells are bacteria, illustrative useful expression control sequences include the trp promoter and operator (Goeddel, et al., Nucl. Acids Res., 8, 4057 (1980)); the lac promoter and operator (Chang, et al., Nature, 275, 615 (1978)); the outer membrane protein promoter (EMBO J., 1, 771-775 (1982)); the bacteriophage λ promoters and operators (Nucl. Acids Res., 11, 4677-4688 (1983)); the α-amylase ( B. subtilis ) promoter and operator, termination sequences and other expression enhancement and control sequences compatible with the selected host cell. When the host cell is yeast, illustrative useful expression control sequences include, e.g., α-mating factor. For insect cells the polyhedrin promoter of baculoviruses can be used (Mol. Cell. Biol., 3, pp. 2156-65 (1983)). When the host cell is of insect or mammalian origin illustrative useful expression control sequences include, e.g., the SV-40 promoter (Science, 222, 524-527 (1983)) or, e.g., the metallothionein promoter (Nature, 296, 39-42 (1982)) or a heat shock promoter (Voellmy, et al., Proc. Natl. Acad. Sci. USA, 82, pp. 4949-53 (1985)). As noted above, when the host cell is mammalian one may use the expression control sequences for the PRV glycoprotein gene but preferably in combination with heterologous expression control sequences.
The plasmid or replicating or integrating DNA material containing the expression control sequences is cleaved using restriction enzymes, adjusted in size as necessary or desirable, and ligated with the PRV glycoprotein gene or fragments thereof by means well known in the art. When yeast or higher animal host cells are employed, polyadenylation or terminator sequences from known yeast or mammalian genes may be incorporated into the vector. For example, the bovine growth hormone polyadenylation sequence may be used as set forth in European publication number 0 093 619 and incorporated herein by reference. Additionally gene sequences to control replication of the host cell may be incorporated into the vector.
The host cells are competent or rendered competent for transformation by various means. When bacterial cells are the host cells they can be rendered competent by treatment with salts, typically a calcium salt, as generally described by Cohen, PNAS, 69, 2110 (1972). A yeast host cell generally is rendered competent by removal of its cell wall or by other means such as ionic treatment (J. Bacteriol., 153, 163-168 (1983)). There are several well-known methods of introducing DNA into animal cells including, e.g., calcium phosphate precipitation, fusion of the recipient cells with bacterial protoplasts containing the DNA, treatment of the recipient cells with liposomes containing the DNA, and microinjection of the DNA directly into the cells.
The transformed cells are grown up by means well known in the art (Molecular Cloning, Maniatis, T., et al., Cold Spring Harbor Laboratory, (1982); Biochemical Methods In Cell Culture And Virology, Kuchler, R. J., Dowden, Hutchinson and Ross, Inc., (1977); Methods In Yeast Genetics, Sherman, F., et al., Cold Spring Harbor Laboratory, (1982)) and the expressed PRV glycoprotein or fragment thereof is harvested from the cell medium in those systems where the protein is excreted from the host cell, or from the cell suspension after disruption of the host cell system by, e.g., mechanical or enzymatic means which are well known in the art.
As noted above, the amino acid sequences of the PRV glycoproteins as deduced from the gene structures are set forth in Charts A-C. Polypeptides displaying PRV glycoprotein antigenicity include the sequences set forth in Chart A-C and any portions of the polypeptide sequences which are capable of eliciting an immune response in an animal, e.g., a mammal, which has been injected with the polypeptide sequence and also immunogenically functional analogs of the polypeptides.
As indicated hereinabove the entire gene coding for the PRV glycoprotein can be employed in constructing the vectors and transforming the host cells to express the PRV glycoprotein, or fragments of the gene coding for the PRV glycoprotein can be employed, whereby the resulting host cell will express polypeptides displaying PRV antigenicity. Any fragment of the PRV glycoprotein gene can be employed which results in the expression of a polypeptide which is an immunogenic fragment of the PRV glycoprotein or an analog thereof. As is well known in the art, the degeneracy of the genetic code permits easy substitution of base pairs to produce functionally equivalent genes and fragments thereof encoding polypeptides displaying PRV glycoprotein antigenicity. These functional equivalents also are included within the scope of the invention.
Charts D-S are set forth to illustrate the constructions of the Examples. Certain conventions are used to illustrate plasmids and DNA fragments as follows:
(1) The single line figures represent both circular and linear double-stranded DNA.
(2) Asterisks (*) indicate that the molecule represented is circular. Lack of an asterisk indicates the molecule is linear.
(3) Endonuclease restriction sites of interest are indicated above the line.
(4) Genes are indicated below the line.
(5) Distances between genes and restriction sites are not to scale. The figures show the relative positions only unless indicated otherwise.
Most of the recombinant DNA methods employed in practicing the present invention are standard procedures, well known to those skilled in the art, and described in detail, for example, in Molecular Cloning, T. Maniatis, et al., Cold Spring Harbor Laboratory, (1982) and B. Perbal, A Practical Guide to Molecular Cloning, John Wiley & Sons (1984), which are incorporated herein by reference.
EXAMPLE 1
In this example we set forth the sequencing, cloning and expression of PRV glycoprotein gp50.
1. Sequencing of the gp50 Gene
The BamHI 7 fragment of PRV Rice strain DNA (Chart D) which encodes the gp50 gene is isolated from pPRXh1 [NRRL B-15772], supra., and subcloned into the BamHI site of plasmid pBR322 (Maniatis et al., supra.).
Referring now to Chart E, the fragment is further subcloned using standard procedures by digesting BamHI 7 with PvuII, isolating the two BamHI/PvuII fragments (1.5 and 4.9 kb) and subcloning them between the BamHI and PvuII sites of pBR322 to produce plasmids pPR28-4 and pPR28-1 incorporating the 1.5 and 4.9 kb fragments respectively (see also, Rea et al., supra.). These subclones are used as sources of DNA for DNA sequencing experiments.
Chart F shows various restriction enzyme cleavage sites located in the gp50 gene and flanking regions. The 1.5 and 4.9 kb fragments subcloned above are digested with these restriction enzymes. Each of the ends generated by the restriction enzymes is labeled with γ- 32 P-ATP using polynucleotide kinase and sequenced according to the method of Maxam and Gilbert, Methods Enzymol., 65, 499-560 (1980). The entire gene is sequenced at least twice on both strands. The DNA sequence for gp50 is set forth in Chart A. This DNA may be employed to detect animals actively infected with PRV. For example, one could take a nasal or throat swab, and then do a DNA/DNA hybridization by standard methods to detect the presence of PRV.
2. Expression of gp50
Referring now to Chart G, a NarI cleavage site is located 35 base pairs upstream from the gp50 gene initiation codon. The first step in expression is insertion of the convenient BamHI cleavage site at the point of the NarI cleavage site. Plasmid pPR28-4 from above is digested with restriction endonuclease NarI to produce DNA fragment 3 comprising the N-terminus encoding end of the gp50 gene and a portion of the gX gene. BamHI linkers are added to fragment 3 and the fragment is digested with BamHI to delete the gX sequence thus producing fragment 4. The BamHI ends are then ligated to produce plasmid pPR28-4 Nar2.
Referring now to Chart H, we show the assembly of the complete gp50 gene. pPR28-4 Nar2 is digested with BamHI and PvuII to produce fragment 5 (160 bp) comprising the N-terminal encoding portion of the gp50 gene. Plasmid pPR28-1 from above is also digested with PvuII and BamHI to produce a 4.9 kb fragment comprising the C-terminal encoding portion of the gp50 gene (fragment 6). Plasmid pPGX1 (constructed as set forth in U.S. patent application Ser. No. 760,130)), or, alternatively, plasmid pBR322, is digested with BamHI, treated with bacterial alkaline phosphatase (BAP) and then ligated with fragments 5 and 6 to produce plasmid pBGP50-23 comprising the complete gp50 gene.
Referring now to Chart I, we show the production of plasmid pD50. Plasmid pBG50-23 is cut with restriction enzyme MaeIII (K. Schmid et al., Nucl. Acids Res., 12, p. 2619 (1984)) to yield a mixture of fragments. The MaeIII ends are made blunt with T4 DNA polymerase and EcoRI linkers are added to the blunt ends followed by EcoRI digestion. The resulting fragments are cut with BamHI and a 1.3 kb BamHI/EcoRI fragment containing the gp50 gene (fragment 7) is isolated. Plasmid pSV2dhfr (obtained from the American Type Culture Collection, Bethesda Research Laboratories, or synthesized according to the method of S. Subramani, et al., Mol. Cell. Biol., 2, pp. 854-64 (1981)) is digested with BamHI and EcoRI and the larger (5.0 kb) fragment is isolated to produce fragment 8 containing the dihydrofolate reductase (dhfr) marker. Fragments 7 and 8 are then ligated to produce plasmid pD50 comprising the gp50 gene and the dhfr marker.
Referring now to Chart J, the immediate early promoter from human cytomegalovirus Towne strain is added upstream from the gp50 gene. pD50 is digested with BamHI and treated with bacterial alkaline phosphatase to produce fragment 9. A 760 bp Sau3A fragment containing the human cytomegalovirus (Towne) immediate early promoter is isolated according to the procedure set forth in U.S. patent application Ser. No. 758,517 to produce fragment 10 (see also, D. R. Thomsen, et al., Proc. Natl. Acad. Sci. USA, 81, pp. 659-63 (1984)). These fragments are then ligated by a BamHI/Sau3A fusion to produce plasmid pDIE50. To confirm that the promoter is in the proper orientation to transcribe the gp50 gene the plasmid is digested with SacI and PvuII and a 185 bp fragment is produced.
Referring now to Chart K, the 0.6 kb PvuII/EcoRI fragment containing the bovine growth hormone polyadenylation signal is isolated from plasmid pGH2R2 (R. P. Woychik, et al., Nucl. Acids Res., 10, pp. 7197-7210 (1982) by digestion with PvuII and EcoRI or from pSVCOW7 (supra.) to produce fragment 11.
Fragment 11 is cloned between the EcoRI and SmaI cleavage sites of pUC9 (obtained from Pharmacia/PL or ATCC) to give pCOWT1. pCOWT1 is cut with SalI, the ends made blunt with T4 DNA polymerase, EcoRI linkers are added, the DNA is cut with EcoRI, and the 0.6 kb fragment (fragment 12) is isolated. This is the same as fragment 11 except that it has two EcoRI ends and a polylinker sequence at one end.
Plasmid pDIE50 is cut with EcoRI, and fragment 12 is cloned into it to produce plasmid pDIE50PA. Digestion with BamHI and PvuII produces a fragment of 1.1 kb in the case where the polyadenylation signal is in the proper orientation. The plasmid can also be constructed by cloning in the polyadenylation sequence before the promoter.
Plasmid pDIE50PA is used to transfect CHO dhfr − cells (DXB-11, G. Urlaub and L. A. Chasin, Proc. Natl. Acad. Sci. USA, 77, pp. 4216-20 (1980)) by calcium phosphate co-precipitation with salmon sperm carrier DNA (F. L. Graham and A. J. Van Der Eb, Virol., 52, pp. 456-67 (1973)). The dihydrofolate reductase positive (dhfr + ) transfected cells are selected in Dulbecco's modified Eagle's medium plus Eagle's non-essential amino acids plus 10% fetal calf serum. Selected dhfr + CHO cells produce gp50 as detected by immunofluorescence with anti-gp50monoclonal antibody 3A-4, or by labelling with 14 C-glucosamine and immunoprecipitation with 3A-4. Monoclonal antibody 3A-4 is produced as described in copending U.S. patent application Ser. No. 817,429, filed Jan. 9, 1985. Immunoprecipitation reactions are performed as described previously (T. J. Rea, et al., supra.) except for the following: The extracts are first incubated with normal mouse serum, followed by washed Staphylococcus aureus cells, and centrifuged for 30 minutes in a Beckman SW50.1 rotor at 40,000 rpm. After extracts are incubated with monoclonal or polyclonal antiserum plus S. Aureus cells, the cells are washed three times in 10 mM Tris HC1, pH 7.0, 1 mM EDTA, 0.1 M NaCl, 1% NP40 and 0.5% deoxycholate. Analysis of proteins is done on 11% SDS polyacrylamide gels (L. Morse, et al., J. Virol., 26, pp. 389-410 (1984)). In preliminary immunofluorescence assays it was found that 3A-4 reacted with the pDIE50PA-transfected CHO cells but not with untransfected CHO cells. When the transfected CHO cells were labelled with 14 C-glucosamine, 3A-4 immunoprecipitated a labelled protein from cells containing pDIE50PA but not from control cells making human renin. The precipitated protein co-migrated on SDS-polyacrylamide gels with the protein precipitated by 3A-4 from PRV-infected cells.
A clone of these transfected CHO cells producing gp50 can be grown in roller bottles, harvested in phosphate buffered saline plus 1 mM EDTA, and mixed with complete Freund's adjuvant for use as a vaccine.
The gp50 gene can also be expressed in a vaccinia vector. In this embodiment, after pBG50-23 is digested with MaeIII and the ends made blunt with T4 DNA polymerase, the DNA is digested with BamHI. The 1.3 BamHI/blunt-ended fragment containing the gp50 gene is isolated. Plasmid pGS20 (Mackett, et al., J. Virol., 49, pp. 857-64 (1984)) is cut with BamHI and SmaI, and the larger 6.5 kb fragment is isolated by gel electrophoresis. These two fragments are ligated together to produce pVV50. Plasmid pVV50 is transfected into CV-1 cells (ATCC CCL 70) infected with the WR strain of vaccinia virus (ATCC VR-119), and selected for thymidine kinase negative recombinants by plating on 143 cells (ATCC CRL 8303) in 5-bromodeoxy-uridine (BUdR) by the methods described by Mackett, et al. in DNA Cloning, Volume II: A Practical Approach, D. M. Glover, ed., IRL Press, Oxford (1985). The resulting virus, vaccinia-gp50, expressed gp50 in infected cells, as assayed by labelling of the proteins of the infected cell with 14 C-glucosamine and immunoprecipitation with monoclonal antibody 3A-4.
EXAMPLE 2
In this example we set forth the protection of mice and swine from PRV challenge using the gp50 of Example 1 as an immunogenic agent.
In Tables 1-3, infra, the microneutralization assay was done as follows: Serial two-fold dilutions of serum samples were done in microtiter plates (Costar) using basal medium Eagle (BME) supplemented with 3% fetal calf serum and antibiotics. About 1000 pfu (50 μl) of PRV were added to 50 μl of each dilution. Rabbit complement was included in the virus aliquot at a dilution of 1:5 for the mouse serum assays but not the pig serum assays. The samples were incubated for either 1 hr (swine sera) or 3 hrs (mouse sera) at 37° C. After the incubation period, an aliquot (50 μl) of porcine kidney-15 (PK-15) cells (300,000 cells/ml) in Eagle's Minimum Essential Medium was added to each serum per PRV sample. The samples were subsequently incubated at 37° C. for 2 days. Neutralizing titers represent the reciprocals of the highest dilutions which protected 50% of the cells from cytopathic effects.
Table 1 sets forth the protection of mice from challenge by virulent PRV by immunization with gp50 produced in vaccinia virus. Mice were immunized by tail scarification with 25 μl or by the footpad route with 50 μl. Mice were immunized 28 days prior to challenge (except mice given PR-Vac which were immunized 14 days prior to challenge).
TABLE 1
Immunizing
Dose
Neutralizing
%
Agent
(PFU)
Route
Titers a
Survival b
gp50
3.0 × 10 7
Tail
1024
93
gp50
6.0 × 10 7
Footpad
1024
100
gp50
7.5 × 10 6
Tail
512
93
vaccinia c
7.5 × 10 6
Tail
<8
27
BME d
—
Tail
<8
20
PR-Vac e
—
Footpad
512
90
a Neutralizing titer against PRV at day of challenge (+ complement).
b Challenged with 10 LD50 of PRV Rice strain by intraperitoneal route.
c Control virus.
d Basal medium Eagle, negative control.
e Norden Laboratories, Lincoln, NE, inactivated PRV vaccine, positive control.
Table 2 sets forth the protection of mice from challenge by virulent PRV by immunization with gp50 produced in CHO cells. Mice were immunized at 28 days, 18 days and 7 days prior to challenge. Mice received preparations with adjuvants subcutaneously on the first dose and preparations in saline intraperitoneally on the second and third doses. Each mouse received 10 6 disrupted cells/dose.
TABLE 2
Immunizing
Neutralizing
%
Agent/Adjuvant
Titers a
Survival b
gp50/CFA c
512
100
(10/10)
gp50/CFA (2 doses)
ND
80
(4/5)
gp50/IFA d
1024
90
(9/10)
gp50/saline
256
100
(3/3)
CHO-renin e /CFA
<8
10
(1/10)
Nontreated
<8
0
(0/10)
PR-Vac f
4096
90
(9/10)
a Neutralizing titer against PRV at day of challenge (+ complement).
b Challenged with 30 LD50 of PRV Rice strain by footpad route.
c Complete Freund's adjuvant.
d Incomplete Freund's adjuvant.
e Control cells expressing renin.
f Norden Laboratories, Lincoln, NE, inactivated PRV vaccine, positive control.
Table 3 sets forth the protection of swine from challenge by virulent PRV by immunization with gp50 produced in CHO cells. Swine were immunized at 21 days and 7 days prior to challenge. Swine received 2×10 7 disrupted cells per dose. The first dose was mixed with complete Freund's adjuvant while the second dose was suspended in saline. Both doses were given intramuscularly.
TABLE 3
Immunizing
Geometric Mean
%
Agent/Adjuvant
Titer a
Survival b
gp50/CFA
25
100
CHO-renin/CFA
<8
0
a Neutralizing titer against PRV at day of challenge.
b Challenge with PRV Rice strain 1 × 10 5 pfu/pig by the intranasal route.
These three tables demonstrate that gp50 can raise neutralizing antibodies and protect mice and swine from lethal PRV challenge.
In another aspect of the instant invention we produced a derivative of glycoprotein gp50 by removing the DNA coding for the C-terminal end of gp50. The resulting polypeptide has a deletion for the amino acid sequence necessary to anchor gp50 into the cell membrane. When expressed in mammalian cells this gp50 derivative is secreted into the medium. Purification of this gp50 derivative from the medium for use as a subunit vaccine is much simpler than fractionation of whole cells. Removal of the anchor sequence to convert a membrane protein into a secreted protein was first demonstrated for the influenza hemagglutinin gene (M.-J. Gething and J. Sambrook, Nature, 300, pp. 598-603 (1982)).
Referring now to Chart L, plasmid pDIE50 from above is digested with SalI and EcoRI. The 5.0 and 0.7 kb fragments are isolated. The 0.7 kb fragment encoding a portion of gp50 is digested with Sau3A and a 0.5 kb SalI/Sau3A fragment is isolated. To introduce a stop codon after the truncated gp50 gene, the following oligonucleotides are synthesized:
5′ GATCGTCGGCTAGTGAGTAGGTAGG 3′
3′ CAGCCGATCACTCATCCATCCTTAA 5′
The 5.0 kb EcoRI/SalI fragment, the 0.5 kb SalI/Sau3A fragment and the annealed oligonucleotides are ligated to produce plasmid pDIE50T. Digestion with EcoRI and SailI produces a 580 bp fragment. pDIE50T is cut with EcoRI and the 0.6 kb EcoRI fragment containing the bGH polyA site (fragment 12) is cloned in to produce plasmid pDIE50TPA. Digestion of pDIE50TPA with BamHI and PvuII yields a 970 bp fragment when the polyadenylation signal is in the proper orientation.
pDIE50TPA is used to transfect CHO dhfr − cells. Selected dhfr + CHO cells produce a truncated form of gp50 which is secreted into the medium as detected by labelling with 35 S-methionine and immunoprecipitation.
EXAMPLE 3
In this example we set forth the isolation, cloning and sequencing of the gp63 and gI genes.
1. Library Construction
PRV genomic DNA was prepared as described previously (T. J. Rea, et al., supra.). Fragments of 0.5-3.0 kb were obtained by sonicating the PRV genomic DNA of the PRV Rice strain twice for 4 sec each time at setting 2 with a Branson 200 sonicator. After blunt ending the fragments with T4 DNA polymerase, the fragments were ligated to kinased EcoRI linkers (T. Maniatis, et al., supra). After over-digestion with EcoRI (since PRV DNA does not contain an EcoRI site, methylation was unnecessary), excess linkers were removed by agarose gel electrophoresis. The PRV DNA fragments in the desired size range were eluted by the glass slurry method, (B. Vogelstein and D. Gillespie, Proc. Natl. Acad. Sci. USA, 76, pp. 615-19 (1979)). A library of 61,000 λ/PRV recombinants (λPRVs) was constructed by ligating 500 ng of PRV DNA fragments to 750 ng of EcoRI digested λgt11 (R. A. Young and R. W. Davis, supra.) DNA in 50 mM Tris (pH 7.4), 10 mM MgCl 2 , 10 mM dithiothreitol, 1 mM spermidine, 1 mM ATP, 400 units of T4 DNA ligase (New England Biolabs), in a final volume of 10 μl. The ligated DNA was packaged into bacteriophage λ virions using the Packagene extract (Promega Biotec, Madison, Wis.).
2. λPRV Library Screening
The λPRV library was screened as previously described (J. G. Timmins, et al., supra.; R. A. Young and R. W. Davis, supra.). 20,000 phages were screened per 150 mm LB-ampicillin plate. The screening antisera were raised by injecting mice with size fractions of PRV infected cell proteins (ICP's) eluted from SDS-polyacrylamide gels (J. G. Timmins, et al., supra.). Plaques giving positive signals upon screening with antisera were picked from the agar plates with a sterile pasteur pipette, resuspended in 1 ml SM buffer (T. Maniatis, et al., supra) and rescreened. The screening was repeated until the plaques were homogeneous in reacting positively.
Approximately 43,000 λPRV recombinants were screened with mouse antisera to PRV infected Vero cell proteins, isolated from SDS-polyacrylamide gels. Sixty positive λPRV phages were isolated.
3. Phage Stock Preparation
High titer phage stocks (10 10 -10 11 pfu/ml) were prepared by the plate lysate method (T. Maniatis et al., supra). A single, well-isolated positive signal plaque was picked and resuspended in 1 ml SM. 100 μl of the suspension was adsorbed to 300 μl of E. coli Y1090 (available from the American Type Culture Collection (ATCC), Rockville, Md.) at 37° C. for 15 min, diluted with 10 ml LB-top agarose, poured evenly on a 150 mm LB-ampicillin plate and incubated overnight at 42° C. The top agarose was gently scraped off with a flamed glass slide and transferred to a 30 ml Corex tube. 8 ml of SM and 250 μl of chloroform were added, mixed and incubated at 37° C. for 15 min. The lysate was clarified by centrifugation at 10,000 rpm for 30 min in the HB-4 rotor. The phage stock was stored at 4° C. with 0.3% chloroform.
4. Fusion Protein Preparation and Analysis
LB medium (Maniatis, et al., supra.) was inoculated 1:50 with a fresh overnight culture of E. coli K95 (sup − , λ − , gal − , str r , nusA − ; D. Friedman, supra.) and grown to an OD 550 =0.5 at 30° C. 25 ml of culture was infected with λPRV phage at a multiplicity of 5 and incubated in a 42° C. shaking water bath for 25 min, followed by transfer to 37° C. for 2-3 hours. The cells were pelleted at 5,000 rpm for 10 min in the HB-4 rotor and resuspended in 100 μl of 100 mM Tris (pH 7.8), 300 mM NaCl. An equal volume of 2×SDS-PAGE sample buffer was added, and the sample was boiled for 10 min. 5 μl of each sample was analyzed by electrophoresis on analytical SDS-polyacrylamide gels as described in L. Morse et al., J. Virol, 26, pp. 389-410 (1978). The fusion polypeptide preparations were scaled up 10-fold for mouse injections. The β-galactosidase/PRV fusion polypeptides were isolated after staining a strip of the gel with coomassie blue (L. Morse et al., supra; K. Weber and M. Osborn, in The Proteins, 1, pp. 179-223 (1975)). Fusion polypeptide quantities were estimated by analytical SDS-PAGE. Cell lysates from λPRV infected E. coli K95 cultures were electrophoresed in 9.25% SDS-polyacrylamide gels. Overproduced polypeptide bands with molecular weights greater than 116,000 daltons, absent from λgt11-infected controls, were β-galactosidase-PRV fusion polypeptides. The β-galactosidase-PRV fusion polypeptides ranged in size from 129,000 to 158,000 daltons. Approximately 50-75 μg of fusion polypeptide was resuspended in complete Freund's adjuvant and injected subcutaneously and interperitoneally per mouse. Later injections were done intraperitoneally in incomplete Freund's adjuvant.
5. Antisera Analysis
Immunoprecipitations of 14 C-glucosamine ICP's, 35 S-methionine ICP's and 14 C-glucosamine gX were done as previously described (T. J. Rea, et al., supra.). These techniques showed that gp63 and gI had been isolated in a λgt11 recombinant phage. We called these phages λ37 and λ36 (gp63) and λ23 (gI).
6. λDNA Mini-preps
Bacteriophage were rapidly isolated from plate lysates (T. J.-Silhavy et al., Experiments With Gene Fusions, (1984)). 5% and 40% glycerol steps (3 ml each in SM buffer) were layered in an SW41 tube. A plate lysate (˜6 ml) was layered and centrifuged at 35,000 rpm for 60 min at 4° C. The supernatant was discarded and the phage pellet was resuspended in 1 ml SM. DNAse I and RNAse A were added to final concentrations of 1 μg/ml and 10 μg/ml. After incubation at 37° C. for 30 min, 200 μl of SDS Mix (0.25 M EDTA, 0.5 M Tris (pH 7.8), 2.5% SDS) and proteinase K (to 1 mg/ml) were added and incubated at 68° C. for 30 min. The λDNA was extracted with phenol three times, extracted with chloroform, and ethanol precipitated. An average 150 mm plate lysate yields 5-10 μg of λDNA.
7. λPRV DNA Analysis
PRV DNA was digested to completion with BamHI and KpnI, electrophoresed in 0.8% agarose and transferred to nitrocellulose by the method of Southern (J. Mol. Biol., 98, pp. 503-17 (1975)). The blots were sliced into 4 mm strips and stored desiccated at 20-25°. λPRV DNAs were nick-translated (Amersham) to specific activities of approximately 10 8 cpm/μg. Pre-hybridization was done in 6×SSC, 30% formamide, 1× Denhardt's reagent (0.02% each of ficoll, polyvinylpyrrolidone and bovine serum albumin), 0.1% SDS, 50 μg/ml heterologous DNA at 70° C. for 1 hour. Hybridization was done in the same solution at 70° C. for 16 hours. Fifteen minute washes were done twice in 2×SSC, 0.1% SDS and twice in 0.1×SSC, and 0.1% SDS, all at 20-25°. The blots were autoradiographed with an intensifying screen at ˜70° C. overnight.
By Southern blotting the PRV glycoprotein genes contained in λ23, λ36 and λ37 mapped to the BamHI 7 fragment in the unique small region (see T. J. Rea, et al., supra.). Finer mapping of this fragment showed that λ23 (gI) gene mapped distal to the gX gene and that λ37 mapped to the internal region of BamHI 7, as shown in Chart D.
8. Sequencing The gp63 and gI Genes
The PRV DNA in λ36 and λ37 was determined to contain a StuI cleavage site. There is only one StuI cleavage site in the BamHI 7 fragment; therefore, the open reading frame that included the StuI cleavage site was sequenced. Chart E shows various restriction enzyme cleavage sites located in the gp63 gene and flanking regions. BamHI 7 was subcloned and digested with these restriction enzymes. Each of the ends generated by the restriction enzymes was labeled with γ- 32 P-ATP using polynucleotide kinase and sequenced according to the method of Maxam and Gilbert, Methods Enzymol., 65, 499-560 (1980).
Plasmid pPR28 is produced by cloning the BamHI 7 fragment isolated from pUC1129 into plasmid pSV2 gpt (R. C. Mulligan and P. Berg, Proc. Natl. Acad. Sci. USA, 78, pp. 2072-76 (1981)).
Plasmid pPR28-1 was produced by digesting pPR28 with PvuII and then recircularizing the piece containing the E. coli origin of replication and bla gene to produce a plasmid comprising a 4.9 kb PvuII/BamHI 7 PRV fragment containing the DNA sequence for gI.
Chart N shows various restriction enzyme cleavage sites located in the gI gene and flanking regions. BamHI 7 was subcloned, digested, labeled and sequenced as set forth above.
The DNA sequences for glycoproteins gp63 and gI are set forth in Charts B and C respectively. This DNA may be employed to detect animals actively infected with PRV. For example, one could take a nasal or throat swab, and then by standard DNA/DNA hybridization methods detect the presence of PRV.
EXAMPLE 4
In this example we set forth the expression of gI in mammalian cells.
A BamHI 7 fragment containing the gI gene is isolated from plasmid pPR28 (see above) by digesting the plasmid with BamHI, separating the fragments on agarose gel and then excising the fragment from the gel.
Referring now to Chart O, the BamHI 7 fragment isolated above is then cloned into plasmid pUC19 (purchased from Pharmacia/PL) to produce plasmid A. Plasmid A is digested with DraI. DraI cleaves the pUC19 sequence in several places, but only once in the BamHI 7 sequence between the gp63 and gI genes (Chart D) to produce, inter alia, fragment 1. BamHI linkers are ligated onto the DraI ends of the fragments, including fragment 1, and the resulting fragment mixture is digested with BamHI. The product fragments are separated by agarose gel electrophoresis and fragment 2 (2.5 kb) containing the gI gene is purified. Fragment 2 is cloned into pUC19 digested with BamHI to produce plasmid pUCD/B. Of the two plasmids so produced, the plasmid containing the gI gene in the proper orientation is determined by digesting the plasmids with BsmI and EcoRI; the plasmid in the proper orientation contains a characteristic 750 bp BsmI/EcoRI fragment.
Referring now to Chart P, plasmid pUCD/B (Chart O) is digested with BsmI and EcoRI and the larger fragment (fragment 3, 4.4 kb) is purified by agarose gel electrophoresis. The following two oligonucleotides are synthesized chemically by well-known techniques or are purchased from a commercial custom synthesis service:
5′ CGCCCCGCTTAAATACCGGGAGAAG 3′
5′ AATTCTTCTCCCGGTATTTAAGCGGGGCGGG 3′
These oligonucleotides are ligated to fragment 3 to replace the coding sequence for the C-terminus of the gI gene which was deleted by the BsmI cleavage. The resulting plasmid, pGI, contains a complete coding region of the gI gene with a BamHI cleavage site upstream and an EcoRI cleavage site downstream from the gI coding sequences.
Plasmid pGI is digested with EcoRI and BamHI and a 1.8 kb fragment comprising the gI gene (fragment 4) is purified on an agarose gel.
Plasmid pSV2dhfr, (supra.) is cut with EcoRI, and is then cut with BamHI to produce fragment 5 (5.0 kb) containing the dhfr marker, which is isolated by agarose gel electrophoresis. Then fragments 4, and 5 are ligated to produce plasmid pDGI which comprises the dihydrofolate reductase and ampicillin resistance markers, the SV40 promoter and origin of replication, and the gI gene.
Referring now to Chart Q, the immediate early promoter from human cytomegalovirus Towne strain is added upstream from the gI gene. Plasmid pDGI is digested with BamHI to produce fragment 6. The human cytomegalovirus (Towne) immediate early promoter is isolated (supra.) to produce fragment 7. Fragments 6 and 7 are then ligated to produce plasmid pDIEGIdhfr. To confirm that the promoter is in the proper orientation the plasmid is digested with SacI and BstEII restriction enzymes. The production of an about 400 bp fragment indicates proper orientation.
A 0.6 kb PvuII/EcoRI fragment containing the bovine growth hormone polyadenylation signal is isolated from the plasmid pSVCOW7 (supra.) to produce fragment 8. Fragment 8 is cloned across the SmaI/EcoRI sites of pUC9 (supra.) to produce plasmid pCOWT1. pCOWT1 is cut with Sal, treated with T4 DNA polymerase, and EcoRI linkers are ligated on. The fragment mixture so produced is then digested with EcoRI and a 0.6 kb fragment is isolated (fragment 9). Fragment 9 is cloned into the EcoRI site of pUC19 to produce plasmid pCOWT1E. pCOWT1E is digested with EcoRI to produce fragment 10 (600 bp).
Plasmid pDIEGIdhfr is digested with EcoRI and ligated with fragment 10 containing the bGH polyadenylation signal to produce plasmid pDIEGIPA. The plasmid having the gI gene in the proper orientation is demonstrated by the production of a 1400 bp fragment upon digestion with BamHI and BstEII.
The resulting plasmid is transfected into dhfr − Chinese hamster ovary cells and dhfr + cells are selected to obtain cell lines expressing gI (Subramani, et al, Mol. Cell Biol., 1, pp. 854-64 (1981)). The expression of gI is amplified by selecting clones of transfected cells that survive growth in progressively higher concentrations of methotrexate (McCormick, et al, Mol. Cell Biol., 4, pp. 166-72 (1984).
EXAMPLE 5
In this example we set forth the expression of gp63 in mammalian cells.
The BamHI 7 fragment of PRV DNA (supra.) is isolated from pPRXh1 [NRRL B-15772], and subcloned into the BamHI site of plasmid pBR322 as in Example 1 for use in sequencing and producing more copies of the gp63 gene.
Referring now to Chart R, from within BamHI 7 a 1.9 kb BstEII/K-pnI fragment (fragment 1) is subcloned by cutting BamHI 7 with BstEII, treating the ends with T4 DNA polymerase, and then cutting with KpnI. Fragment 1 is isolated and cloned between the KpnI and SmaI sites in pUC19 (purchased from Pharmacia/PL, Piscataway, N.J.) to yield plasmid pPR28-1BK.
Plasmid pPR28-1BK is cut with DraI plus MaeIII to yield fragment 2 (1.1 kb). The DraI cleavage site is outside the coding region of the gp63 gene and downstream from its polyadenylation signal. The MaeIII cleavage site cuts 21 bases downstream from the ATG initiation codon of the gp63 gene. To replace the coding region removed from the gp63 gene, the following two oligonucleotides are synthesized chemically or purchased from commercial custom synthesis services (fragment 4):
5′
GATCCGCAGTACCGGCGTCGATGATGATGGTCGCGCGCGAC
3′
3′
GCGTCATGGCCGCAGCTACTACTACCACCGCGCGCTGCACTG
5′
Plasmid pSV2dhfr, supra., is cut with EcoRI, treated with T4 DNA polymerase, then cut with BamHI and the larger (5.0 kb) fragment is isolated to produce fragment 4 containing the dhfr marker. Then fragments 2, 3, and 4 are ligated to produce plasmid pGP63dhfr.
Referring now to Chart S, the immediate early promoter from human cytomegalovirus Towne strain is added upstream from the gp63 gene. pGP63dhfr is digested with BamHI and treated with bacterial alkaline phosphatase to produce fragment 5. A 760 bp Sau3A fragment containing human cytomegalovirus (Towne) immediate early promoter is isolated to produce fragment 6. These fragments are then ligated to produce plasmid pIEGP63dhfr. To confirm that the promoter is in the proper orientation the plasmid is digested with SacI and PvuII and a 150 bp fragment is produced.
The resulting plasmid is transfected into dhfr − Chinese hamster ovary cells and dhfr + cells are selected to obtain cell lines expressing gp63. Since the levels of synthesis of gp63 by this system were too low to detect by the methods we used, we produced the polypeptide in vaccinia virus as set forth below.
EXAMPLE 6
In this example we set forth the expression of gp63 in vaccinia virus. The method used herein incorporates aspects of other syntheses referred to above.
Fragments 1, 2, 3, and 4 are produced according to Example 5.
Plasmid pGS20 (Mackett, et al., J. Virol., 49, pp. 857-64 (1984)) is cut with BamHI and SmaI, and the larger 6.5 kb fragment is isolated by gel electrophoresis. Fragment 2, the oligonucleotides, and the pGS20 fragment are ligated together to produce plasmid pVV63. This plasmid is transfected into CV-1 cells (ATCC CCL 70) infected with the WR strain of vaccinia virus (ATCC VR-119), selected for thymidine kinase negative recombinants by plating on 143 cells (ATCC CRL 8303) in BUdR by the methods described by Mackett, et al. in DNA Cloning, Volume II: A Practical Approach, D. M. Glover, ed., IRL Press, Oxford (1985). The resulting virus, vaccinia-gp63, expresses gp50 in infected cells, as assayed by labelling of the proteins of the infected cell with 14 C-glucosamine and immunoprecipitation with anti-gp63 antiserum.
The BamHI/EcoRI fragment from plasmid pGI, the DraI/MaeIII fragment from plasmid pPR28-1BK, or the BamHI/MaeIII fragment from pBGP50-23 all described above, may also be treated with Ba131 and inserted in pTRZ4 (produced as set forth in copending U.S. patent application Ser. No. 606,307) as described in Rea, et al., supra., and used to transform E. coli. By this method, gp50, gp63, and gI can be produced as a fusion protein in E. coli.
Also, by substituting, for example, pSV2neo (available from the American Type Culture Collection) for pSV2dhfr in the above example, the recombinant plasmid comprising the PRV glycoprotein gene could be transformed into other host cells. Transformed cells would be selected by resistance to antibiotic G418 which is encoded by the plasmid.
One can also express the polypeptides of the instant invention in insect cells as follows: By putting a BamHI linker on the EcoRI site of pD50 and digestion with BamHI, or putting a BamHI linker on the EcoRI site of pGP63dhfr and digestion with BamHI, or by digestion of pUCD/B with BamHI, one obtains BamHI fragments containing the gp50, gp63, or gI genes respectively. These BamHI fragments can be cloned into a BamHI site downstream from a polyhedrin promoter in pAC373 (Mol. Cell. Biol., 5, pp. 2860-65 (1985)). The plasmids so produced can be co-transfected with DNA from baculovirus Autographa californica into Sf9 cells, and recombinant viruses isolated by methods set forth in the article. These recombinant viruses produce gp50, gp63, or gI upon infecting Sf9 cells.
A vaccine prepared utilizing a glycoprotein of the instant invention or an immunogenic fragment thereof can consist of fixed host cells, a host cell extract, or a partially or completely purified PRV glycoprotein preparation from the host cells or produced by chemical synthesis. The PRV glycoprotein immunogen prepared in accordance with the present invention is preferably free of PRV virus. Thus, the vaccine immunogen of the invention is composed substantially entirely of the desired immunogenic PRV polypeptide and/or other PRV polypeptides displaying PRV antigenicity.
The immunogen can be prepared in vaccine dose form by well-known procedures. The vaccine can be administered intramuscularly, subcutaneously or intranasally. For parenteral administration, such as intramuscular injection, the immunogen may be combined with a suitable carrier, for example, it may be administered in water, saline or buffered vehicles with or without various adjuvants or immunomodulating agents including aluminum hydroxide, aluminum phosphate, aluminum potassium sulfate (alum), beryllium sulfate, silica, kaolin, carbon, water-in-oil emulsions, oil-in-water emulsions, muramyl dipeptide, bacterial endotoxin, lipid X, Corynebacterium parvum (Propionobacterium acnes), Bordetella pertussis, polyribonucleotides, sodium alginate, lanolin, lysolecithin, vitamin A, saponin, liposomes, levamisole, DEAE-dextran, blocked copolymers or other synthetic adjuvants. Such adjuvants are available commercially from various sources, for example, Merck Adjuvant 65 (Merck and Company, Inc., Rahway, N.J.). Another suitable adjuvant is Freund's Incomplete Adjuvant (Difco Laboratories, Detroit, Mich.).
The proportion of immunogen and adjuvant can be varied over a broad range so long as both are present in effective amounts. For example, aluminum hydroxide can be present in an amount of about 0.5% of the vaccine mixture (Al 2 O 3 basis). On a per dose basis, the concentration of the immunogen can range from about 1.0 μg to about 100 mg per pig. A preferable range is from about 100 μg to about 3.0 mg per pig. A suitable dose size is about 1-10 ml, preferably about 1.0 ml. Accordingly, a dose for intramuscular injection, for example, would comprise 1 ml containing 1.0 mg of immunogen in admixture with 0.5% aluminum hydroxide. Comparable dose forms can also be prepared for parenteral administration to baby pigs, but the amount of immunogen per dose will be smaller, for example, about 0.25 to about 1.0 mg per dose.
For vaccination of sows, a two dose regimen can be used. The first dose can be given from about several months to about 5 to 7 weeks prior to farrowing. The second dose of the vaccine then should be administered some weeks after the first dose, for example, about 2 to 4 weeks later, and vaccine can then be administered up to, but prior to, farrowing. Alternatively, the vaccine can be administered as a single 2 ml dose, for example, at about 5 to 7 weeks prior to farrowing. However, a 2 dose regimen is considered preferable for the most effective immunization of the baby pigs. Semi-annual revaccination is recommended for breeding animals. Boars may be revaccinated at any time. Also, sows can be revaccinated before breeding. Piglets born to unvaccinated sows may be vaccinated at about 3-10 days, again at 4-6 months and yearly or preferably semi-annually thereafter.
The vaccine may also be combined with other vaccines for other diseases to produce multivalent vaccines. It may also be combined with other medicaments, for example, antibiotics. A pharmaceutically effective amount of the vaccine can be employed with a pharmaceutically acceptable carrier or diluent to vaccinate animals such as swine, cattle, sheep, goats, and other mammals.
Other vaccines may be prepared according to methods well known to those skilled in the art as set forth, for example, in I. Tizard, An Introduction to Veterinary Immunology, 2nd ed. (1982), which is incorporated herein by reference.
As set forth above, commercial vaccine PRV's have been found to have the gI and gp63 genes deleted. Therefore gI and gp63 polypeptides produced by the methods of this invention can be used as diagnostic agents to distinguish between animals vaccinated with these commercial vaccines and those infected with virulent virus.
To differentiate between infected and vaccinated animals, one could employ, for example, an ELISA assay. gI or gp63 protein, produced, for example, in E. coli by recombinant DNA techniques (Rea, et al., supra.), is added to the wells of suitable plastic plates and allowed sufficient time to absorb to the plastic (e.g., overnight, 20-25° C.). The plates are washed and a blocking agent (e.g., BSA) is added to neutralize any unreacted sites on the plastic surface. A wash follows and then the pig serum is added to the wells. After about 1 hour incubation at 20-25° C., the wells are washed and a protein A-horseradish peroxidase conjugate is added to each well for an about 1 hour incubation a 20-25° C. Another wash follows and the enzyme substrate (o-phenylenediamine) is added to the wells and the reaction is terminated with acid. Absorbency is measured at 492 nanometers to quantitate the amount of gI or gp63 antibody present in the serum. Lack of gI or gp63 indicates that an animal is not infected. By testing for other PRV antigens, one could establish whether or not a given animal was vaccinated.
CHART A.
27
54
ATG CTG CTC GCA GCG CTA TTG GCG GCG CTG GTC GCC CGG ACG ACG CTG GGT GCG
Met Leu Leu Ala Ala Leu Leu Ala Ala Leu Val Ala Arg Thr Thr Leu Gly Ala
81
108
GAC GTG GAC GCC GTG CCC GCG CCG ACC TTC CCC CCG CCC GCG TAC CCG TAC ACC
Asp Val Asp Ala Val Pro Ala Pro Thr Phe Pro Pro Pro Ala Tyr Pro Tyr Thr
135
162
GAG TCG TGG CAG CTG ACG CTG ACG ACG GTC CCC TCG CCC TTC GTC GGC CCC GCG
Glu Ser Trp Gln Leu Thr Leu Thr Thr Val Pro Ser Pro Phe Val Gly Pro Ala
189
216
GAC GTC TAC CAC ACG CGC CCG CTG GAG GAC CCG TGC GCG GTG GTG GCG CTG ATC
Asp Val Tyr His Thr Arg Pro Leu Glu Asp Pro Cys Gly Val Val Ala Leu Ile
243
270
TCC GAC CCG CAG GTG GAC CGG CTG CTG AAC GAG GCG GTG GCC CAC CGG CGG CCC
Ser Asp Pro Gln Val Asp Arg Leu Leu Asn Glu Ala Val Ala His Arg Arg Pro
297
324
ACG TAC CGC GCC CAC GTG GCC TGG TAC CGC ATC GCG GAC GGG TGC GCA CAC CTG
Thr Tyr Arg Ala His Val Ala Trp Tyr Arg Ile Ala Asp Gly Cys Ala His Leu
351
378
CTG TAC TTT ATC GAG TAC GCC GAC TGC GAC CCC AGG CAG GTC TTT GGG CGC TGC
Leu Tyr Phe Ile Glu Tyr Ala Asp Cys Asp Pro Arg Gln Val Phe Gly Arg Cys
405
432
CGG CGC CGC ACC ACG CCG ATG TGG TGG ACC CCG TCC GCG GAC TAC ATG TTC CCC
Arg Arg Arg Thr Thr Pro Met Trp Trp Thr Pro Ser Ala Asp Tyr Met Phe Pro
459
486
ACG GAG GAC GAG CTG GGG CTG CTC ATG GTG GCC CCG GGG GGG TTC AAC GAG GGC
Thr Glu Asp Glu Leu Gly Leu Leu Met Val Ala Pro Gly Arg Phe Asn Glu Gly
513
540
CAG TAC CGG CGC GTG CTG TCC GTC GAC GGC GTG AAC ATC CTC ACC GAC TTC ATG
Gln Thr Arg Arg Leu Val Ser Val Asp Gly Val Asn Ile Leu Thr Asp Phe Met
567
594
GTG GCG CTC CCC GAG GGG CAA GAG TGC CCG TTC GCC GCC GTG GAC CAG CAC CGC
Val Ala Leu Pro Glu Gly Gln Glu Cys Pro Phe Ala Arg Val Asp Gln His Arg
621
648
ACG TAC AAG TTC GGC GCG TGC TGG AGC GAC GAC AGC TTC AAG CGG GGC GTG GAC
Thr Tyr Lys Phe Gly Ala Cys Trp Ser Asp Asp Ser Phe Lys Arg Gly Val Asp
675
702
GTG ATG CGA TTC CTG ACG CCG TTC TAC CAG CAG CCC CCG CAC CGG GAG GTG GTG
Val Met Arg Phe Leu Thr Pro Phe Tyr Gln Gln Pro Pro His Arg Glu Val Val
729
756
AAC TAC TGG TAC CGC AAG AAC GGC CGG ACG CTC CCG CGG GCC CAC GCC GCC GCC
Asn Tyr Trp Tyr Arg Lys Asn Gly Arg Thr Leu Pro Arg Ala His Ala Ala Ala
783
810
ACG CCG TAC GCC ATC GAC CCC GCG CGG CCC TCG GCG GGC TCG CCG AGG CCC GGG
Thr Pro Tyr Ala Ile Asp Pro Ala Arg Pro Ser Ala Gly Ser Pro Arg Pro Arg
837
864
CCC CGG CCC CGG CCC CGG CCC CGG CCG AAG CCC GAG CCC GCC CCG GCG ACG CCC
Pro Arg Pro Arg Pro Arg Pro Arg Pro Lys Pro Glu Pro Ala Pro Ala Thr Pro
891
918
GCG CCC CCC GAC CGC CTG CCC GAG CCG GCG ACG CGG GAC CAC GCC GCC GGG GGC
Ala Pro Pro Asp Arg Leu Pro Glu Pro Ala Thr Arg Asp His Ala Ala Gly Gly
945
972
CGC CCC ACG CCG CGA CCC CCG AGG CCC GAG ACG CCG CAC CGC CCC TTC GCC CCG
Arg Pro Thr Pro Arg Pro Pro Arg Pro Glu Thr Pro His Arg Pro Phe Ala Pro
999
1026
CCG GCC GTC GTG CCC AGC GGG TGG CCG CAG CCC GCG GAG CCG TTC CAG CCG CGG
Pro Ala Val Val Pro Ser Gly Trp Pro Gln Pro Ala Glu Pro Phe Gln Pro Arg
1053
1080
ACC CCC GCC GCG CCG CGC GTC TCG CGC CAC CGC TCG GTG ATC GTC GGC ACG GGC
Thr Pro Ala Ala Pro Gly Val Ser Arg His Arg Ser Val Ile Val Gly Thr Gly
1107
1134
ACC GCG ATG GGC GCG CTC CTG GTG GGC GTG TGC GTC TAC ATC TTC TTC CGC CTG
Thr Ala Met Gly Ala Leu Leu Val Gly Val Cys Val Tyr Ile Phe Phe Arg Leu
1161
1188
AGG GGG GCG AAG GGG TAT CGC CTC CTG GGC GGT CCC GCG GAC GCC GAC GAG CTA
Arg Gly Ala Lys Gly Tyr Arg Leu Leu Gly Gly Pro Ala Asp Ala Asp Glu Leu
1215
AAA GCG CAG CCC GGT CCG TAG
Lys Ala Gln Pro Gly Pro
CHART B.
27
54
ATG ATG ATG GTG GCG CGC GAC GTG ACC CGG CTC CCC GCG GGG CTC CTC CTC GCC
Met Met Met Val Ala Arg Asp Val Thr Arg Leu Pro Ala Gly Leu Leu Leu Ala
81
108
GCC CTG ACC CTG GCC GCC CTG ACC CCG CGC GTC GGG GGC GTC CTG TTC AGG GGC
Ala Leu Thr Leu Ala Ala Leu Thr Pro Arg Val Gly Gly Val Leu Phe Arg Gly
135
162
GCC GGC GTC AGC GTG CAC GTC GCC GGG AGC GCC GTC CTC GTG CCC GGC GAC GCG
Ala Gly Val Ser Val His Val Ala Gly Ser Ala Val Leu Val Pro Gly Asp Ala
189
216
CCC AAC CTG ACG ATC GAC GGG ACG CTG CTG TTT CTG GAG GGG CCC TCG CCG AGC
Pro Asn Leu Thr Ile Asp Gly Thr Leu Leu Phe Leu Glu Gly Pro Ser Pro Ser
243
270
AAC TAC AGC GGG CGC GTG GAG CTG CTG CGC CTC GAC CCC AAG CGC GCC TGC TAC
Asn Tyr Ser Gly Arg Val Glu Leu Leu Arg Leu Asp Pro Lys Arg Ala Cys Tyr
297
324
ACG CGC GAG TAC GCC GCC GAG TAC GAC CTC TGC CCC CGC GTG CAC CAC GAG GCC
Thr Arg Glu Tyr Ala Ala Glu Tyr Asp Leu Cys Pro Arg Val His His Glu Ala
351
378
TTC CGC GGC TGT CTG CGC AAG CGC GAG CCG CTC GCC CGG CGC GCG TCC GCC GCG
Phe Arg Gly Cys Leu Arg Lys Arg Glu Pro Leu Ala Arg Arg Ala Ser Ala Ala
405
432
GTG GAG GCG CGC GGG GTG CTG TTC GTC TCG CGC CCG GCC CCG CCG GAC GCG CGG
Val Glu Ala Arg Arg Leu Leu Phe Val Ser Arg Pro Ala Pro Pro Asp Ala Gly
459
486
TCG TAC GTG CTG CGG GTG CGC GTG AAC GGG ACC ACG GAC CTC TTT GTG CTG ACG
Ser Tyr Val Leu Arg Val Arg Val Asn Gly Thr Thr Asp Leu Phe Val Leu Thr
513
540
GCC CTG GTG CCG CCC AGG GGG CGC CCC CAC CAC CCC ACG CCG TCG TCC GCG GAC
Ala Leu Val Pro Pro Arg Gly Arg Pro His His Pro Thr Pro Ser Ser Ala Asp
567
594
GAG TGC CGG CCT GTC GTC GGA TCG TGG CAC GAC AGC CTG CGC GTC GTG GAC CCC
Glu Cys Arg Pro Val Val Gly Ser Trp His Asp Ser Leu Arg Val Val Asp Pro
621
648
GCC GAG GAC GCC GTG TTC ACC ACG CGG CCC CCG ATC GAG CCA GAG CCG CCG ACG
Ala Glu Asp Ala Val Phe Thr Thr Pro Pro Pro Ile Glu Pro Glu Pro Pro Thr
675
702
ACC CCC GCG CCC CCC GGG CGG ACC GGC GCC ACC CCC GAG CCC CGG TCC GAC GAA
Thr Pro Ala Pro Pro Arg Gly Thr Gly Ala Thr Pro Glu Pro Arg Ser Asp Glu
729
756
GAG GAG GAG GAC GAG GAG GGG GCG ACG ACG GCG ATG ACC CCG GTG CCC GGG ACC
Glu Glu Glu Asp Glu Glu Gly Ala Thr Thr Ala Met Thr Pro Val Pro Gly Thr
783
810
CTG GAC GCG AAC GGC ACG ATG GTG CTG AAC GCC AGC GTC GTG TCG CGC GTC CTG
Leu Asp Ala Asn Gly Thr Met Val Leu Asn Ala Ser Val Val Ser Arg Val Leu
837
864
CTC GCC GCC GCC AAC GCC ACG GCG GGC GCC CGG GGC CCC CGG AAG ATA GCC ATG
Leu Ala Ala Ala Asn Ala Thr Ala Gly Ala Arg Gly Pro Gly Lys Ile Ala Met
891
918
GTG CTG GGG CCC ACG ATC GTC GTC CTG CTG ATC TTC TTG GGC GGG GTC GCC TGC
Val Leu Gly Pro Thr Ile Val Val Leu Leu Ile Phe Leu Gly Gly Val Ala Cys
945
972
GCG GCC CGG CGC TGC GCG CGC GGA ATC GCA TCT ACC GGC CGC GAC CCG GGC GCG
Ala Ala Arg Arg Cys Ala Arg Gly Ile Ala Ser Thr Gly Arg Asp Pro Gly Ala
999
1026
GCC CGG CGG TCC ACG CGC CGC CCC CGC GCC GCC CGC CCC CCA ACC CCG TCG CCG
Ala Arg Arg Ser Thr Arg Arg Pro Arg Gly Ala Arg Pro Pro Thr Pro Ser Pro
1053
GGG CGC CCG TCC CCC AGC CCA AGA TGA
Gly Arg Pro Ser Pro Ser Pro Arg
CHART C.
27
54
ATG CGG CCC TTT CTG CTG CGC GCC GCG CAG CTC CTG GCG CTG CTG GCC CTG GCG
Met Arg Pro Phe Leu Leu Arg Ala Ala Gln Leu Leu Ala Leu Leu Ala Leu Ala
81
108
CTC TCC ACC GAG GCC CCG AGC CTC TCC GCC GAG ACG ACC CCG GGC CCC GTC ACC
Leu Ser Thr Glu Ala Pro Ser Leu Ser Ala Glu Thr Thr Pro Gly Pro Val Thr
135
162
GAG GTC CCG AGT CCC TCG GCC GAG GTC TGG GAC CTC TCC ACC GAG GCC GGC GAC
Glu Val Pro Ser Pro Ser Ala Glu Val Trp Asp Leu Ser Thr Glu Ala Gly Asp
189
216
GAT GAC CTC GAC GGC GAC CTC AAC GGC GAC GAC CGC CGC GCG GGC TTC GGC TCG
Asp Asp Leu Asp Gly Asp Leu Asn Gly Asp Asp Arg Arg Ala Gly Phe Gly Ser
243
270
GCC CTC GCC TCC CTG AGG GAG GCA CCC CCG GCC CAT CTG GTG AAC GTG TCC GAG
Ala Leu Ala Ser Leu Arg Glu Ala Pro Pro Ala His Leu Val Asn Val Ser Glu
297
324
GGC GCC AAC TTC ACC CTC GAC GCG CGC GGC GAC GGC GCC GTG GTG GCC GGG ATC
Gly Ala Asn Phe Thr Leu Asp Ala Arg Gly Asp Gly Ala Val Val Ala Gly Ile
351
378
TGG ACG TTC CTG CCC GTC CGC GGC TGC GAC GCC GTG GCG GTG ACC ATG GTG TGC
Trp Thr Phe Leu Pro Val Arg Gly Cys Asp Ala Val Ala Val Thr Met Val Cys
405
432
TTC GAG ACC GCC TGC CAC CCG GAC CTG GTG CTG GGC CGC GCC TGC GTC CCC GAG
Phe Glu Thr Ala Cys His Pro Asp Leu Val Leu Gly Arg Ala Cys Val Pro Glu
459
486
GCC CCG GAG CGG GGC ATC GGC GAC TAC CTG CCG CCC GAG GTG CCG CGG CTC CAG
Ala Pro Glu Arg Gly Ile Gly Asp Tyr Leu Pro Pro Glu Val Pro Arg Leu Gln
513
540
CGC GAG CCG CCC ATC GTC ACC CCG GAG CGG TGG TCG CCG CAC CTG ACC GTC CGG
Arg Glu Pro Pro Ile Val Thr Pro Glu Arg Trp Ser Pro His Leu Thr Val Arg
567
594
CGG GCC ACG CCC AAC GAC ACG GGC CTC TAC ACG CTG CAC GAC GCC TCG GCG CCG
Arg Ala Thr Pro Asn Asp Thr Gly Leu Tyr Thr Leu His Asp Ala Ser Gly Pro
621
648
CGG GCC GTG TTC TTT GTG GCG GTG GGC GAC CGG CCG CCC GCG CCG CTG GCC CCG
Arg Ala Val Phe Phe Val Ala Val Gly Asp Arg Pro Pro Ala Pro Leu Ala Pro
675
702
GTG GGC CCC GCG CGC CAC GAG CCC CGC TTC CAC GCG CTC GGC TTC CAC TCG CAG
Val Gly Pro Ala Arg His Glu Pro Arg Phe His Ala Leu Gly Phe His Ser Gln
729
756
CTC TTC TCG CCC GGG GAC ACG TTC GAC CTG ATG CCG CGC GTG GTC TCG GAC ATG
Leu Phe Ser Pro Gly Asp Thr Phe Asp Leu Met Pro Arg Val Val Ser Asp Met
783
810
GGC GAC TCG CGC GAG AAC TTC ACC GCC ACG CTG GAC TGG TAC TAC GCG CGC GCG
Gly Asp Ser Arg Glu Asn Phe Thr Ala Thr Leu Asp Trp Tyr Tyr Ala Arg Ala
837
864
CCC CCG CGG TGC CTG CTG TAC TAC GTG TAC GAG CCC TGC ATC TAC CAC CCG CGC
Pro Pro Arg Cys Leu Leu Tyr Tyr Val Tyr Glu Pro Cys Ile Tyr His Pro Arg
891
918
GCG CCC GAG TGC CTG CGC CCG GTG GAC CCG GCG TCC AGC TTC ACC TCG CCG GCG
Ala Pro Glu Cys Leu Arg Pro Val Asp Pro Ala Cys Ser Phe Thr Ser Pro Ala
945
972
CGC GCG GCG CTG GTG GCG CGC CGC GCG TAC GCC TCG TGC AGC CCG CTG CTC GGG
Arg Ala Ala Leu Val Ala Arg Arg Ala Tyr Ala Ser Cys Ser Pro Leu Leu Gly
999
1026
GAG CGG TGG CTG ACC GCC TGC CCC TTC GAC GCC TTC GGC GAG GAG GTG CAC ACG
Asp Arg Trp Leu Thr Ala Cys Pro Phe Asp Ala Phe Gly Glu Glu Val His Thr
1053
1080
AAC GCC ACC GCG GAC GAG TCG GGG CTG TAC GTG CTC GTG ATG ACC CAC AAC GGC
Asn Ala Thr Ala Asp Glu Ser Gly Leu Tyr Val Leu Val Met Thr His Asn Gly
1107
1134
CAC GTC GCC ACC TGG GAC TAC ACG CTC GTC GCC ACC GCG GCC GAG TAC GTC ACG
His Val Ala Thr Trp Asp Tyr Thr Leu Val Ala Thr Ala Ala Glu Tyr Val Thr
1161
1188
GTC ATC AAG GAG CTG ACG GCC CCG GCC CGG GCC CCG GGC ACC CCG TGG GGC CCC
Val Ile Lys Glu Leu Thr Ala Pro Ala Arg Ala Pro Gly Thr Pro Trp Gly Pro
1215
1242
GGC GGC GGC GAC GAC GCG ATC TAC CTG CAC CGC GTC ACG ACG CCG GCG CCG CCC
Gly Gly Gly Asp Asp Ala Ile Tyr Val Asp Gly Val Thr Thr Pro Ala Pro Pro
1269
1296
GCG CGC CCG TGG AAC CCG TAC GGC CGG ACG ACG CCC GGG CGG CTG TTT GTG CTG
Ala Arg Pro Trp Asn Pro Tyr Gly Arg Thr Thr Pro Gly Arg Leu Phe Val Leu
1323
1350
GCG CTG GGC TCC TTC GTG ATG ACG TGC GTC GTC GGG GGG GCC GTC TGG CTC TGC
Ala Leu Gly Ser Phe Val Met Thr Cys Val Val Gly Gly Ala Val Trp Leu Cys
1377
1404
GTG CTG TGC TCC CGC CGC CGG GCG GCC TCG CGG CCC TTC CGG GTG CCG ACG CGG
Val Leu Cys Ser Arg Arg Arg Ala Ala Ser Arg Pro Phe Arg Val Pro Thr Arg
1431
1458
GCG GGG ACG CGC ATG CTC TCG CCG GTG TAC ACC AGC CTG CCC ACG CAC GAG GAC
Ala Gly Thr Arg Met Leu Ser Pro Val Tyr Thr Ser Leu Pro Thr His Glu Asp
1485
1512
TAC TAC GAC GGC GAC GAC GAC GAC GAG GAG GCG GGC GAC GCC CGC CGG CGG CCC
Tyr Tyr Asp Gly Asp Asp Asp Asp Glu Glu Ala Gly Asp Ala Arg Arg Arg Pro
1539
1566
TCC TCC CCC GGC GGG GAC AGC GGC TAC GAG GGG CCG TAC GTG AGC CTG GAC GCC
Ser Ser Pro Gly Gly Asp Ser Gly Tyr Glu Gly Pro Tyr Val Ser Leu Asp Ala
1593
1620
GAG GAC GAG TTC AGC AGC GAC GAG GAC GAC GGG CTG TAC GTG CGC CCC GAG GAG
Glu Asp Glu Phe Ser Ser Asp Glu Asp Asp Gly Leu Tyr Val Arg Pro Glu Glu
1647
1674
GCG CCC CGC TCC GGC TTC GAC GTC TGG TTC CGC GAT CCG GAG AAA CCG GAA GTG
Ala Pro Arg Ser Gly Phe Asp Val Trp Phe Arg Asp Pro Glu Lys Pro Glu Val
1701
1728
ACG AAT GGG CCC AAC TAT GGC GTG ACC GCG AGC CGC CTG TTG AAT GCC CGC CCC
Thr Asn Gly Pro Asn Tyr Gly Val Thr Ala Ser Arg Leu Leu Asn Ala Arg Pro
1755
GCT TAA
Ala
CHART D
BamHI 7 Fragment of PRV
X = glycoprotein X (gX)
50 = glycoprotein 50 (gp 50)
63 = glycoprotein 63 (gp 63)
I = glycoprotein I (gI)
CHART E
Construction of pPR28-4 and pPR28-1
(a) BamHI 7 is digested with BamHI and PvuII to yield fragments 1
(1.5 kb) and 2 (4.9 kb).
(b) Fragments 1 and 2 are inserted separately between the BamHI and
PvuII sites of pBR322 to produce
CHART F
Restriction Enzyme Cleavage Sites Used for pg50 Sequencing
CHART G
Construction of pPR28-4 Nar2
(a) pPR28-4 is digested with NarI to produce fragment 3.
(b) BamHI linkers are added fragment and then it is treated with
BamHI to produce fragment 4.
(c) Fragment 4 is circularized with DNA ligase to produce pPR28-4
Nar2.
CHART H
Assembly of Complete gp50 Gene
(a) pPR28-4 Nar2 is digested with BamHI and PvuII to produce fragment
5 (160 bp).
(b) pPR28-1 is digested with BamHI and PvuII to produce fragment 6
(4.9 kb).
(c) pPGX1 is digested with BamHI, treated with BAP and then ligated
with fragments 5 and 6 to produce pBGP50-23.
CHART I
Production of Plasmid pD50
(a) pBGP50-23 is cut with MaeIII, blunt-ended with T4 DNA polymerase
and EcoRI linkers are added and digested with EcoRI, and then cut with
BamHI to produce fragment 7 (1.3 kb).
(b) Plasmid pSV2dhfr is cut with BamHI and EcoRI to obtain fragment 8
(5.0 kb).
(c) Plasmid pD50 is produced by ligating fragments 7 and 8.
dhfr = Dihydrofolate reductase gene
SV40 Ori = SV40 promotor and origin of replication
Amp R = Ampicillin resistance gene
CHART J
Production of Plasmid pDIE50
(a) pD50 is digested with BamHI and treated with BAP to produce
fragment 9.
(b) Fragment 10 (760 bp) containing the human cytomegalovirus (Towne)
immediate early promoter is isolated.
(c) Fragments 9 and 10 are ligated to produce plasmid pDIE50.
CHART K
Production of plasmid pDIE50PA
(a) Plasmid pSVCOW7 is cut with PvuII and EcoRI to produce fragment
11.
fragment 11
(b) Fragment 11 is cloned into pUC9 to produce plasmid PCOWT1.
(c) pCOWT1 is cut with SalI, blunt-ended with T4 DNA polymerase, and
EcoRI 1inkers are added followed by digestion with EcoRI to produce
fragment 12 (0.6 kb).
(d) Plasmid pDIE50 is cut with EcoRI and fragment 12 is cloned
therein to produce plasmid pDIE50PA.
A = Bovine growth hormone polyadenylation signal
G = Genomic bovine growth hormone
P = Human cytomegalovirus (Towne) immediate early promoter
CHART L
Production of plasmid pDIE50T
(a) Plasmid pDIE50 is digested with SalI and EcoRI to produce a 5.0
kb fragment,
and a 0.7 kg fragment.
(b) The 0.7 kb fragment is digested with Sau3AI and a 0.5 kb
SalI/Sau3AI fragment is isolated.
(c) The 5.0 kb EcoRI/SalI fragment, the 0.5 kb SalI/Sau3AI fragment
and the annealed oligonucleotides (see text) are ligated to produce
plasmid pDIE50T.
T = stop codon
CHART M
Restriction Enzyme Cleavage Sites Used for pg63 Sequencing
CHART N
Restriction Enzyme Cleavage Sites Used for gI Sequencing
CHART O
Construction of Plasmid pUCD/B
(a) A BamHI 7 fragment is cloned into plasmid pUC19 to produce
plasmid A.
(b) Plasmid A is digested with DraI to produce fragment 1
(c) BamHI linkers are added to fragment 1, followed by digestion
with BamHI to produce fragment 2 (2.5 kb).
(d) Fragment 2 is cloned into pUC19 digested with BamHI to produce
plasmid pUCD/B.
7 = BamHI 7 fragment
I = glycoprotein gI
CHART P
Construction of Plasmid pDGI
(a) Plasmid pUCD/B is digested with BsmI and EcoRI to produce
fragment 3 (4.4 kb).
(b) The following two synthetic oligonucleotides are obtained:
5′ CGCCCCGCTTAAATACCGGGAGAAG 3′
5′ AATTCTTCTCCCGGTATTTAAGCGGGGCGGG 3′
(c) The synthetic oligonucleotides and fragment 3 are ligated to
produce plasmid pGI.
(d) Plasmid pGI is digested with EcoRI and BamHI to produce fragment
4 (1.8 kb).
(e) Plasmid pSV2dhfr is cut with EcoRI and then cut with BamHI to
obtain fragment 5 (5.0 kb).
(f) Fragments 4 and 5 are then ligated to produce plasmid pDGI.
dhfr = Dihydrofolate reductase
SV40 Ori = SV40 promoter and origin of replication
Amp R = Ampicillin resistance
CHART Q
Construction of Plasmid pDIEGIPA
(a) Plasmid pDGI is cut with BamHI to produce fragment 6.
(b) Fragment 7 (760 bp) containing the human cytomegalovirus (Towne)
immediate early promoter is isolated.
(c) Fragments 6 and 7 are ligated to produce plasmid pDIEGIdhfr.
(d) Plasmid pSVCOW7 is cut with PvuII and EcoRI to produce fragment 8.
Fragment 8
(e) Fragment 8 is cloned in pUC9 to produce plasmid pCOWT1
(f) pCOWT1 is cut with SalI, treated with T4 DNA polymerase, and
EcoRI linkers are ligated on followed by digestion with EcoRI to
produce fragment 9 (0.6 kb).
(g) Fragment 9 is cloned into the EcoRI site of pUC19 to produce
plasmid pCOWT1E.
(h) pCOWT1E is digested with EcoRI to produce fragmnent 10 (600 bp).
(i) Plasmid pDIEGIdhfr is digested with EcoRI and ligated with
fragment 10 containing the bGH polyadenylation signal to produce
plasmid pDIEGIPA.
A = Bovine growth hormone polyadenylation signal
G = Genomic bovine growth hormone
P = Human cytomegalovirus (Towne) immediate early promoter
CHART R
Construction of pGP63dhfr
(a) BamHI 7 is digested with BstEII, treated with
T4 DNA polymerase, and then cut with KpnI to
yield fragment 1 (1.9 kb).
(b) Fragment 1 is then cloned between the KpnI and
SmaI sites of plasmid pUC19 to yield plasmid
pPR28-1BK.
(c) Plasmid pPR28-1BK is cut with DraI and MaeIII
to yield fragment 2 (1.1 kb).
(d) Plasmid pSV2dhfr is cut with EcoRI, treated
with T4 DNA polymerase, and then cut with BamHI to
obtain fragment 3 (5.0 kb).
(e) No oligonucleotides are synthesized to produce
fragment 4.
5′
GATCCGCAGTACCGGCGTCGATGATGATGGTGGCGCGCGAC 3′
3′
GCGTCATGGCCGCAGCTACTACTACCACCGCGCGCTGCACTG 5′
(f) Fragments 2, 3, and 4 are then ligated to pro-
duce plasmid pGP63dhfr.
dhfr = Dihydrofolate reductase
SV40 Ori = SV40 promotor and origin of replication
Amp R = Ampicillin resistance
CHART S
(a) pGP63dhfr is digested with BamHI and treated with BAP to
produce fragment 5.
(b) Fragment 6 (760 bp) containing the human cytomegalovirus
(Towne) immediate early promoter is isolated.
(c) Fragments 5 and 6 are ligated to produce plasmid
pIEGP63dhfr.
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The present invention provides recombinant DNA molecules comprising a sequence encoding a pseudorabies virus (PRV) glycoprotein selected from the group consisting of gI, gp50 and gp63 host cells transformed by said recombinant DNA molecule sequences, the gI, gp50 and gp63 polypeptides. The present invention also provides subunit vaccines for PRV, methods for protecting animals against PRV infection and methods for distinguishing between infected and vaccinated animals.
| 2
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BACKGROUND OF THE INVENTION
1. Field of the Invention
This invention relates to surfactant mixtures with improved dermatological compatibility and advantageous low-temperature behavior which contain alkyl oligoglucosides having a selected chain length composition.
2. Statement of Related Art
Alkyl oligoglycosides, especially alkyl oligoglucosides, are nonionic surfactants which are acquiring increasing significance by virtue of their excellent detergent properties and their high ecotoxicological compatibility. The production and use of these substances have been described just recently in a number of synoptic articles of which the articles by H. Hensen in Skin Care Forum, 1, (October 1992), D. Balzer and N. Ripke in Seifen-Ole-Fette-Wachse 118, 894 (1992) and B. Brancq in Seifen-Ole-Fette-Wachse 118, 905 (1992) are cited as representative.
Although alkyl oligoglucosides are extremely mild on the skin, there is still a growing need for substances having further improved dermatological compatibility. For example, attempts have been made in the past to improve the dematological compatibility of alkyl oligoglucosides by addition of amphoteric surfactants.
A starting point for the production of particularly high-performance alkyl oligoglucosides is to mix species differing in their chain length. For example, it is proposed in hitherto unpublished patent application U.S. Ser. No. 07/876,967 (Henkel Corp.) to mix two alkyl oligoglucosides having chain lengths of C 8-10 and C 12-16 in a ratio of 50:50 to 90:10 parts by weight. However, this application teaches using a mixing ratio of 60:40 to 80:20, i.e. using the short-chain species in excess.
DE-A1 40 05 958 (Huls) describes a liquid foaming cleaning preparation which may contain 3 to 40% by weight of a C 7-10 alkyl oligoglucoside and 3 to 40% by weight of a C 11-18 alkyl oligoglucoside (ad 100% by weight water). It is proposed to use the relatively short-chain and relatively long-chain species in a ratio by weight of 10:90 to 50:50 and preferably in a ratio of 17:83 to 33:67. There is no reference in this document to particular advantages arising out of the dermatological compatibility of the mixture.
In the past, alkyl oligoglucosides differing in their chain length have been mixed primarily with a view to obtaining optimal performance properties. Although the mixtures according to the prior art may be satisfactory, for example, in regard to their foaming and cleaning power, their dermatological compatibility is not optimal.
Now, the problem addressed by the present invention was to provide new mixtures of alkyl oligoglucosides differing in their chain lengths which would be free from the disadvantages mentioned above.
DESCRIPTION OF THE INVENTION
The present invention relates to ultramild surfactant mixtures containing
a) 48 to 52% by weight of an alkyl oligoglucoside corresponding to formula (I):
R.sup.1 --O--(G).sub.p (I)
in which R 1 is a C 6-12 alkyl radical, G is a glucose unit and p is a number of 1.3 to 1.8 and
b) 48 to 52% by weight of an alkyl oligoglucoside corresponding to formula (II):
R.sup.2 --O--(G).sub.p (II)
in which R 2 is a C 10-18 alkyl radical, G is a glucose unit and p is a number of 1.3 to 1.8.
It has surprisingly been found that products showing particularly high dermatological compatibility and low-temperature stability can be obtained within a very narrow mixing range of alkyl oligoglucosides differing in their chain length. Although similar mixtures of short-chain and long-chain alkyl oligoglucosides in a ratio of 50:50 are mentioned as lower limits in DE-A1 40 05 958 (Huls), the selection made in accordance with the present application is both new and inventive because neither the mixtures as such nor the surprising effect associated with them have been described before and because the teaching of the cited document points in the direction of mixing ratios at which the advantageous dermatological compatibility and the improved low-temperature behavior are no longer present.
Alkyl oligoglucosides
Alkyl oligoglucosides are known substances which may be obtained by the relevant methods of preparative organic chemistry. EP-A1-0 301 298 and WO 90/3977 are cited as representative of the extensive literature available on this subject.
The index p in general formulae (I) and (II) indicates the degree of oligomerization (DP degree), i.e. the distribution of monoglucosides and oligoglucosides and is a number of 1.3 to 1.8. Whereas p in a given compound must always be an integer and, above all, may assume a value of 1.3 to 1.6, the value p for a certain alkyl oligoglucoside is an analytically determined calculated quantity which is generally a broken number.
The alkyl radical R 1 may be derived from primary alcohols containing 6 to 12 and preferably 8 to 10 carbon atoms. Typical examples are caproic alcohol, caprylic alcohol, 2-ethylhexyl alcohol, capric alcohol, undecyl alcohol and lauryl alcohol and technical mixtures thereof such as are obtained, for example, in the hydrogenation of technical fatty acid methyl esters or in the hydrogenation of aldehydes from Roelen's oxosynthesis. C 6-12 alkyl oligoglucosides (DP=1.3 to 1.6), which are obtained as first runnings in the separation of technical C 8-18 coconut oil fatty alcohol by distillation and which contain essentially C 8-10 alkyl radicals, are preferred. Alkyl oligoglucosides corresponding to formula (I) which have the following C chain distribution in the alkyl radical are particularly preferred:
C 6 : 0-5% by weight
C 8 : 40-66% by weight
C 10 : 30-59% by weight
C 12 : 0-6% by weight
The alkyl radical R 2 may be derived from primary alcohols containing 10 to 18 and preferably 12 to 16 carbon atoms. Typical examples are capric alcohol, lauryl alcohol, myristyl alcohol, cetyl alcohol, stearyl alcohol, isostearyl alcohol, arachyl alcohol, behenyl alcohol and technical mixtures thereof which may be obtained as described above. Alkyl oligoglucosides based on hydrogenated C 10-18 coconut oil alcohol (DP=1.3 to 1.6), in which the alkyl radicals essentially contain 12 to 16 carbon atoms, are preferred. Alkyl oligoglucosides corresponding to formula (II) which have the following C chain distribution in the alkyl radical are particularly preferred:
C 10 : 0-3% by weight
C 12 : 60-75% by weight
C 14 : 21-30% by weight
C 16 : 0-12% by weight
C 18 : 0-3% by weight
Production of the mixtures
The alkyl oligoglucosides corresponding to formulae (I) and (II) may be mixed by methods known per se. For example, the concentrated pastes may be stirred with one another at an elevated temperature of 40° C. and may be diluted to the in-use concentration during making up into end products. However, dilute solutions may also be mixed with one another in the same way. This entails a purely mechanical operation involving no chemical reaction.
In one preferred embodiment of the invention, however, the relatively short-chain alkyl oligoglucosides may also be added to the relatively long-chain alkyl oligoglucosides during their production, for example before the final bleaching step. In addition, it is possible--taking the differences in reactivity into account--to acetalize fatty alcohols of suitable chain composition with glucose by methods known per se and thus to produce the mixtures in situ. In both these cases, uniform products are obtained.
Industrial Applications
The surfactant mixtures according to the invention are distinguished by particularly high dermatological compatibility and do not irritate the skin, even in the form of 50% by weight aqueous pastes. At the same time, they show particularly advantageous low-temperature stability.
Surfactants
The surfactant mixtures according to the invention may be used together with other anionic, nonionic, cationic and/or amphoteric or zwitterionic surfactants.
Typical examples of anionic surfactants are alkyl benzenesulfonates, alkanesulfonates, olefin sulfonates, alkyl ether sulfonates, glycerol ether sulfonates, α-methyl ester sulfonates, sulfofatty acids, alkyl sulfates, fatty alcohol ether sulfates, glycerol ether sulfates, hydroxy mixed ether sulfates, monoglyceride sulfates, fatty acid amide (ether) sulfates, sulfosuccinates, sulfosuccinamates, sulfotriglycerides, amide soaps, ether carboxylic acids, fatty acid isethionates, sarcosinates, taurides, alkyl oligoglucoside sulfates, alkyl (ether) phosphates and vegetable or animal protein hydrolyzates or condensation products thereof with fatty acids. Where the anionic surfactants contain polyglycol ether chains, they may have a conventional homolog distribution although they preferably have a narrow homolog distribution.
Typical examples of nonionic surfactants are fatty alcohol polyglycol ethers, alkyl phenol polyglycol ethers, fatty acid polyglycol esters, fatty acid amide polyglycol ethers, fatty amine polyglycol ethers, alkoxylated triglycerides, alk(en)yl oligoglycosides, fatty acid glucamides, polyol fatty acid esters, sugar esters, sorbitan esters and polysorbates. Where the nonionic surfactants contain polyglycol ether chains, they may have a conventional homolog distribution although they preferably have a narrow homolog distribution.
Typical examples of cationic surfactants are quaternary ammonium compounds and quaternized difatty acid trialkanolamine esters.
Typical examples of amphoteric or zwitterionic surfactants are alkyl betaines, alkyl amidobetaines, aminopropionates, aminoglycinates, imidazolinium betaines and sulfobetaines.
All the surfactants mentioned are known compounds. Information on the structure and production of these substances can be found in relevant synoptic works, cf. for example J. Falbe (ed.), "Surfactants in Consumer Products", Springer Verlag, Berlin 1987, pp. 54-124 or J. Falbe (ed.), "Katalysatoren, Tenside und Mineraloladditive", Thieme Verlag, Stuttgart, 1978, pp. 123-217.
Surface-active preparations
The present invention also relates to the use of the surfactant mixtures according to the invention for the production of surface-active preparations, more particularly laundry detergents, dishwashing detergents and cleaning products and also hair-care and personal-care products, in which they may be present in quantities of 1 to 99% by weight and preferably in quantities of 5 to 30% by weight, based on the particular preparation. The following are typical examples of such preparations:
Powder-form universal detergents containing 10 to 30% by weight--based on the detergent--of the mixture according to the invention of alkyl oligoglucosides corresponding to formulae (I) and (II) and anionic, nonionic, cationic and/or amphoteric or zwitterionic surfactants and, optionally, other typical auxiliaries and additives.
Liquid universal detergents containing 10 to 70% by weight--based on the detergent--of the mixture according to the invention of alkyl oligoglucosides corresponding to formulae (I) and (II) and anionic, nonionic, cationic and/or amphoteric or zwitterionic surfactants and, optionally, other typical auxiliaries and additives.
Liquid light-duty detergents containing 10 to 50% by weight--based on the detergent--of the mixture according to the invention of alkyl oligoglucosides corresponding to formulae (I) and (II) and anionic, nonionic, cationic and/or amphoteric or zwitterionic surfactants and, optionally, other typical auxiliaries and additives.
Liquid cleaning and disinfecting preparations containing 10 to 30% by weight--based on the preparation--of the mixture according to the invention of alkyl oligoglucosides corresponding to formulae (I) and (II) and anionic, nonionic, cationic and/or amphoteric or zwitterionic surfactants and, optionally, other typical auxiliaries and additives.
Hair shampoos containing 10 to 30% by weight--based on the shampoo--of the mixture according to the invention of alkyl oligoglucosides corresponding to formulae (I) and (II) and anionic, nonionic, cationic and/or amphoteric or zwitterionic surfactants and, optionally, other typical auxiliaries and additives.
Hair rinses containing 10 to 30% by weight--based on the hair rinse--of the mixture according to the invention of alkyl oligoglucosides corresponding to formulae (I) and (II) and anionic, nonionic, cationic and/or amphoteric or zwitterionic surfactants and, optionally, other typical auxiliaries and additives.
Foam baths containing 10 to 30% by weight--based on the foam bath--of the mixture according to the invention of alkyl oligoglucosides corresponding to formulae (I) and (II) and anionic, nonionic, cationic and/or amphoteric or zwitterionic surfactants and, optionally, other typical auxiliaries and additives.
Syndet soaps containing 10 to 50% by weight--based on the soap--of the mixture according to the invention of alkyl oligoglucosides corresponding to formulae (I) and (II) and anionic, nonionic, cationic and/or amphoteric or zwitterionic surfactants and, optionally, other typical auxiliaries and additives.
Detergents and cleaning products based on the detergent mixtures according to the invention may contain, for example, builders, salts, bleaches, bleach activators, optical brighteners, redeposition inhibitors, solubilizers, foam inhibitors and enzymes as auxiliaries and additives.
Typical builders are sodium aluminium silicates (zeolites), phosphates, phosphonates, ethylenediamine tetraacetic acid, nitrilotriacetate, citric acid and/or polycarboxylates. Suitable salts or diluents are, for example, sodium sulfate, sodium carbonate or sodium silicate (waterglass). Typical individual examples of other additives are sodium borate, starch, sucrose, polydextrose, TAED, stilbene compounds, methyl cellulose, toluene sulfonate, cumene sulfonate, long-chain soaps, silicones, mixed ethers, lipases and proteases.
Hair shampoos, hair lotions or foam baths based on the detergent mixtures according to the invention may contain, for example, emulsifiers, oil components, fats and waxes, thickeners, superfatting agents, biogenic agents, film formers, fragrances, dyes, pearlescers, preservatives and pH regulators as auxiliaries and additives.
Typical oil components are such substances as paraffin oil, vegetable oils, fatty acid esters, squalene and 2-octyl dodecanol. Suitable fats and waxes are, for example, spermaceti, beeswax, montan wax, paraffin and cetostearyl alcohol. Superfatting agents may be selected from such substances as, for example, polyethoxylated lanolin derivatives, lecithin derivatives and fatty acid alkanolamides, the fatty acid alkanolamides also serving as foam stabilizers. Suitable thickeners are, for example, polysaccharides, more particularly xanthan gum, guar guar, agar agar, alginates and tyloses, carboxymethyl cellulose and hydroxyethyl cellulose, also relatively high molecular weight polyethylene glycol monoesters and diesters of fatty acids, polyacrylates, polyvinyl alcohol and polyvinyl pyrrolidone and electrolytes, such as sodium chloride and ammonium chloride. Biogenic agents are understood to be, for example, vegetable extracts, protein hydrolyzates and vitamin complexes. Typical film formers are, for example, polyvinyl pyrrolidone, vinyl pyrrolidone/vinyl acetate copolymers, polymers of the acrylic acid series, quaternary cellulose derivatives and similar compounds. Suitable preservatives are, for example, formaldehyde solution, p-hydroxybenzoate or sorbic acid. Suitable pearlescers are, for example, glycol distearic acid esters, such as ethylene glycol distearate, and also fatty acid monoglycol esters. The dyes used may be selected from any of the substances which are permitted and suitable for cosmetic purposes, as listed for example in the publication "Kosmetische Farbemittel" of the Farbstoffkommission der Deutschen Forschungsgemeinschaft, published by Verlag Chemie, Weinheim, 1984. These dyes are typically used in concentrations of 0.001 to 0.1% by weight, based on the mixture as a whole
The following Examples are intended to illustrate the invention without limiting it in any way
EXAMPLES
I. Alkyl oligoglucosides used
Comp. I:
C 8-10 alkyl oligoglucoside
C chain distribution in the alkyl radical: 45% C 8 , 55% C 10
DP degree: 1.59
Plantaren® APG 225, a product of Henkel KGaA, Dussel-dorf, FRG
Comp. II:
C 12-16 coconut oil alkyl oligoglucoside
C chain distribution in the alkyl radical: 68% C 12 , 26%
C 14 , 6% C 16
DP degree: 1.38-1.53
Plantaren® APG 600, a product of Henkel KGaA, Dussel-dorf, FRG
All the products were used in the form of 50% by weight aqueous pastes.
II. Application Examples
Irritation of the skin was determined by OECD Method No. 404 and EEC Directive 84/449 EEC, Part B.4. The total irritation scores shown were compiled from the irritation scores obtained after 24, 48 and 72 hours. The total irritation score determined in comparison test Cl for a 100% C 12-16 alkyl oligoglucoside (DP=1.38) was put at 100% and the total irritation scores obtained in the other tests were related to that score.
To determine their long-term behavior at low temperatures, the products were stored for 5 months at 10° C. Even after this period, the mixtures according to the invention were liquid whereas most of the comparison mixtures had crystallized.
The results are set out in Table 1 and FIG. 1.
TABLE 1______________________________________Results of performance testsComp. I Comp. II Total irritation scoreEx. % by weight % by weight DP % rel.______________________________________1 48 52 1.38 532 48 52 1.53 473 50 50 1.41 534 52 48 1.38 55C1 0 100 1.38 100C2 0 100 1.45 95C3 0 100 1.53 95C4 17 83 1.38 72C5 20 80 1.38 80C6 33 67 1.38 75C7 40 60 1.38 69C8 60 40 1.38 67C9 63 37 1.38 70C10 80 20 1.38 72C11 90 10 1.38 75C12 100 0 1.38 78C12 100 0 1.59 71______________________________________
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An ultramild surfactant mixture consisting of
a) from about 48 to about 52% by weight of at least one alkyl oligoglucoside corresponding to formula (I):
R.sup.1 --O--(G).sub.p (I)
in which R 1 is an alkyl radical containing 8 to 10 carbon atoms, G is a glucose unit and p is a number of 1.3 to 1.8; and
b) from about 48 to about 52% by weight of at least one alkyl oligoglucoside corresponding to formula (II):
R.sup.2 --O--(G).sub.p (II)
in which R 2 is an alkyl radical containing 12 to 16 carbon atoms; G is a glucose unit and p is a number of 1.3 to 1.8.
Also, finished compositions containing the above surfactant mixture.
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This is a divisional application of Ser. No. 654,683, filed Sept. 26, 1984, now U.S. Pat. No. 4,668,118.
BACKGROUND OF THE INVENTION
This invention concerns a tool with at least one wear-resistant hard metal part which serves to process production pieces, such as stone or the like, which is firmly connected to a metallic carrier by means of solder located in at least one soldering aperture between the hard metal part and the metallic carrier. Among such tools are bits, such as drill bits, turning tools, and the like and processing tools to remove shavings, from lathing, milling, and the like.
Hard metal has a substantially smaller coefficient of expansion than a carrier consisting mostly of steel. Even during the soldering of the hard metallic part to the carrier, strains arise between the hard metallic part and the carrier. Because of the forces and temperature increases which may occur during operation, the strain may increase still further, and often causes tension cracks in the hard metal part, and thus causes failure of the tool.
Using a soft solder to reduce the danger of the formation of tension cracks is known. This solder connection is, however, not sufficient in many cases, especially for high performance tools. Thus, hard solder is preferred.
The greater the cross section and length of the hard metal part, the greater is the danger of tension cracks in the hard metal part. Even in high performance tools, the hard metal part must be supported in the carrier over a large surface area, in order to be able to absorb the considerable forces and momentum.
SUMMARY OF THE INVENTION
It is an objective of this invention to create, by using a common hard solder, and in a tool of the type described above, a connection between the hard metal part and the carrier, whereby the danger of the formation of tension cracks in the hard metal part is substantially reduced.
This objective is achieved as specified by the invention in the following manner: at least one predetermined weak point is created within the soldering aperture.
Because of the at least one predetermined weak point created in the soldering aperture, the ability of the solder to transmit force, such as tension and/or compressive and/or shearing forces, is reduced, and thus the danger of the formation of tension cracks in the hard metallic part, can be practically eliminated in a simple, cost-effective, and reliable manner, while retaining firm support of the hard metallic part.
The predetermined weak point can be an opening or a cavity where the solder does not bind to a surface. An equalization of tension can occur in the area of this weak point.
In accordance with one embodiment, an opening in the soldering aperture can be created in a simple manner by having partial areas of the solder aperture walls formed by the hard metal part, and/or providing the carrier with a surface layer having partial areas which do not bind to the solder during soldering. The solder then abuts the solder aperture walls in the area of these weak points but does not, however, solidly bind to these.
A further embodiment for the formation of weak points is characterized as follows: at least one lining which is more variable in volume and more elastic than the solder, is positioned in the solder aperture. The volume change of the lining brings about an equalization of tension in the solder aperture. The equalization of tension can be further improved if the lining has, in its interior, at least one opening or cavity.
In bits, a bolt-shaped hard metal part is preferably soldered into a blind end bore of the carrier. For this type of tool, one embodiment has proven especially advantageous, namely, in a casing-like or a container-like solder aperture, having a ring, a casing, or a hollow spiral sealed at both ends, placed in the solder aperture as a lining.
An equalization of tension in the area of the lining is accomplished, in accordance with another embodiment, in that the lining is formed in multiple layers, and, between two layers, it forms a required weak point, with the layers being bound less solidly to one another than the solder is with the hard metal part and the carrier.
If the lining comprises non-solderable particles, grains, or the like, then a great number of openings form in the solder aperture on the surfaces.
To form further openings and thus weak points along the surfaces facing the solder, the lining may be bound to these only in the partial areas.
If the lining itself has a sufficient capacity for equalization of tension, then another embodiment provides that the lining is bound to the surfaces facing the solder. This facilitates the insertion of the solder and the production of the lining.
Another embodiment is characterized as follows: the solder aperture walls formed by the hard metal part and the carrier are connected with each other by means of individual solder bridges separated from each other by means of cavities. The cavities between the separated bridges form weak points in the solder aperture.
If the solder is a hard solder, preferably having a silver or copper base, then, despite the weak points in the solder aperture, a firm connection between the hard metal part and the carrier sufficient for high performance tools is obtained.
BRIEF DESCRIPTION OF THE DRAWING
The invention is illustrated more fully in the different embodiments depicted in the drawing, wherein:
FIG. 1 shows a partially cut-away lateral view of a cylindrical bit;
FIG. 2 shows enlarged cross section Z in FIG. 1;
FIG. 3 shows the cross section Z of another embodiment showing a differently shaped cylindrical bit;
FIG. 4 shows the cross section Z of a third embodiment of a cylindrical bit;
FIG. 5 shows the cross section Z of a fourth embodiment of a cylindrical bit;
FIG. 6 shows the cross section Z of a fifth embodiment of a cylindrical bit;
FIG. 7 shows in cross section, a further embodiment of a cylindrical bit; and
FIG. 8 shows in cross section, an embodiment of a rotatable bit.
DESCRIPTION OF PREFERRED EMBODIMENTS
The cylindrical bit (10) shown in FIGS. 1 and 2 has a rotationally symmetrical shaft, which on the forward front end, has a central bore formed as a blind-end hole, in which hard metal part (13) formed as a hard metal point is soldered by means of solder (14). The solder (14) is preferably a hard solder with a silver and/or copper base, with a melting point of between about 700° to 1100° C. The shaft serves as carrier (11) for the tool. Hard metal part (13) is encompassed by a lining (16) in central bore (12), which comprises a spiral helically coiled band (15), which is both axially and radially expansible and compressible. Solder aperture (41) between hard metal part (13) and central bore (12) in carrier (11) is filled with solder (14), so that the spiral is embedded. Metal band (15) has a rectangular cross section, in which the larger dimension is directed parallel to the longitudinal central axis of the hard metal part (13). The spiral extends 30 to 80 percent of the depth of the central bore (12).
The external and internal broad sides (17, 18) of metallic band (15) bear surface coatings, which do not bind to the solder (14), so that crack-like openings form on these surfaces as weak points in the solder aperture (41). This can be attained by alitizing the band (15). The narrow sides (19, 20) of band (15) do not bind to the solder (14). If, with large temperature increases, tensions are exerted on carrier (11) and hard metal part (13), then these are so reduced at the weak points that no tension cracks arise in hard metal part (13). The tensions function radially, that is, at right angles to the solder aperture (41), as tension or pressure (force R in FIG. 2), or along the solder aperture (41), axially or tangentially, as the force of gravity (S). The openings in the solder connection permit small displacements, which suffice to reduce these forces very sharply. Also, the malleability of the spirals facilitates equalization of the tension. The helical shape of the spiral forms an opening (35) which is filled by means of solder bridge (39), extending from the peripheral wall (36) of central shaft (12) to the periphery (37) of hard metal part (13).
Cylindrical bit (10) depicted in FIG. 3 in cut-away portion, has lining (16'), which is likewise formed as a spiral. Metal band (15') comprises at least two layers (22, 23), which are less firmly connected to each other than the solder (14) is connected to lining (16'), carrier (11), and hard metal part (13). The surfaces of lining (16') which face the solder (14) can be completely or only partially bound to the solder (14), if lining (16') has areas which are not solderable. The solder (14) cannot penetrate between both layers (22, 23), so that this weak point is retained after embedding the spiral in the solder (14), and can equalize the tension, so that this connection between the two layers (22, 23) can partially loosen. The connection between layers (22, 23) represents a required weak point, which may give upon the appearance of tension.
In the embodiment of a cylindrical bit as shown in FIG. 4, from which, also, only section Z as specified in FIG. 1 is shown, line 16" is a spiral formed from metal tube 15", which is closed on both ends. The cavity (24) of the spiral creates a lining (16") which can change volume, and which is expansible and compressible. The surfaces of the spiral which face the solder (14) can completely bind to the solder (14), since the spiral can equalize the tension. The closed ends of the spiral impede the entrance of solder (14) into cavity (24), which is wrapped helically around the hard metal part (13). Metal tube (15") is a flat tube, the larger dimension of which is again directed parallel to the central 1ongitudinal axis of the hard metal part (13).
In the embodiment of FIG. 5, lining (16a) is formed as a container, which is perforated in the base and in the container wall. The internal and the external surfaces of the container are provided with a non-solderable coating. Solder (14) penetrates through holes (35') of the container, to form solder bridges (39), and can moreover bind to the solder aperture walls. Solder aperture (41) can, again, through lining (16a), equalize tension, since the non-soldered surfaces of the lining form breaking points in the solder aperture (41), while solder bridges (39) ensure sufficient support of the hard metal part (13) in carrier (11).
In the cylindrical bit (10) as shown in FIG. 6, carrier (11) is of steel, and fluid solder (14) moistens the surfaces of carrier (11) and hard metal part (13). Thread (46) is cut in carrier (11), with ridges (4a) of the thread and grooves (44) forming the depressions. Between the thread ridges (49) and hard metal part (13), a very narrow helical aperture (62) is formed, in which, during soldering, the fluid solder (14) rises, through capillary action, to the upper end of thread (46). The sides of the thread (60) and the thread base (61) are not moistened with solder (14), so that a helical cavity (45) opened upwards is formed in the solder aperture (41), which proceeds to the base level of central bore (12). The base of central bore (12) is completely covered with solder (14). The thread form may be rectangular, trapezoidal, or rounded. The cavity (45) forms the predetermined weak point for the equalization of tension.
In the bit shown in FIG. 7, central bore (12) is biconical, as it first expands conically, and then narrows conically. Hard metal part (13) is formed as a peg, likewise biconically, so that solder aperture (41) is formed. Linings (l6e) comprise particles or grains, which preferably have a lower specific weight than the solder (14), are more elastic than the solder, and are not bound to the solder (14). The melting temperature of the particles is higher than the melting temperature of the solder (14), which is inserted as powder with the particles in solder aperture (41). By heating up to the melting point of the solder (14), the particles are floatingly embedded in the solder (14), since they can leak out of the narrow place at the upper end of solder aperture (41). The particles form weak points in solder aperture (41), and form openings throughout solder (14), so that an excellent equalization of tension is attained.
Finally, FIG. 8 shows a rotating bit (10'), in which, by means of the solder aperture (41), hard metal part (13') formed as a hard metal plate is solidly connected with the carrier (11'). The surfaces of hard metal part (13') and of carrier (11') are provided, in the area of solder aperture (41) and at places distributed in a predetermined manner, with very thin coatings (40), which do not bind to solder (14). In this manner, a great number of weak points are distributed, evenly or unevenly, over the entire solder aperture (41). Coatings (40) may be provided only on carrier (11'), or, alternatively, only on hard metal part (13'). Silicon carbide (SiC), aluminum oxide (Al 2 O 3 ) or other suitable oxide ceramics, yield satisfactory results as a coating (40), which covers at least 20 percent of the solder aperture wall.
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This invention relates to a tool with at least one wear-resistant hard metal part which serves to process production pieces, stones, or the like, wherein the hard metal part is firmly connected with a metallic carrier by solder located in at least one solder aperture. In order to reduce the danger of formation of tension cracks in the hard metal part, the invention provides that at least one predetermined weak point is created in the solder aperture.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to a digital speech-synthesis process.
2. The Prior Art
Three processes are essentially known in the synthetic generation of speech with computers.
In formant synthesis, the resonance properties of the human vocal tract and its variations in the course of speaking, which are caused by the movements of the speech organs, are simulated by a filtered excitation signal. Such resonances are characteristic of the structure of vowels and their perception. For limiting the computing expenditure, the first three to five formants of a speech are generated synthetically with the excitation source. Therefore, with this type of synthesis, the memory location requirements in a computer are low. Furthermore, a simple change can be realized in duration and in the fundamental of the rule set excitation waveforms. However, the drawback is that an extensive rule set is needed for speech synthesis output, which often requires the use of digital processors. Furthermore, it is a disadvantage that the speech output sounds unnatural and metallic, and that it has special weak points in connection with nasals and obstruents, i.e., with plosives /p, t, k, b, d, g/, affricates /pf, ts, tS/ and fricatives /f, v, s, z, S, Z, C, j, x, h/.
In the present text, the letters shown between slashes (//) represent sound symbols according to the SAMPA-notation; cf: Wells, J.; Barry, W. J.; Grice, M.; Fourcin, A.; Gibbon, D. [1992]; Standard Computer-Compatible Transcription, in: ESPRIT PROJECT 2589 (SAM); Multi-Lingual Speech Input/ Output Assessment, Methodology and Standardization; Final Report; Doc. SAM-UCL-037, pp 29 ff.
In articulatory synthesis, the acoustic conditions in the vocal tract are modeled, so that the articulatory gestures and movements during speaking are simulated mathematically. Thus an acoustic model of the vocal tract is computed, which leads to substantial computing expenditure and which requires a high computing capacity. However, the automatic speech generated this way still sounds unnatural and technical.
Furthermore, the concatenation synthesis is known, where parts of really spoken utterances are concatenated in such a way that new utterances are generated. The individual speech segments thus form units for the generation of speech. The size of the segments may reach from words and phrases up to parts of sounds depending on the field of application. Demi-syllables or smaller demi-units can be used for speech synthesis with an unlimited vocabulary. Larger units are useful only if a limited vocabulary is to be synthesized.
In systems which do not use resynthesis, the choice of the correct cutting point of the speech components is decisive for the synthesis quality, and melodic and spectral jumps have to be avoided. Concatenative synthesis processes then achieve—especially with larger units—a more natural sound than the other methods. Furthermore, the controlling expenditure for generating the sounds is quite low. The limitations of this process lie in the relatively high memory requirements for the speech components needed. Another limitation of this process is that components, once recorded, can be changed (e.g. in duration or frequency) in the known systems only by costly resynthesis methods, which, furthermore, have an adverse effect on the sound of the speech and its comprehensibility. For this reason, also a number of different realizations of a speech unit are recorded, which, however, increases memory requirements.
The concatenation synthesis processes essentially comprise four synthesis methods permitting the speech synthesis without limitation of the vocabulary.
A concatenation of sounds or phones is carried out in phone synthesis. For Western European languages with a sound inventory of about 30 to 50 sounds and an average sound duration of about 150 ins, the memory requirements are acceptably low. However, these speech signal units lack the perceptively important transitions between the individual sounds, which, furthermore, can be recreated only incompletely by fading over individual sounds or even more complicated resynthesis methods. The quality of synthesis is, therefore, not satisfactory. Even storing allophonic variants of sounds in separate speech signal units in the so called allophone synthesis does not significantly enhance the speech result due to disregard of the articulatory-acoustic dynamics.
The most widely applied form of concatenation synthesis is the diphone synthesis, which employs speech signal units reaching from the middle of an acoustically defined speech sound up to the middle of the next speech sound. The perceptually important transitions from one sound to the next are taken into account in this way, such transitions appearing in the acoustic signal as a result of the movements of the speech organs. Furthermore, the speech signal units are thus concatenated at spectrally relatively constant places, which reduces the potentially present interferences of the signal flow on the joints of the individual diphones. The sound inventory of Western European languages consists of 35 to 50 sounds. For a language with 40 sounds, this theoretically results in 1600 pairs of diphones, which are then really reduced to about 1000 by phonotactic constraints. In natural speech, unstressed and stressed sounds differ in sound quality and duration. Different diphones are recorded in some systems for stressed and unstressed sound pairs in order to adequately take said differences into account in the synthesis. Therefore, 1000 to 2000 diphones with an average duration of about 150 ms are required depending on the projected configuration, resulting in a memory requirement for the speech signal units of up to 23 MB depending on the requirements with respect to dynamics and signal bandwidth. A common value amounts to approximately 8 MB.
The triphone and the demi-syllable syntheses are based on a principle similar to the one of the diphone synthesis. In this case too, the cutting point is disposed in the middle of the sounds. However, larger units are covered, which permits taking into account larger phonetic contexts. However, the number of combinations increases proportionally. In demi-syllable synthesis, one cutting point for the units used is in the middle of the vowel of a syllable. The other cutting point is at the beginning or at the end of a syllable, so that depending on the syllable structure, speech signal units can consist of sequences of several consonants. In German, about 52 different sound sequences exist in starting syllables of morphemes, and about 120 sound sequences for medial or final syllables of morphemes, resulting in a theoretical number of 6240 demi-syllables for the German language, of which some are uncommon. As demi-syllables are mostly longer than diphones, the memory requirements for speech signal units exceed those with diphones considerably.
The substantial memory requirements therefore pose the greatest problem in connection with a high-quality speech synthesis system. For reducing these requirements, it has been proposed, for example to exploit the silence in the closure of plosives for all plosive closures. A speech synthesis system is known from EP 0 144 731 Bl, where segments of diphones are used for several sounds. Said document describes a speech synthesizer which stores speech signal units which are generated by dividing a pair of sounds and relates such units with defined expression symbols. A synthesizing device reads the standard speech signal units from the memory in accordance with the output symbols of the converted sequence of expression symbols. Based on the speech segment of the input symbols it is determined whether two read standard speech signal units are connected directly when the input speech segment of the input symbols is voiceless, or whether a preset first interpolation process is applied when the input speech segment of the input symbol is voiced, the same standard signal unit being used both for a voiced sound /g, d, b/ and for its corresponding voiceless sound /k, t, p/. Furthermore, standard speech signal units representing the vowel segment after a consonant or the vowel segment preceding a consonant are to be stored in the memory as well. The transition ranges from a consonant to a vowel, or from a vowel to a consonant, can be equated in each case for the consonants k and g, t and d, as well as p and b. Respectively the memory requirements are reduced in this way; however, the aforementioned interpolation process requires a not insignificant computing expenditure.
A process for the synthesis of speech is known from DE 27 40 520 Al, in which each phone is formed by a phoneme stored in a memory, periods of sound oscillations being obtained from natural speech or are synthesized artificially. The text to be synthesized is grammatically and phonetically analyzed sentence by sentence according to the rules of the language. In addition to the periods of the sound oscillations, each phoneme is opposed to certain types and a number of time slices of noise phonemes with the respective duration, amplitude, and spectral distribution. The periods of the sound oscillations and the elements of the noise phonemes are stored in a memory in the digital form as a sequence of amplitude values of the respective oscillation, and are changed in the reading process according to the frequency characteristic or in order to increase the naturalness.
Accordingly, a digital speech synthesis process according to the concatenation principle and conforming to the introductory part of patent claim 1 is known from that document.
So as to make memory requirements as low as possible, individual periods of sound oscillations with characteristic formant distribution are stored according to the synthesis process of DE 27 40 520 Al. While maintaining the basic characteristics of the sentence, the types and the number of stored periods of sound oscillations associated with each phoneme are determined and then jointly form the acoustic speech impression. Accordingly, extremely short units of the length of a period of the basic oscillation of a sound are recalled from the memory and successively repeated depending on the number of repetitions previously determined. In order to realize smooth phoneme transitions synthetic periods with formant distributions which correspond to the transition between phonemes are used, or the amplitudes within the range of the respective transitions are reduced.
The drawback is that no adequate naturalness of the speech reproduction is achieved, because of the multiple reproduction of identical period segments, which may be reduced or extended only synthetically, if need be. Moreover, the substantially reduced memory requirements are gained at the expense of increased analysis and interpolation expenditure, costing computing time.
A process similar to the speech-synthesis process of DE 27 40 520 Al is known from WO 85/04747, which, however, is based on a completely synthetic generation of the speech segments. The speech segments, which represent phonemes or transitions, are generated from synthetic waveforms, which are reproduced repeatedly in a predetermined manner, if necessary reduced in length and/or voiced. Especially at phoneme transitions, an inverted reproduction of certain units is used as well. It is a drawback also in this process that even though the memory location requirements are considerably reduced, a substantial computing capacity is required due to extensive analyzing and synthesizing processes. Furthermore, the speech reproduction lacks the natural variance.
SUMMARY OF THE INVENTION
Therefore, the problem of the invention is to specify on the basis of DE 27 40 520 Al a speech-synthesis process in which high-quality speech output is achieved with low memory requirements and without high computing costs.
According to the speech-synthesis process as defined by the invention, a generalization is achieved in the use of the speech signal units in the form of microsegments. Thus it is avoided to apply separate speech signal units for each of the possible combinations of two speech signal units as required in diphone synthesis. The microsegments required for the speech output can be classified in three categories, which are:
1. Segments for vowel halves and semi-vowel halves which, in the dynamics of the spectral structure, indicate the movements of the speech organs from or to the place of articulation of the adjacent consonant. Consonant-vowel-consonant sequences are frequently found due to the syllable structure of most languages. Since, due to the relatively unmovable parts of the vocal tract, the movements are comparable for a given place of articulation, irrespective of the manner of articulation i.e. independently of the preceding or the following consonant type, only one microsegment is required for each vowel per global place of articulation of the preceding consonant (=first half of the vowel), and one microsegment per place of articulation of the following consonant (=second half of the vowel).
2. Segments for quasi-stationary vowel parts: These segments are separated from the middle of long vowel realizations which are perceived in terms of sound quality relatively constantly. Said segments are inserted in various contexts, for example at the beginning of the word, after the semi-vowel segments following certain consonants or consonant sequences, in German for example after /h/, /j/, as well as /?/, for phrase-final lengthening, between non-diphthongal vowel-vowel sequences, and in diphthongs as target positions.
3. Consonantal segments: The consonantal segments are formed in such a way that they can be used irrespectively of the type of adjacent sounds either generally for several occurrences of the sound, or in context with certain sound groups as especially in connection with plosives.
Of importance is that the microsegments classified in three categories can be used multiple times in different phonetic contexts, i.e., that the perceptually important transitions from one sound to the other in sound transitions are taken into account without separate acoustic units being required for each of the possible combinations of two speech sounds. The division in microsegments as defined by the invention, permits the application of identical units for different sound transitions for a group of consonants. With this principle of generalization in the application of speech signal units, the memory requirements for storing the speech signal units is reduced; however, the quality of the synthetically output speech is nevertheless very good because the perceptually important sound transitions are taken into account.
Because segments are identical for vowel halves and semi-vowel halves in one consonant-vowel or vowel-consonant sequence, for each of the global places of articulation of the adjacent consonants, namely labial, alveolar or velar, multiple utilization of the microsegments for different sound contexts is made possible with the speech segments for vowels, which means that a substantial reduction is achieved in the memory requirements.
If the segments for quasi-stationary vowel components are provided for vowels at the beginning of words as well as for vowel-vowel sequences, a substantial enhancement of the tonal quality of the synthetic speech is achieved for word starts, diphthongs or vowel-vowel sequences with a low number of additional microsegments.
Further generalization of the speech segments is obtained because consonantal segments for plosives are divided in two microsegments: a first segment comprising the closure phase and a second segment comprising the release phase. In particular, the closure phase can be represented by a series of statistical values of zeros for all plosives. No memory location is therefore required for this part of the sound reproduction.
The release phase of the plosives is differentiated according to the sound following in the context. Further generalization can be obtained in this connection in that a distinction is made in the release into vowels only based on the following four vowel groups: front unrounded vowels; front rounded vowels; low or centralized vowels; and back rounded vowels; and in a release into consonants only based on three different articulation places: labial alveolar or velar, so that for instance for German language, 42 microsegments have to be stored for the six plosives /p, t, k, b, d, g/ for the three consonant groups after the articulation place, and for four vowel groups. This reduces the memory requirements further due to the multiple use of microsegments in different phonetic contexts.
This has the advantage that, when a vowel segment is shortened, the start position is always reached with a vowel extending from a place of articulation towards the middle of a vowel and the end position is always reached with a vowel segment extending from the middle of the vowel towards the following articulation place, whereas the trajectory towards or from the “center of the vowel” is shortened. Such shortening of microsegments simulates, for example unstressed syllables, reflecting deviations from the spectral target quality of the respective vowel found in the natural, running speech and thus increasing the naturalness of the synthetic speech. Furthermore, it is advantageous in this connection, that no further memory for the segments is needed for such linguistic variations.
A manipulation of the microsegments is achieved with the analysis of the text to be spoken, such manipulation depending on the result of the analysis. It is possible in this way to reproduce such modifications of the pronunciation in dependence of the structure of the sentence and the semantics both sentence by sentence and word by word within sentences without requiring additional microsegments for different pronunciations. The memory requirements can thus be kept low. Furthermore, the manipulation in the time domain does not require any extensive computing procedures. The speech generated by the speech-synthesis process has nevertheless a very good natural quality.
In particular, it is possible by means of the analysis to detect speech pauses in the text to be output as speech. The phoneme string is extended in said places with pause symbols to form a symbol string, digital zeros being inserted on the pause symbols in the series of statistical values signal when the microsegments are concatenated. The additional information about a pause position and its duration is determined based on the sentence structure and predetermined rules. The pause duration is realized by the number of digital zeros to be inserted in dependence of the sampling rate.
Because the analysis detects phrase boundaries and the phoneme string is extended to a symbol string by introducing lengthening symbols at the phrase boundaries, phrase-final lengthening can be simulated in speech synthesis by lengthening the duration of the microsegments on the basis of the symbol string. Such manipulation in the time domain is carried out on the already-allocated microsegments. Therefore, no additional speech units are required for realizing final lengthening, which keeps the memory location requirements low.
Because stresses are detected by means of the analysis and that the phoneme string is extended in such places with stress symbols for different stress levels to form a string of symbols, a change taking place in the duration of the speech sounds on the microsegments with stress symbols as the microsegments are concatenated, the types of stress occurring in natural speech are simulated. The main information about word stress realized by durational modification sis found in a lexicon. The stress then to be selected for sentence accents which carry an intonation movement is determined by means of the analysis of the text to be output as speech on the basis of its syntax and predetermined rules. Depending on the determined stress, the respective microsegment is replayed unabbreviated or abbreviated by omitting certain sections of the microsegment. For generating a highly variable speech at acceptable computing expenditure, it was found that five levels of shortening are adequate for vowel microsegments, so that six playback durations are possible. Such levels of shortening are marked on the previously stored microsegment and are controlled in the context sensitive text analysis in accordance with the result of the analysis; i.e., in accordance with the stress level to be selected.
Both the lengthening of the playback duration with phrase-final syllables and the various levels of shortening for stress levels are preferably realized with the same leels of shortening in the microsegments. As opposed to syllables to be stressed where lengthening in terms of time is uniformly distributed across all microsegments, provision is made for progressive lengthening of the playback duration in connection with phrase-final syllables, namely of speech units noted in the written language with the punctuation marks comma, semicolon, period and colon. This is accomplished by increasing the playback duration of the microsegments in connection with phrase-final syllables in each case by one step, starting with the second microsegment.
For example, with the German-language sentence “Er hat in Paris gewohnt” [He has resided in Paris], the last syllable “-wohnt” —pronounced /vo:nt/—is lengthened in such a way that the microsegment string represented in the first line of the table is converted with the normal duration level—if said syllable is not at the end of the phrase—specified in brackets to the microsegment string represented in the third line in accordance with the lengthening symbols. The value range for the levels of duration reaches from 1 to 6, higher numbers conforming to longer durations. Symbol “%” does not generate a change in duration.
Normal
[2v]o
v[50]
[50]n
[2n]t
t[2t]
[2t]
. . .
Symbol
%
%
+1
+2
+3
+4
Lengthened
[2v]o
v[50]
[60]n
[4n]t
t[5t]
[6t]
. . .
The process is similar in other languages or dialects. In English, final lengthening, for example of the sentence “He saw a shrimp” would be realized with microsegments for the last word as follows:
Normal
t25]r
[2r]I
r[31]
[31]m
[2m]p
p[2p]
[2p]
. . .
Symbol
%
%
%
+1
+2
+3
+4
Lengthened
[2S]r
[2r]I
r[31]
f41]m
[4m]p
p[5p]
[6p]
. . .
With open syllables, i.e., with syllables ending with a vowel such as, for example, in “Er war da” [He was there] the playback duration of the second microsegment of “da” —pronounced /da:/—is increased by 2 steps:
Normal
d[2d]
[2d]a
d[4a]
[4a]
. . .
Symbol
%
%
%
+2
Lengthened
d[2d]
[2d]a
d[4a]
[6a]
. . .
This procedure is carried out until the longest duration stage (=6) has been reached.
The melody of spoken utterances is simulated by allocating intonations based on the analysis and by extending the phoneme string in such places with intonation symbols to form a symbol string, which is used for changing the fundamental frequency of defined parts of the periods of microsegments, which is applied in the time domain when the microsegments are concatenated. The change in fundamental frequency preferably takes place by skipping and adding defined sample values. The previously recorded voiced microsegments; i.e., vowels and sonorants are marked for this purpose. The first part of each pitch period, in which the vocal folds are together and which contains important spectral information, is processed separately from the second, less important part, in which the vocal folds are apart. The markings are set in such a way that during signal output, only the second part of each period—which are spectrally not critical—are shortened or lengthened for changes in fundamental frequency. This does not significantly increase the memory requirements for reproducing intonations in the speech output, and the computing expenditure is kept low due to the manipulation in the time domain.
When concatenating a sequence of different microsegments for speech synthesis, an acoustic transition between successive microsegments that is free of interferences to the highest possible degree is achieved in that the microsegments start with the first sample value after the first positive zero crossing, i.e., a zero crossing with a positive signal increase, and end with the last sample value before the last positive zero crossing. The digitally stored series of statistical values of the micro-segments are thus concatenated almost without discontinuities, which prevents clicks caused by digital leaps. Furthermore, closure phases of plosives or word interruptions and general speech pauses represented by digital zeros can be inserted at any time without introducing discontinuities.
BRIEF DESCRIPTION OF THE DRAWINGS
An exemplified embodiment of the invention is described in greater detail in the following with the help of the drawings, in which:
FIG. 1 shows a flow diagram of the speech-synthesis process.
FIG. 2 shows a spectrogram and speech pressure waveform of the word “Phonetik” [phonetics]; and
FIG. 3 shows the word “Frauenheld” [lady's man] in the time domain.
FIG. 4 shows a detailed flow diagram of the process according to the invention.
FIG. 5 shows a flow diagram of the syntactic-semantic analysis of the process according to the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The process steps of the speech-synthesis process as defined by the invention are represented in FIG. 1 in a flow diagram. The input for the speech-synthesis system is a text, for example a text file. By means of a lexicon stored in the computer, a phoneme string is associated with the words of the text, said phoneme string representing the pronunciation of the respective word. In the language, particularly in the German language, words are newly formed frequently by compounding words and word components, e.g. with prefixes and suffixes. The pronunciation of words such as “Hausbau” [=house construction], “Bebauung” [=constructing upon], “bebaubar” [=suitable for construction purposes] can be derived from a word stem, here “bau”, and connected with the pronunciation of the pre- and suffixes. Also connecting sounds such as “s” in “Gerichtsdiener” [=bailiff], “es” in “Landessportschule” [=state sports school] and “n” in “Grubenarbeiter” [=mine worker] can be taken into account in this connection as well. Therefore, in case a word is not included in the lexicon, various substitute mechanisms are engaged in order to verify the pronunciation of the word. An attempt is made first in this connection to compound the word searched for from other entries of the lexicon as described above. If this is not possible, an attempt is made to arrive at a pronunciation via a lexicon of syllables containing syllables with their pronunciations. If this should fail as well, rules are available by which sequences of letters have to be converted to phoneme sequences.
Below the phoneme string generated as shown above, FIG. 1 shows the syntactic-semantic analysis. In addition to the known data on pronunciation contained in the lexicon, said analysis contains syntactic and morphological information which, together with certain key words of the text, permits a local linguistic analysis with phrase boundaries and accented words. As output, the The phoneme string originating from the pronunciation data of the lexicon is modified based on said analysis and additional information about pause duration and intonation values is inserted. A phoneme-based, prosodically enriched symbol string is formed, which supplies the input for the actual speech output.
For example, the syntactic-semantic analysis takes into account word accents, phrase boundaries and intonation. The gradations in the stress level of syllables within a word are marked in the lexicon entries. The stess level for the reproduction of the microsegments forming said word are thus preset. The stress level stage of the microsegments of a syllable results from the following:
The phonological length of a sound, which is marked for each phoneme, for example /e:/ for a long e′ in /fo′ne:tIK/ [=phonetics];
the stress of the syllable, which is marked in the phoneme string before the stressed syllable, for example /fo′ne:tIK/;
the rules for phrase-final lengthening and, if need be, from other rules that are based on the sequence of accented syllables such as, for example, the lengthening of two stressed successive syllables.
The phrase boundaries, where the phrase-final lengthening takes place in addition to certain intonatory processes, are determined by linguistic analysis. The boundary of phrases is determined by given rules based on the sequence of parts of speech. The conversion of the intonation is based on an intonation and pause description system, in which a basic distinction is made between intonation curves taking place at phrase boundaries (rising, falling, remaining constant, falling-rising), and those which are located around accents (low, high, rising, falling). The intonation curves are allocated based on the syntactic and morpholigic analysis, including defined key words and key signs in the text. For example, questions starting with a verb (recognizable by the question mark at the end and by the information that the first word of the sentence is a finite verb) have a low accent tone and a high-rising boundary tone. Normal statements have a high accent tone and a falling final phrase boundary. The intonation curve is generated according to preset rules.
For the actual output of speech, the phoneme-based symbol string is converted into a microsegment sequence. The conversion of a sequence with two phonemes into microsegment sequences takes place via a set of rules by which a sequence of microsegments is allocated to each phoneme sequence.
In said process, the additional information relating to stress, pause duration, final lengthening and intonation is taken into account when the successive microsegments specified by the microsegment sequence are concatenated. The microsegment sequence is modified exclusively in the time domain. In the series of statistical values signal of the concatenated microsegments, for example, a speech pause is realized by inserting digital zeros in the place marked by a corresponding pause symbol.
The output of speech then takes place by digital-to-analog conversion, for example via a “soundblaster” card arranged in the computer.
For the word example “Phonetik” [phonetics], FIG. 2 shows in the upper part a spectrogram and in the lower part the speech pressure waveform associated with the latter. The word “Phonetik” is shown in symbols as a phoneme sequence between slashes as follows: /fo′ne:tIk/. This phoneme sequence is plotted in the upper part of FIG. 2 on the abscissa representing the time axis. The ordinate of the spectrogram in FIG. 2 denotes the frequency content of the speech signal, the degree of blackening being proportional to the amplitude of the corresponding frequency. In the speech pressure waveform shown in FIG. 2 at the top, the ordinate corresponds with the instantaneous amplitude of the signal. The microsegment boundaries are shown in the center field by vertical lines. The letter grammalogs shown therein denote the symbolic representation of the respective microsegment. The word example “Phonetik” thus consists of twelve microsegments.
The naming conventions of the microsegments are chosen in such a way that the sounds outside the brackets characterize the context, the current sound being indicated in brackets. The transitions of the speech sounds depending on their context are taken into account in this way.
The consonantal segments . . . (f) and (n)e are segmented on the respective sound boundaries. The plosives /t/ and /k/ are divided in a closure phase (t(t) and k(k), which is digitally reproduced by sample values set to zero and which is used for all plosives; as well as in a short release phase (here: (t)I and (k) . . . ), which is context-sensitive. The vowels each are split into vowel halves, whereby the cutting points are disposed at the start and in the middle of the vowel.
FIG. 3 shows another word example “Frauenheld” [lady's man] in the time domain. The phoneme sequence is stated by /fraU@nhElt/. The word shown in FIG. 3 comprises 15 microsegments, quasi-stationary microsegments occurring here as well. The first two microsegments . . . (f) and (r)a are consonantal segments; their context is specified only toward one side. Vowel half r(a), which comprises a transition of the velar articulation place to the middle of the “a”, is followed by the start position a(a) of the diphthong /aU/. aU(aU) contains the perceptually important transition between the start position and the end position U(U). (U)@ contains the transition from /U/ to /@/, which normally should be followed by @(@). This, however, would make the duration of /@/ too long, so this segment is omitted at /@/ and /6/ for duration reasons and only the second vowel half (@)n is played back. (n)h represents a consonantal segment. Other than with vowels, the transition of consonants to /h/ is not specified. Therefore, no segment n/h/ exists. (h)E contains the aspirated part of vowel /E/, which is followed by the quasi-stationary E(E). (E)l contains the second vowel half of /E/ with the transition to the dental articulation place. E(l) is a consonantal microsegment, where only the pre-context is specified. The /t/ is divided in a closure phase t(t) and a release phase (t).., which leads into silence ( . . . ).
FIG. 4 shows a detailed flow diagram of the process according to the invention, in which utterances are divided into microsegments and stored on a PC. FIG. 5 shows a syntactic-semantic analysis according to the invention, in which text is transformed into a microsegment string.
According to the invention, the multitude of possible articulation places is limited to three important regions. The combination of the groups is based on the similar movements carried out for forming the sounds of the articulators. The spectral transitions between the sounds are similar to each other within each of the three groups specified in table 1 because of the comparable articulator movements.
TABLE 1
Articulators and articulation places and their
designations
Summary
Designation
Articulator
Articulation Place
Labial
Bilabial
Lower lip
Upper lip
Labiodental
Lower lip
Upper incisors
Alveolar
Dental
Tip of tongue
Upper incisors
Alveolar
Tip or blade
Perineum of teeth,
of tongue
alveoli
Velar
Palatal
Anterior dorsal
Hard palate,
region of
palatum
tongue
Velar
Medium dorsal
Soft palate,
region of
velum
tongue
Uvular
Posterior
Uvula
dorsal region
of tongue
Pharyngeal
Root of tongue
Posterior
pharyngeal wall
Glottal
Vocal fold
Vocal fold
Therefore, for each vowel only one microsegment per articulation place of the preceding consonant (=1st half of the vowel) and one microsegment per articulation place of the following consonant (=2nd half of the vowel) is used. For example, the same two vowel halves can be used for each of the following syllables because the starting consonant is formed in each case with the closing of the two lips (bilabial) and the final consonant by lifting the tip of the tongue up to the perineum of the teeth (=alveolar):
/pat
pad
pas
paz
pa(ts)
/bat
bad
bas
baz
ba(ts)
/mat
mad
mas
maz
ma(ts)
/(pf)at
(pf)ad
(pf)as
(pf)az
(pf)a(ts)
/fat
fad
fas
faz
fa (ts)
/vat
vad
vas
vaz
va(ts)
Continuation:
pa(tS)
pa(dZ)
(pan)
pal/
ba(tS)
ba(dZ)
(ban)
bal/
ma(tS)
ma(dZ)
(man)
mal/
(pf)a(tS)
(pf)a(dz)
(pf)an)
(pf)ah/
fa(tS)
fa(dZ)
(fan)
fal/
va(tS)
va(dZ)
(van)
val/.
In addition to the labial and alveolar articulation places there is the velar one. Further generalization is achieved by grouping the postalveolar consonants /S/ (as in stitch) and /z/ (as in fee) with the alveolar, and the labiodental consonants /f/ and /v/ with the labial ones, so that also /fa(tS)/, /va(tS)/, /fa(dZ)/ and /va(dZ)/ may contain the same vowel segments as shown above. Therefore, the following applies to the microsegments of the exemplified syllables shown above: p(a)=b(a)=m(a)a=(pf)(a)=f(a)=v(a); and (a)t=(a)d=(a)s=(a)z=(a)(ts)=(a)(tS)=(a)(dZ)=(a)n=(a) 1 .
In addition to the vowel halves described above for vowel “a”, the following microsegments belong to the category of vowel halves and semi-vowel halves as well:
The first halves of the monophthongs /i:, I, e:, E, E:, a(:), O, o;, U, u:, y:, Y, 2:, 9, @, 6/, which appear after a labial, alveolar or velar sound;
the second halves of the monophthongs /1:, I, e:, E, E:, a(:), O, o:, U, u:, y:, Y, 2:, 9, @, 6/ before a labial, alveolar or velar sound;
first and second halves of the consonants /h/ and /j/ from the contexts:
nonopen unrounded front vowel /i:, I, e, E, E:/,
nonopen rounded front vowel /y:, Y, 2:, 9/,
open unrounded central vowel /a(:), @, 6/,
nonopen rounded back vowel /O, o:, U, u:/.
Furthermore, segments are required for quasi-stationary vowel parts cut out from the middle of a long vowel realization. Such microsegments are inserted in the following positions:
word-initially;
after the semi-vowel segments /h/, /j/, as well as around /?/;
for final lengthening when complex sound movements have to be realized on phrase-final syllables;
between non-diphthongal vowel-vowel sequences; as well as in
diphthongs as target positions.
The multiplication effect of sound combinatorics caused in diphone-synthesis is substantially reduced by the multiple use of microsegments in different sound contexts without impairing the dynamics of articulation.
With the generalization in the speech units as defined by the invention, 266 microsegments are theoretically sufficient for German, namely 3 articulation places, one stationary, and final for each of 16 vowels; 6 plosives for 3 consonant groups after the articulation place and for 4 vowel groups; and /h/, /j/ and /?/ for more differentiated vowel groups. For enhancing the quality of the sound of the synthetically generated speech, the number of microsegments required for the German language should amount to between 320 and 350 depending on the sound differentiation. Due to the fact that the microsegments are relatively short in terms of time, this leads to a memory requirement of about 700 kB at 8 bit resolution and 22 kHz sampling rate. As compared to the known diphone-synthesis this supplies a reduction by a factor 12 to 32.
For further enhancing the sound quality of the synthetically generated speech, provision is made for providing markings in the individual microsegments, such markings permitting a shortening, lengthening or frequency change on the microsegment in the time domain. The markings are set on the zero crossings with positive rise of the time signal of the microsegment. A total number of five levels of shortening are realized, so together with the unshortened reproduction the microsegment has six different levels of playback duration. The following procedure is employed for the reductions: With a vowel segment extending from an articulation place to the middle of the vowel, the start position, and with a vowel segment extending from the middle of the vowel to the following articulation place, the end position (=articulation place of the following consonant) is always reached, whereas the movement to or from the “vowel center” is shortened. This method permits a further generalized application of the microsegments: The same signal units supply the basic elements for long and short sounds both in stressed and unstressed syllables. The reductions in words which, in terms of the sentence, are unaccented, are derived from the same microsegments as well, the latter being recorded in sentence-accentuated position.
Furthermore, the intonation of linguistic utterances can be generated by a change in the fundamental frequency of the periodic parts of vowels and sonorants. This is carried out by manipulating the fundamental frequency of the microsegment within the time domain, by which hardly any loss is caused in terms of sound quality. The spectrally important part (1st part=phase of the closed glottis) of each voiced period, said part carrying the important information, and the less important second part (=phase of the open glottis) are treated separately. The first voiced period and the “closed phase” (1st part of the priod) contained therein, which phase has to be maintained constant, are marked. Due to the monotonous quality of the speech it is possible to automatically find all other periods in the microsegment and to thus define the closed phases. In the output of the signal, the spectrally noncritical “open phases” are shortened proportionally for increasing the frequency, which effects a reduction in the overall duration of the periods. When the frequency is lowered, the open phase is extended in proportion to the degree of reduction. Frequency increases and frequency reductions are uniformly carried out via one microsegment. This causes the intonation curve to develop in steps, which is largely smoothened by the natural “auditory integration” of the listening human. It is basically possible, however, to change the frequencies also within a microsegment, up to the manipulation of individual periods.
The recording and the segmentation procedure of microsegments as well as the speech reproduction are described in the following.
Individual words containing the respective sound combinations are spoken by a person monotonously and stressed. Such actually spoken utterances are recorded and digitalized. The microsegments are cut from such digitalized speech utterances. The cutting points of the consonantal segments are selected in such a way that the influences of adjacent sounds on the microsegment boundaries are minimized and the transition to the next sound is no longer exactly audible. The vowel halves are cut from the environment of voiced plosives, noisy components of the closure phase being eliminated. The quasi-stationary vowel components are separated from the middle of long sounds.
All segments are cut from the digital signal of the utterances contained therein in such a way that the segments start with the first sample value after the first positive zero crossing and end with the last sample value before the last positive zero crossing. Clicks are avoided in this way.
For limiting the memory requirements, the digital signal has a bandwidth of, for example 8 bit, and a sampling rate of 22 kHz.
The microsegments so cut out are addressed according to the sound and the context and stored in a memory.
A text to be output as speech is supplied to the system with the appropriate address sequence. The selection of the addresses is determined by the sound sequence. The microsegments are read from the memory according to said address sequence and concatenated. This digital time series is converted into an analog signal in a digital-to-analog converter, for example in a so-called soundblaster card, and said signal can be output via speech output devices, for example via a loudspeaker or headsets.
The speech-synthesis system as defined by the invention can be realized on a common PC, with 4 MB operating memory. The vocabulary realizable with the system is practically unlimited. The speech is clearly comprehensible, and the computing expenditure for modifications of the microsegments, for example reductions or changes in the fundamental frequency, is low as well, because the speech signal is processed within the time domain.
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A digital speech synthesis process in which utterances in a language are recorded, and the recorded utterances are divided into speech segments which are stored so as to allow their allocation to specific phonemes. A text which is to be output as speech is converted to a phoneme chain and the stored segments are output in a sequence defined by the phoneme chain. An analysis of the text to be output as speech is carried out and thus provides information which completes the phoneme chain and modifies the timing sequence signal for the speech segments which are to be strung together for output as speech. The process uses microsegments consisting of: segments for vowel halves and semi-vowels and extending as far as the vowel middle, and a second vowel half from the vowel middle to just before the vowel end; segments for quasi-stationary vowel components cut from the middle of a vowel; consonant segments beginning shortly before the front phoneme boundary and ending shortly before the rear phoneme boundary; and segments for vowel-vowel sequences cut from the middle of a vowel-vowel transition.
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CROSS REFERENCE TO RELATED APPLICATIONS
Reference is made to the following prior disclosures in which subject matter relating to the basic mechanical and electrical features of copier/duplicators having fixed and movable optical systems is disclosed as well as the overall operating modes of copier/duplicators having large document copying capabilities: Ser. No. 284,687 filed Aug. 29, 1972, (now abandoned) and continuation application Ser. No. 367,996, filed June 7, 1973; Ser. No. 393,546, filed Aug. 31, 1973, now U.S. Pat. No. 3,900,258, (now abandoned) and continuation application in the name of L. R. Sohn entitled "Dual Mode Control Logic For A Multi-Mode Copier/Duplicator" filed in November, 1974 (D/73383C). Reference is also made to concurrently filed applications in the name of Thomas J. Mooney entitled "Adaptive Fuser Controller", U.S. application Ser. No. 564,173 and in the name of W. L. Valentine entitled "Chain-Feed Control Logic In A Multi-Mode Copier/Duplicator" U.S. application Ser. No. 564,172, both applications assigned to the same assignee as the instant invention.
BACKGROUND OF THE PRIOR ART
1. Field of the Invention
The invention is in the field of photocopy machines and copier/duplicator machines which have multiple modes of operation. In particular, the invention pertains to cycle-out logic circuitry for delaying mode changing operations in machines having large document copying modes of operation, as well as base modes of operation.
2. Description of the Prior Art
Multi-mode copier/duplicator machines are known in the prior art and may, for example, utilize fixed and movable optical systems for operation in different modes such as a BASE Mode and a Large Document Copying (LDC) mode, respectively. In the BASE Mode of operation, documents up to 81/2 inches × 14 inches may be copied, whereas in the large document copying mode, documents up to 18 inches × 14 inches may be copied. An example of such machines is described in detail in copending application, Ser. No. 369,997, filed June 7, 1973 and Ser. No. 528,163, filed Nov. 29, 1974 (D/73383C). In such machines, the operator may change modes from, for example, a first or BASE Mode to a second or LDC mode of operation by moving a mechanical lever, pressing a button or the like. In such instances, the operator may, in fact, change modes during a copying cycle, and such mode changing has resulted in improper operation of the control logic circuitry. In some cases the control logic would go into some undefined state or result in an erroneous jam indication. In other cases, mode changing in the middle of a machine cycle would lead to the new mode dominating machine operations which results in an inability to detect copy paper jams for the copy in process. In general, mode changes by the operator initiated before the major photographic functions of the copier/duplicator result in undesired operation of the machine inasmuch as the control logic mode change is incompatible with the machine mode in process.
SUMMARY OF THE INVENTION
It is an object of the instant invention to overcome the disadvantages of the prior art by providing a cycle-out control logic circuit for operation of a copier/duplicator having multiple modes of operation.
It is another object of the invention to provide a cycle-out control logic in a copier/duplicator having a large document copying mode of operation and a BASE Mode of operation.
Yet another object of the invention is to provide a cycle-out control logic in a copier/duplicator having a large document copying mode of operation, as well as a chain feeding mode of operation.
Another object of the invention is to provide a cycle-out logic circuit which delays the mode changing logic signals initiated by the operator in changing from one machine mode to another.
Still a further object of the invention is to provide a cycle-out logic circuit which enables a multi-mode copier/duplicator to continue in performing essential machine functions for a copy in process irrespective of a mode change initiated by the operator.
The invention pertains to a cycle-out control logic circuit for use in a multi-mode copier/duplicator. The circuit comprises means for delaying the mode changing logic during a photocopy machine cycle even though the operator may activate mode changing switches or levers. The mode changing logic enables the logical mode change to be made only after the present key photocopy processes are completed thus preventing the multi-mode copier from entering undesirable and undefined running condition. The logic essentially allows the present machine to cycle-out in its present mode of operation before changing to a new mode.
BRIEF DESCRIPTION OF THE DRAWINGS
Other objects and features of the invention will become more readily apparent from the following detailed description when read in conjunction with the accompanying drawings, in which like reference numerals designate like parts throughout the figures thereof, and wherein:
FIG. 1 is a schematic side view of a copier/duplicator in which the chain feeding control logic of the instant invention may be utilized;
FIG. 2 shows a schematic top view of the document feeding means that may be used as an accessory to the base machine when the machine is operating in the LDC Mode;
FIG. 3 shows a perspective view of the copier/duplicator of FIG. 1 illustrating the position of control switches and sensing elements;
FIG. 4 is a block diagram of the cycle-out control logic showing its interconnection to the multi-mode copier/duplicator;
FIGS. 5A-5B are timing diagrams showing the sequence of operations of the copier/duplicator in the chain feed mode of operation utilizing a small cassette;
FIGS. 5C-5D are timing diagrams showing the sequence of operations of the copier/duplicator utilizing a large cassette.
FIG. 5E is a timing diagram showing the sequence of operation of the copier/duplicator utilizing a small cassette in the BASE Mode of operation.
FIG. 5 illustrates the arrangement of FIGS. 5A-5E to form the timing diagram;
FIGS. 6-14 show the detailed logic diagram of the cycle-out control logic of the instant invention and its interconnection to the copier/duplicator;
FIG. 15 illustrates the arrangement of FIGS. 6-14 to form the detailed logic diagram; and
FIGS. 16A-16D illustrate circuit details and truth tables associated with key logic elements of the instant invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
1. Mechanical Overview of the Multi-Mode Copier/Duplicator
The control circuitry of the present invention will be described in the context of a xerographic copier/duplicator machine of a specific design. However, it should be noted from the outset that although the description is in the context of the xerographic machine, the scope of the present invention is not limited to the xerographic machine. Clearly as will be evident from the following description, the principles of the present invention can be applied to other types of machines having similar operational requirements. Now referring to the drawings, as shown in FIG. 1, a xerographic copier/duplicator machine typically includes various elements for implementing xerographic steps. It comprises a drum 10 that may be driven clockwise about an axis 11. The drum includes a photosensitive insulating layer surface 12 around the periphery of which various controlled elements are situated; namely, charging station A, imagewise exposing station B, developing station C, image transfer station D, cleaning station E, and fusing station F, etc., for effecting the usual steps involved in making xerographic copies. The machine may be further provided with a suitable feeding means PF for feeding copy sheets of paper from a paper supply in a cassette 15 and a suitable paper transfer means 17 for transferring the imaged paper onto the fusing station F where the toner image is fused onto the paper and then feed out to a suitable receptacle means 19.
The xerographic copier/duplicator machine may be designed to operate in different modes. In a first, or BASE Mode, conventional documents up to a certain size are copied and in a second, or LDC Mode, larger size documents are processed. For example, in the BASE Mode, the machine is designed to employ a moving optical scanning arrangement 21-24 to scan a stationary original placed on a platen 20 in making copies up to 14 inches in length and 8.5 inches in width. In the LDC Mode, the scanning arrangement is held at a stationary position, and the document original is moved past a scanning station SS. In the LDC Mode, document originals up to 14 inches by 18 inches may be copied.
Referring to FIGS. 1-3, in BASE Mode operation, the scanning arrangement 21 is moved across the width of the platen 20 by a carriage (not shown) so that the associated optical means 22-25 projects the image of the original on the xerographic drum surface 12 at the image exposing station B. In BASE Mode operation, the machine is designed so that, in each copy run after an initial warm-up period, each successive xerographic copying cycle is accomplished in the same given time interval. The cycle time starts as the scanning means leaves the start scan position near the Home Switch S1 and continues to move past the platen and ends as it reaches the end of scan position at the End of Scan Sensing Switch S2. The next cycle begins as the scanning means automatically flies back to the home or start scan position. In BASE Mode, the operator may initiate a multiple copy mode by setting dial 99 to the desired number of copies.
In the LDC Mode of operation, a large document original is fed through a feeding means 30 such as that shown in a pending U.S. application Ser. No. 205,911 filed on Dec. 8, 1971, or in the U.S. Pat. No. 3,731,915 issued to Guenther. For example, as shown in the aforementioned copending application Ser. No. 284,687, the document feeding means 30 may be stationed outside of the platen 20 and be in a disengaged position when the machine is to operate in the BASE Mode as shown in dotted lines of FIG. 1. It includes a lever 31 which is designed so that by moving it clockwise the feeding means 30 is brought into or engaged into a position as shown in solid lines so that it can operate in the LDC Mode. In this position, the document original can be fed past the scanning station SS. A suitable mechanism 33 is provided in the machine for coupling feed rollers 34 to the main drive M when the document feeding means 30 is moved to the LDC position. Once engaged, the rollers 34 driven by the main drive M feeds the document original to the left past the scanning station SS. The speed with which the paper is fed past the scanning SS is synchronized with the speed with which the copy paper 36 from the paper cassette 15 is fed into a transfer relationship with the photosensitive insulating layer 12 by a suitable paper feeding means PF. When it is desired to operate the machine in the BASE Mode, the document feeding means is simply moved out of the way of the platen by rotating the lever 31 counter-clockwise rotation. The counter-clockwise rotation of the lever 31 moves the document feeding means 30 to the right as shown in dotted lines and out of the path of the scanning station SS. At the same time, the driving mechanism 33 disengages the feed rollers 34 from the main drive M to render the document feeding means inoperative. While in the illustrative embodiment, it is shown that the document original feeding means is moved from one position to another to engage or disengage the machine in the LDC Mode, it need not be so limited. For example, the document feeding means could be held at a fixed stationary position using suitable actuating means such as a push button to engage or disengage document feed rollers and thus selectively engage the feeding means for the LDC Mode.
In the BASE Mode, a control circuitry of a conventional design may be used to provide signals necessary for the selective enabling of certain elements such as charging, exposing, developing, image transferring, fusing and cleaning means that implement the steps necessary in making a copy. The circuitry may be of electro-mechanical or electronic components such as that shown in the U.S. Pat. No. 3,301,126 issued to R. F. Osborne et al. on Jan. 31, 1967, or that shown in the pending application Ser. No. 348,828 filed on Apr. 6, 1973, now U.S. Pat. No. 3,813,157, which acts to implement various xerographic process steps at appropriately timed intervals at various points in the processing operation under conditions where necessary timing is desired from a clock or cam mechanism or other suitable means. Generally, as described in the above mentioned copending application Ser. No. 367,996 for BASE Mode, the timing of the xerographic copying cycle is keyed to the scanning operation of the scanning means. Thus, in the BASE Mode, each cycle of xerographic processing steps during the making of successive copies in a copy run is keyed to the start and end of the scanning operation involving the movement of the scanner carriage between the home position (at Switch S1 in FIG. 1 or 2) and the end of scan position (at Switch S2 in FIG. 1 or 2).
In addition, the control circuitry is also provided with a suitable design such as that shown in the U.S. Pat. No. 3,588,472 issued to Thomas H. Glaster et al. on June 28, 1971 or in the U.S. patent application Ser. No. 344,322 filed on Mar. 23, 1973, now U.S. Pat. No. 3,832,065, for detecting various malfunctions of the machine. For example, referring to FIGS. 1 and 2, the machine may include a detack detecting means 37 for detecting the failure of copy paper separation from the drum surface 12, a jam detection means 38 for detecting a paper jam that may occur along the paper path, and heat sensing element 39 for monitoring the temperature of the fusing station F. The output of these detecting means form a part of the input signals to the control circuitry of the present system.
In the present machine, various sensing elements in the form of switches are used to provide certain necessary input signals to the control circuitry. These switches are shown schematically in FIGS. 1-3; Table 1 contains a brief functional description of each.
TABLE 1__________________________________________________________________________ FUNCTIONAL DESCRIPTION OF INPUT SWITCHES__________________________________________________________________________(See FIGS. 1-3 for switch locations;FIGS. 6 and 9 for switch interconnections)__________________________________________________________________________HOME SWITCH The Home Switch S1 is used for indicating that the optics scanning carriage is at the home or start position of the scan cycle. It is actuated when the optics scanning carriage is at the home position and provides two complementary outputs to the control logic circuitry. The outputs denote (in positive true logic terms) the "At Home" and "Off Home" condition of the optics scanning carriage.END OF SCANSWITCH: The End of Scan Switch S2 is used to sense the presence of the optics scanning assembly at the end of scan position. It is normally deactuated and is actuated when the scanning assembly reaches the desired position. Upon actuation it provides a logical "O" level to the control logic.TRAILINGEDGE SWITCH: The Trailing Edge Switch S3 is utilized to detect the trailing edge of a sheet of copy paper as it leaves feed rollers adjacent the paper cassette. It is normally deactuated and exhibits an open circuit. In the presence of copy paper it is actuated providing a logical "O"; on passage of the trailing edge it again opens removing the logical "O" from the control logic.LARGECASSETTESWITCH The Large Cassette Switch S4 is utilized to sense the presence of the large paper cassette in the paper tray. It is normally deactuated; it actuates in the presence of the large paper cassette thereupon providing a logical "1" to the control logic.MODE CHANGESWITCH: The Mode Change Switch S5 senses the movement of the document feeding means 30 into the LDC Mode position. It is normally in the open state. It closes momentarily as the document feeding means 30 moves into position for the LDC Mode of operation and starts the process of initializing the control logic circuitry. S5 is a one-way roll-over type switch that actuates in one way when the machine goes from the BASE Mode to the LDC Mode but not vice versa. It serves the function of the Print Button in initializing logic components in going from BASE Mode to LDC Mode.LDC MODESWITCH: The LDC Mode Switch S6 is actuated as the document feeding means 30 moves to the LDC Mode position from BASE Mode position. It is normally open. On actuation, it provides a logical "O" to the control logic circuitry. The logical "O" from this switch indicates a mode change of the machine from the BASE Mode to the LDC Mode; and further, of the continued operation of the machine in the LDC Mode.DOCUMENTSWITCHES: The Document Switches S7 and S8 are utilized to sense the document original being fed into the copier. The switches are normally closed, are connected in series, and provide a logical "O" to the control logic. One or both switches open in the presence of the document original to signify its presence. When thus opened, the logical "O" is removed from the control logic. Operation of either one or both is utilized to signify the presence of the document original as well as the leading and trailing edges of the document original__________________________________________________________________________
Briefly stated, the switches S1-S8 above are connected to operate and provide the following functions. The Home Switch S1 when actuated shows that the scan carriage is at the home position. The End of Scan Switch S2 is in a non-actuated condition at this point. Now suppose the operator wishes to operate the machine in an LDC Mode. The lever arm 31 is moved clockwise to place the document feeding means 30 to the left and thereby place the machine in the large document copying mode. As the lever arm 31 is rotated, the LDC Mode Switch S6 is actuated and then the switch S5 is momentarily actuated. This initializes the control circuitry for the LDC Mode of operation.
In response to such initializing, the control circuitry causes the scanning arrangement and associated optics to move into the LDC position, that is, to the end of the scan position associated with switch S2. Furthermore, the control logic associated with LDC Mode of operation is so designed that the action of copy paper feed solenoid II in selectively feeding copy paper is prevented or inhibited while the scanning elements 21 and 22 move to the end of the scan position. When the scanning elements reach the end of the scan position, this is sensed by the End of Scan Switch S2. In turn, the Switch S2 provides the End of Scan Signal. In response, the scanning and optic elements are retained in that position by a suitable pawl and ratched mechanism. For a detailed discussion of an exemplary mechanism of this type, one may refer to the above mentioned copending application Ser. No. 367,996. This prevents the scan carriage means from automatically returning to the home switch position as is done in BASE Mode operations, and when the scanning means reaches the end of scan position, the main drive M drives the document original feed rollers 34.
In response to the end of the scan signal, the control circuitry removes the constraints on the operation of the solenoid II to allow the copy paper feeding means PF to selectively operate. With the solenoid enabled, the drive belt means 41 and 42 are prevented from engaging with the main drive M and no copy paper is fed. When Solenoid II is de-actuated by the control logic in response to an actuation of the Document Switches S7 and S8, as the document original passes thereby, the drive means engage and the main drive M is allowed to drive the copy paper feed rollers 44 in synchronism with the speed with which the document original is fed past the scanning station SS. The switches S7 and S8 actuate as the document original paper is fed therepast in the paper feeding means 30, and enables the control logic to proceed with LDC Mode of copying operation. Absent any malfunction, the machine proceeds to complete the copying operation.
There are a number of indicating means that may be provided in the copier/duplicator machine, as shown in FIG. 2, to provide the following functions:
______________________________________WAIT This is a visual indication means 50. It is connected in a manner to provide the "Wait" indicia when document feeding means 30 is moved to the LDC position, and this condition is main- tained by the control circuitry until the scanning element 21 moves to the end of the scan position and the machine is ready to make copies. The lighted indicating means 50 comes to the view of the operator during this time and alerts the operator to wait until the indication terminates before the document original sheet is fed through the feeding means 30. The indicating means 50 may include a suitable notation "WAIT" for the operator's convenience. Preferably, the light indicating means 50 may be positioned above the console of the base machine as shown in FIG. 2 at a position where it will be hidden behind the housing of the paper feeding means 30 when the same is positioned for BASE Mode operation. The Wait light comes on from the time of charging until exposure is turned off.ADD An indicating means 51 "ADD PAPER" is providedPAPER to apprise an operator that attention to the paper supply is necessary. It may be so connected that it is energized by the control circuitry when the paper supply runs out or when the incorrect size paper supply is present.JAM ORCLEAR This indicating means 52 is provided to signifyPAPER to the operator the paper jam condition is presentPATH and requires clearing.______________________________________
In addition, certain controls are provided in the machine for inputting particular command signals to the control circuitry. For example:
______________________________________PRINT This input, button 53, is used to enable the operator to start the machine in the BASE Mode or in the alternative in the LDC Mode if the machine is already held in the LDC Mode. The Print button serves to actuate the Initialization Circuit to supply power to logic elements.LIGHT This input, button 54, serves the function ofORIGINAL starting the appropriate machine cycle when the original is light and it is desired to provide a darker copy. If the machine is in the BASE Mode, it may be placed in the LDC Mode by moving the lever arm clockwise and movement of the lever is accomplished by the operation of the momentary switch S5 and the LDC Mode Switch S6 to provide the print command signal. However, if the machine is already in the LDC Mode, then a depressing of either the PRINT button 53 or LIGHT ORIGINAL button 54 provides the print command signal.COPY This input, dial 99, is used to enable theQUANTITY operator to select the number of copies desiredDIAL of a single original document. It is operative only in the BASE Mode of operation.STOP The STOP input, button 55, is used for stopping the machine in the middle of its operation and causes the control circuitry to stop the machine at the end of the copying cycle in process.______________________________________
The features tabulated above are common to many copier/duplicators well known in the art and their use in multi-mode copier/duplicators is more fully set forth in the above mentioned copending application of L. R. Sohm entitled "Dual Mode Control Logic For A Multi-Mode Copier/Duplicator" (D/73383C).
2. Block Diagram Description
FIG. 4 is a block diagram of the overall electronics associated with the multi-mode copier/duplicator having the cycle-out logic circuitry of the instant invention. The copier/duplicator comprises a BASE LOGIC circuit 300 which comprises a plurality of latches (coincidence latch, development latch, etc) which form part of the copier/duplicator in its BASE Mode of operation. These latches control the basic xerographic processes which are well-known in the art. A plurality of other conventional circuits are shown in the BASE LOGIC 300 and are explained more fully below in connection with the Chain Feed Logic of the instant invention. The copier/duplicator also comprises a LDC LOGIC circuit which modifies the BASE LOGIC circuitry to enable the copier/duplicator to photocopy large documents (14 inchs × 18 inches). A detailed description of the interconnection of the LDC LOGIC 302 with the BASE LOGIC 300 is set forth in copending application, Ser. No. 528,163, filed Nov. 29, 1974 (D/73383C) mentioned above. The instant invention pertains to a Cycle-Out Logic 404 which is shown interconnected to the LDC LOGIC 302 by a plurality of lines 406. In addition, a Chain Feed Logic 400 is connected to the Cycle-Out Logic circuit 404 via lines 402, and the Chain Feed Logic is connected to the LDC Logic 302 by a plurality of lines 402. Finally, an Adaptive Fuser Controller 408 is connected to the LDC LOGIC 302 by a plurality of lines 410. Both the Chain Feed Logic 400 and the Adaptive Fuser Controller 408 form the subject of concurrently filed applications, namely, "Cycle-Out Logic in a Multi-Mode Copier/Duplicator" in the name of W. L. Valentine and "Adaptive Fuser Controller" in the name of Thomas J. Mooney, both applications assigned to the same assignee as the instant invention.
The following description emphasizes the features of the LDC LOGIC in 302 as well as the BASE LOGIC 300 which are particularly germane to the understanding of the Cycle-Out Logic 404 of the instant invention.
3. Timing Diagram Description
As may be seen by reference to FIGS. 5A-5E, the multi-mode copier/duplicator operation is divided into a plurality of time sequences in which different xerographic functions take place and different portions of the copy cycle are executed. The logic circuits utilized to control the xerographic functions are clock controlled and thus may be described in terms of the counter states of a Master Counter 318, Program Counter 316, and Fuser Counter 306A utilized to control machine parameters.
As an example to illustrate the counter state description used herein, consider the designation CT72M-SQ3 (FIG. 5C). This designation indicates that the Master Counter (M = Master Counter, P = Program Counter, F = Fuser Counter) has accumulated 72 clock pulses, and the designation refers to the counter signals which are decoded in the conventional manner by sampling the pertinent stages of the Master Counter. Also in the usual notation, "bar" is used to denote the logical inverse of the counter state; i.e., this particular signal will exhibit a low logic level (logical 0) on the accumulation of the 72nd clock pulse, when suitably decoded. The designation SQ3 denotes the third sequence in a particular operating mode. Note for example that FIGS. 5A and 5C show the LDC Mode of operation consisting of four distinct sequences. When a particular sequence is further conditioned by size of the copy paper cassette, the appropriate designation is appended to so indicate by the addition of /SC or /LC denoting Small Cassette or Large Cassette Modes respectively.
It is noted that the Large Document Copying Mode enables the document feeding means 30 to convey subsequently fed documents into the copier/duplicator. In this sense, both the LDC/LC (Large Document Copying/Large cassette) Mode as well as the LDC/SC (Large Document Copying/Small Cassette) Mode may be thought of as chain feeding modes of operation. In another sense, inasmuch as a second separate counter (the Program Counter) is utilized to run in parallel with the Master Counter, only in the LDC/SC Mode of operation, the main time saving advantages of the chain feeding copier/duplicator are most noticeable when utilizing the machine in the LDC/SC Mode. Thus, the LDC/SC Mode is often referred to as the chain feeding mode of operation.
FIGS. 5A and 5B show the LDC/SC timing diagram; FIGS. 5C and 5D show similar diagrams for the LDC/LC Mode of operation; and FIG. 5E shows a timing diagram for the BASE Mode of operation. By comparing these diagrams, it is seen that for all Large Document Copying Modes of operation, the following events occur: insertion of the document in the document feeding means 30 activates the Document Switches, turns on the charge corotron and resets the Master Counter 318. At CT13M, the Scan Latch is set which effectively means that a copy paper feeding solenoid is energized to initiate the copy paper feeding mechanism. (Scanning of the exposure lamp 21 is not needed in the LDC Mode as the fixed optical system is employed. However, the function of feeding the copy paper is controlled by the Scan Latch). At CT16M, the LDC Exposure Latch is set and the exposure lamp is turned on. At CT20M, the copy paper feed solenoid (via the Scan Latch) is deenergized and the Master Counter is reset. CT8M designates the point at which the Develop Latch is set initiating the development process in the development station. At CT141M-SQ2, the Coincidence Latch is set. The Coincidence Latch is set whenever the numbers of copies exposed is equal to the number of copies ordered by the operator on quantity dial 99. The Coincidence Latch will always be set at CT141M-SQ2 in the LDC Mode as all LDC Modes of operation are single copy modes. The Master Counter is also reset at coincidence. After coincidence, the remaining xerographic processes depend upon whether a small cassette or a large cassete is utilized.
For the LDC/SC Mode (FIGS. 5A and 5B) a second counter means, or Program Counter, is run in parallel with the Master Counter. At CT13M (CT13P), the LDC Exposure Latch is turned off which deactivates the exposure lamp. After CT13P, the states of the Master Counter are not utilized throughout Sequence 3 unless a chain feeding mode of operation is initiated by a subsequent feeding of a document by the document feeding means 30. Assuming no subsequent document is fed, only the Program Counter states are significant after CT13P in Sequence 3. The Development Latch within the BASE LOGIC 300 is turned off slightly before CT72P by the copy paper Trailing Edge Switch. The Trailing Edge Switch also initiates the clocking of still a third counter, the Fuser Counter which is utilized strictly to govern the fuser turn-off time period. At CT72P, the Fuser Counter is reset and full fuser turn-on is achieved. At CT80P, a motion sensing circuit is activated which senses the paper motion of the copy paper in its travel from the transfer station to the fuser station. At CT150P, the motion sensing circuit is deactivated. Between counts 150P and 158P, the billing process is activated and completed. If in fact no subsequent documents were fed into the document feeding means before CT158P, the Master Counter would also be at a state of 158M. In this event, the Master Counter is ready to proceed in controlling the power-down functions of Sequence 4. At CT256M-SQ4, the Program Counter is added in series with the Master Counter to provide a single counter having extended capabilities. (The Master Counter as well as the Program Counter are each eight bit counters). At CT1024 (M + P) the machine is powered down.
In the LDC/LC timing sequence, shown in FIGS. 5C and 5D, the Coincidence Latch also resets the Master Counter at CT141M-SQ2. Here, however, there is no second or Program Counter connected to run in parallel with the Master Counter. Thus, in Sequence 3 the fuser is turned on at CT72M, and the motion sensing circuit is activated during CT84M-CT148M. As different sizes of copy paper may be used in the large cassette in the LDC/LC Mode, the LDC LOGIC 302 interrogates the Trailing Edge Switch at CT157M-SQ3 to see if the copy paper is still being fed into the machine. If the copy paper has passed by the Trailing Edge Switch, the copy would be nominally less than 15 inches long (in the direction of copy paper travel through the machine). The billing functions are then started at CT157M-SQ3 and are complete (13) Master Counts later provided the original document has deactivated the Document switches. A Done Latch is reset at CT157M-SQ3 which enables the Exposure Latch to turn off the exposure lamp at CT13M after resetting of the Done Latch. The resetting of the Done Latch also serves to turn off the charge corotron and the Develop Latch.
If the document is still present at CT157M-SQ3, (document nominally greater than 15 inches), the Master Counter is reset and continues clocking into Sequence 4. The Done Latch is now reset by the Trailing Edge Switch, S3, which is deactivated when the copy paper trailing edge passes thereby. The Trailing Edge Switch also turns on the Fuser Counter. As the exact time at which the Trailing Edge Switch is deactivated depends on the size of copy paper used, an X indicates the appropriate Master Counter State as shown in Sequence 4 in FIG. 5C. Again, resetting the Done Latch turns off the Develop Latch and the charge corotron. At X + 13M, the LDC Exposure Latch is reset and the exposure lamp turned off. The Fuser is turned off at CT208F, and the Master Counter, extended by the series addition of the Program Counter continues to clock, shutting down power at 1536 (M + P). In the power-down sequence, the Program Counter does nothing more than extend the range of the Master Counter for power-down purposes, and a larger Master Counter would work as well. In this connection, the Master Counter is not "Free" to control a subsequently fed document until the end of the billing function whether that be at 157M-SQ3 + 13M or X + 13M. In the chain-feed mode of operation one essentially frees the Master Counter at a much earlier time in using the small cassete (FIG. 5A), by employing a second counter, the Program Counter, to control the motion sensing and billing functions. The chain feed control circuit essentially frees the Master Counter after exposure of the first document is complete. The time saved over the conventional LDC/LC Mode of operation is indicated in FIG. 5C with respect to documents less than and greater than 15 inches. A full description of the chain-feed operation is given in the concurrently filed application by W. L. Valentine entitled "Chain-Feed Control Logic for a Multi-Mode Copier/Duplicator".
In describing the Chain Feed Logic 400 and the LDC Logic 302, reference is made to the following tables wherein input and output connections are described.
In the BASE Mode of operation as shown in FIG. 5E, the Master Counter is reset and the exposure lamp is turned on in response to the operator pressing the PRINT button 53. At CT64M the charge corotron is turned on. At CT80M the Master Counter is reset and the scan solenoid is actuated thereby starting the scanning process for the optical elements 21 and 22 as well as the copy paper feeding mechanism. The Develop Latch is set at CT8M-SQ2 thereby starting the development process. If the operator is operating in a single copy run, having set the number 1 in the paper quantity dial 99, the Coincidence Latch is set at CT141M-SQ2, and the machine procedes immediately to CTOM-SQ4, the Master Counter being reset at coincidence. At CT52M-SQ4 the Develop Latch is reset and the developer is turned off. The fuser is turned on to full power at CT72M-SQ4 and the Fuser Counter clocks to CT184F before shutting off the fuser. In the BASE Mode of operation only the small paper cassette is utilized, and thus the fuser is turned on and off at fixed times in relation to other machine fuser times. Between CT84M-SQ4 and CT148M-SQ4 the copy paper motion sensing unit is activated and billing takes place between CT148M-SQ4 and CT157M-SQ4. The machine then enters Sequence 5, and powers-down at CT1024(M + P). If the operator orders more than one copy of a document original a multiple copy run takes place in the BASE Mode as indicated in Sequence 3 in FIG. 5E. The Coincidence Latch is then set only after the last copy of the multiple copy run. Upon setting the Coincidence Latch the machine enters Sequence 4 as in the single copy run case above.
4. Detailed Logic Description -- General
A detailed description of the LDC LOGIC 302 of FIGS. 6-11 is found in copending application Ser. No. 528,163, filed Nov. 29, 1974. The description set forth below emphasizes those features of the multi-mode copier electronics which are particularly germane to the Cycle-Out Control Circuit (FIG. 13) of the instant invention.
In describing the Cycle-out Logic 404 and the LDC Logic 302, reference is made to the following tables wherein input and output connections are described.
TABLE 2__________________________________________________________________________INPUTS LINES FROMBASE LOGIC TO LDC LOGIC(See FIGS. 6 and 9)__________________________________________________________________________DEVF This input provides the status of the Develop[LD2] Latch located in the BASE LOGIC; it exhibits a logical "O" to enable the developing means through multiplexer 122M.MAIN DRIVE This input provides the status of the Main Drive[LD3] Latch (not shown) in the BASE LOGIC; it exhibits a logical high when the main drive M is not running and logical "O" when it is running.SCAN This input from BASE LOGIC provides a Scan Signal[LD4] to the Scan Solenoid Mux 124M in the BASE Mode of operation. It is a logical "1" to activate the scanning means in the BASE Mode.EXPOF This input provides the status of the Base Expose[LD5] Latch located in the BASE LOGIC. It exhibits a logical "1" when enabling the exposure means.PAPSW This input provides the status of the paper[LD6] sensing switch. When sufficient copy paper is present it exhibits a logical "1".PRINT This input provides the status of the PRINT[LD7] Button 53 to the multiplexer 123M. During actuation of the PRINT Button 53, it exhibits a logical "O".CT 13M, 4M, This input refers to count signals correspondingetc. to 13, 4, etc. of the master counter, provided in[LD9, LD11] the form of a high or logical "1" signal.DEVF This input provides the status of the develop[LD10] Latch located in the BASE LOGIC. It is the inverse of DEVF mentioned above; thus when developer C actuating signals are provided by the Development Latch this goes to a logic "1" or high from logical "O".HOME SW This input provides the status of the Home Switch[LD12] S1. In the actuated state, i.e., when the scanning elements 21-22 are at the home position, it exhibits a logical signal "1".8M This signal is a binary signal from the Master[LD13] Counter which is high for eight counts and low for the next eight counts and so forth. It is used to provide a slight delay (8 counts) before actuation of the Scan Latch in mode changing operations.HOME SW This input provides the status of the Home Switch[LD14] S1. It is the inverse of the above i.e., when the scanning elements 21-22 have left the home position the Home Switch S1 is deactivated thereby providing a logical "1" signal via this line.INITIAL This input provides the initializing signals[LD15] developed in the BASE LOGIC. When INITIAL level is a logical "O", a power up sequence is occurring and this signal is used to initialize the elements contained in the LDC LOGIC.CHARGEF This input provides the status of the charge[LD16] Latch located in the BASE LOGIC. A logical "1" indicates the activation of the charging means E of the xerographic machine.COINF. DEVF. This input provides the composite status of theMPX two named latches. It exhibits a logical "1" when[LD17] the Coincidence Latch (COINF) is set and the Development Latch is not set. Both latches are located in the BASE LOGIC.COINF This is the Coincidence Signal from the BASESIGNAL LOGIC which is high at CT 141M whenever the[LD17a] copier/duplicator is in a single copy run (LDC Modes) or the last copy of a multiple copy run.PROG CLK This input provides a signal associated with the[LD18] incrementing of the Program Counter. It exhibits a logical "1" when the counter is being incremented; and reverts to a logical "O" upon termination of each incrementing signal. The Program Counter is used to keep track of the number of copies made in a Multiple Copy, BASE Mode run and is incremented at CT141M-SQ2.__________________________________________________________________________
TABLE 3__________________________________________________________________________OUTPUT LINES FROM LDC LOGIC(See FIGS. 8 and 11)__________________________________________________________________________ADD PAPER This output is applied to the ADD PAPER[00] indicator to advise as to a copy paper supply run out condition.COINF SET This output is applied to the Base Logic. It[01] goes to logical "O" setting the Coincidence latch in the Base Logic.LDC BILLING This output signal is applied to an LDC billing[02] meter, the details of which are shown in the above- mentioned copending application, Serial No. 393,545.EXPOF MPX This output from the multiplexer 121M is used to(PRINT actuate or energize the exposure means when theDISABLE) document original being scanned must be image[161] exposed on to a photoreceptor. This signal also disables the PRINT button in the BASE Mode oper- ation.DEVF-MPX This output from the multiplexer 122M controls[162] the developing means. With DEVF MPX of logical "1" the developing means is not on and when it switches to logical "O", the developing means is turned on.LDC DEV BIAS This output from the 110 123M is appliedRESET MPX to the Bias Latch (not shown) of the machine and[163] provides a normal bias level.SCAN MPX This output from the multiplexer 124M is used[164] to selectively energize the scanning solenoid means in the machine, as well as the copy paper feed solenoid.DONE-L This output signal signifies that the machine[04] has completed a copy cycle while operating in LCD Mode. It is fed to the Base Exposure Latch in BASE LOGIC 300.EXP MPX This output signal is applied to the exposure[165] means to selectively maintain it in a non-actuated state. It is also applied to the Base input of multiplexer 121M.MAIN DRIVE This output from the multiplexer 125M is usedMPX to enable the main drive M.[166]FUSER MPX This output from the multiplexer 127M is[334] applied to the Fuser Latch to selectively energize the fuser element.CHARGE MPX This output from the multiplexer 128M is applied[168] to the charging means to selectively energize the charge corotron.LDC This output signifies the operating mode of the[07] machine, it exhibits a logical "O" to denote LDC operation.LDC EXPOF This output, when a logical "O", resets the[08] BASE Mode Exposure Latch which normally controls the jam detection timing. Since the jam detection requirements of the LDC Mode are different from the BASE Mode, the Exposure Latch must be reset.DEV SET LDC This output, when a logical O, sets the Developer[09] Latch at the proper time in the LDC Mode, since this time is different than the time required for the BASE Mode. The BASE Mode signal is inhibited by the LDC output which is logical "O" when the machine is in the LDC Mode.LDC 13 + This output when a logical "O", sets theCOIN RESET Coincidence Latch at a count of 13 and Done Latch[010] set signifying that the machine is not processing a piece of copy paper. This output is used to set the Coincidence Latch to logical "1", thereby cycling out the machine if copy is not started.LDC MASTER This output, when logical "1", signifies that the -CTR CLR MASTER COUNTER is conditioned to count and when[012] logical "O", the counter is cleared and held at a count of zero.HOME + LDC These signals are actually LDC (the complement of[013] and LDC). They perform the function of disabling thePWR INIT HOME Switch LATCH (not shown) while in the LDC+LDC Mode and simulating a power initialize pulse when[014] the machine is changed from the BASE Mode to the LDC Mode.141 DISABLE This signal, when a logical "O", inhibits the[015] 60Hz clock signal to the Program Counter Latch once coincidence has been set.LDC EXT This signal, when a logical "O" is used to power-SHUT DN down the machine in the LDC/LC Mode. The output[016] provided represents a timing count in the Master Counter/Program Counter which extends the shutdown time (e.g., 26 seconds) from a shorter shut-down (e.g., 16 seconds) used in the BASE Mode.LDC ONE This output, when a logical "O" signifies thatSHOT CLR the One Shot 213 has been triggered and this[06] causes the resetting of the Master Counter.__________________________________________________________________________
TABLE 4__________________________________________________________________________SIGNAL EXCHANGE BETWEENLDC LOGIC AND CHAIN FEED LOGIC__________________________________________________________________________DEVF This signal comes from the "Q" node of theSIGNAL Develop Latch in the BASE LOGIC 300 and is used[L502,502a to condition the Scan Latch via NAND gate 502L506] and line L506 to be actuated only if the develop- ment function has terminated e.g., the DEVF signal is low. The signal is also passed along line L502a to reset the Coin Go Latch.LDC MODESWITCH This signal comes from the LDC Mode Switch viaSIGNAL the pull-up network 101A. It forms an enable[L504] to NAND gate 704 to set the LDC Mode Latch.LDC MODE This signal comes from AND gate 526 (FIG. 13)LATCH . JAMF and is high when the LDC Mode Latch is set and[L505] no jams exist.PROG CLK This signal is high, logical "1", for one clockSIGNAL pulse whenever there is a coincidence i.e. the[L508] Program Counter keeps track of the number of copies made in the BASE Mode multiple copy runs and is incremented once for all LDC Mode operations at CT141M. It is used to force coincidence in changing modes from BASE, multiple copy runs to LDC Mode.CT20M This signal is a low pulse at CT20M and is used[L510] to reset the Develop Simulate Latch.LDC MODELATCH This signal is high whenever the LDC Mode Latch[L512] is set.COINF SET In the LDC/SC Mode, this signal is fed to OR gate[LD18, L514] 504 to provide a negative going pulse at coin- cidence (CT141M-SQ2) which is used in connection with the resetting of the Done Latch and the setting of the Develop Simulate Latch.INITIAL This signal is fed to NAND gate 702 in the Cycle-[LD15, L516] Out Logic 404 to condition the LDC Mode Latch.FAILSAFE This signal initiates the failsafe timer whichTIMER times the scanning of the optical carriage from the[L518] Home Position to the End of Scan Position.LARGE This signal comes from the Large Cassette SwitchCASSETTE via pull-up network 101D. It is used to inhibitSWITCH SIGNAL the setting of the Chain Feed Latch in Large[356] Cassette modes.TRAILINGEDGE This signal is fed to OR gate 506 to conditionSWITCH SIGNAL the Develop Simulate Latch, and to NAND gate[342,342a] 550 to condition the Develop Latch.END OF SCAN This signal is low when the scanning carriage isSIGNAL at the End of Scan (EOS) Position and forces the[L520] resetting of the Done Latch until carriage reaches EOS.DONEF SIGNAL This signal is fed to NAND gate 524 to allow[L522] actuation of the Scan Latch for a second copy before completion of the development process of a first copy in a Chain Feed Mode of operation.DONE RESET This signal is used to reset the Done Latch at[L524] Coincidence in the LDC/SC Mode of operation.EOS . LDC This signal is fed to inverting gate 118 and is lowMODE whenever the carriage is at the EOS position and[L525] the LDC Mode Latch is set.LDC MODE LATCHSIGNAL This signal is low whenever the LDC Mode Latch[L526] is set. It is fed to NAND gate 216.LDC MODE LATCH This signal is low whenever the LDC Mode Latch is set. JAMF SIGNAL and no jams are present. It is fed to the "select"[330] or "C" terminals of the multiplexers 121M-128M.DONE . LDC This signal is used to reset the Develop LatchMODE when the Done Latch is reset in the LDC Mode[L528] via NAND gate 550.LDC MAS CTR This signal originates from NAND gate 712 when theCLR SIGNAL Coin Go Latch of the Cycle-Out Logic 404 is set to[L529, 012] force a coincidence and reset the Master Counter in mode changing operations.PAPER FEED This signal is used to inhibit the feeding of copyINHIBIT paper when the scanning carriage is not in theSIGNAL End of Scan position, and the LDC Mode Latch is[L540] set.WAIT SIGNAL This signal is used to energize the "wait" visual[L542] indication means 50 when the Done Latch is set or when the machine is in the LDC Mode but the scanning carriage is not at the End of Scan position. It is also energized when the paper supply is depleted.FUSERSIGNALS[L328a, These signals connect the Fuser Turn-On LogicL328b, Circuit 304 of the Adaptive Fuser Controller to370] the Fuser and Exposure multiplexers.__________________________________________________________________________
In the LDC LOGIC 302 shown in FIGS. 6-11, the gate and circuit designates remain the same as those in the above-mentioned copending application. Several simplifications have been made to the drawing, however for ease of understanding the instant Cycle-Out Logic Circuit. In particular, only pull-up circuit 101A has been shown in detail although all such circuits 101A, B, C, etc., are identical. In addition, the multiplexers have been indicated in block form only as they are all identical to the multiplexer shown in detail in FIG. 16A. Finally, the latches are shown in block form and are all identical to the latch shown in detail in FIG. 16A. Finally, the latches are shown in block form and are identical to the latch shown in detail in FIG. 16D. The latches are operated in the R/S (reset/set) mode, and for simplicity, the memory reset signal (MR) has not been drawn. The memory reset signal is supplied by the Initialization Circuit 320 in a conventional manner.
In general, key xerographic functions are controlled by actuating signals fed through the 2:1 multiplexers 121M-128M. The multiplexers are conditioned to pass through the logical equivalent of a selected input signal at terminal A or B depending upon whether the copier is in the LDC Mode or BASE Mode respectively. The C or select terminal (shown on multiplexers 121M and 128M) serve to select which input signal is fed to the multiplexer output. The signal feeding the select terminal comes from the LDC Mode Latch (FIG 13) via NAND gate 526, inverting gate 528 and line 330. A high signal, logical 1, indicates the LDC Mode. In incorporating the instant invention into the LDC LOGIC 302, a key difference in the instant circuit over that of the afore-mentioned copending application involves replacing the dependency of most logic components, particularly the mulfiplexers, from the LDC Mode Switch, S6, to the LDC Mode Latch. Other features of the LDC LOGIC 302 (FIGS 6-11) will become clear in connection with the description of the Cycle-Out Control Circuit described below.
BASE-to-LDC Mode Change
The LDC Mode Latch
In order to change the copier/duplicator from the BASE Mode to the LDC Mode, the operator moves lever arm 31 in a clockwise direction thereby actuating the LDC Mode Switch. Actuation of the LDC Mode Switch (from BASE to LDC Mode) removes the ground from pull-up network 101A so that a high input signal is applied to the a input of NAND gate 704 (FIG. 13) via lines L504 and L504a. Mode change does not automatically take place, however, as the b input to NAND gate 704 is controlled by the output of NAND gate 702. The output of NAND gate 702 must be high to feed a high signal to the b input of NAND gate 604 thereby setting the LDC Mode Latch. To obtain a high output from NAND gate 702 one or both of the inputs must be low. The a input is supplied by the EXP MUX signal via line 370 which is low whenever the exposure lamp is de-energized (LDC or BASE Mode). The b input to NAND gate 702 is the INITIAL Signal via the BASE LOGIC and lines LD15 and L516. The INITIAL Signal is low only during a power-up sequence and cannot be low during any BASE Mode exposure essentially because the EXP MUX signal is fed to the Print Disable MUX 121M which keeps the INITIAL Signal high during BASE Exposure (maintaining INITIAL high is equivalent to disabling the PRINT button). Thus, in all events, a low input to the a or b input of NAND gate 702 is supplied only if exposure is off, namely the EXP MUX Signal is low. This constraint essentially limits the setting of the LDC Mode Latch to Sequence 5 in the BASE Mode (FIG. 5E) when the exposure goes off. Inasmuch that the LDC Mode Latch controls the multiplexers 121M-128M which in turn control the key xerographic operation, the Cycle-Out Logic 404 essentially delays any BASE-to-LDC Mode Charge as initiated by the operator so that the logical mode change takes place in Sequence 5 of the BASE Mode. In practice, if the operator moves the lever 31 during a BASE Mode Exposure, the feeding head will physically move into the LDC position, but the machine electronics (multiplexers) will not be switched to the LDC Mode until Sequence 5 when the exposure goes off and the LDC Mode Latch is set. If the operator moves the lever 31 while exposure is off, and the machine is in standby, the Mode Change Switch S5 (roll-over switch, will be actuated and triggers the initialization circuit to supply a low INITIAL Signal.
The significance of delaying the mode change until Sequence 5 is readily seen in that one desires to finish key xerographic function of the copy in process, including the copy paper jam sensing and billing functions. The earliest time at which such key events are completed is CT157M-SQ4 when the BASE Exposure Latch is reset. The Fuser Counter is at this time already clocking and will independently turn-off the fuser at CT184F irrespective of any Master Counts resetting the LDC Mode Operations
Non-Last Copy Run
Assume now that the BASE Mode is in a Multiple Copy Run wherein several copies of a single document original are to be made and the copier/duplicator is not making the last copy. In this event it is desirable to get out of the multiple copy cycle at the earliest opportunity completing just the copy in process, but no additional copies. To achieve this end, the Cycle-Out Logic forces a coincidence at CT141-SQ3 regardless of how many copies are left to be made in the multiple copy run.
To force the coincidence, the operation, as before, moves the lever 31 into the LDC Mode thereby placing a high signal on line L504 via pull-up network 101A. The high signal is passed along lines L504 and L504b to an inverting gate 710 (FIG. 13) thereby feeding a low signal to the S mode of a CoinGo Latch. The D node of the CoinGO Latch is fed by the Develop Signal, DEVF, via lines L502 and L502a. DEVF is always high in Sequence 3 of the BASE Mode, and thus the CoinGO Latch will set whenever the LDC Mode Switch is actuated. The high Q output of the set CoinGO Latch is fed to a b input terminal of a NAND gate 712. The a input of NAND gate 712 is supplied with the high DEVF signal and the c input is fed by the PROG CLK Signal via lines L508. Thus, upon CT141M-SQ3, the PROG CLK high pulse drives the output of NAND gate 712 low, and the low signal is fed to the S node of the Coincidence Latch in BASE LOGIC 300. The Coincidence Latch is thereby set at CT141M-SQ3 even if additional copies were originally ordered by the operator (via dial 99) in the Multiple Copy Run of the BASE Mode of operation. The output of the CoinGO Latch also serves to reset the Master Counter via inverting gate 714 and lines L529 and 012. Thus, the Master Counter is reset and Sequence 4 of the Base Mode is entered. As before, the setting of the LDC Mode Latch, which marks the control logic entry into the LDC Mode, takes place at CT157M-SQ4.
Last Copy Run
If one is running in the single copy BASE Mode or the last copy of a Multiple Copy Run, the LDC Mode Latch is set at CT157M-SQ4 as coincidence will have been set at CT141M-SQ2 or SQ3. As before the delayed switch of the multiplexer 121M-128M permits key photographic functions to take place and allows copy paper jam sensing and billing to be achieved. In effect all Master Counter controlled functions must be completed before the logic is ready to switch to the LDC Mode, as the LDC Mode uses the Master Counter to control its operations.
Carriage Position
The operator may move the LDC lever 31 at any time during a BASE Mode operation. In order for the machine to be mechanically in the LDC mode, the scanning carriage or scanning elements 21 and 22 must be locked at the End of Scan position.
Assume first that the scanning carriage is not at the End of Scan position but is at the Home Position when the operator makes the BASE-to-LDC Mode Change. In reference to FIG. 9, pull-up network 101H supplies a high signal along line LD12 to the b input of NAND gate 116. The a input of NAND gate 116 is fed to a high signal from inverting gate 118 which receives a low signal from NAND gate 510. The two inputs to NAND gate 510 are both high as the machine is not in the End of Scan position (line L520 high), and the LDC Mode Switch is activated (NAND gate 704 output low and inverting gate 706 output high). The C input of NAND gate 116 is supplied with the binary 8M signal which is high for eight Master Counter Counts and low for the next eight counts, etc. Thus, no later than eight Master Counter clock pulses after the LDC Mode Switch is activated, NAND gate 116 exhibits a low output. This low output signal is fed to NOR gate 121 (FIG. 10) producing a high signal therefrom which is fed to the A input terminal (LDC input terminal) of the Scan Solenoid MUX 124M. The A input to the Scan Solenoid MUX 124M is only controlling if the LDC Mode Latch is set. In practice, during a BASE Mode run, End of Scan is reached approximately 14-20 Master Counter counts after coincidence (CT141-SQ2) and flyback is complete when the Home position is reached approximately 30-50 Master Counter counts after coincidence. Consequently, the scanning carriage remains in the Home position until the LDC Mode Latch is set. Upon setting the LDC Mode Latch, the high input to terminal A of multiplexer 124M produces a high SCAN MPX signal along line 164 to actuate the scan solenoid and bring the scanning carriage from the Home position to the End of Scan position. The scanning carriage is mechanically locked into the End of Scan position as is required for the fixed optical system of the LDC Mode of operation.
During the mode-change scanning operation, it is not desired to feed copy paper simultaneously with the carriage movement as is done in the BASE Mode. To inhibit such copy paper feeding, a low EOS . LDC Mode Switch Signal from NAND gate 104 via line L540a is fed to inverting gate 113 (FIG. 10), and a high signal is thereby fed to inhibit the actuation of copy feed solenoid II via line L540 (FIG. 14).
Once the carriage reaches the End of Scan position, it is mechanically locked into place. The End of Scan Switch is then actuated which produces a low EOS Signal at the output of pull-up network 101B. This low signal is fed to NAND gate 104 driving its output high. The high output is inverted by inverting gate 113 and the low output of inverting gate 113 allows copy paper feeding for subsequent settings of the Scan Latch.
If the scanning carriage is neither at the Home position nor at the End of Scan position during mode change, it must be scanning the document or in a flyback mode. In either event, a high signal is fed from pull-up network 101G to the b input of NAND gate 117. The a input of NAND gate 117 is fed by a high signal from inverting gate 118 which is fed by a low signal from NAND gate 510. A low signal from NAND gate 510 occurs if both its inputs are high. The a input to NAND gate 510 is high as this signal comes from the output of pull-up network 101B via line L520 which is high assuming the carriage is not at the End of Scan position. The b input to NAND gate 510 comes from the output of inverting gate 706 which is fed by NAND gate 704. In order to have NAND gate 704 deliver the requisite low output signal to inverting gate 706, both of its inputs must be high. The b input to NAND gate 704 is high as the LDC Mode Switch is in the LDC Mode position. The b input to NAND gate 704 is high as either the exposure is off EXP MUX signal low or the Initialization Signal is low e.g. one is initializing.
The two highs to NAND gate 117 drives its output low, and the low output is fed to NOR gate 190 driving its output high. The high output from NOR gate 190 is fed along line 012 to reset the Master Counter. In addition, the low output of NAND gate 117 is fed via line L518 to start the Failsafe timer 608. The failsafe timer is essentially an independent timer that resets the JAM Latch if the scanning carriage is off the Home or off the End of Scan position for longer than a preset time interval, i.e., 3-6 seconds. If there is no carriage malfunction, the carriage will reach either the End of Scan position and be mechanically locked in place or else the carriage will return to the Home position. If the carriage returns to the Home position the scanning solenoid will be actuated via NAND gate 116, NOR gate 121 Scan Solenoid Mux 124M as explained above.
LDC Mode-to-BASE Mode
If the operator moves lever 31 in a counterclockwise direction the feeding head is moved from the LDC Mode position to the BASE Mode position. It is desired to maintain the logic circuitry in the LDC Mode, however, until the machine is powered-down at the end of Sequence 4 (FIGS. 5A and 5C). This result is achieved by logically equating the change of the LDC Mode Switch from the LDC to the BASE Modes to the closure of the Document Switches indicating no document present. Thus, the output of AND gate 102a goes low upon a LDC-to-BASE Mode change and this low forces the output of NAND gate 211 high just as if the document had physically left the Document Switches S7 and/or S8. Note however, that the LDC Mode Latch is still set with its Q output high and thus the remaining logic functions are carried out as usual in the LDC Mode (e.g. FIGS. 5A-5D).
Certain modifications and improvements of the instant invention will be apparent to those of skill in the art and the claims are intended to cover all such modifications and improvements which do not depart from the spirit or scope of the invention.
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Apparatus and method for use in a multi-mode copier/duplicator for delaying mode changes in response to operator commands to permit vital copier/duplicator functions to be continued without interruption for the copy in process.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to semiconductor memories, and, in particular, to non-volatile, Erasable Programmable Read-Only Memory (EPROM), and Electrically Erasable and Programmable Read-Only Memory (EEPROM).
2. Prior Art
Metal Oxide Semiconductor (MOS) semiconductor memory devices, in particular, floating gate MOS transistor structures used as memory cells, are well-known in the art. In general, such devices operate by charging or discharging a floating gate, which floating gate then affects whether the device will easily conduct or will not easily conduct current from drain to source of the MOS transistor. The status of the floating gate as either electrically charged or discharged, which controls the conductance of the channel of the MOS device so that the device can be tested to identify a storage state, makes the device useful in the same fashion as other bi-stable data storage devices such as magnetic cores, flip-flops, and so forth. Memory arrays made of such devices are programmed to one state or the other depending upon the memory storage requirement for each particular cell. By choosing an appropriate convention for an EEPROM, a "0", for example, may be represented as the presence of conduction or, at least relatively high conduction through a cell, and a "1" as the absence of conduction, or relatively low conduction, through a cell, or vice-a-versa.
In EEPROM devices, two mechanisms are generally used for electrically charging or discharging the floating gate: Fowler-Nordheim tunneling and channel hot-electron injection. By Fowler-Nordheim tunneling, the floating gate is charged or discharged by use of a relatively high potential across a thin dielectric layer such as silicon dioxide, causing tunneling of electrons onto or out of the floating gate.
By applying suitable voltages to the gate, drain and source, channel hot electron injection can be made to occur when the channel is near pinch-off, causing an increase in the number of "hot" or high energy electrons, some of which have sufficient energy to transit the insulation layer barrier which separates the channel, from the floating gate. Charges on the floating gate remain after the programming conditions are removed due to the insulation layer such as silicon dioxide which surrounds it.
To make a useful device from the single memory cell which has been described, a plurality of such cells is arranged into rows and columns, groups of drains of memory cells generally being connected by lines called a "bitlines" and groups of gates of memory cells being connected by lines called "wordlines". Each individual cell within the array can be addressed, and its contents can be read-out, by applying appropriate signals to the selected bitline and wordline associated with that particular cell. When so addressed, the existence of charge (or its absence) on the floating gate is determined by interrogating the cell individually and sensing whether it is conductive or non-conductive between the source and the drain. In practical arrays, the individual bits are not read out singly, but are rather read out as bytes: groups of eight related bits.
The geometry of a conventional EPROM cell comprises a channel disposed between drain and source. Overlying the channel and isolated from it by a thin insulating layer is a floating gate. The floating gate is sandwiched between the channel and a select gate and isolated from them by insulating layers. A contact on the drain provides for connection to the bit-line. A wordline extends to each cell. A source line is common to a group of cells. Adjacent cells are isolated by thick field oxide. Such a cell requires space for the contact and the thick field oxide regions which occupy substantial, expensive "real estate" on the silicon substrate.
Recently, EPROM/EEPROM cells which do not require field oxide and contacts were reported. (See, for example, R. Kazerounian, et al.; IEDM Technical Digest Papers, paper 11.5.1, pp 311-314, (1991) or B. J. Woo, et al.; IEDM Technical Digest Papers, paper 5.1.1, pp 91-94, (1990). or Yoshimitsu Yamauchi:, et al; IEDM91, pp 319 to 322.)
Gill, U.S. Pat. No. 5,051,796, issued Sep. 24, 1991, describes buried bitline construction of memory arrays.
Such buried bitlines offer many improvements in construction over the earlier structures, and can provide a theoretically higher density than cells having contacts, in that the area occupied by the cell is reduced by the absence of the metallic contact. However, the buried bitline has high capacitance and, in particular, causes high drain-to-gate capacitance. This causes a reduction in the immunity of the cells to spurious signals which frequently occur during programming.
As memory storage size demands increase, the demands for miniaturization of each individual cell increase correspondingly, the goal being ever-expanding capacity in ever-decreasing physical size, while the cost per bit remains steady or, preferably, decreases. To increase the chip density, the individual cell size must be decreased through various methods such as eliminating contacts, replacing field oxide isolation by junction isolation, and the like. To further reduce cell size, the capacitance coupling ratio of the floating gate to the control gate must be increased, and the control and select methods must be made more reliable.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide a non-volatile semiconductor memory cell having improved size and density capability and high reliability through improved immunity to spurious signal during programming.
it is a further objective of the present invention to provide an improved non-volatile semiconductor memory cell having improved gate capacitance coupling ratio.
These and other objects of the present invention are accomplished by providing an improved design of a non-volatile semiconductor memory cell which has an improved cell structure.
In general terms, the device geometry is comprised of a semiconductor substrate of a first conduction type (P-type substrate), and two regions of a second conduction type (N-type) different from the first conduction type, which are separate from one another, formed on a principal surface of the substrate. Each of the second conduction type (N-type) regions can be used either as a source or as a drain of a transistor, depending upon the voltages applied to the regions.
In between any two adjacent second conduction type (N-type) regions is an associated channel region. A control gate, denominated the "control Y gate", is formed over an insulating dielectric layer on the principal surface of the substrate above a portion of the channel region and a portion of one of the second conduction type (N-type) regions. For explanation purposes, the region closest to the control Y gate is denominated a "source". The other conduction region is defined as a "drain". A floating gate is formed on an insulation layer above the control Y gate and the remainder of the channel that is not covered by the control Y gate, and extends over a portion of the other second conduction type (N-type) region. Another control gate, denominated "control X gate", is formed on an insulation layer above the floating gate and the second conduction type regions. Isolation between the source and drain regions not covered by the control X and Y gates, is accomplished by implanting ions of the first conduction type (P-type) to form a junction, or by relatively thick oxide isolation, or by oxide filled trench isolation.
The cell structure described has the following desirable characteristics: the gate capacitance coupling ratio is increased dramatically; memory cells are isolated from bit-line high voltage disturbances during programming because the control Y gates of unselected cells are at ground voltage; the cell array can be programmed or erased down to a single bit or byte level, rather than being limited to block level programming or erasure; the diffusion bit-line can be extended wider whenever voltage is applied to the control Y gate, so that the diffusion bit-line resistance is greatly reduced. These multiple attributes are the direct result of the unique cell geometry of the present invention.
The above, the other, features and advantages of the present invention will be set forth more completely in the description of the preferred embodiment, including the following drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a top plan view of a non-volatile memory cell in accordance with the preferred embodiment of present invention.
FIG. 2 is a cross-sectional view taken along line 3--3 of FIG. 1.
FIG. 3 is a cross-sectional view along line 3--3 of FIG. 1.
FIG. 4 is a schematic diagram showing the arrangement of the memory cells in accordance with the preferred embodiment of the present invention within an array.
FIG. 5 is a table illustrating the particular voltage which would appear at the various elements of a memory cell or array of cells in accordance with the present invention during the various operations.
FIG. 6a is a top plan view of a non-volatile memory cell used in prior art EPROM/EEPROM device.
FIG. 6b is a cross-sectional view taken along line 6b--6b of FIG. 6a.
FIG. 6c is a cross-sectional view taken along line 6c--6c of FIG. 6a.
FIG. 7a is a top plan view of the array of FIG. 4, in accordance with the present invention.
FIG. 7a is a cross-sectional view taken along line 7b--7b of FIG. 7a.
FIG. 7c is a cross-sectional view taken along line 7c--7c of FIG. 7a.
FIGS. 8a-8d are sequential drawings showing the top plan view of the fabrication steps at various stages of the process of the preferred embodiment of the present invention.
FIGS. 8e-8f are sequential drawings showing the cross-sectional views corresponding to FIGS. 8a-8d, respectively, of the fabrication steps at various stages of the process of the preferred embodiment of the present invention.
FIG. 9, is a schematic depiction of the equivalent circuit of a memory cell in accordance with the preferred embodiment of the present invention.
FIG. 10a is a simplified cross-sectional view of the memory cell's arrangement in a cell array in accordance with the present invention, showing a mirror image arrangement of the floating gates of adjacent cells, a variation on the preferred embodiment.
FIG. 10b is a simplified cross-sectional view of the memory cell's arrangement in a cell array in accordance with the present invention, showing a floating gate structure which overlaps the control Y gate, a variation on the preferred embodiment.
FIG. 10c is a simplified cross-section view of the memory cell's arrangement in a cell array in accordance with the present invention, showing a mirror image arrangement of a floating gate like that of FIG. 10b.
FIG. 10d is a simplified cross-sectional view of the memory cell's arrangement in a cell array in accordance with the present invention, showing an arrangement in which the floating gate surrounds and the control gate and the cells are mirror-images of one another, symmetrical about the control Y gate.
DESCRIPTION OF THE PREFERRED EMBODIMENT
In FIGS. 1, 2 and 3, the geometry of a memory cell in accordance with the preferred embodiment the present invention is shown. The structure and function of the cells is best understood by first referring to the structure of the prior art EPROM/EEPROM cells, an example of which is shown in FIG. 6. The various regions of both of the cells are formed in a manner which is well-known in the art. However, due to the new geometry of the present device, a memory array of greater density, and more programming flexibility than the prior art devices is possible.
Prior Art EPROM/EEPROM Cell
Considering first, for comparison, the conventional EPROM/EEPROM cell, the geometry of such a cell 61 is shown in FIGS. 6a, 6b and 6c. In the figures, a channel 68 is disposed between drain 63 and source 65. Overlaying the channel, but isolated from it by a thin insulating layer 69 is a floating gate 66. Above the floating gate 66, and similarly isolated from it by an insulating layer 70 is a select gate 64. Metallic contact 62 on the drain 63 provides for connection to a "bitline". A wordline 64 extends to each cell. Field oxide 67 is used to isolate one cell from another. When appropriate signals are applied to the wordline 64 and bitline 71 connected to contact 62 of the cell, current flow can occur between drain 63 and source 65, provided the floating gate 66 is not charged with an excess of electrons.
Such a cell works well, but is not optimally small because of the need for the metallic contact 62 and thick field oxide 67 which is used for isolation.
EPROM/EEPROM Cell of Present Invention
The geometry of the EEPROM memory cell of the present invention is shown in FIG. 1. FIGS. 2 and 3 are cross-sectional views taken along line 2--2 and line 3--3, respectively, of FIG. 1.
Each individual cell which may be used to make up an array; comprises two N+ diffusion regions source-drain 6, a control X gate 10, a floating gate 9 and a control Y gate 8. As shown in FIG. 1, control X gate 10 and control Y gate 8 are generally elongated in shape and are disposed on the top of semiconductor substrate 5 generally perpendicular to each other.
Any given N+ region along a bitline may serve at one time as the source of one line of transistors and at another time as the drain of adjacent transistors, hence the term "source-drain". In FIGS. 1, 2 and 3, source-drain 6s is denominated the "source" while source-drain 6d is denominated the "drain" on any given cell under consideration. However, the function of the source-drain 6 depends upon the voltages applied to the individual cell.
The cell is constructed on a semiconductor substrate 5, typically a P-type silicon substrate if the cell is to be a N-channel device. The N+ diffusion regions 6s and 6d are heavily doped to provide conductance. Between the N+ regions 6s and 6d is the channel region 7. Constructed in an array, the N+ regions are preferably linear and parallel to one another. Moreover, all source-drains placed on a given line, are connected to one another and form the bitlines of each cell of the array. Since the P- substrate also occupies the area between cells, it creates, if uncorrected, an unwanted channel between the source 6s of one cell and the drain 6d of another cell which is adjacent to the first cell on the same bitline. Conduction could occur between cells through this unwanted channel when the cell elements are at certain potentials. To prevent such unwanted conduction, adjacent cells are isolated from one another by a P+ isolation region 11 which is formed between adjacent cells in the region next to the drain, as is described below and shown in FIG. 3 which is a cross-sectional view taken along line 3--3 of FIG. 1. Cell to cell isolations are also shown in FIG. 7c which is the cross-sectional view taken along line 7c--7c of FIG. 7a.
Disposed between the source 6s and drain 6d is the channel 7. The control Y gate 8, the floating gate 9, and the control X gate 10 are dielectrically separated from and formed over the surface of the substrate, overlapping the source 6s, the drain 6d and the channel 7 as described in detail in the process stages below. Each gate is dielectrical separated from the other and from the source 6s and drain 6d by insulating layers, such as silicon dioxide films. The insulating film between floating gate 9 and channel 7 is the thinner tunneling region 19 in the vicinity of the drain side of the channel. Although the N+-type regions are denominated "source-drain", for any given cell the function as source or drain is clear. For the cell under consideration, the drain 6d is the N+ region adjacent to the tunneling region 19 of the first dielectric layer 20. That same N+-type region, when considered as a part of the next cell of the array functions as the source 6s for that cell.
The floating gate 9 extends at least partially over the control Y gate 8 and the channel 7, and at least partially over the drain 6d, and may have a tunneling area 25 which extends into the tunneling region 19 of the oxide layer 20.
First insulating layer 18 includes a tunneling region 19 which has a thinner thickness. First insulating layer 18 can be an oxide film. A second insulating layer 24, an oxide film in this case, typically covers the control Y gate 8. A third insulating layer 26, also an oxide film in this case, covers the floating gate 9.
The insulating films formed between each of the gates 8, 9, and 10 and the silicon substrate have a thickness of, for example, about 500 angstroms. The thickness of the thin tunneling region 19 is, for example, about 100 angstroms.
The capacitances between the elements of the cell are of paramount importance. If the capacitance ratios are unfavorable, the cell will be difficult to program and susceptible to disturbances. However, if the capacitance ratios are favorable, these effects are ameliorated.
In FIG. 2, the capacitances are depicted as lumped constant elements, although it will be appreciated that they are actually distributed constants. They are labeled in accordance with the following conventions:
Capacitor C x 27 is the capacitance of the floating gate 9 of the cell with respect to the control X gate 10.
Capacitor C y 28 is the capacitance of the floating gate 9 of the cell with respect to the control Y gate 8.
Capacitor C b 29 is the capacitance of the floating gate 9 of the cell with respect to the substrate 5.
Capacitor C d 30 is the capacitance of the floating gate 9 of the cell with respect to the drain 6d.
For these distributed capacitances, the relative effect of each can be described in terms of capacitance ratios K x , K y , K b and K d respectively. ##EQU1##
These ratios have an effect on the voltage V f to which the floating gate 9 is driven in the absence of hot-electron or Fowler-Nordheim Tunneling current flow as follows:
V.sub.f =K.sub.x V.sub.x +K.sub.y V.sub.y +K.sub.b V.sub.b +K.sub.d V.sub.d
where V x , V y , V b , V d are the voltages applied to control X gate, control Y gate, substrate and the drain of this cell respectively.
From comparing the equation to the figures, it can be seen that the terms relating to C y are absent from a conventional cell. Consequently, the memory cell of the present invention is improved by the amount of the C y terms.
It is desired for maximum capacitance coupling that the K x ratio and the K y ratio be large and that the K b and K d ratios be small.
Conduction between the drain 6d and source 6s through the channel 7 is controlled by the status of the gates 8, 9 and 10. Although the cell is described herein as conducting or non-conducting, it will be appreciated by those skilled in the art that even when "non-conducting" some current flow through the cell occurs, and that when "conducting" some resistance to conduction exits in the channel. Discrimination between the two conditions of being programmed or erased therefore is a matter of relative conduction values, not a matter of absolute presence or absence of conduction.
Referring now to FIG. 9, a schematic depiction of the cell shows how, in effect, the device functions as two series transistors. In the figure, the cell has been functionally divided into two transistors, 91 and 92. The same partition is also shown in FIG. 2 with parenthesis. The first equivalent transistor 91 is comprised of the source-drain 6s, which functions as the source, the source-drain 6d, which functions as a drain, the floating gate 9, and the control Y gate 8. The first equivalent transistor 91 is primarily controlled by control Y gate 8. The second equivalent transistor 92 is comprised of the source-drain 6s, which functions as the source, the source-drain 6d, which functions as a drain, and the floating gate 9. The second equivalent transistor is primarily controlled by control X gate 10 and floating gate 9. The interconnect point 93 between the two transistors 91 and 92 physically resides in channel 7 shown in FIG. 2 and is included in the figure for the sake of illustration.
Since the equivalent circuit depicts two transistors in series, control Y gate 8 can cause a blockage of conduction through the channel, regardless of the status of the floating gate 9.
Of course, if the cell is programmed by negatively charging the floating gate 9, then the effect of the control X gates 10 is obscured by the charge on the floating gate 9 itself. That is to say, the floating gate charge will cause the cell to appear to be non-conducting even when the control Y gate 8 and control X gate 10 enable the cell for read-out. If the cell is erased, the cell will be conducting when control Y gate 8 and control X gate 10 enable the cell for read-out.
Array Schematic
To be useful as a practical device, the single cell memory elements must be organized into an array having the capability of being programmed. Typically, the array is organized into a matrix rows and columns.
The electrical diagram of such an array is shown in FIG. 4. Although only nine complete cells are shown by way of illustration, it will be appreciated that the number of cells may be increased substantially.
The advantages of the new cell technology are illustrated by the array. Control lines CL x apply control potentials to control X gates 10 while control lines CL y apply control potentials to the control Y gate 8. As discussed above, the cell which is selected by the intersection of the control lines will conduct or not conduct indicating whether the floating gate 9 is not charged or charged, and therefore whether the cell is erased or programmed.
To read out any cell, moderate voltages, specifically voltages below the programming potentials, are applied to control Y gates 8 and control X gate 10 through control lines CL y and CL x , respectively. If the cell is to be erased, i.e., programmed for conduction, modest potentials on the bitlines, for example +2 volts, will cause a current to flow in the cell so addressed. If the cell is programmed to not conduct, then no current, or at least a relatively low current, will flow. By appropriate programming of all of the cells, the desired digital storage pattern is established in the array.
Operating Potentials
The applied potentials for erasing, and programming information into, and reading information out of a cell are described in FIG. 5.
Fowler-Nordheim tunneling occurs when the potential of the floating gate is great enough to cause the required high-field intensity across thin dielectric layer (100 Angstroms of silicon dioxide) in the vicinity of the drain. Under this condition, electrons are tunneled into or out of the floating gate, causing the potential of the floating gate 9 to change.
Hot-electron injection occurs when electrons achieve a high-enough energy level to migrate across the insulating layer barrier, in region 23 (part of layer 20 near thin layer 19) and 19 onto the floating gate 9. These "hot" electrons are produced when a moderate potential of +6 volts is applied across the drain 6d with respect to the source 6s. A high potential of +12 volts is applied to the control X gate 10, and +2 volts is applied to control Y gate 8 (See FIG. 5 "Program 2").
FIG. 5 shows the condition of applied voltages required for the four operating modes: "ERASE", "PROGRAM 1", "PROGRAM 2" and "READ". Each of the modes will be described seriatim.
"Erase" means the withdrawal of electrons from the floating gate so that the gate is positively charged, causing the threshold voltage of the MOS transistor to be low.
"Program" means the injection of surplus electrons into the floating gate 9 so that the gate is negatively charged, causing the threshold voltage of the MOS transistor to be high.
Fowler-Nordheim tunneling can occur in either direction producing either negative or positive charges in the floating gate 9. These two modes are depicted in FIG. 5, as the ERASE and PROGRAM 1 modes.
PROGRAM 2 describes programming the cell to have a high threshold voltage by hot-electron injection causing the floating gate 9 negatively charged.
Erase
Data is erased when electrons are extracted out of the floating gate 9. Electrons are extracted when a negative voltage, typically -20 volts with respect to the source 6s, and drain 6d is applied to the control Y gate 8, and the control X gate 10 and zero volts applied to source-drain and substrate. The positively charged floating gate 9 then assists the conduction of the channel. Thus, conduction will occur through the channel 7 during read operations.
Program Modes
Information may be programmed into the cell by two distinct program modes, the first, "PROGRAM 1", involving Fowler-Nordheim tunneling, the second, "PROGRAM 2", involving channel hot-electron injection.
Program 1
When information is programmed into the cell using the first mode PROGRAM 1, Fowler-Nordheim tunneling is employed. A positive voltage, typically +20 volts with respect to the source 6s, is applied to the control Y gate 8, and to the control X gate 10. Under these conditions, electrons are tunneled into the floating gate by Fowler-Nordheim tunneling through the thin dielectric oxide 19.
Program 2
By applying +12 volts to the control X gate 10, 2 volts to the control Y gate 8, and 5 volts to the drain 6d, hot electrons are created, some of which electrons have sufficient energy to transit the insulation layer 19 and 23 and are injected into floating gate 9.
Read
When information is desired to be read out from the cell, a positive voltage of, for example, +5 volts, with respect to the source 6s, is applied to both control Y gate 8, and the control X gate 10, and +2 volts to the drain 6d. If the previous condition of the cell was an erase condition, then there would be an electrical current flow from the drain 6d to the source 6s. If the cell is programmed there would be no current from the drain 6d to the source 6s.
Since the presence or absence of current flowing between source 6s and drain 6d indicates whether the floating gate of the cell was charged or discharged. The cell can be said to have "stored" the information that was applied to it.
Process Steps
Referring now to FIGS. 7 and 8, a representative set of process steps is shown, by which cells and arrays of cells in accordance with present invention may be fabricated.
FIG. 7a shows in plan view of a completed array, and FIGS. 7b and 7c are cross-sectional views taken along lines 7b--7b and 7c--7c, respectively, of FIG. 7a. Control Y gate 8 of each of the cells are connected together. Similarly, control X gate 10 of each of the cells are connected together. Control Y gate 8 and control X gate 10 are dielectrically separated from each other and in this embodiment, disposed atop the semiconductor substrate 5 perpendicular to each other.
FIG. 8 shows, in sequence, the procedure for fabricating the arrays.
For the example, an N-channel device, is described. However, it will be understood by those skilled in the art, that the principles described can be applied to materials of other polarities.
In FIGS. 8a and 8e the starting semiconductor material is P-type silicon substrate. A layer of gate insulation oxide is grown approximately 500 Angstroms thick.
In FIGS. 8b and 8f a first polysilicon deposition layer having a thickness of approximately 4500 Angstroms is deposited on the gate insulation layer 20. The polysilicon is doped to a 4Ω resistance. Then is masked and etched to from the control Y gate 8 shown. An insulation layer 24 is then formed over the control Y gates 8 and the surface of silicon substrate. In the case of EEPROM the tunnel region 19, may then be masked and etched. Approximately 100 Angstroms of tunnel oxide is grown.
Referring now to FIGS. 8c and 8g, the second polysilicon layer is deposited having a thickness of approximately 2500 Angstroms. The second polysilicon layer is then doped, to a 7Ω resistance followed by conventional masking and etching steps to form the floating gate.
The source-drain 6 region is then implanted with arsenic ions to give the region N+ characteristics. An insulation layer 26, such as silicon oxide or oxide-nitride-oxide (ONO) is applied.
In FIGS. 8d and 8h, a third polysilicon and silicide layer, having a total thickness of approximately 4500 Angstroms, is deposited. The layer has a resistance of approximately 4Ω. The layer is then masked and etched to form the control X gate 10.
A self-aligned etching step is then performed to etch off unwanted second polysilicon to form individual floating gate 9 for each memory cell.
Finally, P+ regions 11 are formed by implantation of boron ions in order to isolate adjacent cells from one another. (See FIG. 3, and FIG. 7)
Process steps related to peripheral are well known in the art and circuits are not included here. Steps described above may also be done in a different sequence, because of the requirements of the peripheral circuitry.
Improvements of the Present Invention
The memory cell according to the present invention has clear advantages over the prior art.
The geometry of the present invention is a one transistor geometry, and is "contactless". That is to say, not every cell requires a physical electrical metallic contact which must be wired to other cells typically by a metalization step. In practical arrays, the use of more than a certain number of cells connected to a diffused bitline becomes unworkable because of resistance in the bitline (which has to connect to the largest number of cells). To lower the bitline resistance, the usual solution is to divide it into segments of, for example, sixteen-bit lengths having contacts in the center of the segment, which contacts are then wired together by low resistance conductors. To make the bitline broader by using higher applied potentials is another approach to reducing bitline resistance, but at a certain point, this becomes impractical due to the interference with adjacent cells which this entails.
However, the control Y gate 8 of the present invention allows the bitline to become wider whenever voltage is applied to the control Y gate 8, thereby reducing the bitline resistance and effectively allowing more cells to be connected by the diffused bitline.
The coupling ratio of the floating gate voltage to the control gate voltage is greatly increased over the conventional cell, due to the fact that the floating gate is dielectrically sandwiched between the control X and Y gates 10 and 8.
Instead of being programmable or erasable in blocks or bytes, the present invention can be programmed, erased, or read out down to a single bit level because control X and Y gates, 10 and 8 can select the particular cell to be programmed or erased. The cell selected is the cell under the intersection of the energized control X and Y gates 10 and 8.
Variations of the Preferred Embodiment
In FIGS. 10a to 10c, embodiments of the present invention are depicted. In FIG. 10a, the floating gates are arranged as mirror-images of one another. In FIG. 10b, the floating gate 9 surrounds the control Y gate 8. In FIG. 10c, the cells of FIG. 10b are arranged as mirror-images. The floating gate is symmetrical with respect to the source, as in FIG. 10a and the floating gate surrounds the control Y gate 8 as in FIG. 10b. In FIG. 10d, the floating gate 9 surrounds and is symmetrical to control Y gate 8, and the cells are arranged as mirror images with respect to one another. These and other arrangements of the elements of the cell are useful in some applications.
Although particular embodiments have been described, it will be appreciated by those skilled in the art that the present invention is not limited merely to those embodiments shown. Many variations and modifications can be made without departure from the spirit of the present invention. For example the materials, the particular shapes, and the arrangement of the gates 8, 9, and 10 can be changed from those which are specifically illustrated. Moreover, the semiconductor materials may be formed of opposite materials (P-type substituted for N-type, and vice versa) when a different polarity device is desired. Accordingly, the preferred form and particularity of the present invention as described may be undertaken without departure from the scope of the invention which is defined only by the claims which follow.
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A non-volatile semiconductor memory cell comprises a P-type semiconductor substrate (5) and N+ diffusion regions (6) spaced apart from each other on the principal surface of a P-type substrate (5). Each N+ diffusion region (6) can be used as source or drain of a transistor. Between any two adjacent N+ diffusion regions and under the gates is located the channel region (7). A control Y gate (8) is formed on an insulation layer above a portion of the channel and extends over a portion of N+ diffusion region (6). A floating gate (9) is formed on an insulation layer above the control Y gate (8) and the rest of the channel, and extends over a portion of another N+ diffusion region (6). A control X gate (10) is formed on an insulation layer above the floating gate (9) and N+ diffusion regions (6). Isolation between N+ diffusions (6), not covered by the control X gate (10), is provided by P+ diffusion regions (11) diffused into the substrate between each cell and its adjacent cells, or by oxide filled trench, or by relatively thick field oxide. The resulting structures are reliable contactless EPROM's or EEPROM's.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates, in general, to magnetic tape head assemblies for use in conjunction with magnetic contact recording media, and more particularly to a tape head with a transducer support assembly with protective edges, i.e., at the leading and trailing edges, adjacent the core to create an increased height or radius adjacent the core and read/write gap to enhance air removal and to provide wear protection for the softer core materials during high speed operations with a number of recording media or tape having varying stiffness.
2. Relevant Background
Magnetic head assemblies typically contain one or more raised strips or supports that have surfaces over which the magnetic recording media, e.g., tape, passes. Embedded in each support surface is a transducer which may be a recording transducer (i.e. recording or writing head) for writing information (i.e., bits of data) onto the media or a reproducing transducer (i.e., reproducing or reading head) for reading information from the media. An embedded recording transducer produces a magnetic field in the vicinity of a small gap in the core of the recording transducer that causes information to be stored on the magnetic media as it streams across the support surface. In contrast, a reproducing transducer detects a magnetic field near the surface of the magnetic media in the vicinity of a small gap as the media streams over the support surface.
There is typically some microscopic separation between the gap of the transducer core and the recording media. During operation, this separation must be tightly monitored and controlled to avoid or minimize “spacing loss.” The separation reduces the magnetic field coupling between the recording transducer and the media during writing and between the media and the reproducing transducer during reading. The magnetic field coupling decreases exponentially both with respect to increases in the separation between the media and the support and with respect to increases in the recording density. The amount of media area required to store a bit of data is a factor in determining recording density and as less media area is required to store a bit of data, the recording density increases. Thus, while a higher, more easily obtainable amount of head-to-media separation may be acceptable at low recording densities, the growing demand for higher recording densities has led to the need for tighter control over the head-to-media separation that can be tolerated to obtain useful levels of magnetic coupling.
To control spacing loss, a tension is applied to the tape as the tape passes at a wrap angle around a support surface and an adjacent transducer core surface each having a height and a width. Due to this tension, the tape exerts a pressure against the support surface, and if the support surface and core surface have uniform widths and heights, the pressure is substantially uniform along a longitudinal axis of the support. The pressure is essentially proportional to the tension and the wrap angle and inversely proportional to the support width.
In some tape head assembly designs, the pressure is intentionally increased to control spacing loss. For example, the pressure can be increased by increasing the tension in the tape, by modifying the wrap angle of the tape on the support surface, and/or by modifying the width of the support surface. However, increased pressure is accompanied by negative consequences including reduced tape life, increased possibility of tape damage and data loss, and support and core surface wear leading to a shortened head life. Moreover, increased pressure can result in uneven wear along the support surface, which can be particularly troublesome between regions of the support and the transducer core. As can be appreciated, increased and uneven wear rates become more serious problems as operational speeds for magnetic head assemblies are increased.
Operational problems with head wear and uneven wear have recently grown with the use of magnetic media having varying stiffness. For example, a magnetic head assembly may be used to read and write to a magnetic tape with a given stiffness that causes the magnetic tape to have a corresponding natural radius and contours. The support surfaces and core typically will wear to fit better this radius and natural contours of the tape. When the magnetic head assembly is then used with a magnetic tape having a different stiffness, e.g., a higher stiffness tape, a larger and sometimes unacceptable separation distance may initially exist until again the magnetic media is worn or broken in to match the new tape stiffness. Hence, there is a need for a magnetic head assembly that address the need for wear control that is also useful for magnetic media of varying stiffness.
Several magnetic head assembly designs have been developed in attempt to address these wear problems. In many tape head assembly designs, the pressure at the core is increased to enhance magnetic coupling by providing an elongated support assembly in which the width of the core and adjacent surfaces is less than the width of the adjacent elongated support surfaces. This smaller width makes the pressure applied non-uniform along the longitudinal axis of the support with higher pressure being applied at the core area and providing a better contact area. Unfortunately, this head design often results in higher wear rates at the core area that may lead to uneven wear within the support assembly. In some cases, higher core wear rates and pressures have been addressed with the use of wear resistant materials for the core center and/or in the adjacent supporting surfaces that are either parallel to the travel path of the media over the core or on all sides of the core.
In a different design approach, the support area near the core is made wider than the adjacent elongated support surfaces to obtain a softer or lower pressure mating of core and magnetic media. Wider core area designs are described in detail in U.S. Pat. Nos. 5,426,551 and 5,475,533 to Saliba, which are both incorporated herein by reference. The wider support surface near the core results in less pressure being applied at the core which is beneficial in controlling uneven wear. The wear rate is further controlled by providing wear surfaces of glass or other nonmagnetic material adjacent the magnetic ferrite core positioned parallel to the travel path of magnetic media. The wear rate is self-regulated to be relatively uniform along the longitudinal axis of the support assembly because the pressure is less than on the elongated support surfaces that are fabricated of a more wear resistant material. While addressing some industry problems, these wider core area devices tend to function well initially but then also develop problems of uneven wear on support surfaces and of core wear as the entire support assembly experiences wear. Additionally, the height of the core and adjacent wear surfaces typically are selected for a particular media and media thickness and experience wear that makes the device better suited for continued use with that media rather than for several media with varying stiffnesses.
Additionally, air flowing under the magnetic media during higher speed operations can cause spacing losses, and airflow needs to be addressed during magnetic head assembly design. During operation, air is moved within the magnetic head assembly as the magnetic media rapidly advances across the surfaces of the assembly facing and supporting the magnetic media, such as the support surface and the core. Spacing losses can develop when the flowing air passes between the core and read/write gap and the magnetic media. In the narrower core area devices, air tends to be channeled over the core because it first strikes the wider adjoining support surfaces and then is forced into the narrower core area. The wider core area devices provide better airflow control with the air first striking the wider core area and being channeled away towards the adjacent, narrower support areas where reading and/or writing is not occurring. However, for both types of head assemblies, the use of numerous magnetic media with differing stiffness often results in airflow problems that result in spacing losses. Also, over the lifetime of the head assemblies, wear (and particularly, uneven wear) often results in changing airflow paths that can lead to airflow problems even in devices that initially functioned effectively.
Hence, there remains a need for a magnetic head assembly that better controls airflow over a magnetic core and provides enhanced wear control in surfaces contacting the magnetic media, which may have varying stiffness.
SUMMARY OF THE INVENTION
The present invention addresses the above discussed and additional problems by providing a wider core area design for a transducer support assembly that controls uneven wear problems while also providing improved airflow control to limit spacing losses (e.g., to minimize “floating” separation). The inventor recognizes that the use of a wider core area relative to narrower adjacent, elongated support surfaces often results in the contact pressure applied by the media, e.g., magnetic recording tape, being concentrated at the edges of the wider core area, i.e., core support. Hence, as the tape passes over the transducer support assembly, the edges (note, both edges act as leading and trailing edges depending on the direction of travel of the media) are worn down at a faster rate, which can cause airflow problems and spacing losses.
To address this problem that is generally unique to wider core area designs in tape head assemblies, the core support is initially manufactured to include wear surfaces of a harder, more wear-resistant material at the two leading/trailing edges to extend the useable life of tape head assemblies. In a preferred embodiment, the wear-resistant edge members are raised (or, alternatively, the edge members may initially be coplanar with softer adjacent wear surfaces and allowed to become raised due to wear occurring in an initial break-in wear period) to provide a larger height than the core. After a break in or initial wear period the edge members and core contact surfaces become generally arcuate in cross-section with the initially larger radius of the edge members controlling wear on core. In operation, the arcuate surfaces typically form a single continuous curved surface with a single radius that contacts the recording media. Having an edge member that always has a larger or equal radius to the adjacent core surface is especially beneficial for high speed operations as it better directs airflow (e.g., strips away air being moved with the tape from the core area) and protects the transducer core from wear.
More particularly, a magnetic head is provided for writing to and reading from magnetic recording media, such as tapes of varying stiffness. The head includes first and second elongated supports spaced apart on a facing surface and having support surfaces extending along a longitudinal axis. During operation, the magnetic recording media travels transversely across the support surfaces applying a contact pressure. A core support is positioned between the two elongated supports. The core support has a width as measured perpendicularly to the longitudinal axis of the support surfaces that is greater than the widths of the support surfaces thus creating a nonuniform pressure distribution along the longitudinal axis (e.g., when contact surfaces are coplanar or the same radius, greater pressure is applied on the narrower support surfaces).
The core support includes a transducer core with an elongated contact surface positioned to extend transverse to the longitudinal axis of the support surfaces. An edge member is positioned adjacent the contact surface of the transducer core to control wear and direct airflow. In this regard, the edge member includes a wear surface for contacting the media that is fabricated of a material, such as aluminum titanium carbide or zirconium, that is harder and has a greater wear resistance than the transducer core. In a preferred embodiment, a second edge member is provided on the opposite side of the contact surface of the transducer core to accommodate multiple tape travel directions. After initial fabrication, the wear surfaces of the edge members are substantially coplanar and raised relative to the contact surface of the transducer core and the support surfaces. Additionally, the contact surface itself may be raised relative to the support surfaces with these two surfaces have similar hardness and wear resistance characteristics (e.g., both surfaces may be magnetic ferrite or the like). In this manner, the magnetic head provides self-regulating wear regions that adjust to distribute the contact pressure and wear such that the wear surfaces of the edge members are generally raised relative to the contact surface of the transducer core and the support surfaces.
After break in and during the operational life of the head, the wear surfaces of the edge members are arcuate with a radius that is larger than the adjacent wear surfaces. In this fashion, the edge members control the contact with the magnetic media and the rate of wear in the adjacent protected core area. The contact surface of the core that was initially lower than the wear surfaces of the edge members eventually becomes arcuate and has a radius that is substantially equal to or slightly less than the wear surfaces of the edge members. The contact surface of the core and the wear surfaces of the edge members generally form a continuous contact surface that is raised (or at a larger radius) than the adjacent elongated supports to provide good coupling and contact with the recording media.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of a linear tape head assembly in which the principles of the present invention are particularly suited.
FIG. 2 is an illustration of the linear tape head assembly of FIG. 1 during operation showing the positioning and movement of a magnetic media, i.e., a magnetic recording tape, relative to tape facing surfaces and to three elongated transducer support assemblies.
FIG. 3 is an enlarged perspective view of one embodiment of a transducer core for use with the tape head assembly of FIG. 1 showing the read/write gap.
FIG. 4 is an enlarged partial view one of the transducer support assemblies of FIG. 1 illustrating the use of two elongated supports to sandwich and support a core support having raised, wear-resistant edge members according to a significant feature of the invention.
FIG. 5 is an end elevation view of the transducer support assembly of FIG. 4 showing a preferred embodiment in which the height of the wear-resistant edge members is greater than the height of the wear surface of the nonmagnetic support member adjacent the transducer core and the height of the support surfaces of the elongated supports.
FIG. 6 is a view of the transducer support assembly after an initial break in period illustrating the relative radii of the contact surfaces that is substantially retained for the operational life of the assembly.
FIG. 7 is a side view of the assembly of FIG. 6 illustrating that edge member surface areas, the nonmagnetic support member surface areas, and the core form a substantially continuous curved surface with a single radius suited to the critical radius of the recording medium.
FIG. 8 is a view similar to FIG. 4 showing an alternate embodiment of a core support in which raised, wear-resistant edge members are curved to enhance aerodynamic features of the transducer support assembly.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention provides the features of enhanced airflow control and media contact surface wear control by providing a unique transducer support assembly. The assembly utilizes a pair of edge members (leading or trailing depending on travel direction of the magnetic media) in a wider core support design. The wear surfaces of the edge members are fabricated from a wear-resistant material, such as aluminum titanium carbide (ALTC) or zirconium, that is harder than the adjacent nonmagnetic support member (e.g., glass, ceramic material, and the like) and transducer core (e.g., ferrite such as single crystal ferrite or metal in gap ferrite (MIG)). The wear surfaces of the edge members may be configured to be initially raised relative to the nonmagnetic support member, transducer core, and elongated supports or facing members or due to the higher relative hardness, the edge members may become relatively raised due to uneven initial wear rates during operation. The raised leading and trailing edges provides improved air control as it blocks or redirects flowing air from passing over the transducer core and gap and ensures that the radius (e.g., height) of the transducer core remains greater than the critical or natural radius of the magnetic medium.
The invention is described in the following discussion as being particularly useful as part of a linear tape head assembly for use in a magnetic tape head assembly with transducer elements that are ferrite cores. However, those skilled in the art will understand that the transducer element or core may be a core inductive head, a magneto resistive read element, a thin film gap head, and other types of transducer elements in which it is useful to protect the core and gap from wear and airflow and to control the radius or height of the transducer element to manage spacing losses. Additionally, the magnetic media discussed for use with the invention is magnetic recording tape of varying stiffness, but the invention may be useful with other media such as contact hard disks, floppy disks, and the like.
Referring now to FIGS. 1 and 2, a linear tape head assembly 20 according to the invention is shown for use in writing to and reading from a magnetic recording tape 28 . The head assembly 20 includes tape facing surfaces 22 and three transducer support assemblies 24 for contacting and supporting the tape 28 as it moves in either direction shown by arrow 32 . In this manner, the transducer support assemblies 24 provide wear surfaces for the assembly 20 . The tape 28 is at a selectable tension that causes the tape 28 to apply a contact pressure on the transducer support assemblies 24 during reading and writing operations of the linear tape head assembly 20 . The transducer support assemblies 24 as shown include a pair of transducer cores 26 (as best seen in FIG. 3) for providing read and write functions of the assembly 20 .
The linear tape head assembly 20 is provided by way of example, and it should be understood that other types of tape head assemblies may be configured to include the transducer support assembly 24 of the present invention. For example, a helical tape drive assembly (not shown) may be designed with a rotating magnetic tape head that includes the transducer support assembly 24 and core(s) 26 . In this embodiment, the rotating magnetic tape head records information in helical form on a magnetic media (such as a tape 28 ) and reproduces information from the helical form stored on the magnetic media. The transducer support assembly 24 of the present invention will now be discussed in conjunction with the linear tape head assembly 20 using a ferrite core. However, the core support and transducer support assembly of the present invention may be used with other types of transducer elements (not shown).
Referring to FIG. 3, a typical core 26 (e.g., a magnetic ferrite core such as a single crystal ferrite) is shown. The core 26 has a gap 38 . The core 26 typically is one element in a transducer (not shown) that may be a recording transducer or a reproducing transducer. Each recording transducer provides a magnetic field in the vicinity of the gap 38 in the surface of the core 26 . Each reproducing transducer detects a magnetic field near the surface of the magnetic tape 28 in the vicinity of the gap 38 . The gap 38 has a gap length, G L , a gap width, G W , and a gap height, G H (which is often referred to as the pole tip height and is defined by the poles 34 ). The gap width, G W , is generally equal to the width of a track on the tape 28 , i.e., the tape track width, which is often about two milliinches. The gap length, G L , may be varied to provide desired read and write functionality, and in one embodiment, is about ten microinches.
According to an important feature of the invention, the tape head assembly 20 includes a transducer support assembly 24 that provides enhanced airflow control and wear resistance. Referring to FIG. 4, an enlarged view of a representative portion 30 of one embodiment of the transducer support assembly 24 of FIG. 1 is illustrated as it would appear after initial fabrication (i.e., before a break in period or extended use). As shown, the transducer support assembly 24 includes the core 26 that is supported within a core support 50 , which is itself sandwiched between elongated support 40 and elongated support 44 . The elongated supports 40 , 44 include planar support or facing surfaces 42 , 48 , respectively, for contacting the tape 28 and providing wear surfaces for the transducer support assembly 24 . In a preferred embodiment, the elongated supports 40 , 44 are fabricated from the same material as the core 26 , such as a ferrite. However, other types of magnetic material such as nickel zinc, magnesium zinc, and other well-known materials may be used for the support surfaces 42 , 48 to provide wear resistance. The support surfaces 42 , 48 are raised relative to the tape facing surfaces 22 of the head assembly 20 to a first height, H 1 , and have a support width, W S , for providing a contacting surface with the tape 28 during operations.
The core support 50 of the transducer support assembly 24 provides the significant structural features that provide the necessary magnetic coupling between the transducer core 26 and the tape 28 . As discussed previously, the core support 50 is designed to strip air away from the rapidly moving tape 28 to control floating or lifting of the tape 28 away from the core 26 and minimize spacing losses during read/write operations. Additionally, the core support 50 is configured to be useful with different magnetic media, such as tapes, that have differing stiffnesses, which cause the tapes to be wrapped on the head assembly at different radii and/or contours. Significantly, the structural features of the core support 50 are selected such that the most wear resistant features are always as high or higher relative to the facing surfaces 22 than the softer core and wear surfaces. In this manner, the core support 50 can be thought of as creating a larger, wear resistant radius that is suited for nearly any tape stiffness and tension, e.g., from the lowest stiffness tape to the highest stiffness tape utilized as a magnetic media.
Turning to FIGS. 4 and 5, the core support 50 illustrated includes a pair of wear-resistant edge members 54 and 58 with wear surfaces 56 and 60 , respectively, that contact the tape 28 . The edge members 54 , 58 are positioned at each end of the core 26 such that the tape 28 contacts the edge members 54 , 58 in either direction of movement (as shown by arrow 32 in FIG. 2 ). In one embodiment, the core 26 is secured within the core support 50 with a nonmagnetic support member 64 that has wear surfaces 66 . The nonmagnetic support member 64 may be fabricated from numerous nonmagnetic materials including many ceramics and glasses. In one embodiment, the nonmagnetic support member 64 comprises calcium titinate, nonmagnetic ferrite, or barium titinate.
Importantly, the edge members 54 , 58 are fabricated from a material that is more wear resistant than the adjacent core 26 , the wear surface 66 of the nonmagnetic support 64 , and the support surfaces 42 , 48 of the elongated supports 40 , 44 . This results in the wear-resistant edge members 54 , 58 wearing at a lower rate than the other wear and support surfaces 26 , 66 , 42 , and 48 when a relatively uniform pressure or wearing force is applied by the tape 28 . When the contact pressure is more concentrated at the raised edge members 54 , 58 the wear rate along the transducer support assembly 24 is more uniform. A number of wear resistant materials may be utilized with the key consideration being that the selected material provide a wear rate that is lower than the other surface materials at a similar contact pressure or wearing force. In one embodiment, the edge members 54 , 58 (and more particularly, the wear surfaces 56 , 60 ) are fabricated from aluminum titanium carbide (ALTC) and in another embodiment, zirconium is employed to provide the desired lower wear rate.
In the illustrated “as-fabricated” embodiment of the core support 50 , the wear surfaces 56 and 60 of the edge members 54 , 58 are at a height, H 3 , relative to the facing surface 22 of the head assembly 20 . This height is preferably equal to or greater than the height, H 2 , of the wear surfaces 66 of the nonmagnetic support member 64 and the core 26 . This may be achieved by initially fabricating the wear surfaces 56 , 60 at a height, H 3 , greater than the height, H 2 , of the wear surface 66 of the nonmagnetic member 64 . Further, in the illustrated embodiment, the support surfaces 42 , 48 of the elongated supports 40 , 44 are at a height, H 1 , relative to the facing surface 22 , which is less than or equal to the height, H 2 , of the core 26 and the nonmagnetic support member 64 wear surface 66 (see, for example, FIG. 5 which illustrates this height differential). Of course, many heights may be utilized in initial fabrication, such as having H 1 being about equal to H 2 . The important design factor is that the edge members 54 , 58 be harder and/or more wear resistant than the nonmagnetic support element 64 and core 26 and in some embodiments, harder and/or more wear resistant than the support surfaces 42 , 48 . This hardness differential will typically result in the illustrated heights after tape 28 is run over the transducer support assembly 24 for a period of time.
In another preferred embodiment, the support surfaces 42 , 48 , the wear surfaces 66 of the nonmagnetic support member 64 , the core 26 , and the wear surfaces 54 , 60 of the wear-resistant edge members 54 , 58 are initially fabricated to be substantially coplanar and at the same initial height (i.e., H 1 =H 2 =H 3 ). In this initial configuration, all of the wearing and support surfaces of the transducer support assembly 24 provide a relatively flat, coplanar surface that mates with the inner radius and contours of the tape 28 in the head assembly 20 . As the tape 28 is run across the wear and support surfaces that have differing wear rates (i.e., the wear surfaces 56 , 60 of the edge members 54 , 58 being lower or more wear resistant) the contacting surfaces will experience a pressure that is nonuniform along the length of the wear and support surfaces (i.e., along the longitudinal axis, a,). As discussed previously, a higher contact pressure is placed on the narrower support surfaces (i.e., w S is less than the width, w CS , of the core support 50 ). Because the wear surfaces 56 , 60 of the edge members 54 , 58 are fabricated from a more wear resistant material such as ALTC, the support surfaces 42 , 48 wear more rapidly and the height, H 3 , of the wear surfaces 56 , 60 of the edge members 54 , 58 quickly becomes larger than the height, H 1 , of the support surfaces 42 , 48 . After this break in period, the height differential remains for the life of the head assembly 20 resulting in controlled airflow and wear protection.
Often, the core 26 and wear surface 66 of the nonmagnetic support member 64 are fabricated of materials similar in hardness as the support surfaces 42 and 48 but because these surfaces are protected by the edge members 54 , 58 the wear rates experienced are less than those experienced at the support surfaces 42 , 48 . Hence, after the initial break in period of wear, the height, H 2 , is less than the height, H 3 , of the wear surfaces 56 , 60 of the edge members 54 , 58 but greater than the height, H 1 , of the support surfaces 42 , 48 of the elongated supports. The contact pressure becomes relatively uniform throughout the wear and support surfaces of the transducer support assembly 26 with some concentration of pressure remaining on the harder, wear-resistant edge members 54 , 58 .
Referring back to FIGS. 2 and 4, during read/write operations with the tape head assembly 20 , the tape 28 will run over each of the wear surfaces 56 , 60 , 66 , over the core 26 and gap 38 , and the support surfaces 42 , 48 of the elongated supports 40 , 44 . The axis, a 1 , of the support surfaces is substantially perpendicular to the tape travel direction 32 while the core support 50 is wider with its axis being substantially parallel to the tape travel direction 32 . The technique of providing a wider tape wear surface in the area around the transducer element and a more narrow wear surface in adjacent regions of a transducer support assembly is described in detail in U.S. Pat. No. 5,426,551, entitled “Magnetic Contact Head Having A Composite Wear Surface” and U.S. Pat. No. 5,475,553 entitled “Tape Head With Self-Regulating Wear Regions,” both issued to George Saliba and both being incorporated fully herein by reference. These two patents describe in detail useful dimensions and geometries for the wear surfaces 66 , 26 and support surfaces 42 , 48 of the transducer support assembly 24 that are readily applicable by those skilled in the art to the present invention.
Note, these patents do not suggest the use of a harder, more wear-resistant leading edge member, such as members 54 , 58 , and teach that wear would be expected to be substantially uniform on the surfaces of the wider transducer core support. In contrast, the present invention recognizes that even with a relatively uniform contact pressure along the longitudinal axis, a 1 , of the transducer support assembly 24 , localized higher pressure points typically will arise in head assemblies 20 and need to be addressed.
As illustrated in FIG. 4, the wear surfaces 56 , 60 of the edge members 54 , 58 and support surfaces 42 , 48 of elongated supports 40 , 44 are illustrated as rectangular but numerous initial shapes may be utilized to assist in initial manufacturing and to provide desired airflow conditions within the head assembly 20 . In operation, it will be understood that wear by the tape 28 alters the shapes of the contacting surfaces of the transducer support assembly 24 . For example, initially the surfaces are in an unworn condition, such as that shown in FIG. 4, and as the tape 28 begins to repeatedly advance across the wear surfaces the pressure exerted by the tape 28 is less on the wider core support 50 surfaces than on the narrower support surfaces 42 , 48 of the elongated supports 40 , 44 . This lower contact pressure may appear undesirable for providing good read/write contact, but the nonuniform contact pressure results in initial nonuniform wear such that after a short break in period the pressure becomes more uniform.
Due to the initial nonuniform wear on the wear surfaces the wider core support 50 becomes raised relative to the support surfaces 42 , 48 of the elongated supports 40 , 44 . Specifically, in an embodiment that utilizes materials of similar wear resistance for the core 26 , the nonmagnetic support member 64 , and the elongated supports 40 , 44 , the core 26 and wear surface 66 of the nonmagnetic support member 64 become raised relative to the support surfaces 42 , 48 due to the nonuniform pressure (i.e., H 2 becomes greater than H 1 ). Further, the use of more wear-resistant materials for the wear surfaces 56 , 60 of the edge members 54 , 58 results in these surfaces becoming raised relative to both the nonmagnetic support member 64 and the elongated supports 40 , 44 (i.e., H 3 becomes greater than H 2 and H 1 ).
The wear results in a changing profile of the elements of the transducer support assembly 24 , as is best seen in FIGS. 6 and 7. As shown in FIG. 2, the tape 28 is wrapped around the tape head assembly 20 to form a tape radius or arc at each of the contacting transducer support assemblies 24 . The wear pattern of the tape 28 on the surfaces of the transducer support assembly 24 typically results in the surfaces obtaining rounded edges or curved planar surfaces. As illustrated in FIGS. 6 and 7, the profile of the transducer support assembly 24 shown in FIG. 5 formed by three arcuate wear or contact surfaces having slightly different radii (or, as will be explained below, the radius of the wear surfaces 56 , 60 of the edge members 54 , 58 may be substantially equal to the radius of the core 26 ).
As shown, the support surfaces 42 , 48 have an arcuate cross-sectional shape when viewed along the axis, a 1 , that has a radius, R 1 . The two wear surfaces 56 and 60 of the edge members 54 and 58 are also curved or arcuate surfaces that are generally on the same arc having radius, R 3 . The surfaces 66 of the nonmagnetic support member 64 and the contact surface of the core 26 generally form a single curved or arcuate surface that has a radius, R 2 . Due to the selection of a harder and/or more wear resistant material for the wear surfaces 56 , 60 and their location in the assembly 24 , these surfaces 56 , 60 control the rate of wear in the assembly 24 . Pressure is initially concentrated on these surfaces 56 , 60 and they wear more rapidly at first until wear begins to occur on the adjacent surfaces 26 , 66 , and 42 , 48 . After an initial break in period or service period, the assembly takes on an appearance or configuration as shown in FIGS. 6 and 7.
As shown, the radius, R 3 , of the wear surfaces 56 , 60 is greater than or equal to the radius, R 2 , of the surface formed by surfaces 66 and the core 26 . In turn, the radius, R 2 , is greater than or equal to the radius, R 3 , of the support surfaces 42 , 48 . In a preferred embodiment (as illustrated), the wear surfaces 56 , 60 , the core 26 , and the nonmagnetic surfaces 66 form a single, substantially continuous, arcuate surface for contacting the tape 28 and having a radius greater than or equal to the radius, R 2 , of the core 26 . During operation, the edge members 54 , 58 control the wear rate and the radius, R 3 , is self-regulating to remain greater than or equal to the radius, R 2 , of the core. For example, the radius, R 3 , of the wear surfaces 56 , 60 may be in the range of about 0.3 to 0.7 milliinches while the radius, R 2 of the wear surface 66 of the nonmagnetic support member 64 and core 26 may be in the range of about 0.3 to 0.5 milliinches and the radius, R 1 , of the support surfaces 42 , 48 may be less than about 0.3 to about 0.2 milliinches.
The break in period can also be accelerated or eliminated during manufacturing through the use of an abrasive lapping tape to remove or reduce any sharper contact edges. Significantly, the use of the harder, more wear-resistant material for the wear surfaces 56 , 60 of the edge members 54 , 58 allows these two surfaces 56 , 60 to remain at substantially the same radius, R 3 , that is raised above or at the same radius as the adjacent surfaces and to contact the tape 28 , e.g., at a radius that is larger than the other contact radii and that better matches or suits the contour of the tape 28 as it is placed in tension within the head assembly 20 .
Once the break in period is completed, the wear rate becomes more uniform along the longitudinal axis, a 1 , of the transducer support assembly 24 and the core support 50 surfaces remain raised above or at a larger radius than the elongated supports 40 , 44 . Relatively uniform wear is achieved according to the invention by utilizing more wear-resistant materials, such as ALTC, at the locations of higher contact pressure (i.e., at the edge members 54 , 58 ). The process of wear on the tape contact surfaces of the transducer support assembly 24 is essentially self-regulating for the operational life of the head assembly 20 . When the raised core support 50 surfaces become relatively too high or low, the contact pressure along the longitudinal axis, a 1 , becomes more nonuniform until the radii, R 1 , R 2 , and R 3 , again adjust to acceptable differential levels (e.g., R ≧R 2 >R 1 ) to better distribute the contact pressure applied by the tape 28 .
During operation of the head assembly 20 , the movement of the tape 28 as shown by arrow 32 across the tape facing surfaces 22 causes air to be moved or pushed toward the transducer support assembly 24 . Without airflow control, this moving air can lift the tape 28 away from the core 26 causing spacing losses. According to the invention, however, the combined use of a raised, wear-resistant edge member 54 , 58 and a wider core support 50 effectively strips air from under the tape 28 at the important point of contact between the gap 38 of the core 26 . In practice, the air being moved by the tape 28 initially contacts the wider core support 50 at the leading one of the edge members 54 , 58 which forces the air to the sides toward the elongated supports 40 , 44 .
Additionally, the wear surfaces 56 , 60 of the edge members 54 , 58 are raised which enables the edge members 54 , 58 to better contact the tape 28 to strip or direct away air moving along with the tape 28 . The redirected air instead flows over the lower support surfaces 42 , 48 of the elongated support 40 , 44 which provide a path of less resistance for the flowing air or down the channels on the facing surfaces 22 between the transducer support assemblies 24 on the head assembly 20 . In this manner, the present invention significantly enhances airflow control to provide better magnetic coupling between the core 26 and the moving tape 28 .
To modify the aerodynamics or airflow control of the invention, additional configurations can be used that provide different edge configurations between the support and wear surfaces to provide airflow that at the leading contact profile that may be useful for obtaining better contact with the media and/or wear. For example, another preferred embodiment of a transducer support assembly 124 is shown in FIG. 8 that includes a wider core support 150 . As in the transducer support assembly 24 (as initially manufactured), elongated supports 40 , 44 are provided with support surfaces 42 , 48 at a height, H 1 , and a width, W s , made of material such as ferrite or other material with a hardness and wear resistance similar to the materials of the included magnetic ferrite or other magnetic material core 26 . The core support 150 supports and surrounds the core 26 and gap 38 and nonmagnetic support member 164 and is wider than the width, W S , of the support surfaces 42 , 48 to control the contact pressure applied by the tape 28 at the core 26 (as discussed above). A nonmagnetic support member 164 fabricated of ceramic material or other nonmagnetic material having wear surfaces 166 at a height, H 2 , is provided to support and isolate the core 26 (with H 2 being greater or equal to H 1 initially or after a break in period).
To alter aerodynamics, the core support 150 includes sloped and curved edge members 154 , 158 with wear resistant surfaces 156 , 160 fabricated of a higher wear-resistant material such as ALTC, zirconium, and the like and at a height, H 3 , greater than H 1 and H 2 initially or after break in wear. The shape of the surfaces 156 , 160 is shown as substantially a semicircle but other shapes may be used in the invention as long as the surface extends beyond the surfaces 166 of the nonmagnetic support member 164 .
The semicircle shape facilitates the wear of the surfaces 156 , 160 to a raised, smoother mound without sharp edges. This configuration is useful for reducing turbulent airflow that may cause the tape 28 to lift in the vicinity of the core 26 and also better distributes contact pressures to reduce the magnitude of concentrated tape pressure. Of course, the more rectangular wear surfaces 56 , 60 shown for transducer support assembly 24 will wear in response to concentrated pressures at the leading edges and corners resulting in the surfaces 56 , 60 taking on a more curved or semi-circle shape (as discussed with reference to FIGS. 6 and 7 ).
Although the invention has been described and illustrated with a certain degree of particularity, it is understood that the present disclosure has been made only by way of example, and that numerous changes in the combination and arrangement of parts can be resorted to by those skilled in the art without departing from the spirit and scope of the invention, as hereinafter claimed. For example, the inventive transducer support assembly 24 , 124 was illustrated for use in a linear tape head assembly 20 but the features of the transducer support assembly 24 , 124 make it useful in numerous other tape head assembly configurations (not shown) such as a helical tape head assembly and in head assemblies in which the tape 28 runs transversely across the transducer support assembly at an angle other than 90 degrees. These different tape head assemblies may result in differing concentration of contact pressure that can readily be addressed with the use of the wear resistant edge members 54 , 58 with or without modification to their shape and location relative to the core 26 .
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A magnetic head is provided for use with magnetic recording media of varying stiffness. The head includes a first and a second elongated support spaced apart on a facing surface with support surfaces extending along a longitudinal axis. A core support is positioned between the two elongated supports and is wider than the support surfaces to distribute tape contact pressures. The core support includes a transducer core with an elongated contact surface positioned to extend transverse to the longitudinal axis of the support surfaces. An edge member is positioned adjacent the contact surface of the transducer core to control wear and direct airflow. The edge member includes a wear surface of a material with greater wear resistance than the transducer core. A second edge member is provided on the opposite side of the contact surface of the transducer core to accommodate multi-direction tape travel.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority to U.S. Ser. No. 60/514,946 filed Oct. 3, 2002, the entire disclosure of which is incorporated herein by reference and U.S. Ser. No. 60/514,883 filed Oct. 27, 2003, the entire contents of which is incorporated herein by reference.
BACKGROUND
[0002] In the hydrocarbon exploration and recovery arts it is often desirable to employ valves in the downhole environment to control the migration of fluids. In some cases these valves include a closure member that is positionable across a flow area of a tubing string to shut in the wellbore below the closure member. Such valves are often called safety valves. Tubing retrievable safety valve(s) (TRSV) are commercially available from Baker Oil Tools, Houston, Tex., under part number H826103110. These valves have been extensively and reliably employed all over the world. Due to harsh conditions downhole however, all downhole components have limited life spans. When a TRSV fails to operate at optimum, cost associated with profitable hydrocarbon recovery can rise. In such cases, it is desirable to lock the original TRSV open and provide for communication with, and thus control over, a wireline run safety valve to be installed to assume the function of the original TRSV. Devices configured to provide such communication are known to the art but each has drawbacks. Advancements in the art are always beneficial and well received.
SUMMARY
[0003] Disclosed herein is a communication and lock open device. The device includes a lock open portion including a latch configured to engage a shifting profile on a closure member of a safety valve. The device further includes a communication portion configured to rotationally align a cutter with a non-annular hydraulic bore in the safety valve and axially cut into the hydraulic bore with the cutter.
[0004] Further disclosed herein is a selective collet which includes a sleeve having one or more fingers, at least one of the fingers having an attachment feature and an upset extending radially outwardly of the sleeve. The sleeve further includes a latch hold down engageable with a latch to prevent engagement thereof with another structure.
[0005] Also disclosed herein is a tubing retrievable safety valve that includes a housing, a flow tube mounted at the housing, a closure member mounted at the housing by a selectively shearable thread, the closure member operable responsive to the flow tube, a biasing member in operable communication with the flow tube, and a hydraulic control fluid in pressurizable communication with the flow tube.
[0006] Also disclosed herein is a method for replacing the function of a tubing retrievable safety valve while employing an original control line including running a communication and lock open tool in a wellbore, locating the tool in a tubing retrievable safety valve and shearing a thread in the tubing retrievable safety valve to render longitudinally moveable a closure member of the tubing retrievable safety valve. The method further includes shifting the closure member to lock the member in an open position, orienting a cutter and longitudinally establishing fluid communication with a piston bore of the tubing retrievable safety valve.
BRIEF DESCRIPTION OF THE DRAWINGS
[0007] Referring now to the drawings wherein like elements are numbered alike in the several Figures:
[0008] FIGS. 1 A-C are a cross-sectional view of a TRSV modified slightly from the commercial embodiment identified in the background section of this application;
[0009] FIGS. 2 A-G, 3 A-G, 4 A-G, 5 A-G, 6 A-G, 7 A-G, 8 A-G, 9 A-G, 10 A-G and 11 A-G, are all extended view of one embodiment of the communication and lockout device in progressive actuation positions;
[0010] FIG. 12 is an enlarged view of tab 110 to illustrate the chisel edge; and
[0011] FIGS. 13-16 illustrate alternate components for certain components illustrated in FIGS. 2 A-G to FIGS. 11 A-G.
DETAILED DESCRIPTION
[0012] Referring to FIGS. 1 A-C, one of skill in the art should recognize most of the components of the TRSV 10 illustrated. These are not discussed specifically herein other than incidentally to the discussion of the communication and lock open tool and with respect to features of the TRSV that are themselves new. Components of the illustrated TRSV that are distinct from the commercially available TRSV and do represent a portion of the invention includes a thread 12 and a profile 14 . Thread 12 is not visibly changed from the prior art TRSV but is indeed modified. Thread 12 is in one embodiment, constructed as a narrow cross-section thread (about ½ thickness of standard square thread profile for example). The thread may be made from an alloy such as nickel alloy and may be annealed to a specified yield strength (lower than mating parts). Further, in some applications, sections of the thread are removed (milled from substantially to completely through from inside dimension to outside dimension) to achieve the desired shear value. Any shear valve can be obtained. This also accommodates the disassembly of the tool to allow removal of the sheared part. Upon shearing, the flapper (closure member) 16 is longitudinally moveable relative to the TRSV housing 11 . By shifting (moving) the flapper relative to housing 11 , to a location where part of the flapper is behind a lock tab 18 in the TRSV 10 . The flapper 16 is no longer closeable and is thus locked open. It is noted that the shear strength of the thread 12 is selected to be equivalent in strength to any and all of the other commercial components of the flapper assembly. This prevents unintended shearing and related problems.
[0013] As noted above, another new addition to the commercial TRSV is profile 14 . The profile itself is relevant to the function described herein and not what supports that profile. In the illustrated embodiment, profile 14 is occasioned by a sleeve 104 , but it could easily be an integral portion of housing 11 of TRSV 10 , if desired. The purpose of profile 14 is to orient an alignment device such as an alignment collet, which orients a cutter, which is part of the communication and lock open tool discussed further hereunder. Profile 14 ensures that the cutter will create communication by cutting into a non-annular hydraulic chamber comprising a piston bore 20 (hydraulic chamber) of the original TRSV 10 . It will be appreciated by one of ordinary skill in the art that original piston bore 20 is fluidly connected to a control line 22 , commonly hydraulic, that is in operable communication with a control location, which may be remote, and may be a surface location. By cutting into piston bore 20 , the communication medium employed by piston bore 20 (e.g., hydraulic fluid) is available at an inside dimension of the TRSV 10 and therefore available to communicate with an after-installed replacement valve such as a wireline retrievable safety valve (WRSV). Such communication with the after-installed valve means that the after-installed valve is controllable from the original remote or surface location using the original control line 22 .
[0014] Referring to FIGS. 2 A-G, the communication and lock open device 30 described herein is illustrated disposed at an inside dimension of the TRSV 10 in a non-actuated condition, having been run there on a suitable string (not shown) due to a desire to replace the function of TRSV 10 . Device 30 comprises many components that cooperate with one another and move relative to one another in a predetermined sequence wherein components, for example, at an uphole end of device 30 and a more downhole portion of device 30 may actuate simultaneously or in sequence. For clarity, the interconnection of the various components is described first, with operation of those components only alluded to where such allusion provides for better understanding. A detailed description of the operation of device 30 follows this initial component description. In connection with the component description, reference, to FIGS. 2 A-G is largely sufficient without reference to other figures. It is pointed out however that due to movement of the tool, some figures may make viewing some components easier. Components are numbered in each of the drawings to avoid any ambiguity. Reference to other of the drawings may be helpful.
[0015] Beginning at the uphole end of the device 30 (at the left of the drawings) a fishing neck 32 is in communication with an upper shaft sleeve 34 . Fishing neck 32 also includes at a downhole end thereof a spring washer 36 for decreasing impact force when the tool is fully stroked. Fishing neck 32 is threadedly connected to upper shaft 38 at thread 40 . Upper shaft 38 , at a downhole end thereof is threadedly connected to shaft 42 at thread 44 . In order to prevent the unintentional unmating of thread 44 , one or more set screw(s) 46 are employed in one embodiment. On an outside dimension of upper shaft 38 , near thread 44 (which is on an inside dimension of the upper shaft), is dog recess 48 having beveled edges 50 . Edges 50 communicate with beveled edges 52 on dogs 54 . Dogs 54 communicate with upper latch mandrel 56 . Upper latch mandrel 56 further includes an upper C-ring 58 and extends in a downhole direction to one or more shear screw(s) 60 . Shear screw(s) 60 , releasably affix upper latch mandrel 56 to upper latch collet 62 which is threadedly connected to upper latch extension 64 through thread 66 and set screws 68 . Upper latch extension 64 includes on its inside dimension, a recess (or plurality of recesses) 70 to receive a portion of dogs 54 during actuation of the device 30 .
[0016] Upper latch collet 62 extends in a downhole direction to culminate at collet profile 72 , which is configured to engage a lock profile 74 in the TRSV 10 . It will be appreciated that lock profile 74 includes a shoulder 76 that provides a no-go when combined with shoulder 78 on collet profile 72 . In one embodiment, the shoulders are reverse cut to hold without support for a position of the operation. Collet profile 72 is supported in engaged condition with lock profile 74 by latch support 80 when the device 30 is actuated. Support is provided by surface 82 of latch support 80 . It will be appreciated that approach ramp 84 assists in allowing movement of latch support 80 to the support position under collet profile 72 .
[0017] Device 30 may be run selectively or non-selectively with respect to the action of upper latch collet 62 . This is occasioned by selective collet 81 having an upset 83 , a collet attachment 85 and latch collet hold down 87 . Attachment 85 communicates with recess 91 in latch mandrel 56 in one of two ways. One way is that attachment 85 is engaged with recess 91 ab initio and the tool is not in selective engagement mode. The second is that attachment 85 is not engaged with recess 91 . In this configuration, latch collet hold down 87 is in communication with the upper latch collet 62 urging collet profile 72 inwardly, which prevents engagement thereof with TRSV profile 74 . This configuration would be employed when several TRSVs are in the well, and one deeper than the first is targeted. In the selective mode, the upset 83 is employed to release the collet 62 at the appropriate depth. Since the seal bore in the TRSV is the smallest internal dimension, the upset will catch on it. If it catches on it in an upward movement, the selective collet 81 is moved out of communication with profile 72 and will allow profile 72 to engage the TRSV profile 74 . Thus, in use, the device 30 is run to a location just downhole of the target TRSV and then pulled back to selectively engage with that TRSV. Upon actuation of the selective collet 81 , the attachment 85 engages recess 91 to prevent later interference of selective collet 81 with the operation of latch collet 56 .
[0018] Latch support 80 is driven, through shear screw(s) 86 , by upper latch mandrel 56 . Once latch support 80 is in the desired location, angle surface 88 will shoulder on bevel 90 . Subsequent downhole force on upper latch mandrel 56 will shear screw(s) 86 .
[0019] A downhole end 92 of upper latch mandrel 56 is inter-engaged with guide 94 (numbered in two places to make extent of component clear). Guide 94 provides support and articulation to cutter retainer 96 and cutter dog 98 . Cutter dog 98 includes a bumper 99 to limit radial movement in the illustrated embodiment. Cutter dog 98 is configured to rotate to an aligned position with the non-annular hydraulic piston bore 20 , up to about 180° (in one embodiment) while extending cutter blade 100 to a position commensurate with a larger diametral dimension than an outer dimension of device 30 and having a position aligned with and uphole of piston bore 20 in TRSV 10 . Cutter dog 98 is configured to cut into piston bore 20 with axial only (as illustrated) or axial and radial movement together (with manipulation of the timing of interaction of the relevant components) coincident axially downward movement of components of device 30 including upper latch mandrel 56 and associated components moveable therewith as discussed hereinabove and detailed hereinbelow.
[0020] The movement of cutter dog 98 is caused by profile 102 in a sleeve 104 disposed at an inside dimension of TRSV 10 through alignment collet 108 which includes alignment tab 110 . Alignment collet 108 is urged outwardly to follow profile 102 by mandrel 112 , which includes frustoconical sections 114 and 116 . The two angled frustocones are provided to urge the cutter dog into the cutting position. Two angles are provided as opposed to one for clearance between guide 94 and mandrel 112 to increase initial radial cutter movement, and to ensure radial movement is complete prior to cutting into the bore 20 . Mandrel 112 is maintained in position while alignment collet 108 is urged downhole to effect the wedging outward of alignment collet 108 . Maintenance of mandrel 112 in place is effected by an uphole end thereof where mandrel 112 is threadably engaged with latch support 80 at thread 118 , and set screw(s) 120 . Thus mandrel 112 is hung from latch support 80 . It is noted that sleeve 104 further includes a slot 106 to positively locate alignment tab 110 .
[0021] Movement of alignment collet 108 causes movement of guide 94 through alignment collet slides 122 in grooves 124 of guide 94 .
[0022] A downhole end of guide 94 is axially slidably mounted at cap screw(s) 126 through a downhole end of alignment collet 108 to a collar 128 , which slides on mandrel 112 and functions to centralize the collet 108 and guide 94 . Guide 94 further includes slot(s) 127 to cooperate with cap screw(s) 126 .
[0023] Mandrel 112 extends downhole for a distance in one embodiment of about 27 inches to accommodate the length of the flow tube and power spring in the TRSV. A downhole end of mandrel 112 is threadedly connected to inner sleeve 134 through thread 130 and set screw(s) 132 . Inner sleeve 134 attaches at a downhole end thereof via shear screw(s) 146 to outer sleeve 148 . Outer sleeve 148 is attached at a downhole end thereof to lower latch mandrel 150 through thread 152 and set screw(s) 154 . Within mandrel 112 , shaft 42 extends downhole beyond the downhole end of mandrel 112 to terminate by threaded connection 136 and set screw(s) 138 to slide 140 . Slide 140 is slidingly received in inner sleeve 134 . Mounted within inner sleeve 134 is spring pin 142 and downhole end 144 of slide 140 . At an inner dimension of slide 140 is lower shaft 156 , which is shear screwed 158 to slide 140 at 144 . Spring pin 142 slides with slide 140 at recesses 145 . Lower shaft 156 continues downhole through lower latch mandrel 150 to a dimensionally enlarged downhole terminus having angled surfaces 160 , and 164 which function to urge lower latch collet 162 outwardly at an appropriate time in the actuation sequence described hereunder to engage surface 163 with TRSV shifting profile 165 . Surfaces 160 and 164 define a single angled surface interrupted by a machining groove utilized in manufacture of the devices to simplify the same with respect to room for machining.
[0024] Threadedly connected to lower shaft 156 via thread 166 and set screw(s) 168 is lower shaft extension 170 . Lower shaft extension 170 is disposed within mandrel extension 172 which itself is connected via cap screw(s) 174 to lower latch mandrel 150 . Outwardly disposed at the mandrel extension 172 is dog support 174 . Dog support 174 includes a profiled uphole section 176 having uphole and downhole facing angled surfaces 178 , 180 . Surfaces 178 , 180 function to actuate locating dogs 182 . Actuation of dogs 182 occurs when profile 176 is moved uphole or downhole of dog pivot point(s) 184 . Dogs 182 themselves include an uphole actuation surface 186 and a downhole retraction surface 188 whose interaction with profile 176 services to actuate the dogs and retract the dogs, respectively. A C-ring 190 is disposed around dog support 174 . The C-ring interacts with grooves 192 and 194 to maintain actuation and retraction positions of dog support 174 subsequent to sufficient actuation force to move the support to the desired position by collapsing the C-ring over rib 196 . A snap ring 195 is also set around mandrel extension 172 to move dog support 174 upon downward movement of other components, whose movement will be clear from the operation discussion hereunder. Grooves 192 and 194 are provided in a dog housing 197 . Dog housing 197 is connected to cap 198 by thread 200 . Cap 198 is further connected by thread 202 and set screw(s) 204 to lower shaft extension 170 . Further, cap 198 includes an o-ring 206 .
[0000] Operation
[0025] The communication and lock open tool has been described from an uphole end to a downhole end and with light reference to the interplay of components. In this section applicant will describe the complete operation of the device with reference to all of the figures of the application. It will be appreciated that this device is to be run in the hole to a TRSV 10 having the features described herein as unique over prior art TRSVs. Referring to FIGS. 2 A-G, the tool is in a run-in position, no actuation having been started. Referring to FIGS. 3 A-G actuation has begun in that the collet profile 72 has naturally snapped outwardly into lock profile 74 with a TRSV 10 . In the illustrated embodiment the selective collet 81 has not been employed and is thus shown as of run-in engaged at attachment 85 with recess 91 . It is noted that due to the reverse cut of shoulder 78 on the collet profile 72 and shoulder 76 of the lock profile 74 of TRSV 10 the tool in this position can and does hold some weight. The weight that is held by the reverse cut is sufficient to allow angle 50 of upper shaft 38 to bear against dogs 54 causing the dogs 54 and the upper latch mandrel 56 to move downhole. Such movement of course will cause shear screw(s) 60 to shear under that load. The load provided to shear shear screw(s) 60 is only present until dogs 54 move radially outwardly into recess 70 of upper latch extension 64 . Upon dogs 54 moving into recess 70 , angle 50 no longer bears upon dogs 54 and therefore the load is removed. At this point, the dogs 54 and upper latch mandrel 56 simply sit in the position illustrated in FIG. 3D until further actuated as described hereunder. Upper shaft 38 and components thereabove, and indeed components therebelow, which are discussed hereunder, continue to move downhole. It will be noted that latch support 80 will move under collet profile 72 at the same time that dogs 54 snap into recess 70 . Once the latch support 80 is properly positioned under collet profile 72 the communication and lockout device is indeed locked into the TRSV 10 and will not move from that position until collet profile 72 is unsupported by latch support 80 .
[0026] Simultaneously, with the support of collet profile 72 , shaft 42 continues to move downhole causing slide 140 to move downhole with spring pin 142 , lower shaft 156 , lower shaft extension 170 , cap 198 , dog housing 197 and dogs 182 . It will be noted that mandrel extension 172 does not move downhole and that because of snap ring 125 at a downhole end of mandrel extension 172 , dog support 174 cannot move downhole with dog housing 197 . Because dog support 174 cannot move downhole, the profiled uphole section 176 of dog support 174 is urged into contact with actuation surface 186 of dogs 182 uphole of pivot 184 causing the dogs to move outwardly. The outward movement of the dogs has two functions, firstly to open flapper 16 fully so that it may move behind tab 18 in TRSV 10 when thread 12 is sheared and secondly to locate and hold weight on shoulder 185 of dogs 182 in communication with shoulder 183 of TRSV 10 . Helping to maintain the dogs in the desired position is C-ring 190 , which moves over rib 196 into recess 194 from its original retraction position of recess 192 .
[0027] With the locating dogs 182 in the located position, components 156 , 170 , 198 , 197 and 182 can no longer move downhole. Thus, further movement of slide 140 in a downhole direction causes shearing of shear screw(s) 158 that previously connected slide 140 to lower shaft 156 and allowing slide areas 145 to slide past spring pin 142 until downhole end 144 of slide 140 contacts lower latch mandrel 150 . Downward movement of lower latch mandrel 150 causes lower latch collet 162 to move outwardly on surfaces 160 and 164 thereby increasing its diametral dimension until surface 163 engages shifting profile 165 within TRSV 10 . Simultaneously, lower latch mandrel 150 through cap screws 174 causes mandrel extension 172 as well as lower latch collet 162 to move further downhole. Upon this movement and referring to FIGS. 3F and 4F directly, the thread 12 is sheared causing flapper 16 to move behind tab 18 to lock open the flapper 16 . As noted above, mandrel extension 172 is also moving downhole simultaneously. That downhole movement without other effect is limited by shoulder 173 which will contact shoulder 175 of dog support 174 . Upon contact between shoulders 173 and 175 , C-ring 190 is moved from recess 194 back into recess 192 causing profiled uphole section 176 of dog support 174 to interact with the retraction surface 188 of dogs 182 thereby causing dogs 182 to disengage from TRSV shoulder 183 and retract to their pre-actuation position. At the same time that dogs 182 retract, the lower latch collet 162 reaches a downhole facing surface 167 of lower shaft 156 which allows lower latch collet 162 to snap back into its pre-actuation dimension but in a different position downhole of surface 167 . This movement disengages the lower end of the tool from the TRSV and concludes the lock open operation. The fact that the lock open operation has been concluded is signaled to an operator by a drop of the tool approximately eight inches once dogs 182 and collet 162 are disengaged from TRSV 10 . The positions of the components of the tool following the approximately eight-inch drop are illustrated in FIGS. 4A-4G .
[0028] With the lock out operation concluded, it is time to create communication with the old piston bore 20 such that a new wireline retrievable safety valve can be installed and operated from the original control line 22 . With the tool in the position indicated in FIGS. 4A and 4B , one will note that upper shaft sleeve 34 has come into contact with dogs 54 thereby reloading those dogs which were unloaded at the beginning of the lock open operation by moving into recess 70 . Referring to FIG. 6 , with the further downhole movement of uphole components 32 , 36 , 34 , 38 , one will appreciate that dogs 54 have been urged downhole thereby urging upper latch mandrel 56 downhole as well. This movement loads shear screw(s) 86 and shears them at a selected load causing guide 94 to begin moving downhole, which itself urges alignment collet 108 downhole. It should be noted at this point that the urging of alignment collet 108 downhole does not occur from the uphole edge of alignment collet 108 at alignment tab 110 but rather occurs at short collet ends 109 which are visible in broken lines to show location in each of the drawings but are also shown deflected in broken lines in FIGS. 8D, 9D and 10 D to illustrate how they function relative to mandrel 112 . It is apparent herefrom that the short collet fingers are urged inwardly through the combined action of angle 95 and mandrel neck down 113 .
[0029] As the alignment collet 108 moves downhole it will move outwardly in a recess area 111 of the original TRSV 10 such that alignment tab 110 will land on alignment profile 14 . In order to make the drawings most clearly illustrate the movement of the device, the alignment tab has been originally illustrated in a position 180 degrees off from its final desired aligned position. It will be understood that the alignment profile 14 occurs around the perimeter of the TRSV, such as a mule shoe, so that regardless of the orientation of the communication and lock open device upon initial run-in the alignment tab 110 will be picked up by some portion of the alignment profile 14 and will thereby be rotated into alignment to allow for the cutting device to create the communication desired. Also noted is that normally device 30 is not used until a sufficient time has passed from original well completion that it is likely scale has built up on surfaces downhole. Because of this likely condition, it is desirable to provide a chisel-like cutting edge on tool tab 110 to cut through the scale allowing the tab to follow profile 14 as intended. A schematic view of the chisel-like cutting feature is illustrated as numeral 208 in FIG. 12 .
[0030] Referring to FIGS. 7C and 7D the device has now rotated the alignment collet 108 and thereby the guide 94 into the appropriate position. In the appropriate aligned position, cutter dog 98 and cutter 100 are positioned longitudinally uphole of the piston bore 20 of original TRSV 10 . Further downhole movement of upper shaft 38 and related components causes the upper latch mandrel 56 , the guide 94 and cutter dog 98 with cutter 100 to continue to move downhole into contact with mandrel 112 frustoconical sections 114 and 116 to position the cutter to open a communication channel with the piston bore 20 . Once the cutter is positioned correctly the purpose of slot 127 becomes apparent. At this point in the procedure the alignment collet 108 has been rotated and dropped into its retaining slot in the TRSV 10 and can no longer move downhole, yet the cutter 100 is still uphole of the piston bore 20 . Further downhole movement of upper latch mandrel 56 and related components as set forth hereinabove cause the cutter 100 to move longitudinally downhole onto frustocones 114 and 116 and into piston bore 20 of TRSV 10 , cutting a path into piston bore 20 and thereby opening communication to the inside dimension of TRSV 10 from the original control line surface or other remote location. In order for the movement of guide 94 downhole to allow the cutter to enter piston bore 20 guide 94 must be able to move relative to alignment collet 108 . Slots 127 allow for such movement. FIG. 8D illustrates the cutter inside the space of piston bore 20 . At this point and referring to FIG. 9 the tool is to be withdrawn from the downhole environment thus making way for a later run WRSV or other replacement valve or tool. Upon the beginning of the uphole pull on fishing neck 32 , upper shaft 38 moves upwardly within upper latch mandrel 56 until a bottom end angle 48 of upper shaft 38 picks up on ring 58 such that the upper shaft 38 can pull upper latch mandrel 70 uphole. Further, the cutter dog is unsupported from the frustocones 114 , 116 and brought back into its original unactuated position by cutter retainer 96 . This is illustrated in FIGS. 9, 10 and 11 . As the fishing neck reaches full extension, the upper latch mandrel 56 moves back to its original position where its shoulder on upper latch extension 64 and guide 94 comes back into contact with latch support 80 . Further pulling uphole unsupports collet profile 72 so that it is collapsible and therefore disengagable from TRSV 10 and the tool is withdrawn from the hole.
[0031] Further to the foregoing discussion of a first embodiment of the control system communication and lock open tool there are several components that can be replaced with alternatives. The alternative components may be individually substituted for those described above, may be substituted in groups or may all collectively be substituted for like components as described above.
[0032] In one alternate component the cutter dog 98 represented in FIG. 2C is modified to slide upon the outside dimension of the mandrel 112 . Cutter dog 98 a (see FIG. 13 ) is formed to include slide area 400 , which has an angle calculated to match an outside dimension of the mandrel 112 relative to the angle of the cutter. This area 400 slides upon the outside dimension of mandrel 112 during use. The arrangement provides for greater stability of the cutter dog 98 a, as a greater percentage of the surface area of the dog remains supported throughout its motion. This may be beneficial in some applications. In other respects the tool operates as above described.
[0033] In another alternate component, the lower shaft 156 introduced in FIG. 2E is modified and illustrated in FIG. 14 as lower shaft 156 a. A set of segments 404 are located such that they engage a recess 402 while remaining in contact with slide 140 at interface 406 . Segments 404 are maintained in the engaged position by the inside dimension of inner sleeve 134 . A relief 407 is provided in the inside dimension of inner sleeve 134 a to allow the segments 404 to move outwardly and disengage recess 402 in lower shaft 156 a. Once disengaged, the operation of the device is as disclosed hereinabove.
[0000] This alternate construction allows the tool to sustain an impact load on the lower shaft while the tool is being run downhole without premature shearing of the shear screws 158 .
[0034] Yet another component, referring to FIG. 15 , modifies lower shaft 156 and lower shaft extension 170 as those components are illustrated in FIG. 2F . As above described, and illustrated in FIG. 2F , lower shaft 156 is threadedly attached to lower shaft extension 170 . Set screws 168 are also employed to prevent relative rotation of the two parts. Illustrated in FIG. 15 , the lower shaft and lower shaft extension are replaced by an extended lower shaft 408 . Shaft 408 includes a collet support 410 , which is attached to shaft 408 by shear members 412 . Collet support 410 provides the angle that was previously provided by surfaces 160 and 164 in FIG. 2F . Therefore it will be appreciated that the purpose of collet support 410 is too urge lower latch collet 162 outwardly at an appropriate time in the operation of the device. As noted above, collet support 410 is attached to shaft 408 by shear members 412 such as shear screws and therefore can be detached from shaft 408 if desired by placing a load of sufficient predetermined magnitude on the shear screws to shear them. This is of importance when and if the tool encounters an impediment to the proper expansion of the latch into its intended groove. Such may occur due to, inter alia, debris or mislocation problems. In such situation it is possible for the tool as described in FIG. 2F to become stuck. The modification detailed in FIG. 15 resolves that potential by allowing the device to continue to function by shearing the screws 412 , allowing the extended lower shaft 408 to move relative to the collet support 410 .
[0035] In a final alternate component of that hereinbefore described, and referring to FIG. 16 , the cap 198 of FIG. 2G is modified to exist in two parts: a cap mount 414 and a cap head 416 . Cap mount 414 is mounted to lower shaft extension 170 or extended lower shaft 408 depending upon which embodiment is utilized. For purposes of discussing the FIG. 16 view, shaft 408 is illustrated with the understanding that either shaft could be used. The mounting is at thread 418 and setscrews 420 ensure prevention of relative motion between these parts. Cap mount 414 retains thread 200 from the previously described embodiment, illustrated in FIG. 3G . The cap mount 414 is attached cap head 416 . As illustrated cap head 416 is fastened utilizing thread 422 . Cap head 416 includes fluid bypass openings 424 to reduce fluid resistance while running the tool. Also noted is that the cap head may be constructed of brass or other softer material to alleviate seal bore damage as the tool is run in the hole.
[0036] It is to be understood that any one component, any group of components or all of these alternate components may be employed with the tool as described earlier in this application.
[0037] While preferred embodiments have been shown and described, various modifications and substitutions may be made thereto without departing from the spirit and scope of the invention. Accordingly, it is to be understood that the present invention has been described by way of illustration and not limitation.
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Disclosed herein is a communication and lock open device which includes a lock open portion including a latch configured to engage a shifting profile on a closure member of a safety valve. Further included is a communication portion configured to rotationally align a cutter with a non-annular hydraulic bore in the safety valve and axially cut into the hydraulic bore with the cutter. Also disclosed is a method for replacing the function of a safety valve while employing an original control line including running a communication and lock open tool in a wellbore, locating the tool in a tubing retrievable safety valve and shearing a thread in the valve to render moveable a closure member of the tubing retrievable safety valve. The method includes shifting the closure member to lock the member in an open position, orienting a cutter and establishing fluid communication with a bore of the valve.
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CROSS-REFERENCE TO RELATED APPLICATION
This application for patent claims priority under 35 U.S.C. 119(e) from U.S. provisional application No. 60/676,188, filed Apr. 29, 2005.
TECHNICAL FIELD
This invention relates to surface treatment of materials, and in particular relates to a method for changing the molecular bonds at or near the surface of a material and within a solution in order to facilitate certain desirable reactions. It also relates to energy generation, in particular, preparation of the surface of material to facilitate an exothermic reaction in a liquid medium.
BACKGROUND ART
The problem to be solved is to provide one means of sustaining an exothermic reaction in the throat of a nozzle such that a fluid medium can undergo a change in phase from an incompressible to a compressible liquid at that point. When thrusting laterally around a shaft, such a nozzle can be used to provide rotational drive. Such a nozzle is described in a prior U.S. patent application Ser. No. 10/797,255 of the present inventor, entitled “Implementation and Application of Phase Change in a Fluid Flowing Through A Nozzle”.
SUMMARY DISCLOSURE
The invention is a protocol that prepares the surface of a material, such as palladium, for an exothermic reaction. The protocol consists of a specific series of steps applying compounded and concurrent electrical, photonic, and vibratory stimuli between palladium electrodes immersed in a solution containing lithium sulfate as an electrolyte and anionic silica hydride as a surfactant while that solution is maintained at an elevated temperature at or near the boiling point. The solution is buffered to a pH in the range of 6.5 to 8.9. After preparation of the surface, a final step of the protocol calls for stimulation of the cathode with a DC voltage.
The protocol shows evidence that the bonding of the palladium has changed at or near surface, for example, in that it will now stain with methylene blue. It also yields a sustained exothermic reaction at or near the boiling point of the solution.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a photograph of two electrodes, the surfaces of which are in the final stages of being treated, immersed in an electrolytic cell and being stimulated in accord with the method of the present invention.
FIGS. 2 and 3 are graphs of voltage versus time for respective ramped and unramped forms of electrical stimulation applied to the electrodes in the arrangement of FIG. 1 .
FIGS. 4 , 5 and 6 are photographs of scanning electron microscope (SEM) images of electrodes treated in accord with the present invention. FIG. 4 shows ‘volcanic’ crater sites formed on the electrode surface. FIGS. 5 and 6 show silica coatings formed on two different electrodes, with the silica coatings having a stratified and sponge-like texture, respectively.
FIGS. 7 and 8 are photographs of SEM images respectively before and after staining with methylene blue of an electrode sample showing silica coating.
FIG. 9 is a photograph of the same sample after staining as in FIG. 8 , but observed with an optical microscope.
FIGS. 10 and 11 are photographs taken of a magnetic spin bar used in the electrolytic cell of FIG. 1 for stirring the contents, respectively showing deposits of palladium electrode metal upon the Teflon™ (polytetrafluoroethylene or PTFE) coating of the spin bar together with alterations of the PTFE surface itself.
DETAILED DESCRIPTION
In order to improve the performance of other inventions, notably the aforementioned nozzle, a source of energy was sought that can be used as one means to release heat into a system. That heat source must be sufficiently robust to flash water into steam. Changing the phase of a fluid from liquid to gas further implies that the heat source must have a high energy density.
Based upon those requirements, a protocol has been developed that treats the surface of a material, such as that for the throat of a nozzle, in preparation for an exothermic reaction. The protocol is performed in an electrolytic cell consisting of two electrodes, composed for example of palladium, with material surfaces to be treated, immersed in a solution of heavy water (D 2 O), lithium sulfate (Li 2 SO 4 ), and a surfactant. Citric acid or some other pH-buffering agent is added to the solution to keep pH within a specified range. Alternatively, less active results have also been observed using light water (H 2 O).
The electrolytic cell may be of any size needed to accommodate a work piece whose surface is to be treated by this protocol. The work piece or pieces to be treated are used as either one or both of the electrodes, which can be of any shape and size, such as that of a nozzle. It may be a solid metal or alloy, containing for example palladium, or may be metallically plated with the desired surface material. It may also be surface coated with other materials, such as silicates or polymers (such as polytetrafluoroethylene), with either the underlying metal or the coating or both to be treated by the protocol.
The protocol requires a few hours of sample preparation. After the sample has been prepared, the final step is to stimulate it with a voltage of 10 volts or more. That DC stimulus will cause the cathode in the cell to release energy in an exothermic reaction that flashes water into steam on the surface of the palladium cathode. The reaction occurs at or near (within 10° C.) the boiling point of the solution in the beaker. The reactions persist for several hours and the energy released is sufficiently robust as to yield vigorous bubbles of steam that are visible to the naked eye.
Prior to being treated with the protocol, the temperature in the beaker rises in a linear manner as it is heated on a hot plate until it reaches the boiling point. After being treated with the protocol, the rate of change of the temperature increases with a non-linear S-curve as the temperature of the solution approaches within 3° C. of the boiling point. The temperature stabilizes just below the boiling point when the heat carried away by the increasing flow of bubbles equals the heat being added by the hot plate and the cathode. The S-curve shape is caused by energy from the reaction supplementing the energy from the hot plate and increasing the temperature of the solution.
Once stimulated by the DC, the reaction will diminish if the temperature of the solution is lowered and return if it is raised again.
These bubbles will typically form continuously on the cathode when the temperature of the solution is within 1° C. of the boiling point. At temperatures between 1° C. and 3° C. below the boiling point, they tend to release in bursts. FIG. 1 is a photograph of two cathodes in a cell. The cathode on the right is releasing some bubbles that rise without changing size. The cathode on the left has just released a burst, and its bubbles are growing in size as they rise through the liquid. That increasing size indicates that the bubble separated from the cathode with superheated steam that continues to vaporize the surrounding water as it ascends through the liquid.
To verify that the bubbles were steam and not hydrogen, the temperature of an electrolytic cell with one anode and two untreated cathodes was raised to within 2° C. of its boiling point using a hotplate. Over a half-hour, the cell would maintain that temperature within a few tenths of a degree if the hotplate was kept at that initial setting. The untreated cathodes were replaced with two cathodes that had been treated with the protocol. The setting of the hotplate was raised to bring the cell to boiling and a DC voltage applied across the electrodes, as required by the protocol. After observing sustained bubbles rising from the surface of the palladium cathode, the plate was returned to its initial setting. In the absence of an exothermic reaction, one would have expected the temperature of the cell to fall back below the boiling point. It did not; it remained at or near the boiling point for several hours, showing evidence that a gap of approximately 1.5° C. was caused by heat being released within the cell.
The power required to create that temperature gap was determined by performing an empirical experiment, forcing a current through a resistor in the same beaker filled to the same level with the same liquid. Approximately five watts was needed to maintain that temperature gap. If the two cathodes were the only source of heat causing the gap, they would have had an energy density two orders of magnitude greater than that available from chemical batteries. However, it was later determined that palladium had deposited on the magnetic spin bar in the beaker, so the surface area of that palladium may have contributed as a heat source with the cathodes.
The temperature on the surface of the hotplate was measured with a thermocouple throughout this experiment to confirm that the surface temperature returned to the range of its earlier value after the plate was reset to the baseline; it did return to that range.
It is known that various kinds of stimuli, including electricity, vibration, and light, can initiate exothermic reactions. In this protocol, all three of these stimuli are used together in combination. Two of the three stimuli, electricity and vibration, are obtained in a single operation. Specifically, knowing that a percussion sound in audio electronics can be simulated by a series of pulses modulated by sine waves, a signal is created that combines elements of electrical stimulation and vibration, which is referred to as “ramped percussion modulation”.
That stimulus is a time-varying voltage with a baseline near ground potential. It is shown in FIGS. 2 and 3 in a ramped and unramped form, respectively. Observations show that a 3.15 MHz pulse train modulated by a 50 MHz sine wave is effective.
This periodic electrical stimulus does not cause electrolysis. According to classic electrochemistry, alternating currents become ineffective for electrolysis above 400 kHz because the charge carriers of the electrolyte lag in their response to an electric field and no longer migrate between electrodes at high frequencies. Their mobility is limited by their diffusion times and rates and by the double-layer capacitance at the interface of the electrolyte and the electrodes. The pulse frequency of this stimulus is thus almost an order of magnitude too high to stimulate electrolysis, while the modulating sine wave is two orders of magnitude too high.
Further, the voltage levels in electrolysis must exceed a threshold voltage of approximately two volts to break the molecular bonds of the water molecule. While the peak value of the modulated stimulus used to prepare the surface of the cathode for exothermic reactions does exceed two volts, the average value will vary with the impedance across the electrodes and typically is less than half of that. A DC stimulus is applied during a later portion of the protocol, and it does exceed two volts. However, the exothermic reaction does not occur with the DC stimulus alone; the periodic electrical and photonic stimuli are also required.
Finally, bubbles are not generated when this stimulus prepares the surface of the palladium cathode, further suggesting that electrolysis is not occurring.
One objective of the experiments was to test whether a surfactant would facilitate exothermic reaction by changing the conditions at the interface between the cathode and the electrolytic solution. To the best of our knowledge, previous attempts to use surfactants to create exothermic reactions in electrolytic cells have only served to demonstrate that the surfactants contaminate the surface of the electrodes and inhibit the reactions. Significantly, surfactants are typically hydrocarbon chains with a “surfactant tail” that can be twelve or more carbon atoms long. An embodiment of the protocol in accord with the present invention uses either of two commercial products called “MegaH−” and “Super Hydrate”. These commercial products are marketed as dietary supplements for human consumption and are the inventions of Dr. Patrick Flanagan of Watsonville, Calif. They are respectively the powdered and dissolved form of his anionic silica hydride.
Super Hydrate was originally selected because of its surfactant properties. It is reported to lower surface tension in water from 78 to 49 dynes/cm 2 , and it does not have a surfactant tail. The following additional points can be made about these two products: 1) They are described as sources of ionized hydrogen contained within soluble “proprietary microclusters” of silica hydride. 2) This technology is further described in an article published by Drs. Stephanson and Flanagan in the International Journal of Hydrogen Energy in 2003. The article is titled “Synthesis of a novel anionic hydride organosiloxane presenting biochemical properties.” The article can be found at the following URL: http://www.megahydrate.com/IJHE — 28 — 11 — 2003.pdf. 3) Anionic silica hydride is described in the article as consisting of tetrahedral frameworks that encapsulate hydrogen cations. 4) Drs. Stephanson and Flanagan further describe their anionic silica hydride as a silsequioxane, a class of organo-siliceous compounds with the general formula (RSiO 1.5 ) n , where n is an even number and the R constituent group may be one of any number of functional groups. They report that evidence in their analysis suggests that their product has hydroxyl-terminated constituents. 5) In another article Dr. Flanagan indicates that he has applied for a patent on his invention. 6) Both products also contain additives to enhance flavor (irrelevant to the present invention) and to improve handling qualities such as pourability. Pure samples of the products without the additives were not available and the influence of these additives could not be determined. They could either be facilitating the reactions, be inhibiting them, or be neutral in the protocol. 7) According to is package label, Mega H— has potassium citrate, potassium carbonate, and oleic acid added. 8) Super Hydride has potassium carbonate, magnesium sulfate, and oleic acid added. Some of these additives may have a pH buffering affect. Subsequent experiments showed success using MegaH— alone, so the dissolved form is optional.
To the best of our knowledge, pH is not a critical variable in electrolysis. However, it is a critical issue for exothermic reactions in this protocol. The reaction protocol works if the pH of the solution is between 6.5 and 8.9. A pH of 8.0 is recommended for the protocol.
Hydrogen and helium gases were bubbled into the cell while preparing the sample to keep it saturated with those gases. Later, the hydrogen gas was eliminated and some effect still observed, so the hydrogen gas can be considered optional.
In order to find evidence that very high temperatures were reached during the protocol, the cathodes used in these experiments were examined with electron microscopy at analytical testing laboratories. Samples were tested at Accurel Systems International Corp. and Charles Evans & Associates, both in Sunnyvale, Calif.
One early cathode was examined with a Scanning Electron Microscope (SEM). A coating of silica covered the surface of the cathode where it had been immersed in the liquid. Some of the silica had been rubbed off during handling, exposing the palladium surface underneath. Several ‘volcanic’ sites were observed on the metal surface, as shown in FIG. 4 . These sites showed craters that appear to have been formed by very intense, localized heat. The sites feature cones that resemble volcanoes where material has been ejected, leaving a cone that appeared to have been formed by ejected material and signs of sputtering around that cone. Subsequent cross-sectional examinations of other samples showed lateral views of similar sites and confirmed their conical shape. An untreated sample was examined, and no volcanic sites were observed on it.
A second sample showed some different phenomenon. This second sample came from an experiment conducted on Mar. 17, 2005, and tested the next day, Mar. 18, 2005. It was kept under a helium blanket between the experiment and analysis. During FIB preparation of the sample, it was observed that the silica coating had separated completely from the palladium substrate, as shown in FIG. 5 . There was a continuous gap between the palladium and the silica. The cross section of the silica showed a rough external surface, an amorphous layer of silica, and an inner layer of poorly organized crystalline formations whose appearance suggests high temperatures were present in their formation. The various strata revealed by the SEM show that the coating cooled differentially, more quickly at the outer surface and slower near the palladium wire. As it cooled, it formed different crystalline morphologies. In that regard, the strata resemble a geode, commonly called a “dinosaur egg”, another object believed to be formed with extreme heat.
A third sample was tested on April 26 and 27 at the same laboratory. This sample had appeared to have shown more robust heat than the second. The coating in this sample showed a sponge-like texture rather than strata, as shown in FIG. 6 . Electron diffraction microscopy (EDS) showed that coating to be binary mixture consisting entirely of oxygen and silicon.
A fifth sample was tested later after being prepared for microscopy in a different way. This sample was cross-sectioned and polished rather cut with a Focused Ion Beam (FIB). The silica coating on this sample shows clearly as a band approximately 80 nm deep around the cathode in FIG. 7 . In an effort to highlight features in this sample, it was stained with methylene blue. Materials engineering specialists had stated that staining a metal would not reveal any additional information in the analysis. In fact, staining is generally only used on organic samples. However, distinct differences were observed as a result of staining. FIG. 8 shows the same sample as FIG. 7 after staining. One clearly sees a band within the cathode outer surface that has been preferentially stained. The band varied between 1 μm and 2.5 μm in depth.
Examining the same sample with an optical microscope showed something else interesting, as shown in FIG. 9 . There are patches deep within the palladium where the stain adheres to the metal, giving it a mottled appearance. Examination of an untreated sample did not show such patches.
Continued work with the protocol led to another observation. While preparing the samples, the contents of the beaker were stirred using a magnetic spin bar. The spin bars used in the experiments demonstrated a tendency to generate more steam bubbles as they were used in successive tests, so one was examined with a SEM. Following usual procedure, the operator placed the spin bar in a vacuum chamber and attempted to coat it electrostatically with conductive platinum, a standard procedure in the preparation of such samples. The spin bar promptly slammed against the electromagnet and was damaged. However, the damaged sample showed some interesting results. The surface showed numerous deposits of palladium, such as the one shown in FIG. 10 . The spin bar is a magnet coated with Teflon™, and a layer of material had been lifted off the surface of the Teflon and peeled back, as shown in FIG. 11 . It appeared that the surface of the spin bar was affected in some manner by the protocol and that it is susceptible to spalding as shown in the photograph. Of particular interest are the fibrous threads that connect the layers. These threads have a distinctly organic appearance, resembling tissue.
Taken together, the facts that the palladium will take methylene blue stain, that the Teflon behaves differently at or near its surface where it has been treated with the protocol, and that a sustained exothermic reaction occurs at its surface demonstrate that the chemical bonding at the surface of both the palladium and the Teflon have been affected by the protocol.
The data presented above indicates that the electrical-vibratory stimuli are penetrating to the surface of the cathode and affecting it there during the protocol. However, as also stated above, the charge carriers of the electrolyte lag in their response to electric fields varying at the frequencies of the stimuli used in the protocol and no longer migrate between electrodes for the reasons given. The question then arises, how are the electrons penetrating to the surface of the cathode in this protocol?
One possibility is that the combination of electrical, vibrational and photonic stimulation of the electrodes and electrolyte somehow affects the electrons' wave-particle quality. Quantum tunneling permits transitions through classically forbidden energy states, in this case, the double-layer capacitance at the interface of the palladium and the electrolytic solution. That tunneling effect relies upon the wavelike behavior of a particle, in this case, the electron.
This protocol appears to be inducing a shift in the behavior of the electrons from particle- to wave-dominated behavior. The protocol is clearly sensitive to the frequencies of both the pulse train and the sine-wave modulation, suggesting that some resonance is involved. Further, it was observed that magnetism interferes with the protocol, suggesting that magnetism disrupts some interaction with the electromagnetic field of the electron during the protocol. Such a change in the electron's behavior implies that a quantum effect has been induced by the protocol. Alternatively, the protocol modifies the surface of the electrode in order to facilitate electronic tunneling.
Given the scope of the effects, the quantum tunneling induced by the protocol is neither isolated nor random; it occurs with massive regularity.
The specific steps of the protocol are shown below:
Step 1. Prepare a solution beginning with 25 ml of heavy water (D 2 O) in a beaker. Add 1.4 g of Lithium Sulfate Monohydrate (Li 2 SO 4 .H 2 O). Add 100 mg anionic silica hydride in the form of “MegaH−” and 0.45 ml (twenty drops) of “Super Hydrate”. Alternatively, one can use an unadulterated form of anionic silica hydride in equivalent amounts, if available.
Step 2. Then heat the solution above 90° C. on a hot plate and maintain the temperature below the boiling point for 30 minutes. Stir or swirl gently. Optionally, use a magnetic stirrer for this step; implicitly, this will subject the solution to a time-varying magnetic field. At the beginning of this interval the solution has soapy bubbles on its surface, as one would expect with a surfactant. At the end of the period the surface is clear of bubbles, or nearly so.
Step 3. Then add sufficient citric acid solution to lower pH to 8.0. The protocol requires pH be maintained between 6.5 and 8.9.
Step 4. Then condition the surface of, e.g., a palladium wire with the following process: Immerse 1 cm of a palladium wire into the solution described above as a cathode. Immerse a second palladium as an anode into the same solution to the same depth and parallel to it at a distance of 1.7 cm. Stimulate the electrodes and the gap between them for three hours with a time-varying electrical signal having the following characteristics: A series of seven pulses having a baseline at ground potential and increasing in approximately equal increments from 1.2 Volts to 6.9 Volts into a 1 M Ω impedance with a pulse repetition rate of 3.15 MHz, or a period of ˜317 ns. Each pulse is modulated with a sine wave of 50 MHz with peak-to-peak amplitude of 2 Volts. The pulse duty cycle is 50%. The pulse train increases in amplitude in a pattern of excitation followed by a period of relaxation of ˜1.6 ms. Then the pulse train repeats indefinitely. These pulses were generated with a Tektronix model AWG 2021 arbitrary waveform generator. When this stimulus is applied to the electrodes, the impedance across them will be less than the 1 M Ω specified above. It will also be more complex than the controlled impedance of an oscilloscope input. The signal will therefore have less amplitude across the electrodes and exhibit ringing. Simultaneously stimulate the electrodes and the gap between them photonically with two banks of five white LEDs with the part number SBW6018 and a maximum luminous intensity of 6,000 mcd each; they were purchased at Halted Electronics in Sunnyvale, Calif. The LEDs are pulse-modulated by frequency-hopping through the following six frequencies, dwelling at each for five minutes: 464; 1,234; 1,289; 2,008; 3,176; and 5,000 Hz with 50% duty cycles. Bubble helium and hydrogen gases into the solution to saturate it with those gases continuously at the rate of one or two bubbles per second while providing the electrical and photonic stimuli. Optionally, the hydrogen gas can be eliminated. Continue stimulating concurrently with both electrical and photonic stimuli at an elevated temperature of between 90° C. and the boiling point for three hours. Then add an additional 500 mg of Lithium Sulfate Monohydrate and apply a 10V DC across the electrodes for two hours while maintaining the temperature of the liquid in the beaker between 90° C. and 95° C. You should see gas bubbles forming on both the cathode and the anode as a result of electrolysis.
Step 5. Then initiate the exothermic reaction: Continue to bubble helium and hydrogen gases into the solution to maintain saturation with those gases. Continue to illuminate the cathode with two banks of white LEDs pulsed at 464 Hz and impose the 10-volt DC voltage across the electrodes. Raise the setting on the hot plate to increase the temperature of the solution. The bubbles will become more vigorous as the temperature approaches the boiling point. Raise the temperature of the solution to within 1° C. the boiling point. Typically, there will be a burst of bubbles on the cathode as the exothermic reaction initiates. Maintain the temperature within 3° C. of the boiling point.
Step 6. Then remove the DC voltage, the photonic stimulation, and the supply of gases. The bubbles on the anode will cease since there is now no electrolysis. Since the electrolysis will have loaded the palladium with hydrogen, the bubbles on the cathode will initially consist of both hydrogen gas and steam. The hydrogen will be depleted within tens of minutes. If the bubbles decrease, raise the temperature to within 1° C. of the boiling point and reapply the DC voltage momentarily. The exothermic reaction should start again and persist after the voltage is removed. Sustain the reaction by reapplying the voltage in this manner.
Some things have been observed that tend to inhibit this protocol during experiments, and the following cautions are offered to anyone attempting to duplicate it: 1) Use care when handling all parts of the apparatus that will be in contact with the solution. Fingerprints and other contamination inhibit the process. Using rubber gloves is recommended whenever handling the apparatus. Likewise, the apparatus should be cleaned before each run, by rinsing it with alcohol, hydrogen peroxide, and distilled water. 2) Avoid the use of metals that might readily dissolve in or chemically react with the electrolytic solution. At one point, the apparatus included copper, and that quenched the reaction. Palladium is one metal that is not chemically reactive in electrolyte and thus can treated by this protocol. 3) Avoid using a hot plate that is also a magnetic stirrer other than in Step 2 above. Results improved with a Corning ceramic hot plate Model PC 200. It appears that magnetism may interfere with the stimuli.
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A method of preparing a material surface, such as palladium, to facilitate desirable reactions, especially exothermic reactions in a liquid medium, involves placing the material whose surface is to be treated into an electrolytic cell as at least one of the electrodes and then concurrently stimulating the material electrically, vibrationally and photonically. The electrolytic cell includes a solution in water of an electrolyte, a siliceous surfactant and a pH-adjusting agent, all heated and maintained at or just below its boiling point. A series of voltage pulses are applied to the electrodes over an extended time period while also being illuminated with intensity-modulated light pulses. The material surface thus treated exhibits crater sites and silica coatings, evidencing a change in bonding of the palladium surface, as well as a sustained exothermic reaction.
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CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of application Ser. No. 11/182,874 filed Jul. 15, 2005; which is a continuation of application Ser. No. 10/300,056, now U.S. Pat. No. 6,923,827; which is a continuation of application Ser. No. 09/252,322 filed Feb. 18, 1999, now abandoned; which is a continuation of application Ser. No. 08/858,309 filed May 19, 1997, now U.S. Pat. No. 6,120,477; which is a continuation-in-part of application Ser. No. 08/673,635 filed Jun. 26, 1996, now U.S. Pat. No. 5,868,704; which is a continuation-in-part of application Ser. No. 08/532,905 filed Sep. 18, 1995, now U.S. Pat. No. 5,752,934.
FIELD OF THE INVENTION
[0002] The present invention relates to catheter balloons used in a variety of surgical procedures and to balloon covers for use with catheter balloons.
BACKGROUND OF THE INVENTION
[0003] Balloon catheters of various forms are commonly employed in a number of surgical procedures. These devices comprise a thin catheter tube that can be guided through a body conduit of a patient such as a blood vessel and a distensible balloon located at the distal end of the catheter tube. Actuation of the balloon is accomplished through use of a fluid filled syringe or similar device that can inflate the balloon by filling it with fluid (e.g., water or saline solution) to a desired degree of expansion and then deflate the balloon by withdrawing the fluid back into the syringe.
[0004] In use, a physician will guide the balloon catheter into a desired position and then expand the balloon to accomplish the desired result (e.g., clear a blockage, or install or actuate some other device). Once the procedure is accomplished, the balloon is then deflated and withdrawn from the blood vessel.
[0005] There are two main forms of balloon catheter devices. Angioplasty catheters employ a balloon made of relatively strong but generally inelastic material (e.g., polyester) folded into a compact, small diameter cross section. These relatively stiff catheters are used to compact hard deposits in vessels. Due to the need for strength and stiffness, these devices are rated to high pressures, usually up to about 8 to 12 atmospheres depending on rated diameter. They tend to be self-limiting as to diameter in that they will normally distend up to the rated diameter and not distend appreciably beyond this diameter until rupture due to over-pressurization. While the inelastic material of the balloon is generally effective in compacting deposits, it tends to collapse unevenly upon deflation, leaving a flattened, wrinkled bag, substantially larger in cross section than the balloon was when it was originally installed. Because of their tendency to assume a flattened cross section upon inflation and subsequent deflation, their deflated maximum width tends to approximate a dimension corresponding to one-half of the rated diameter times pi. This enlarged, wrinkled bag may be difficult to remove, especially from small vessels. Further, because these balloons are made from inelastic materials, their time to complete deflation is inherently slower than elastic balloons.
[0006] By contrast, embolectomy catheters employ a soft, very elastic material (e.g., natural rubber latex) as the balloon. These catheters are employed to remove soft deposits, such as thrombus, where a soft and tacky material such as latex provides an effective extraction means. Latex and other highly elastic materials generally will expand continuously upon increased internal pressure until the material bursts. As a result, these catheters are generally rated by volume (e.g., 0.3 cc) in order to properly distend to a desired size. Although relatively weak, these catheters do have the advantage that they tend to readily return to their initial size and dimensions following inflation and subsequent deflation.
[0007] Some catheter balloons constructed of both elastomeric and non-elastomeric materials have been described previously. U.S. Pat. No. 4,706,670 describes a balloon dilatation catheter constructed of a shaft made of an elastomeric tube and reinforced with longitudinally inelastic filaments. This device incorporates a movable portion of the shaft to enable the offset of the reduction in length of the balloon portion as the balloon is inflated. The construction facilitates the inflation and deflation of the balloon.
[0008] While balloon catheters are widely employed, currently available devices experience a number of shortcomings. First, as has been noted, the strongest materials for balloon construction tend to be relatively inelastic. The flattening of catheter balloons made from inelastic materials that occurs upon inflation and subsequent deflation makes extraction and navigation of a deflated catheter somewhat difficult. Contrastly, highly elastic materials tend to have excellent recovery upon deflation, but are not particularly strong when inflated nor are they self-limiting to a maximum rated diameter regardless of increasing pressure. This severely limits the amount of pressure that can be applied with these devices. It is also somewhat difficult to control the inflated diameter of these devices.
[0009] Second, in instances where the catheter is used to deliver some other device into the conduit, it is particularly important that a smooth separation of the device and the catheter balloon occur without interfering with the placement of the device. Neither of the two catheter devices described above is ideal in these instances. A balloon that does not completely compact to its original size is prone to snag the device causing placement problems or even damage to the conduit or balloon. Similarly, the use of a balloon that is constructed of tacky material will likewise cause snagging problems and possible displacement of the device. Latex balloons are generally not used for device placement in that they are considered to have inadequate strength for such use. Accordingly, it is a primary purpose of the present invention to create a catheter balloon that is small and slippery for initial installation, strong for deployment, and returns to its compact size and dimensions for ease in removal and further navigation following deflation. It is also believed desirable to provide a catheter balloon that will remain close to its original compact pre-inflation size even after repeated cycles of inflation and deflation. Other primary purposes of the present invention are to strengthen elastic balloons, to provide them with distension limits and provide them with a lubricious outer surface. The term “deflation” herein is used to describe a condition subsequent to inflation. “Pre-inflation” is used to describe the condition prior to initial inflation.
SUMMARY OF THE INVENTION
[0010] The present invention is an improved balloon catheter device for use in a variety of surgical procedures. The balloon catheter device of the present invention comprises a catheter tube having a continuous lumen connected to an inflatable and deflatable balloon at one end of the catheter tube. The catheter tube may have additional lumens provided for other purposes. The balloon can have a burst strength equal to or greater than that of conventional PTA catheter balloons. The balloon also has a maximum inflation diameter in a similar fashion to conventional PTA catheter balloons. The inventive balloon offers the recovery characteristics of a latex balloon that when deflated is of about the same maximum diameter as it was prior to inflation. This allows the inventive balloon to be withdrawn following deflation more easily than conventional PTA balloons which assume a flattened, irregular cross section following deflation and so have a deflated maximum diameter much larger than the pre-inflation maximum diameter. The balloon also has a smooth and lubricious surface which also aids in insertion and withdrawal. The inventive balloon possesses all of the above attributes even when made in small sizes heretofore commercially unavailable in balloon catheters without a movable portion of the catheter shaft or some other form of mechanical assist. The present invention eliminates the need for a movable portion of the shaft and associated apparatuses to aid in balloon deflation.
[0011] The present invention is made from polytetrafluoroethylene (hereinafter PTFE) materials and elastomeric materials. The PTFE is preferably porous PTFE made as taught by U.S. Pat. Nos. 3,953,566 and 4,187,390, both of which are incorporated by reference herein. An additional optional construction step, longitudinally compressing a porous PTFE tube prior to addition of the elastomeric component, allows the balloon or balloon cover to sufficiently change in length to enable the construction of higher pressure balloons, again without the need for mechanical assist. Particularly small sizes (useful in applications involving small tortuous paths such as is present in brain, kidney, and liver procedures) can be achieved by decreasing the wall thickness of the balloon via impregnation of a porous PTFE tube with silicone adhesive, silicone elastomer, silicone dispersion, polyurethane or another suitable elastomeric material instead of using a separate elastomeric member. Impregnation involves at least partially filling the pores of the porous PTFE. The pores (void spaces) are considered to be the space or volume within the bulk volume of the porous PTFE material (i.e., within the overall length, width and thickness of the of the porous PTFE material) not occupied by PTFE material. The void spaces of the porous PTFE material from which the balloon is at least partially constructed may be substantially sealed in order that the balloon is liquid-tight at useful pressures by either the use of a separate tubular elastomeric substrate in laminated relationship with the porous PTFE, or by impregnation of the void spaces of the porous PTFE with elastomeric material, or by both methods. U.S. Pat. No. 5,519,172 teaches in detail the impregnation of porous PTFE with elastomers. In that this patent relates primarily to the construction of a jacket material for the protection of electrical conductors, the suitability of each of the various described materials for in vivo use as catheter balloon materials must be considered.
[0012] The balloon may be made from the materials described herein as a complete, stand-alone balloon or alternatively may be made as a cover for either conventional polyester PTA balloons or for latex embolectomy balloons. The use of the balloon cover of the present invention provides the covered balloon, regardless of type, with the best features of conventional PTA balloons and renders viable the use of elastic balloons for PTA procedures. That is to say, the covered balloon will have high burst strength, a predetermined maximum diameter, the ability to recover to substantially its pre-inflation size following deflation, and a lubricious exterior surface (unless it is desired to construct the balloon such that the elastomeric material is present on the outer surface of the balloon). The balloon cover substantially reduces the risk of rupture of an elastic balloon. Further, if rupture of the underlying balloon should occur, the presence of the balloon cover may serve to contain the fragments of the ruptured balloon. Still further, the inventive balloon and balloon cover can increase the rate of deflation of PTA balloons thereby reducing the time that the inflated balloon occludes the conduit in which it resides.
[0013] The present invention also enables the distension of a vessel and side branch or even a prosthesis within a vessel and its side branch without exerting significant force on the vessel or its branch. Further, it has been shown to be useful for flaring the ends of prostheses, thereby avoiding unwanted constrictions at the ends of the prostheses. Prostheses can slip along the length of prior art balloons during distension; the present invention not only reduces such slippage, it also can be used to create a larger diameter at the end of the graft than prior art materials.
[0014] The inventive balloon and balloon cover also maintain a substantially circular cross section during inflation and deflation in the absence of external constraint. Plus, the balloon and balloon cover can be designed to inflate at lower pressure in one portion of the length than another. This can be accomplished, for example, by altering the thickness of the elastomer content along the length of the balloon in order to increase the resistance to distension along the length of the balloon. Alternatively, the substrate tube may be constructed with varying wall thickness or varying amounts of helically-applied film may be applied along the tube length in order to achieve a similar effect.
[0015] The balloon catheter according to the present invention has opposing ends affixed to the catheter by opposing securing means. The balloon has a length measured between the opposing ends wherein the length preferably varies less than about ten percent, and more preferably less than about five percent, between when the balloon is in a deflated state and when the balloon is inflated to a pressure of eight atmospheres.
[0016] Balloons of the present invention can also be constructed to elute fluids at pressures exceeding the balloon inflation pressure. Such balloons could have utility in delivering drugs inside a vessel.
[0017] A catheter balloon of the present invention is anticipated to be particularly useful for various surgical vascular procedures, including graft delivery, graft distension, stent delivery, stent distension, and angioplasty. It may have additional utility for various other surgical procedures such as, for example, supporting skeletal muscle left ventricular assist devices during the healing and muscle conditioning period and as an intra-aortic balloon.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] FIGS. 1A, 1B and 1 C are perspective views describing manufacture of the tubular component forming the balloon or balloon cover of the present invention.
[0019] FIG. 2 is a perspective view describing the tubular component as it appears when inflated.
[0020] FIGS. 3A and 3B describe longitudinal cross sectional views of a balloon cover of the present invention without elastomer.
[0021] FIGS. 4A and 4B describe longitudinal cross sectional views of a balloon cover of the present invention incorporating a layer of elastomer.
[0022] FIGS. 5A and 5B describe longitudinal cross sectional views of a catheter balloon of the present invention having the same material construction as the balloon cover of FIGS. 4A and 4B .
[0023] FIGS. 6A, 6B and 6 C describe longitudinal cross sectional views of a catheter balloon of the type described by FIGS. 5A and 5B using a non-elastomeric material in place of the layer of elastomer.
[0024] FIG. 7 describes a transverse cross section taken at the center of the length of a flattened, deflated angioplasty balloon which describes how the compaction efficiency ratio of the deflated balloon is determined.
[0025] FIG. 8 describes a longitudinal cross section of a balloon affixed to the shaft of a dual lumen catheter, the balloon having a first PTFE material oriented substantially parallel to the longitudinal axis of the balloon and a second PTFE material oriented substantially circumferential to the longitudinal axis, wherein the PTFE materials is impregnated with an elastomer.
[0026] FIG. 8A describes a longitudinal cross section of an alternative embodiment to that of FIG. 8 wherein the balloon during inflation exhibits a larger diameter at a first portion of its length than at a second portion of its length.
[0027] FIGS. 9 and 9 A describe cross sections of the proximal end of a balloon catheter of the present invention.
[0028] FIGS. 10A-10F describe the construction of an alternative embodiment of a balloon catheter of the present invention wherein the balloon has separate substrate layers of an elastomeric material and a porous PTFE material in laminated relationship and wherein each end of each substrate material is separately affixed to a catheter shaft by separate wrappings of porous PTFE film.
[0029] FIGS. 11A, 11B and 11 C describe the construction of an alternative embodiment of a balloon catheter of the present invention similar to that of FIGS. 10A-10F wherein a catheter shaft is used which comprises a tubular elastomeric material provided with a reinforcing wrapping of porous PTFE film.
[0030] FIGS. 12A, 12B and 12 C describe the construction of an alternative embodiment of a balloon catheter of the present invention wherein a laminated tube of separate substrates of an elastomeric material and helically wrapped porous PTFE film are affixed to a catheter shaft by a wrapping of porous PTFE film at each end of the laminated tube.
DETAILED DESCRIPTION OF THE INVENTION
[0031] The catheter balloon and catheter balloon cover of the present invention are preferably made from porous PTFE films having a microstructure of interconnected fibrils. These films are made as taught by U.S. Pat. Nos. 3,953,566 and 4,187,390. The balloon and balloon cover may also incorporate a porous PTFE substrate tube in the form, for example, of an extruded and expanded tube or a tube constructed of film containing at least one seam. Also, the balloon may be impregnated with an elastomeric material.
[0032] To form the balloon or balloon cover, both of which are made in the shape of a tube, a thin, porous PTFE film of the type described above is slit into relatively narrow lengths. The slit film is helically wrapped onto the surface of a mandrel in two opposing directions, thereby forming a tube of at least two layers. FIGS. 1A, 1B and 1 C describe this procedure. FIG. 1A shows the first layer 14 of porous PTFE film helically wrapped over the mandrel 12 with the traverse direction of the wrap applied in a first direction 20 parallel to the longitudinal axis 18 . The longitudinal axis of a balloon is defined as coincident with the longitudinal axis of the balloon catheter shaft, that is along the length of the shaft. Substantially parallel is defined as between about 0° and 45°, or between about 135° and 180°, with respect to the longitudinal axis of the catheter shaft and substantially circumferential is defined as between about 45° and 135° with respect to the longitudinal axis of the catheter shaft. FIG. 1B describes the application of the second layer of porous PTFE film 16 helically wrapped over the top of the first layer 14 , wherein second layer 16 is wrapped in a second traverse direction 22 parallel to longitudinal axis 18 and opposite to the first traverse direction 20 .
[0033] Preferably both layers 14 and 16 are wrapped with the same pitch angle measured with respect to the longitudinal axis but measured in opposite directions. If, for example, film layers 14 and 16 are applied at pitch angles of 70° measured from opposite directions with respect to longitudinal axis 18 , then included angle A between both 70° pitch angles is 40°.
[0034] More than two layers of helically wrapped film may be applied. Alternate layers of film should be wrapped from opposing directions and an even number of film layers should be used whereby an equal number of layers are applied in each direction.
[0035] Following completion of film wrapping, the helically wrapped mandrel is placed into an oven for suitable time and temperature to cause adjacent layers to heat-bond together. After removal from the oven and subsequent cooling, the resulting film tube may be removed from the mandrel. The film tube is next placed over the balloon, tensioned longitudinally and affixed in place over the balloon.
[0036] During use, the inflated balloon or balloon cover 10 of the present invention has an increased diameter which results in included angle A being substantially reduced as shown by FIG. 2 . The balloon or balloon cover thus reaches its pre-determined diametrical limit as included angle A approaches zero.
[0037] The inventive balloon or balloon cover 10 is reduced in diameter following deflation by one of two ways. First, tension may be applied to the balloon or balloon cover parallel to longitudinal axis 18 to cause it to reduce in diameter following deflation to the form described by FIG. 1C . The application of tension is necessary if low profile is desired. Alternatively, a layer of elastomer, applied to the luminal surface of the balloon 10 and allowed to cure prior to use of the balloon, will cause the balloon to retract to substantially its pre-inflation size shown by FIG. 1C following deflation. The elastomer may take the form of a coating of elastomer applied directly to the luminal surface of the balloon or balloon cover 10 , or an elastomeric balloon such as a latex balloon or a silicone tube may be adhered to the luminal surface of the inventive balloon 10 by the use of an elastomeric adhesive. Alternatively, elastomer can be impregnated into the porous material to create a balloon or balloon cover.
[0038] FIG. 3A describes a cross sectional view of a balloon cover 10 of the present invention in use with a conventional balloon catheter of either the angioplasty or embolectomy type. The figure describes a balloon cover without an elastomeric luminal coating. The balloon cover 10 is closed at distal end 26 of the balloon catheter 11 . Balloon cover 10 extends in length part of the way to the proximal end 27 of balloon catheter 11 whereby balloon cover 10 completely covers catheter balloon 25 and at least a portion of the catheter 11 . FIG. 3B describes the same balloon catheter 11 with catheter balloon 25 in an inflated state. Layers 14 and 16 of balloon cover 10 allow the cover to increase in diameter along with catheter balloon 25 . During or following deflation of catheter balloon 25 , tension is applied to the balloon cover 10 at the proximal end 27 of balloon catheter 11 as shown by arrows 28 , thereby causing balloon cover 10 to reduce in diameter and substantially return to the state described by FIG. 3A . FIG. 4A describes a cross sectional view of a balloon cover 10 of the present invention wherein the balloon cover 10 has a liquid-tight layer of elastomer 34 applied to the inner surface of helically wrapped porous PTFE film layers 14 and 16 . Balloon cover 10 is closed at distal end 26 . The figure describes a ligated closure, such as by a thread or filament, however, other suitable closing means may be used. Proximal end 27 of balloon cover 10 is affixed to the distal end 32 of catheter 24 . Balloon 25 may be of either the angioplasty or embolectomy type. If an elastomeric embolectomy balloon is used, it is preferred that the cover be adhered to the balloon by the use of an elastomeric adhesive to liquid-tight layer of elastomer 34 . During inflation of balloon 25 as shown by FIG. 4B , helically wrapped porous PTFE film layers 14 and 16 and liquid-tight elastomer layer 34 increase in diameter along with balloon 25 . During subsequent deflation, liquid-tight elastomer layer 34 causes helically wrapped porous PTFE film layers 14 and 16 to reduce in diameter as described previously, thereby returning substantially to the state described by FIG. 4A .
[0039] FIGS. 5A and 5B describe cross sectional views of a catheter balloon 10 made in the same fashion as the balloon cover described by FIGS. 4A and 4B . The presence of liquid-tight elastomer layer 34 allows this construction to function as an independent balloon 42 as described previously without requiring a conventional angioplasty or embolectomy balloon.
[0040] FIGS. 6A, 6B and 6 C describe cross sectional views of an alternative embodiment of the catheter balloon 10 of the present invention. According to this embodiment helically wrapped porous PTFE film layers 14 and 16 are provided with a luminal coating 44 which is liquid-tight but is not elastomeric. The resulting balloon behaves in the fashion of a conventional angioplasty balloon but offers the advantages of a lubricious and chemically inert exterior surface. FIG. 6A describes the appearance of the balloon prior to inflation. FIG. 6B describes the balloon in an inflated state. As shown by FIG. 6C , following deflation, collapsed balloon 46 has a somewhat wrinkled appearance and an irregular transverse cross section in the same fashion as a conventional angioplasty balloon made from polyester or similar inelastic material.
[0041] It is also anticipated that the balloon and balloon cover of the present invention may be provided with an additional reinforcing mesh or braid on the exterior or interior surface of the balloon (or balloon cover), or more preferably between layers of the film whereby the mesh or braid is in the middle.
[0042] Alternatively, a mesh or braid of PTFE may be used as a balloon cover without including a continuous tube. A continuous tube does not include openings through its wall as does a conventional mesh or braid.
[0043] The following examples describe in detail the construction of various embodiments of the balloon cover and catheter balloon of the present invention. Evaluation of these balloons is also described in comparison to conventional angioplasty and embolectomy balloons. FIG. 7 is provided as a description of the maximum dimension 72 and minimum dimension 74 (taken transversely to the longitudinal axis of the balloon) of a flattened, deflated angioplasty balloon 70 wherein the figure describes a transverse cross section of a typical flattened angioplasty balloon. The transverse cross section shown is meant to describe a typical deflated, flattened inelastic angioplasty balloon 70 having a somewhat irregular shape. Balloon 70 includes a catheter tube 76 having a guidewire lumen 78 and a balloon inflation lumen 79 and two opposing sides 82 and 84 of balloon 70 . Maximum dimension 72 may be considered to be the maximum width of the flattened balloon 70 while minimum dimension 74 may be considered to be the maximum thickness across the two opposing sides 82 and 84 of the flattened balloon 70 . All balloon and catheter measurements are expressed in terms of dimensions even if the shape is substantially circular.
EXAMPLE 1
[0044] This example illustrates the use of a balloon cover of the present invention over a commercially available angioplasty balloon. The balloon cover provides a means of returning the angioplasty balloon close to its original compact geometry after inflation and subsequent deflation, as well as providing the known chemical inertness and low coefficient of friction afforded by PTFE.
[0045] The balloon used was a MATCH 35® Percutaneous Transluminal Angioplasty (PTA) Catheter model number B508-412, manufactured by SCHNEIDER (Minneapolis, Minn.). This balloon when measured immediately after being removed from the protective sheath provided by the manufacturer had a minimum dimension of 2.04 mm and a maximum dimension of 2.42 mm. These measurements were taken from approximately the center of the balloon, as defined by the midpoint between the circumferentially-oriented radiopaque marker bands located at both ends of the balloon. A Lasermike model 183, manufactured by Lasermike, (Dayton, Ohio) was used to make the measurements while the balloon was rotated about its longitudinal axis. The shaft onto which the balloon was attached had a minimum dimension of 1.74 mm and a maximum dimension of 1.77 mm measured adjacent to the point of balloon attachment closest to the center of the length of the shaft. The balloon, when inflated to 8 atmospheres internal water pressure, had a minimum dimension of 8.23 mm and a maximum dimension of 8.25 mm at the center of the length of the balloon. When deflated by removing the entire volume of water introduced during the 8 atmosphere pressurization, the balloon at its mid-length, had a minimum dimension of 1.75 mm, and a maximum dimension of 11.52 mm as measured using Mitutoyo digital caliper model CD-6″P. Upon completion of the measurements the balloon portion of the PTA catheter was carefully repackaged into the protective sheath.
[0046] The inventive balloon cover was made from a length of porous PTFE film made as described above cut to a width of 2.5 cm. The film thickness was approximately 0.02 mm, the density was 0.2 g/cc, and the fibril length was approximately 70 microns. Thickness was measured using a Mitutoyo snap gauge model 2804-10 and density was calculated based on sample dimensions and mass. Fibril length of the porous PTFE films used to construct the examples was estimated from scanning electron photomicrographs of an exterior surface of film samples.
[0047] This film was helically wrapped onto the bare surface of an 8 mm diameter stainless steel mandrel at an angle of approximately 70° with respect to the longitudinal axis of the mandrel so that about 5 overlapping layers of film cover the mandrel. Following this, another 5 layers of the same film were helically wrapped over the first 5 layers at the same pitch angle with respect to the longitudinal axis, but in the opposite direction. The second 5 layers were therefore also oriented at an approximate angle of 70°, but measured from the opposite end of the axis in comparison to the first 5 layers. Following this, another 5 layers of the same film were helically wrapped over the first and second 5 layers at the same bias angle with respect to the longitudinal axis as the first 5 layers, and then another 5 layers of the same film were helically wrapped over the first, second, and third 5 layers at the same bias angle with respect to the longitudinal axis as the second 5 layers. This resulted in a total of about 20 layers of helically wrapped film covering the mandrel.
[0048] The film-wrapped mandrel was then placed into an air convection oven set at 380° C. for 10 minutes to heat bond the layers of film, then removed and allowed to cool. The resulting 8 mm inside diameter film tube formed from the helically wrapped layers was then removed from the mandrel and one end was ligated onto a self-sealing injection site (Injection Site with Luer Lock manufactured by Baxter Healthcare Corporation, Deerfield, Ill.). A hole was created through the injection site, and the balloon end of the previously measured PTA catheter was passed through this hole, coaxially fitting the film tube over the balloon portion as well as a portion of the shaft of the PTA catheter. The film tube was approximately 25 cm in length. With the film tube over the PTA catheter and attached to the injection site, tension was applied manually to the free end of the film tube while the injection site was held fixed, causing the film tube to reduce in diameter and fit snugly onto the underlying segment of PTA catheter. Next, the film tube was ligated at the distal end of the PTA catheter shaft so that the balloon cover remained taut and snugly fit.
[0049] At this point the now covered balloon was measured in a deflated state. The minimum dimension was found to be 2.33 mm and the maximum dimension 2.63 mm. As before, these measurements were taken from approximately the center of the balloon, as defined by the midpoint between the radiopaque marker bands, and a Lasermike model 183, manufactured by Lasermike, (Dayton, Ohio) was used to make the measurements. The balloon, when inflated to 8 atmospheres internal water pressure had a minimum dimension of 7.93 mm and a maximum dimension of 8.06 mm at the center of the balloon. When deflated by removing the entire volume of water introduced during the 8 atmosphere pressurization, the balloon at its mid-length, had a minimum dimension of 1.92 mm and a maximum dimension of 11.17 mm. Next, tension was manually applied to the injection site causing the balloon cover to reduce the size of the underlying balloon, particularly along the plane of the 11.17 mm measurement taken previously. After the application of tension the covered balloon was measured again, and the minimum and maximum dimensions were found as 3.43 and 3.87 mm respectively.
[0050] This example shows that the balloon cover can be used effectively to compact a PTA balloon which was inflated and subsequently deflated to approximately the geometry of the balloon in an unused state. The measurements taken on the balloon (in both the uncovered and covered states) after inflation and subsequent deflation show that rather than undergoing a uniform circular compaction, the balloon tended to flatten. This flattening can be quantified by calculating the ratio of the minimum dimension to the maximum dimension measured after inflation and subsequent deflation. This ratio is defined as the compaction efficiency ratio. Note that a circular cross section yields a compaction efficiency ratio of unity. For this example, the uncovered balloon had a compaction efficiency ratio of 1.75 divided by 11.52, or 0.15. The balloon, after being provided with the inventive balloon cover, had a compaction efficiency ratio of 3.43 divided by 3.87, or 0.89. Additionally, the ratio of the maximum dimension prior to any inflation, to the maximum dimension after inflation and subsequent deflation, is defined as the compaction ratio. A balloon which has the same maximum dimension prior to any inflation, and after inflation and subsequent deflation, has a compaction ratio of unity. For this example, the uncovered balloon had a compaction ratio of 2.42 divided by 11.52, or 0.21. The balloon, after being provided with the inventive balloon cover, had a compaction ratio of 2.63 divided by 3.87, or 0.68.
EXAMPLE 2
[0051] This example illustrates the use of a balloon cover over a commercially available latex embolectomy balloon. The balloon cover provides a defined limit to the growth of the embolectomy balloon, a substantial increase in burst strength, and the known chemical inertness and low coefficient of friction afforded by PTFE.
[0052] The balloon used was a Fogarty® Thru-Lumen Embolectomy Catheter model 12TL0805F manufactured by Baxter Healthcare Corporation (Irvine, Calif.). This natural rubber latex balloon when measured immediately after being removed from the protective sheath provided by the manufacturer had a minimum dimension of 1.98 mm and a maximum dimension of 2.02 mm. These measurements were taken from approximately the center of the balloon, as defined by the midpoint between the radiopaque marker bands. A Lasermike model 183, manufactured by Lasermike, (Dayton, Ohio) was used to make the measurements while the balloon was rotated about its longitudinal axis. The shaft onto which the balloon was attached had a minimum dimension of 1.64 mm and a maximum dimension of 1.68 mm measured adjacent to the point of balloon attachment closest to the center of the length of the shaft. The balloon, when filled with 0.8 cubic centimeters of water had a minimum dimension of 10.71 mm and a maximum dimension of 10.77 mm at the center of the balloon. When deflated by removing the entire volume of water introduced, the balloon at its mid-length, had a minimum dimension of 1.97 mm and a maximum dimension of 2.04 mm. The balloon when tested using a hand-held inflation syringe had a burst strength of 60 psi.
[0053] Another embolectomy catheter of the same type was covered using a porous PTFE film tube made as described in Example 1. The method used to cover the embolectomy catheter was the same as that used to cover the PTA catheter in Example 1.
[0054] At this point, the now covered balloon was measured in a pre-inflated state. The minimum dimension was found to be 2.20 mm and the maximum dimension 2.27 mm. As before, these measurements were taken from approximately the center of the balloon, as defined by the midpoint between the radiopaque marker bands, and a Lasermike model 183, manufactured by Lasermike (Dayton, Ohio) was used to make the measurements. The balloon, when filled with 0.8 cubic centimeters of water had a minimum dimension of 8.29 mm and a maximum dimension of 8.34 mm at mid-length. When deflated by removing the entire volume of water introduced, the balloon at its mid-length, had a minimum dimension of 3.15 mm and a maximum dimension of 3.91 mm. Next, tension was manually applied to the injection site causing the balloon cover to reduce in size. After the application of tension the covered balloon was measured again, and the minimum and maximum dimensions were found as 2.95 and 3.07 mm respectively. The covered balloon was determined to have a burst strength of 188 psi, failing solely due the burst of the underlying embolectomy balloon. The inventive balloon cover exhibited no indication of rupture.
[0055] This example shows that the inventive balloon cover effectively provides a limit to the growth, and a substantial increase in the burst strength of an embolectomy balloon. The measurements taken on the uncovered balloon show that when filled with 0.8 cubic centimeters of water the balloon reached a maximum dimension of 10.77 mm. Under the same test conditions, the covered balloon reached a maximum dimension of 8.34 mm. The burst strength of the uncovered balloon was 60 psi while the burst strength of the covered balloon was 188 psi when inflated until rupture using a hand-operated liquid-filled syringe. This represents more than a three fold increase in burst strength.
EXAMPLE 3
[0056] This example illustrates the use of a composite material in a balloon application. A balloon made from the composite material described below exhibits a predictable inflated diameter, high strength, exceptional compaction ratio and compaction efficiency ratio, as well as the known chemical inertness and low coefficient of friction afforded by PTFE.
[0057] A length of SILASTIC®aRx50 Silicone Tubing manufactured by Dow Corning Corporation (Midland, Mich.) having an inner diameter of 1.5 mm and an outer diameter of 2.0 mm was fitted coaxially over a 1.1 mm stainless steel mandrel and secured at both ends. The silicone tubing was coated with a thin layer of Translucent RTV 108 Silicone Rubber Adhesive Sealant manufactured by General Electric Company (Waterford, N.Y.). An 8 mm inner diameter film tube made in the same manner described in Example 1 was fitted coaxially over the stainless steel mandrel and the silicone tubing. Tension was manually applied to the ends of the film tube causing it to reduce in diameter and fit snugly onto the underlying segment of silicone tubing secured to the stainless steel mandrel. With the film tube in substantial contact with the silicone tubing, this composite tube was gently massaged to ensure that no voids were present between the silicone tube and the porous PTFE film tube. Next the entire silicone-PTFE composite tube was allowed to cure in an air convection oven set at 35° C. for a minimum of 12 hours. Once cured, the composite tube was removed from the stainless steel mandrel. One end of the composite tube was then fitted coaxially over a section of 5 Fr catheter shaft taken from a model B507-412 MATCH 35® Percutaneous Transluminal Angioplasty (PTA) Catheter, manufactured by SCHNEIDER (Minneapolis, Minn.) and clamped to the catheter shaft using a model 03.3 RER Ear Clamp manufactured by Oetiker (Livingston, N.J.) such that a watertight seal was present. The distal end of the balloon was closed using hemostats for expediency, however, a conventional ligature such as waxed thread may be used to provide a suitable closure. In this manner a balloon catheter was fashioned, utilizing the silicone-PTFE composite tube as the balloon material.
[0058] At this point, the balloon was measured in a pre-inflated state. The minimum dimension was found to be 2.31 mm and the maximum dimension 2.42 mm. As before, these measurements were taken from approximately the midpoint of the balloon, and a Lasermike model 183, manufactured by Lasermike, (Dayton, Ohio) was used to make the measurements while the balloon was rotated about its longitudinal axis. The balloon, when inflated to 8 atmospheres internal water pressure, had a minimum dimension of 7.64 mm and a maximum dimension of 7.76 mm at the center of the balloon. When deflated by removing the entire volume of water introduced during the 8 atmosphere pressurization, the balloon at its mid-length, had a minimum dimension of 2.39 mm and a maximum dimension of 2.57 mm. The silicone-PTFE composite balloon when tested using a hand-held inflation device had a burst strength of 150 psi, reaching a maximum dimension of about 7.9 mm prior to rupture.
[0059] This example illustrates that the balloon made from the silicone-PTFE composite tube exhibited a predictable limit to its diametrical growth as demonstrated by the destructive burst strength test wherein the balloon did not exceed the 8 mm diameter of the porous PTFE film tube component. The compaction ratio as previously defined was 2.42 divided by 2.57, or 0.94, and the compaction efficiency ratio as previously defined was 2.39 divided by 2.57, or 0.93.
EXAMPLE 4
[0060] This example describes the construction of a PTA balloon made by helically wrapping a porous PTFE film having a non-porous FEP coating over a thin porous PTFE tube.
[0061] The FEP-coated porous expanded PTFE film was made by a process which comprises the steps of:
a) contacting a porous PTFE film with another layer which is preferably a film of FEP or alternatively of another thermoplastic polymer; b) heating the composition obtained in step a) to a temperature above the melting point of the thermoplastic polymer; c) stretching the heated composition of step b) while maintaining the temperature above the melting point of the thermoplastic polymer; and d) cooling the product of step c).
[0066] In addition to FEP, other thermoplastic polymers including thermoplastic fluoropolymers may also be used to make this coated film. The adhesive coating on the porous expanded PTFE film may be either continuous (non-porous) or discontinuous (porous) depending primarily on the amount and rate of stretching, the temperature during stretching, and the thickness of the adhesive prior to stretching.
[0067] The FEP-coated porous PTFE film used to construct this example was a continuous (non-porous) film. The total thickness of the coated film was about 0.02 mm. The film was helically wrapped onto an 8 mm diameter stainless steel mandrel that had been coaxially covered with a porous expanded PTFE tube, made as taught by U.S. Pat. Nos. 3,953,566 and 4,187,390. The porous PTFE tube was a 3 mm inside diameter tube having a wall thickness of about 0.10 mm and a fibril length of about 30 microns. Fibril length is measured as taught by U.S. Pat. No. 4,972,846. The 3 mm tube had been stretched to fit snugly over the 8 mm mandrel. The FEP-coated porous PTFE film was then wrapped over the outer surface of this porous PTFE tube in the same manner as described by Example 1, with the FEP-coated side of the film placed against the porous PTFE tube surface. The wrapped mandrel was placed into an air convection set at 380° C. for 2.5 minutes, removed and allowed to cool, at which time the resulting tube was removed from the mandrel. One end of this tube was fitted coaxially over the end of a 5 Fr catheter shaft taken from a model number B507-412 PTA catheter manufactured by Schneider (Minneapolis, Minn.), and clamped to the catheter shaft using a model 03.3 RER Ear Clamp manufactured by Oetiker (Livingston, N.J.) such that a watertight seal was present. The resulting balloon was packed into the protective sheath which was provided by Schneider as part of the packaged balloon catheter assembly. The balloon was then removed from the protective sheath by sliding the sheath proximally off of the balloon and over the catheter shaft. Prior to inflation, the minimum and maximum diameters of the balloon were determined to be 2.25 and 2.61 mm. The distal end of the balloon was then closed using hemostats for expediency, however, a conventional ligature such as waxed thread could have been used to provide a suitable closure. When inflated to a pressure of 6 atmospheres, the minimum and maximum diameters were 8.43 and 8.49 mm. After being deflated the minimum and maximum diameters were 1.19 and 12.27 mm. These diameters resulted in a compaction ratio of 0.21 and a compaction efficiency of 0.10.
EXAMPLE 5
[0068] This example describes a balloon constructed by impregnating silicone dispersion into a porous PTFE tube with helically applied porous PTFE film. A balloon made in this way exhibits a very small initial diameter, predictable inflated diameter, high strength, exceptional compaction ratio and compaction efficiency ratio, as well as the known chemical inertness and low coefficient of friction afforded by PTFE. The impregnation with silicone dispersion enables the construction of a thinner balloon. The use of a thin porous PTFE tube as a substrate provides longitudinal strength to resist elongation of the balloon at high pressures.
[0069] A longitudinally extruded and expanded porous PTFE substrate tube was obtained. The substrate tube was 1.5 mm inside diameter, having a wall thickness of about 0.17 mm and a fibril length of about 45 microns. The tube was fitted coaxially onto a 1.5 mm diameter stainless steel mandrel. Next, a length of porous expanded PTFE film was obtained that had been cut to a width of 2.54 cm. This film had a thickness of about 0.02 mm, a density of about 0.2 g/cc, and a fibril length of about 70 microns. Thickness was measured using a Mitutoyo snap gauge model No. 2804-10. The film bulk density was calculated based on dimensions and mass of a film sample. Density of non-porous PTFE was considered to be 2.2 g/cc. Fibril length of the porous PTFE film used to construct the example was estimated from scanning electron photomicrographs of an exterior surface of samples of the film.
[0070] This film was helically wrapped directly onto the bare metal surface of a 7 mm diameter stainless steel mandrel at about 65° with respect to the longitudinal axis of the mandrel so that about two overlapping layers of film covered the mandrel. Both edges of the film were colored with black ink in order to measure the pitch angles of the film during the construction or use of the completed balloon. Following this, another approximately two layers of the same film were helically wrapped over the first two layers. The second two layers were applied at the same bias angle with respect to the longitudinal axis, but in the opposite direction. This procedure was repeated three times, providing approximately 16 total layers of film. The film-wrapped mandrel was then placed into a convection oven set at 380° C. for 10 minutes to heat-bond the adjacent layers of film, then removed and allowed to cool. The resulting 7 mm inside diameter film tube formed from the helically wrapped layers of films was then removed from the mandrel.
[0071] This 7 mm inside diameter porous PTFE film tube was then fitted coaxially over the 1.5 mm inside diameter PTFE substrate tube and mandrel. The film tube was then tensioned longitudinally to cause it to reduce in diameter to the extent that it fit snugly over the outer surface of the 1.5 mm tube. The ends of this reinforced tube were then secured to the mandrel in order to prevent longitudinal shrinkage during heating. The combined tube and mandrel assembly was placed into an air convention oven set at 380° C. for 190 seconds to heat bond the film tube to the outer surface of the substrate tube. The reinforced tube and mandrel assembly was then removed from the oven and allowed to cool.
[0072] Additional porous PTFE film was then helically applied to outer surface of the reinforced tube to inhibit wrinkling of the tube in the subsequent step. The tube was then compressed in the longitudinal direction to reduce the tube length to approximately 0.6 of the length just prior to this compression step. Care was taken to ensure a high degree of uniformity of compression along the length of the tube. Wire was used to temporarily affix the ends of the tube to the mandrel. The mandrel-loaded reinforced tube with the additional helically applied film covering was then placed into a convention oven set at 380° C. for 28 seconds, removed from the oven and allowed cool.
[0073] The additional outer film was removed from the reinforced tube, followed by removing the reinforced tube from the mandrel. The reinforced tube was then gently elongated by hand to a length of about 0.8 of the length just prior to the compression step.
[0074] The reinforced tube was then ready for impregnation with silicone dispersion (Medical Implant Grade Dimethyl Silicone Elastomer Dispersion in Xylene, Applied Silicone Corp., PN 40000, Ventura, Calif.). The silicone dispersion was first prepared by mixing 2.3 parts n-Heptane (J.T. Barker, lot #J07280) with one part silicone dispersion. Another mixture with n-Heptane was prepared by mixing 0.5 parts with 1 part silicone dispersion. Each mixture was loaded into an injection syringe.
[0075] The dispensing needle of each of the injection syringes was inserted inside one end of the reinforced tube. Wire was used to secure the tube around the needles. One of the dispensing needles was capped and the syringe containing the 2.3:1 silicone dispersion solution was connected to the other. The solution was dispensed inside the reinforced tube with about 6 psi pressure. Pressure was maintained for approximately one minute, until the outer surface of the tube started to become wetted with the solution, indicating that the dispersion entered the pores of the PTFE material. It was ensured that the silicone dispersion coated the inside of the PTFE tube. At this point, the syringe was removed, the cap was removed from the other needle, and the syringe containing the 0.5:1 silicone dispersion solution was connected to the previously-capped needle. This higher viscosity dispersion was then introduced into the tube with the syringe, displacing the lower viscosity dispersion through the needle at the other end, until the higher viscosity dispersion began to exit the tube through the needle. After ensuring that the tube was completely filled with dispersion, both needles were capped. Curing of the silicone dispersion was effected by heating the assembly in a convection oven set at 150° C. for a minimum of one hour. The solvent evaporated during the curing process, thereby recreating the lumen in the tube. The impregnated reinforced tube was removed from the oven and allowed to cool. Both ends of the tube were opened and the 0.5:1 silicone dispersion solution was injected in one end to again fill the lumen, the needle ends were then capped, then the dispersion was cured in the same manner as described above. At this point the balloon construction was complete.
[0076] The above-described process preserved PTFE as the outermost surface of the balloon. Alternatively, longer impregnation times or higher injection pressures during the initial impregnation could cause more thorough wetting of the PTFE structure with the silicone dispersion, thereby driving more dispersion to the outermost surface of the balloon.
[0077] The balloon was then ready for mounting on a 5 Fr catheter shaft obtained from a balloon dilatation catheter (Schneider Match 35 PTA Catheter, 6 mm dia., 4 cm length, model no. B506-412) This balloon was mounted on the 1.67 mm diameter catheter shaft as described by FIG. 8 . Both ends of the balloon were mounted to the shaft. The catheter tip portion plus the balloon of the balloon dilatation catheter were cut off in the dual lumen portion of the shaft leaving only the catheter shaft 24 . Guidewires serving as mandrels (not shown) were inserted into both lumens of the shaft. A 0.32 mm mandrel was inserted into the inflation lumen 87 and a 0.6 mm mandrel was inserted into the wire lumen 83 . The portion 24 A of the shaft 24 containing the inflation lumen 87 was shaved off longitudinally to a length approximately 1 cm longer than the length of the balloon to be placed on the shaft; therefore, this portion 24 A of the shaft 24 then contained only the wire lumen 83 which possessed a semi-circular exterior transverse cross section. (The extra 1 cm length accommodates room for a tip portion of the catheter, without a balloon covering, in the final assembly.) With the mandrels still in place, portion 24 B of the shaft 24 was inserted for about 30 seconds into a heated split die containing 1.5 mm diameter bore when the dies were placed together. The dies were heated to a temperature of 180° C. to form the semicircular cross sectional shape of the portion of the shaft into a round 1.5 mm cross section and to create a landing 91 in the area proximal to the distal end of the inflation lumen 87 . Next, the balloon 10 (having circumferentially oriented film layers 14 and 16 , and longitudinally oriented substrate tube 81 ) was slipped over the modified distal end of the shaft 24 such that the proximal end of the balloon 10 was approximately 0.5 cm from the end of the landing 91 . This approximately 0.5 cm segment of the landing 91 adjacent to the abutment was primed for fifteen seconds (Loctite Prism™ Primer 770, Item #18397, Newington, Conn.) and then cyanoacrylate glue (Loctite 4014 Instant Adhesive, Part #18014, Rocky Hill, Conn.) was applied to that segment. The balloon 10 was moved proximally such that the proximal end of the balloon abutted against the end of the landing 91 and the glue was allowed to set. The distal end of the balloon 10 was attached in the same manner, while ensuring against wrinkling of the balloon during the attachment. At this point, a radiopaque marker could have been fitted at each end of the balloon. The last step in the mounting process involved securing the ends of the balloon with shrink tubing 93 (Advanced Polymers, Inc., Salem, N.H., polyester shrink tubing—clear, item #085100CST). Approximately 0.25 cm of the proximal end of the balloon and approximately 0.75 cm of the shaft adjacent to the end of the balloon were treated with the same primer and glue as described above. Approximately 1 cm length of shrink tubing 93 was placed over the treated regions of the shaft 24 and balloon 10 . The same process was followed to both prepare the distal end the balloon and the adjacent modified shaft portion and to attach another approximately 1 cm length of shrink tubing 93 . The entire assembly was then placed into a convection oven set at 150° C. for at least about 2 minutes in order to shrink the shrink tubing.
[0078] The pre-inflation balloon possessed 2.03 mm and 2.06 mm minimum and maximum dimensions, respectively. the balloon catheter was tested under pressure as described in Example 1. The inflated balloon possessed 5.29 mm and 5.36 mm minimum and maximum dimensions, respectively. The deflated balloon possessed 2.19 mm and 3.21 mm minimum and maximum dimensions, respectively. The resulting compaction efficiency and the compaction ratio were 0.68 and 0.64, respectively.
[0079] The pitch angles of the film were also measured pre-inflation, at inflation (8 atm), and at deflation, yielding values of about 20°, 50°, and 25°, respectively. The balloon was reinflated with 10 atm and the pitch angles of the film were measured for the inflation and deflation conditions. The angles were the same for both inflation pressures.
[0080] The balloon was subjected to even higher pressures to determine the pressure at failure. The balloon withstood 19.5 atm pressure prior to failure due to breakage of the shrink tubing at the distal end of the balloon. Another balloon catheter was made using a piece of the same balloon material, following the same procedures described in this example. This balloon catheter was used to distend a 3 mm GORE-TEX Vascular Graft (item no. V03050L, W. L. Gore and Associates, Inc., Flagstaff Ariz.) from which the outer reinforcing film had been removed. The graft was placed over the balloon such that the distal end of the graft was positioned approximately 1 cm from the distal end of the balloon. The balloon was inflated to 8 atm, the graft distended uniformly without moving in the longitudinal direction with respect to the balloon. Another piece of the same graft was tested in the same manner using a 6 mm diameter, 4 cm long Schneider Match 35 PTA Catheter (model no. B506-412). In this case, the graft slid along the length of the balloon proximally during the balloon inflation; the distal end of the graft was not distended.
EXAMPLE 6
[0081] A balloon catheter was made following all of the steps of Example 5 with one exception in order to provide a balloon that bends during inflation.
[0082] All of the same steps were followed as in Example 5 with the exception of eliminating the manual elongation step that immediately followed the longitudinal compression step. That is, at the point of being impregnated with silicone dispersion, the film-covered porous PTFE tube was 0.6 of its initial length (instead of 0.8 as in Example 5).
[0083] A balloon catheter was constructed using this balloon. The length of the balloon was 4.0 cm. The bend of the balloon was tested by inflating the balloon to 8 atm and measuring the bend angle created by inflation. Measurements were made via the balloon aligned coincident with the 0° scribe line of a protractor, with the middle of the balloon positioned at the origin. The bend angle was 500. The balloon was then bent an additional 90° and allowed to relax. No kinking occurred even at 140°. The angle of the still inflated, relaxed balloon stabilized at 90°.
[0084] The balloon of an intact 6 mm diameter, 4 cm long Schneider Match 35 PTA Catheter (model no. B506-412) was tested in the same manner. The bend angle under 8 atm pressure was 0°. The inflated balloon was then bent to 90°, which created a kink. The inflated balloon was allowed to relax. The balloon bend angle stabilized at 25°. The bending characteristics of an article of the present invention should enable the dilatation of a vessel and a side branch of the same vessel simultaneously. The inventive balloon is easily bendable without kinking. Kinking is defined as wrinkling of the balloon material.
EXAMPLE 7
[0085] This example illustrates an alternative construction for a balloon catheter assembly of the present invention. The described construction relates to a balloon made from tubular substrates of helically-wrapped porous PTFE film and elastomeric tubing in laminar relationship wherein ends of the balloon are secured to a catheter shaft using wraps of porous PTFE film. The balloon does not require an additional layer of porous PTFE having fibrils oriented longitudinally with respect to the lengths of the balloon and catheter shaft.
[0086] As shown by the longitudinal cross section of FIG. 9 , the proximal end of the balloon catheter assembly 100 was created using three segments of catheter tubing joined together at an injection molded Y-fitting. As described in this and subsequent examples, the distal end of the balloon catheter is considered to be the end to which is affixed the balloon and the end which is first inserted into the body of a patient; the proximal end is considered to be the end of the balloon catheter opposite the distal end. All tubing segments were Pebax 7233 tubing unless noted otherwise; all of the described tubing is available from Infinity Extrusions and Engineering, Santa Clara, Calif. unless noted otherwise. The primary component of catheter shaft 101 was a dual lumen segment of tubing 103 having an outside diameter of about 2.3 mm, a guidewire lumen 105 of about 1.07 mm inside diameter and a crescent-shaped inflation lumen 107 of about 0.5 mm height. A transverse cross section of this tubing is described by FIG. 9A . The guidewire lumen 105 of this main shaft 101 was joined at the Y-fitting 109 to one end of a 12 cm length of single lumen tubing 111 having an outside diameter of about 2.34 mm and an inside diameter of about 1.07 mm; the inflation lumen 107 of the main shaft 101 was joined to a 12 cm length of Pebax 4033 single lumen tubing 115 . Joining was accomplished by placing a length of 1.0 mm outside diameter steel wire (not shown) into one end of the guidewire lumen 105 of the dual lumen tubing 103 and sliding one end of single lumen tube 111 onto the opposite end of the steel wire until the ends of dual lumen tube 103 and single lumen tube 111 abutted. A length of 0.48 mm diameter wire (also not shown) having a 30 degree bend at the midpoint of its length was inserted into the crescent-shaped inflation lumen 107 of the dual lumen tubing 103 up to the point of the bend in the wire; the lumen 117 of the second length of single lumen tubing 115 was fitted over the opposite end of this wire until it also reached the bend point of the wire, abutting the end of the dual lumen tubing 103 at that point. The presence of the wires in the region of the abutted tube ends thus maintained the continuity of both lumens at the point of abutment. The region of the abutted tubing ends was placed into the cavity of a mold designed to encapsulate the junction. Using a model IMP 6000 Injection Molding Press (Novel Biomedical Inc., Plymouth Minn.), heated Pebax 7033 was injected into the mold to form Y-fitting 109 . After cooling, the resulting assembly was removed from the mold and the lengths of steel wire were withdrawn from the lumens of the tubing. Finally, a female Luer fitting (part no. 65250, Qosina Corp., Edgewood, N.Y.) was affixed to the remaining ends of each of the single lumen tubes 111 and 115 using Loctite 4014 Instant Adhesive (Loctite Corp., Newington Conn.).
[0087] The distal or balloon end of the catheter assembly 100 was then fabricated as follows, beginning according to the longitudinal cross section shown by FIG. 1A . A 1.00 mm diameter stainless steel wire (not shown) approximately 30 cm long was inserted approximately 15 cm into the distal end of the guidewire lumen 105 of the dual lumen tubing 103 . A 13 cm length of single lumen tubing 119 having an inner diameter of 1.02 mm and an outer diameter of 1.58 mm was placed over the exposed wire protruding from the guidewire lumen 105 such that it abutted the end of the dual lumen tubing 103 . A 0.49 mm stainless steel wire approximately 30 cm long was placed inside the distal end of the crescent-shaped inflation lumen 107 of the dual lumen tubing 103 . The abutted ends of the two tubes 103 and 119 and the resident wires were placed into a PIRF® Thermoplastic Forming and Welding System (part numbers 3220, 3226, 3262 and 3263, Sebra® Engineering and Research Associates, Inc., Tucson Ariz.) and a butt connection between the single lumen tubing 119 and the dual lumen catheter shaft 103 was completed. The 0.49 mm stainless steel wire resident within the distal portion of the crescent-shaped inflation lumen 107 of the dual lumen catheter tubing 103 ensured that the distal end of lumen 107 would remain open during this operation. The heated die used in this step was specifically fabricated to accommodate the dimensions of the dual lumen catheter tubing 103 and the single lumen tubing 119 . The heating and other parameters used in the operation were derived by trial and error to result in adequate reflow and butt welding of the abutted ends of the two tubes.
[0088] Next, with the 1.00 mm stainless steel wire still in place within the guidewire lumens 105 and 121 of abutted tubes 103 and 119 , the 0.49 mm stainless steel wire resident within the distal portion of the inflation lumen 107 of the dual lumen catheter tubing 103 was replaced by a 0.39 mm stainless steel wire approximately 30 cm long (also not shown). Again the wire was placed about 15 cm into the inflation lumen 107 . The assembly consisting of butt welded single lumen tube 119 and dual lumen tube 103 , and the resident wire, was placed into the PIRF® Thermoplastic Forming and Welding System which was refitted with a different die. Upon heating, the assembly was advanced approximately 2.0 cm into the heated die of the system, causing a 2 cm length of the distal end of the outer diameter of the dual lumen catheter tubing 103 to decrease to the same dimension as the 1.83 mm inner diameter of the heated die. The longitudinal cross section of FIG. 10B describes the appearance of the assembly after heating wherein region “a” has the 1.58 mm outside diameter of single lumen tube 119 , region “b” has been modified to the outside diameter of 1.83 mm and region “c” retains the original 2.3 mm outside diameter of dual lumen tubing 103 . The 0.39 mm stainless steel wire resident within the inflation lumen 107 of the dual lumen catheter tubing 103 ensured that the lumen 107 would remain open during this operation. The heating and other parameters used in the operation were derived by trial and error to result in adequate reflow of the dual lumen tubing. Once this operation was completed, the entire outer surface of the full length of the single lumen tubing 119 (region “a,” distal from the butt-weld) was abraded with 220 abrasive paper to facilitate bonding of the ends of a silicone tube 123 as will be described.
[0089] With construction of the catheter shaft 101 completed, a segment of silicone tubing 123 approximately 9 cm in length, having an approximate inner diameter of 1.40 mm, an approximate outer diameter of 1.71 mm, and a durometer of Shore 60A (Beere Precision Silicone, Racine, Wis.) was placed over the distal end of the catheter shaft 101 as shown by the longitudinal cross section of FIG. 10C such that the proximal edge of the silicone tubing 123 was approximately 7.5 mm distal from the point at which the outer diameter of catheter shaft 101 changed from 1.83 mm to 2.3 mm. This was done very carefully to ensure that no section of the silicone tubing 123 was longitudinally stretched (i.e., under tension) when at its final position on the catheter shaft 101 . Isopropyl alcohol was used as a lubricant between the catheter shaft 101 and the silicone tubing 123 .
[0090] While the elastomeric tubing used for this example was silicone tubing, it is believed that tubings made from other elastomeric materials such as polyurethane or fluoroelastomer tubings may also be suitably employed.
[0091] With the silicone tubing 123 placed correctly on the catheter shaft 101 , any residual alcohol was allowed to evaporate for a generous amount of time, ensuring that the shaft 101 was completely dry. Once free of residual alcohol, a small amount of Medical Implant Grade Dimethyl Silicone Elastomer Dispersion In Xylene (Part 40000, Applied Silicone, Ventura, Calif.) was applied between the ends of the silicone tubing 123 and the underlying exterior surface of the catheter shaft 101 . At each end of the silicone tubing 123 , a small blunt needle was inserted between the ends of the silicone tubing 123 and the underlying catheter shaft 101 for a distance of approximately 7.5 mm as measured in a direction parallel to the length of the catheter shaft 101 . The silicone elastomer dispersion was carefully applied, using a 3 cc syringe connected to the blunt needle, around the entire circumference of the catheter shaft 101 such that the dispersion remained within and fully coated the 7.5 mm length of the area to be bonded under the ends of silicone tubing 123 . The silicone elastomer dispersion was then allowed to cure for approximately 30 minutes at ambient temperature, and then an additional 30 minutes in an air convection oven set at 150° C. Next, a length of porous PTFE film as described above, approximately 1.0 cm wide, was manually wrapped over the end regions of the silicone tubing 123 under which the silicone elastomer dispersion was present, and onto the adjacent portions of the catheter shaft 101 not covered by silicone tubing 123 , for a length of approximately 7.5 mm measured from the ends of the silicone tubing 123 . During wrapping, the entire length of the porous PTFE film was coated with a small amount of the silicone elastomer dispersion, the dispersion impregnating the porous PTFE film such that the void spaces in the porous PTFE film were substantially filled by the dispersion. The dispersion was thus used as an adhesive material to affix the porous PTFE film to the underlying components. It is believed that other adhesive material may also be used such as other elastomers (e.g., polyurethane or fluoroelastomers, also optionally in dispersion form), cyanoacrylates or thermoplastic adhesives such as fluorinated ethylene propylene which may be activated by the subsequent application of heat. Great care was taken to ensure that the porous PTFE film was applied so that approximately 3 overlapping layers (depicted schematically as layers 125 in FIG. 10C ) covered each of the regions; the very thin porous PTFE film did not add significantly to the outside diameter of the catheter assembly 100 . At this point the silicone elastomer dispersion used to coat the porous PTFE film was allowed to cure for approximately 30 minutes at ambient temperature, and then an additional 30 minutes in an air convection oven set at 150° C.
[0092] Next, a film tube was constructed in a fashion similar to that described in example 1. A length of porous PTFE film, cut to a width of 2.5 cm, made as described above, was wrapped onto the bare surface of an 8 mm stainless steel mandrel at an angle of approximately 700 with respect to the longitudinal axis of the mandrel so that about 5 overlapping layers of film covered the mandrel (i.e., any transverse cross section of the film tube transects about five layers of film). Following this another, another 5 layers of the same film were helically wrapped over the first 5 layers at the same pitch angle with respect to the longitudinal axis, but in the opposite direction. The second 5 layers were therefore also oriented at an approximate angle of 700, but measured from the opposite end of the axis in comparison to the first 5 layers. In the same manner, additional layers of film were applied five layers at a time with each successive group of five layers applied in an opposing direction to the previous group until a total of about 30 layers of helically wrapped film covered the mandrel. This film-wrapped mandrel was then placed into an air convection oven set at 380° C. for 11.5 minutes to heat bond the layers of film, then removed and allowed to cool.
[0093] The film tube may also be constructed using more film or less film than described above; the use of increasing or decreasing amounts of film will result in a catheter balloon that is respectively stronger (in terms of hoop strength) and less compliant, or weaker and more compliant. The use of slightly different porous PTFE materials (e.g., porosity, thickness and width), the amount of porous PTFE material used and its orientation with respect to the longitudinal axis and adjacent material layers can all be expected to affect the performance properties of the resulting balloon; these variables may be optimized for specific performance requirements by ordinary experimentation.
[0094] The resulting 8 mm inside diameter film tube was then removed from the 8 mm mandrel, fitted coaxially over a 1.76 mm diameter stainless steel mandrel, and manually tensioned longitudinally to cause it to reduce in diameter. The ends of the film tube (extending beyond the mandrel ends) were then placed into a model 4201 Tensile Testing Machine manufactured by Instron (Canton, Mass.) equipped with flat faced jaws and pulled at a constant rate of 200 mm/min until a force between 4.8 and 4.9 kg was achieved. The film tube was then secured to the mandrel ends by tying with wire.
[0095] The 1.76 mm mandrel with the film tube secured onto it was then placed into an air convection oven set at 380° C. for 30 seconds. The mandrel and film tube were then removed, allowed to cool, and then helically wrapped manually (using a pitch angle of about 70 degrees with respect to the longitudinal axis) with a length of 1.9 cm wide porous PTFE film made as described above, so that about 2 overlapping layers of film covered the mandrel and film tube. Following this, another 2 layers of the same film were helically wrapped over the first 2 layers at the same pitch angle with respect to the longitudinal axis, but in the opposite direction. These layers of film (not shown) were applied temporarily as a clamping means to secure the film tube to the outer surface of the mandrel during the subsequent heating and curing process. The 1.76 mm mandrel, with the film tube secured onto it and the layers of porous PTFE film wrapped over the film tube, was then placed into an air convection oven set at 380° C. for 45 seconds, after which it was removed and allowed to cool. Using an indelible pen, marks were then placed along the length of wrapped film tube in 1 cm increments, and the wrapped film tube was compressed longitudinally until these marks were uniformly spaced approximately 5 mm apart. These pen marks were placed on the external, helically-wrapped film such that the ink penetrated the outer film layers and also marked the underlying film tube. The 1.76 mm mandrel, with the longitudinally compressed film tube secured onto it and the layers of porous PTFE film wrapped over the film tube, was then placed into an air convection oven set at 380° C. for 45 seconds, after which it was removed and allowed to cool. Once cool, the layers of porous PTFE film wrapped over the film tube were completely removed, and the resulting 1.76 mm inside diameter film tube was removed from the mandrel. The film tube, having visible pen marks at 5 mm increments, was manually tensioned longitudinally until the pen marks were spaced at approximately 1 cm increments, and then allowed to retract. The resulting 1.76 mm inside diameter film tube then had visible pen marks spaced between 7 mm and 8 mm apart. The film tube was then placed in a jar containing a mixture of 1 part MED1137Adhesive Silicone Type A manufactured by NuSil Silicone Technology (Carpinteria, Calif.) to 6 parts n-Heptane (J.T. Baker, Phillipsburg, N.J.) by weight, wetting the film tube with the mixture. Void spaces within the porous PTFE film tube 127 were thus impregnated with and substantially filled by the silicone adhesive mixture. It is believed that this step may also be accomplished by other types of elastomeric adhesives including fluoroelastomers and polyurethanes.
[0096] The catheter shaft 101 with the silicone tubing 123 affixed to it via porous PTFE film 125 and silicone elastomer dispersion was then carefully coated with a thin layer of a mixture of 2 parts MED1137 Adhesive Silicone Type A manufactured by NuSil Silicone Technology (Carpinteria, Calif.) to 1 part n-Heptane (J.T. Baker, Phillipsburg, N.J.) by weight. The 1.76 mm inside diameter film tube was removed from the silicone-Heptane mixture, and the coated catheter shaft 101 was carefully fitted coaxially within the film tube 127 as shown by the longitudinal cross section of FIG. 10D such that the entire silicone tube 123 affixed to the shaft 101 was covered by film tube 127 , as well as an adjacent portion of the catheter shaft 101 proximal to the point at which the shaft outer dimension changed from 1.83 mm to 2.3 mm. With the catheter shaft 101 and the affixed silicone tube 123 covered by the film tube 127 , the ends of film tube 127 were trimmed so that the proximal end was coincident to the point at which the catheter shaft 101 outer dimension changed from 1.83 mm to 2.3 mm, and the other end was approximately 7.5 mm distal from the distal end of the silicone tubing 123 affixed to the catheter shaft 101 . The exterior surface of film tube 127 was then helically wrapped by hand with a length of 1.9 cm wide porous PTFE film, made as described above, so that about 2 overlapping layers of film covered its length. This film (not shown) was applied temporarily as a securing means desired during the subsequent heating and curing step. This distal portion of the catheter assembly 100 was then placed into a steam bath for a period of time between 15 and 30 minutes to cure the previously applied silicone adhesive mixture.
[0097] The catheter assembly 100 was then removed from the steam bath, and the outer helically-wrapped film layers were removed. Next, lengths of porous PTFE film as described above, approximately 1.0 cm wide, were manually wrapped over the ends of the film tube 127 approximately 15 mm distal from the point at which the shaft outer dimension changed from 1.83 mm to 2.3 mm, and approximately 15 mm distal from the most proximal edge of the porous PTFE film wrapped around the distal end of the silicone tubing. During wrapping, the entire length of the porous PTFE film was coated with a small amount of a mixture of equal parts of MED1137 Adhesive Silicone Type A manufactured by NuSil Silicone Technology (Carpinteria, Calif.) and n-Heptane (J.T. Baker, Phillipsburg, N.J.) by weight. Great care was taken to ensure that the porous PTFE film was applied so that approximately 3 overlapping layers (shown schematically as layers 129 in FIG. 10D ) covered the region without adding significantly to the diameter of the catheter. Because of the reduced diameter at region “b” and the thin character of the porous PTFE film used for layers 129 and 125 , the diameter of the catheter assembly 100 at the location of film layers 129 and 125 was very close to the diameter of catheter tubing 101 proximal to these layers of film. The distal portion of the catheter was then placed into a steam bath for a minimum of 8 hours to achieve final curing. After final curing the distal-most portion of the catheter shaft was cut off transversely at the distal-most edge 131 of the porous PTFE film on the exterior of the film tube. The construction of the distal region of the catheter assembly 100 incorporating the balloon portion was now complete. The resulting balloon portion of this construction is represented as region 133 . The ends of the balloon and the length of the balloon (taken as the distance measured between the ends of the balloon) are defined by the bracketed region 133 , shown as beginning at the edges of porous PTFE film layer 129 (the termination or securing means) closest to the balloon portion 133 .
[0098] The balloon portion 133 thus was secured to the outer surface of the catheter shaft by two separate terminations (or securing means) at each end of the balloon; these take the form of film layers 125 used to secure the silicone tube 123 and film layers 129 used to secure the porous PTFE film tube 127 . The presence of two separate terminations (i.e., separate layers 125 and 129 ) at one end of the balloon can be demonstrated by taking a transverse cross section through the termination region and examining it with suitable microscopy methods such as scanning electron microscopy.
[0099] The inflatable balloon portion 133 was the result of two substrates, porous PTFE film tube 127 and elastomeric silicone tube 123 being joined in laminated relationship. The void spaces of the porous PTFE film tube 127 were thus substantially sealed by the silicone tube 123 and the previously applied silicone adhesive mixture which impregnated the void spaces of the porous PTFE film tube 127 and adhered the film tube to the silicone tube 123 .
[0100] At this point, the diameter of the balloon portion 133 was measured in a pre-inflated state. The minimum diameter was found to be 2.14 mm and the maximum diameter 2.31 mm. As before, these measurements were taken from approximately the midpoint of the balloon, and a Lasermike model 183, manufactured by Lasermike, (Dayton, Ohio) was used to make the measurements while the balloon was rotated about its longitudinal axis. The balloon when inflated to 8 atmospheres internal water pressure (as described by the longitudinal cross section of FIG. 10E ) for a period of 1 minute or less, had a minimum diameter of 6.89 mm and a maximum diameter of 6.93 mm at the center of its length. It was noted during the 8 atmosphere pressurization that the balloon portion 133 was substantially straight with respect to the longitudinal axis of the catheter shaft 101 , and that the distance from the point at which the balloon portion 133 was attached to the catheter shaft 101 to the point on the balloon portion 133 at which the balloon was at its full diameter was relatively short. This is to say that the balloon when inflated possessed blunt ends of substantially the same diameter as the midpoint of the length of the balloon portion 133 , as opposed to having a tapered appearance along the length with a smaller diameter adjacent the balloon ends. When deflated by removing the entire volume of water introduced during the 8 atmosphere pressurization, the balloon at its mid-length had a minimum diameter of 2.22 mm and a maximum diameter of 2.46 mm. This silicone-PTFE composite balloon, when tested using a hand-held inflation device, had a burst pressure of approximately 22 atmospheres (achieved beginning from zero pressure in about 30 seconds), reaching a maximum diameter of about 7.95 mm prior to failure by rupture.
[0101] This example illustrates that the balloon, constructed as described above using silicone and PTFE, exhibited a predictable limit to its diametrical growth as demonstrated by the destructive burst test wherein the balloon did not exceed the 8 mm diameter of the porous PTFE film tube component prior to failure. The compaction ratio as previously defined was 2.31 divided by 2.46, or 0.94, and the compaction efficiency ratio as previously defined was 2.22 divided by 2.46, or 0.90. The ability of the balloon to inflate to the described pressures without water leakage demonstrated effectively that the void spaces of the porous PTFE had been substantially sealed by the elastomeric material.
[0102] A flow chart describing the process used to create the balloon catheter described by this example is presented as FIG. 10F ; it will be apparent that variations on this process may be used to create the same or similar balloon catheters.
EXAMPLE 8
[0103] This example teaches a method of balloon catheter construction using a catheter shaft made of elastomeric material. While this example was made using only a single lumen silicone catheter shaft with the lumen for intended for inflation, it will be apparent that a dual or multiple lumen shaft may also be used.
[0104] A silicone model 4 EMB 40 Arterial Embolectomy Catheter manufactured by the Cathlab Division of American Biomed Inc. (Irvine, Calif.) having a 4 fr shaft outside diameter (about 1.35 mm) and a length of 40 cm was acquired. The embolectomy catheter included a Luer fitting at the proximal end of the shaft and a balloon made of a silicone elastomer at the distal end of the shaft. The most distal 20 cm portion of the catheter (including the balloon) was cut off, and a 0.38 mm diameter wire was inserted completely through the open lumen of the shaft. A cut, approximately 5 mm in length, was made through the shaft wall approximately 6.5 cm proximal from the distal end, exposing the 0.38 mm wire but not damaging the remainder of the shaft. As shown by the longitudinal cross section of FIG. 11A , the resulting opening 201 was intended to serve as the inflation port for the new balloon which was to be constructed over this region of the catheter shaft 219 .
[0105] A segment of silicone tubing 123 approximately 8 cm in length, having an approximate inner diameter of 1.40 mm, an approximate outer diameter of 1.71 mm, and a durometer of Shore 60A (Beere Precision Silicone, Racine, Wis.), was placed over the distal end of the catheter shaft 219 such that the proximal edge of the silicone tubing 123 was approximately 9.8 cm proximal from the distal end of the catheter shaft 219 . This was done very carefully to ensure that no section of the silicone tubing 123 was longitudinally stretched (i.e., under tension) when at its final position on catheter shaft 219 . Isopropyl alcohol was used as a lubricant between the catheter shaft 219 and the silicone tubing 123 .
[0106] While the elastomeric tubing used for this example was silicone tubing, it is believed that other elastomeric tubing materials such as polyurethane tubings may also be suitably employed.
[0107] With the silicone tubing 123 placed correctly on the catheter shaft 219 , any residual alcohol was allowed to evaporate for a generous amount of time, ensuring that the shaft 219 was completely dry. Once free of residual alcohol, a small amount of Medical Implant Grade Dimethyl Silicone Elastomer Dispersion In Xylene (Part 40000, Applied Silicone, Ventura, Calif.) was applied between the ends of the silicone tubing 123 and the underlying exterior surface of the silicone catheter shaft 219 . At each end of the silicone tubing 123 , a small blunt needle was inserted between the ends of the silicone tubing 123 and the underlying silicone catheter shaft 219 for a distance of approximately 7.5 mm as measured in a direction parallel to the length of the catheter shaft 219 . The silicone elastomer dispersion was carefully applied, using a 3 cc syringe connected to the blunt needle, around the entire circumference of the shaft 219 such that the dispersion remained within, and fully coated the 7.5 mm length of the area to be bonded under the ends of the silicone tubing 123 . The silicone elastomer dispersion was then allowed to cure for approximately 30 minutes at ambient temperature, and then an additional 30 minutes in an air convection oven set at 150° C. Next, a length of porous PTFE film as described above, approximately 1.0 cm wide, was manually wrapped over the end regions of the silicone tubing 123 under which the silicone elastomer dispersion was present, and onto the adjacent portions of the silicone catheter shaft 219 not covered by the silicone tubing 123 , for a length of approximately 7.5 mm measured from the ends of the silicone tubing 123 . During wrapping, the entire length of the porous PTFE film was coated with a small amount of the silicone elastomer dispersion. Great care was taken to ensure that the porous PTFE film was applied so that approximately 3 overlapping layers (depicted schematically as layers 125 in FIGS. 11A and 11B ) covered each of the regions; the very thin porous PTFE film did not add significantly to the outside diameter of the catheter assembly 100 . At this point the silicone elastomer dispersion was allowed to cure for approximately 30 minutes at ambient temperature, and then an additional 30 minutes in an air convection oven set at 150° C.
[0108] Next, a film tube was constructed in the same manner as described in Example 7. The silicone catheter shaft 219 with the silicone tubing 123 affixed to it via porous PTFE film 125 and silicone elastomer dispersion was then carefully coated with a thin layer of a mixture of 2 parts MED1137 Adhesive Silicone Type A manufactured by NuSil Silicone Technology (Carpinteria, Calif.) to 1 part n-Heptane (J.T. Baker, Phillipsburg, N.J.) by weight. The 1.76 mm inside diameter film tube was removed from the silicone-Heptane mixture, and the coated silicone catheter shaft 219 was carefully fitted coaxially within the film tube 127 such that the entire silicone tube 123 affixed to the catheter shaft 219 , as well as an adjacent portion of the catheter shaft 219 proximal to both ends of the silicone tube 123 , were covered by the film tube 127 . With the catheter shaft 219 and the affixed silicone tube 123 covered by the film tube 127 , the ends of the film tube 127 were trimmed so that the distal end of the film tube 127 was located 7.5 mm distal from the distal end of the underlying silicone tubing 123 , and the proximal end was located 7.5 mm proximal from the proximal end of the underlying silicone tubing 123 . The exterior surface of film tube 127 was then helically wrapped by hand with a length of 1.9 cm wide porous PTFE film, made as described above, so that about 2 overlapping layers of film covered its length. This film (not shown) was applied temporarily as a securing means desired during the subsequent heating and curing step. This distal portion of the catheter assembly 200 was then placed into a steam bath for a period of time between 15 and 30 minutes.
[0109] The catheter assembly 200 was then removed from the steam bath, and the outer helically-wrapped film layers were removed. Next, lengths of porous PTFE film as described above, approximately 1.0 cm wide were manually wrapped over the ends of the film tube 127 approximately 15 mm proximal from the distal edge of the film tube 127 , and approximately 15 mm distal from the proximal edge of the film tube 127 . These regions were covered by approximately 3 overlapping film layers, shown schematically as layers 129 . Additionally a length of porous PTFE film (shown schematically as layer 221 ) was wrapped helically along the length of the catheter shaft 219 from the proximal edge of the silicone tube 123 to the Luer fitting at the proximal end of the catheter shaft 219 so that about 2 overlapping layers of film covered the catheter shaft 219 , and then another 2 layers of the same film were helically wrapped over the first 2 layers at the same pitch angle (about 70 degrees) with respect to the longitudinal axis, but in the opposite direction. During wrapping, each length of porous PTFE film was coated with a small amount of a mixture of equal parts of MED1137 Adhesive Silicone Type A, manufactured by NuSil Silicone Technology (Carpinteria, Calif.), and n-Heptane (J.T. Baker, Phillipsburg, N.J.) by weight. Great care was taken to ensure that the porous PTFE film was applied without adding significantly to the catheter diameter. This was possible as a result of the thin character of the porous PTFE film. The catheter assembly 200 was then placed into a steam bath for a minimum of 8 hours to achieve curing. After curing the distal-most portion of the catheter shaft 219 was cut off transversely at the distal-most edge 131 of the porous PTFE film 129 on the exterior of the film tube 127 , and the open inflation lumen 107 was sealed by insertion of a 1 cm long section of 0.38 mm wire 225 which was dipped into a mixture of equal parts of MED1137 Adhesive Silicone Type A, manufactured by NuSil Silicone Technology (Carpinteria, Calif.), and n-Heptane (J.T. Baker, Phillipsburg, N.J.) by weight. The catheter assembly 200 was then placed into a steam bath for a minimum of 8 hours to achieve final curing.
[0110] At this point, the diameter of balloon portion 133 was measured in a pre-inflated state. The minimum diameter was found to be 2.13 mm and the maximum diameter 2.28 mm. As before, these measurements were taken from approximately the midpoint of the balloon, and a Lasermike model 183, manufactured by Lasermike, (Dayton, Ohio) was used to make the measurements while the balloon was rotated about its longitudinal axis. The balloon when inflated to 8 atmospheres internal water pressure (as described by the longitudinal cross section of FIG. 11B ) for a period of 1 minute or less, had a minimum diameter of 6.00 mm and a maximum diameter of 6.11 mm at the center of its length. When deflated by removing the entire volume of water introduced during the 8 atmosphere pressurization, the balloon at its mid-length had a minimum diameter of 2.16 mm and a maximum diameter of 2.64 mm. This silicone-PTFE composite balloon, when tested using a hand-held inflation device had a burst pressure of approximately 21 atmospheres (achieved beginning from zero pressure in about 30 seconds), reaching a maximum diameter of about 7.54 mm prior to failure. The balloon failed by developing a leak in the silicone tubing component 123 of the balloon portion 133 . The leak caused separation between the film tube 127 and the silicone tubing 123 , allowing fluid to pass through the film tube 127 .
[0111] This illustrates that the balloon, constructed as described above using silicone and PTFE, exhibited a predictable limit to its diametrical growth as demonstrated by the destructive burst test wherein the balloon did not exceed the 8 mm diameter of the porous PTFE film tube component prior to failure. The compaction ratio as previously defined was 2.28 divided by 2.64, or 0.86, and the compaction efficiency ratio as previously defined was 2.16 divided by 2.64, or 0.82. Additionally, the presence of the porous PTFE film helically wrapped around the silicone catheter shaft 219 provided sufficient strength to enable the silicone catheter shaft 219 to withstand the relatively high pressures associated with angioplasty.
[0112] Another balloon was constructed in an identical manner as described above, except that the length of the silicone catheter shaft 219 from the proximal edge of the silicone tube 123 to the Luer fitting at the proximal end of the shaft 219 was not covered by porous PTFE film 221 . When the balloon portion 133 was measured in a pre-inflated state the minimum diameter was found to be 2.14 mm and the maximum diameter 2.21 mm. These measurements were made as described above. The balloon when inflated to 8 atmospheres internal water pressure for a period of 1 minute or less, had a minimum diameter of 5.98 mm and a maximum diameter of 6.03 mm at the center of its length. When deflated by removing the entire volume of water introduced during the 8 atmosphere pressurization, the balloon at its mid-length had a minimum diameter of 2.10 mm and a maximum diameter of 2.45 mm. This silicone-PTFE composite balloon, when tested using a hand-held inflation device had a burst pressure of approximately 15 atmospheres, reaching a maximum dimension of about 6.72 mm prior to failure. The failure mode of the balloon was shaft rupture.
[0113] This illustrates that the balloon, constructed as described above using silicone and PTFE exhibited a predictable limit to its diametrical growth as demonstrated by the destructive burst test wherein the balloon did not exceed the 8 mm diameter of the porous PTFE film tube component prior to failure. The compaction ratio as previously defined was 2.21 divided by 2.45, or 0.90, and the compaction efficiency ratio as previously defined was 2.10 divided by 2.45, or 0.86. The absence of the porous PTFE film helically wrapped around shaft allowed the balloon to fail at the shaft. The ability of the balloon to inflate to the described pressures without water leakage demonstrated effectively that the void spaces of the porous PTFE had been substantially sealed by the elastomeric material. A flow chart describing the process used to create the balloon catheter described by this example is presented as FIG. 11C ; it will be apparent that variations on this process may be used to create the same or similar balloon catheters.
EXAMPLE 9
[0114] This example describes an alternative method of creating a silicone-PTFE laminated balloon portion, and the use of the balloon portion as an angioplasty balloon.
[0115] First, a catheter shaft was constructed in the same manner as described in Example 7.
[0116] After completion of the catheter shaft, a film tube was created as follows. A length of porous PTFE film, cut to a width of 2.5 cm, made as described above, was wrapped onto the bare surface of an 8 mm stainless steel mandrel at an angle of approximately 70° with respect to the longitudinal axis of the mandrel so that about 5 overlapping layers of film covered the mandrel (i.e., any transverse cross section of the film tube transects about five layers of film). Following this, another 5 layers of the same film were helically wrapped over the first 5 layers at the same pitch angle with respect to the longitudinal axis, but in the opposite direction. The second 5 layers were therefore also oriented at an approximate angle of 70°, but measured from the opposite end of the axis in comparison to the first 5 layers. In the same manner, additional layers of film were applied five layers at a time with each successive group of five layers applied in an opposing direction to the previous group until a total of about 30 layers of helically wrapped film covered the mandrel. This film-wrapped mandrel was then placed into an air convection oven set at 380° C. for 11.5 minutes to heat bond the layers of film, then removed from the oven and allowed to cool. Once cool, the resulting film tube was removed from the 8 mm mandrel.
[0117] Next a 24 cm length of silicone tubing having an approximate inner diameter of 1.40 mm, an approximate outer diameter of 1.71 mm, and a durometer of Shore 60A (Beere Precision Silicone, Racine, Wis.) was fitted coaxially over a 1.14 mm diameter stainless steel mandrel. After one end of the silicone tubing was secured onto the mandrel by tying with thin thread, tension was applied to the other end, stretching the tubing until its overall length was 31 cm. With the tubing stretched to 31 cm the free end was also secured to the mandrel using thin thread.
[0118] The 8 mm inside diameter film tube was then manually tensioned longitudinally, causing it to reduce in diameter. The film tube was then knotted at one end, and a blunt needle was inserted into the other. Using a 20 cc syringe connected to the blunt needle, a mixture of 1 part MED1137 Adhesive Silicone Type A manufactured by NuSil Silicone Technology (Carpinteria, Calif.) to 4 parts n-Heptane (J.T. Baker, Phillipsburg, N.J.) by weight was injected into the film tube. The mixture while in the lumen of the film tube was pressurized manually via the syringe, causing it to flow through the porous PTFE, completely wetting and saturating the film tube.
[0119] Next, the 1.14 mm mandrel and the overlying silicone tubing were coated with a mixture of 2 parts MED1137 Adhesive Silicone Type A manufactured by NuSil Silicone Technology (Carpinteria, Calif.) to 1 part n-Heptane (J.T. Baker, Phillipsburg, N.J.) by weight. The blunt needle was removed from the PTFE film tube. The 1.14 mm mandrel and overlying silicone tubing were then fitted coaxially within the film tube with the ends of the film tube extending beyond the mandrel ends. The ends of the film tube were then placed into a model 4201 Tensile Testing Machine manufactured by Instron (Canton, Mass.) equipped with flat faced jaws and pulled at a constant rate of 200 mm/min until a force between 4.8 and 4.9 kg was achieved. During pulling, the film tube was massaged, ensuring contact between the PTFE and the silicone tubing. Small needle holes were made into the film tube so that the resident silicone-heptane mixture could escape. Once a force between 4.8 and 4.9 kg was achieved, the film tube was left within the jaws of the machine for a minimum of 24 hours, allowing the silicone to cure completely. Once the silicone was completely cured, the resulting silicone-PTFE composite tubing was carefully removed from the 1.14 mm mandrel.
[0120] Although this example used the silicone tubing and the porous PTFE film tube as separate substrates joined together in laminated relationship, the balloon has also been constructed using only the porous PTFE film tube made as described for example 7 and impregnated with the elastomeric material (i.e., the balloon was constructed without the silicone tubing substrate). For such a construction, the use of a silicone elastomer dispersion in Xylene is preferred as the elastomeric material intended to substantially seal the void spaces in the porous PTFE tube (i.e., wherein a substantial portion of the elastomeric material is located within the void spaces within the porous PTFE tube). The balloon so constructed was joined to the catheter shaft in the same manner described as follows. The resulting balloon had a particularly thin wall having excellent compaction efficiency ratio and compaction ratio; a balloon catheter incorporating this balloon is anticipated to be particularly useful as a neural balloon dilatation catheter.
[0121] As shown by the longitudinal cross section of FIG. 12A , a segment of the silicone-PTFE composite tubing 223 (comprising the inner substrate of the elastomeric material (silicone tubing) joined to the outer substrate of the porous PTFE film tube in laminated relationship) approximately 9 cm in length was placed over the distal end of the catheter shaft 101 such that such that the proximal edge of the composite tubing 223 was approximately 7 mm distal from the point at which the catheter shaft 101 outer diameter changed from 1.83 mm to 2.3 mm. This was done very carefully to ensure that no section of the composite tubing 223 was longitudinally stretched (i.e., under tension) when at its final position on the catheter shaft 101 . Isopropyl alcohol was used as a lubricant between the catheter shaft 101 and the composite tubing 223 .
[0122] With the composite tubing 223 placed correctly on the catheter shaft 101 , any residual alcohol was allowed to evaporate for a generous amount of time, ensuring that the catheter shaft 101 was completely dry. Once free of residual alcohol, a small amount of a mixture of equal parts of MED1137 Adhesive Silicone Type A manufactured by NuSil Silicone Technology (Carpinteria, Calif.) and n-Heptane (J.T. Baker, Phillipsburg, N.J.) by weight was applied between the ends of the tubing 223 and the underlying exterior surface of the catheter shaft 101 At each end of the silicone tubing 223 , a small blunt needle was inserted between the ends of the tubing 223 and the underlying catheter shaft 101 for a distance of approximately 7.5 mm as measured in a direction parallel to the length of the catheter shaft 101 . The mixture was carefully applied using a 3 cc syringe connected to the blunt needle, around the entire circumference of the catheter shaft 101 such that the mixture remained within, and fully coated the 7.5 mm length of the area to be bonded under the ends of the composite tubing 223 . To ensure that the adhesive did not migrate into the inflatable length of balloon portion 133 , prior to the application of the adhesive a thin thread was temporarily wrapped around composite tubing adjacent to the edge of porous PTFE film layer 125 closest to balloon portion 133 . Also, to ensure contact between the composite tubing 223 and the catheter shaft 101 , lengths of porous PTFE film as described above, approximately 1.0 cm wide were helically wrapped by hand over the composite tube over the areas in which the silicone mixture was applied. This film (not shown) was applied temporarily as a securing means desired during the subsequent heating and curing step. The silicone mixture was then allowed to cure within a steam bath for approximately 30 minutes. The catheter was then removed from the steam bath, and the 1.0 cm wide PTFE film was removed along with the temporary thread.
[0123] Next, a length of porous PTFE film as described above, approximately 1.0 cm wide was manually wrapped over the end regions of the composite tubing 223 under which the silicone mixture was present, and onto the adjacent portions of the catheter shaft 101 not covered by the composite tube 223 , for a length of approximately 7.5 mm measured from the ends of the composite tubing 223 . During wrapping, the entire length of the porous PTFE film was coated with a small amount of a mixture of equal parts of MED1137 Adhesive Silicone Type A manufactured by NuSil Silicone Technology (Carpinteria, Calif.) and n-Heptane (J.T. Baker, Phillipsburg, N.J.) by weight. Great care was taken to ensure that the porous PTFE film was applied so that approximately 3 overlapping layers (depicted schematically as layers 125 in FIG. 12 ) covered each of the regions without adding significantly to the diameter of the catheter. Because of the reduced diameter region at the distal end of dual lumen tubing 103 and the very thin character of the porous PTFE film used for layers 125 , the diameter of the catheter assembly 100 at the location of film layers 125 was very close to the diameter of catheter shaft 101 proximal to film layers 125 . Finally, the silicone mixture used to coat the porous PTFE film was allowed to cure for a minimum of 8 hours within a steam bath.
[0124] At this point, the diameters of the balloon portion 133 were measured in a pre-inflated state using the same methods described above. The minimum diameter was found to be 2.21 mm and the maximum diameter 2.47 mm. The balloon when inflated to 8 atmospheres internal water pressure (as described by the longitudinal cross section of FIG. 12B ) for a period of 1 minute or less, had a minimum diameter of 6.51 mm and a maximum diameter of 6.65 mm at the center. It was noted during the 8 atmosphere pressurization that the balloon portion was substantially straight with respect to the longitudinal axis of the catheter shaft, and that the distance from the point at which the balloon portion was attached to the catheter shaft to the point on the balloon portion at which the balloon was at its full diameter was relatively short. When deflated by removing the entire volume of water introduced during the 8 atmosphere pressurization, the balloon at its mid-length, had a minimum diameter of 2.28 mm and a maximum diameter of 2.58 mm. This silicone-PTFE composite balloon, when tested using a hand-held inflation device, had a burst pressure of approximately 15 atmospheres (achieved beginning from zero pressure in about 30 seconds), reaching a maximum diameter of about 7.06 mm prior to failure.
[0125] This example illustrates that the balloon, constructed as described above using a silicone-PTFE composite balloon portion, exhibited a predictable limit to its diametrical growth as demonstrated by the destructive burst test wherein the balloon did not exceed the 8 mm diameter of the porous PTFE film tube component. The compaction ratio as previously defined was 2.47 divided by 2.58, or 0.96, and the compaction efficiency ratio as previously defined was 2.28 divided by 2.58, or 0.88. The ability of the balloon to inflate to the described pressures without water leakage demonstrated effectively that the void spaces of the porous PTFE had been substantially sealed by the elastomeric material.
[0126] A flow chart describing the process used to create the balloon catheter described by this example is presented as FIG. 12C ; it will be apparent that variations on this process may be used to create the same or similar balloon catheters.
[0127] While particular embodiments of the present invention have been illustrated and described herein, the present invention should not be limited to such illustrations and descriptions. It should be apparent that changes and modifications may be incorporated and embodied as part of the present invention within the scope of the following claims.
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Balloon catheters having the strength and maximum inflated diameter characteristics of an angioplasty balloon and having the recovery characteristics during deflation of an elastic embolectomy balloon. The balloon catheter can be made in very small sizes and has a lubricious and chemically inert outer surface. The balloon catheter is easy to navigate through tortuous passageways, is capable of rapid inflation and deflation and has high burst strengths. Balloon covers having these same characteristics are also described for use with conventional embolectomy balloons or angioplasty balloons.
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REFERENCES TO EARLIER APPLICATIONS
[0001] The present application is based on U.S. provisional application No. 60/262,418, filed on Jan. 19, 2001.
FIELD OF THE INVENTION
[0002] The invention relates to a device for monitoring the administration of doses by a diabetic. The invention also relates to a system for monitoring the administration of doses by a diabetic.
BACKGROUND OF THE INVENTION
[0003] It is known to use various medicament containers with alarm systems based on timers for drug doses which are to be administered at intervals and are usually in the form of pills, tablets, or corresponding doses to be administered orally, and as an example it is possible to mention the alarm systems for medicament containers disclosed in the application publications GB 2179919 and FR 2666225.
[0004] Diabetes is a rapidly increasing serious metabolic disorder that is caused by lack of insulin as a result of decayed pancreatic islet cells (type 1, i.e. juvenile-onset diabetes mellitus) or by the fact that insulin trasmittors have become “lazy” (type 2, i.e. adult-onset diabetes). When untreated, both types of diabetes will cause an increase in the sugar content of blood, coma and death.
[0005] In principle, there exists a very simple medicament for the treatment of diabetes: the missing insulin is injected from outside the body. In practice, the treatment requires precision and care, because the amount of insulin in the blood circulation has to be correct for the situation in question. The correct amount depends (primarily) on the sugar-forming substances one has eaten as well as on the amount of physical exercise.
[0006] Too small temporary amount of insulin increases the sugar content of blood to an overly high level, and too large amount of insulin results in too low blood sugar level (insulin shock). Thus, a diabetic must constantly balance between two inconvenient phenomena. Of these two the too low sugar content, i.e. insulin shock is, however, more dangerous in the short run.
[0007] During the years, poor treatment (=poor treatment balance), i.e. constant overly high blood sugar content, may cause severe disturbances in peripheral blood circulation, even amputations, weakening of eye sight, difficult skin symptoms, kidney failure, and other serious secondary diseases.
[0008] Normally, a diabetic person has three different injection pens: a morning insulin pen containing typically a mixture of slowly acting insulin and rapidly acting insulin (e.g. Mixtard), a daytime pen containing rapidly acting insulin (e.g. Actrapid, Novorapid), which is typically used in connection with large meals, as well as a so-called evening pen, typically containing slowly acting insulin (e.g. Protaphan). Different types of insulin should be stored—at least—in pens of different colour, preferably even in pens of different manufacturers, because the wrong type of insulin at the wrong time is harmful, to say the least, and in the worst case even lethal.
[0009] Constant control constitutes an important part in the treatment of diabetes. The types of insulin and the injection times as well as the measured blood sugar values are marked in a control book. By comparing these values—together with a doctor and a diabetes nurse—to a so-called long-term blood sugar value measured in a laboratory in periods of few months, it is possible to develop the treatment so that it better corresponds to the way of life of the diabetic in question.
[0010] Temporary blood sugar content can nowadays be easily checked by each diabetic himself/herself by means of a so-called blood sugar indicator from a blood sample taken from the tip of a finger. The indicators are relatively cheap, but disposable strips are significantly expensive.
[0011] Because so-called long-term insulin is always injected “beforehand”, in a way, it is essential that the diabetic remembers to take care of his/her carbohydrate intake regularly, i.e. in practice, a portion of food containing an amount of carbohydrates corresponding to the situation in question should be eaten every couple of hours.
[0012] During the treatment period all diabetics are taught the carbohydrate contents of different nutrients, and for home care there are so-called “conversion tables” which show the average carbohydrate content of nutrients. A scale, the afore-mentioned table, a predetermined meal plan, and the tables in packages containing information on the nutrients become familiar to all diabetics.
[0013] An accustomed diabetic does not necessarily need said tables or scales, but he is able to estimate the carbohydrates on the basis of his/her experience with sufficient reliability.
[0014] It is a common misconception that a diabetic must not eat sugar. Diabetes is not “allergy to sugar”, but actually quite the opposite: diabetics must eat sugar-forming substances, and even quite regularly, and the correct amount at the correct time.
[0015] On an average, a diabetic must perform a treatment action related to the diabetes (snack, insulin injection, measuring of blood sugar) every couple of hours during the entire awake time. When changes occur in the normal way of life, for example a considerable amount of physical exercise is taken, it is necessary to perform such actions even more often. After a day with a large amount of physical exercise, it is necessary to measure the blood sugar in the middle of the night as well. In other words, the life of a diabetic is rather regular and seems to be quite pre-programmed. But it is possible to depart from the routines, as long as you know what you are doing.
[0016] Thus, the treatment of diabetes primarily requires administration of fixed doses of insulin at predetermined times according to the treatment plan. Consequently, devices have been developed for taking insulin doses by means of a syringe.
[0017] U.S. Pat. No. 4,950,246 discloses a syringe intended for the use of a person having diabetes, an “injection pen”, which can be used to meter a predetermined dose of insulin. The syringe has an integrated system with a sensor monitoring the progression of a pump rod inside the syringe and giving information to an electronic control unit for administering a correct dosage at the time of injection. In this syringe, the only alarm is an indication on the emptying of the reservoir to be expected.
[0018] The international publication WO 99/43283 discloses a new regimen for the treatment of diabetes, which can be easily implemented by the equipment available without making structural changes in the injection pen itself. This is implemented by means of special stand that functions as a control device for doses and contains several holes, “sockets” for the injection pens containing insulin. The stand comprises recesses for placing the injection pens in an erect position therein. For each injection pen there is a pair of indicators. The device is arranged to give an alarm in a certain order, wherein the indicator of the respective injection pen gives an alarm that it is time to administer a dose from the injection pen in question. The act of removing this injection pen from the stand is detected by means of a suitable sensor detecting the movement of the injection pen away from the stand. When the removal of the injection pen has been detected, a second indicator is shifted to a state in which it indicates that the dose has been administered. The indication may take place visually, for example by means of a signal light. The publication discloses how the injection pen can be locked to the stand at other times to prevent inappropriate use of the same. The diameters of the pens determine the size of the sockets in such stands. In this publication, an indicating device attachable to an injection pen is also described. This device is arranged to detect the movement of a push-button at the end of the opposite to the needle. The device interpretes the down movement of the push-button operating the piston as the act of administering the insulin dose from the pen. The detection is based on mechanical contact (micro-switch) between the device and the push-button.
SUMMARY OF THE INVENTION
[0019] It is a purpose of the present invention to provide a system, which enables the monitoring of the administration of insulin doses 24 hours a day, and by means of which it is possible to implement home care of diabetics. The monitoring system especially enables the multi-injection treatment of working people who must leave home on a regular basis and who can not take the device with them. The invention enables multi-injection treatment both at home and in work in such a manner that a doctor or another outside expert can constantly monitor and control the treatment at least on a daily basis. The invention is especially well suited for self-care of the diabetic and learning of the self-care, and it is also possible to enhance patient compliance thereby.
[0020] A control device that can be easily mounted on any injection pen and can be carried by the person who must regularly administer the doses improves the applicability of the concept of a multi-injection care of diabetes that can be monitored and controlled by the person himself/herself and outside experts and care personnel, even if the person is not at home at all times. Prevous attempts to provide a simple control device have proven insufficient, because it has required either changes in the internal construction of the injection pen or mounting of mechanical contacts. The invention resolves the problem in a simple manner. The control device is mounted on the cap covering the needle of an injection pen and its removal form the body of the pen can be detected, based on the principle that when the cap is removed, the physical surroundings of the cap and device on it change because the injection member attached to the body, such as a needle, will be absent from the inside of the cap. If the cap is away a sufficient long time, the control device inerpretes this as an injection (administering the dose). The detection takes place in a contactless manner. A sensor complementary to the detection sensor in the control device can be attached to the body, for example at the base of the needle.
[0021] A central part of the monitoring system is a stand-like control device which is located at the diabetic's home and contains data processing and memory capacity and can be programmed, i.e it is a console containing at the same time locations for accomodating several injection pens. It is an aim of the control device to act as a “personal digital diabetes nurse” for every diabetic. Although the device was initially designed for children and elderly people, it facilitates the life of any “independent” diabetic and guides to the correct treatment balance. The basic idea behind the console is to provide an active holder for injection pens (insulin syringes), a snack and treatment reminder as well as “a storage” for treatment data and an information source on nutrition in such a manner that the instructions given by the device adapt to the changes in the daily routine. The instructions given by it can be changed so that they better correspond to the weekly routine of the person in question.
[0022] The control device is pre-programmed with co-operation of the diabetes doctor and/or diabetes nurse and a nutrition therapist in such a manner that it corresponds to the average daily routine of the diabetic in question as closely as possible. The device reminds the patient of snacks, insulin injections and blood sugar measurements according to a predetermined schedule. It is possible that the device contains a programmable calendar of at least a short-time span in which different dates have information of their own for example on the size of the insulin doses. Preferably such a calendar repeats itself in periods of one week if the diabetic follows a set weekly routine. In that case, each day of the week may have pre-programmed instructions of its own but this data can be reprogrammed if it is later discovered that some instructions need altering (for example the size of the doses) either due to a changed weekly routine or for other reasons.
[0023] The device can be taken in use already in the hospital on the first day of the treatment of diabetes, it can be programmed and the program can be changed during the treatment, and when it is time to return home, the device is taken along to support home care.
[0024] In home care the device is connected through a telephone network to a computer of an expert, for example the doctor responsible for the treatment, and the doctor can familiarize himself/herself with the treatment history on the basis of the insulin amounts, injection times and measured blood sugar information, and change the treatment instructions in real time by remote control via a data transmission line (e.g. telephone network), if necessary. The doctor can also discuss the treatment results with the diabetic and make an agreement on changes before making them via remote control.
[0025] The control device is also based on the fact that each action reminded upon by the control device must be acknowledged either as performed or postponed (wherein the device reminds the user on the undone treatment action within a fixed period of time from the first reminder). According to the principle described hereinbelow the administration of the injection is automatically registered with certain conditions, whereas certain actions related to the treatment must be acknowledged via a user interface by using buttons, etc. The device can give a warning with a special warning signal if the diabetic is about to make a mistake, especially a so-called double injection (another injection within a short time due to forgetfulness). The device can also be programmed in such a manner that it sends an automatic alarm to a desired place (for example to a relative of the diabetic, or to an emergency exchange) if the actions are not acknowledged as performed within a predetermined period of time.
[0026] These automatic warning and alarm functions of the control device substantially increase safety. The device prevents for example a double injection in such a manner that after the injection the injection pen is lowered down to such a position that it can be taken out only by pressing the buttons on the user interface. Even an accustomed “independent” diabetic may sometimes forget either to take the insulin injection or—even worse—that he has already taken the injection, and thus injects himself/herself twice (double injection, which can be fatal).
[0027] The function also prevents the injection of a wrong type of insulin, because only the correct pen is available at the correct time. The control device is advantageously provided with a dialog function before each insulin injection, it is, for example, possible to input information in the control device on earlier physical exercises as well as on the probable amount of exercise in the period of next two hours, and the device can thus give a recommendation on the insulin dose and/or snack amounts depending on the programming. In that case the device has computing capacity.
[0028] On the other hand, the device can contain pre-entered information on the weekly schedule, and before each injection, the control device can display default information on such actions of the diabetic on just the day of the week and injection moment in question in the weekly schedule which have either been performed or should be performed after taking the dose and which affect the insulin dosage, for example: “day: Wednesday, dosage: morning insulin; action: going swimming?”. By means of the buttons in the user interface the diabetic can confirm these pieces of default information as correct or incorrect, wherein the device can determine the most suitable values on the basis of the changed information.
[0029] An important additional feature of the console-type control device is that it is designed to receive information from the device that is on the portable pen. The control device of the portable pen can be charged by the console with simulataneous change of information between the console and the control device of the portable pen.
BRIEF DESCRIPTION OF THE DRAWINGS
[0030] In the following, the invention will be described in more detail with reference to the appended drawings, in which
[0031] [0031]FIG. 1 shows a side-view of the control device according to the invention,
[0032] [0032]FIG. 2 shows top view of the control device of FIG. 1,
[0033] [0033]FIG. 3 shows the operation of the control device in a situation where the indicator indicates an event of administration of a dose,
[0034] [0034]FIG. 4 shows a way of using the sockets of the control device,
[0035] [0035]FIG. 5 shows the charging of a portable device,
[0036] [0036]FIG. 6 shows the principle of recognizing an event of administration of a dose in a portable injection pen,
[0037] [0037]FIG. 7 shows another embodiment of the portable injection pen,
[0038] [0038]FIG. 8 shows combining of blood sugar measurement with the control device, and
[0039] [0039]FIG. 9 shows a chart of the monitoring system in its entirety.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0040] [0040]FIGS. 1 and 2 show a control device for doses which forms a stand for two or more medicament dosage units 3 , in this case injection pens. The stand is intended to be placed for example on a table and hereinbelow the term “table control device” or “console” will also be used for the same. The stand is an electronic device whose data processing unit contains a programmable processor and memory capacity for storing information, as well as a clock device i.e. time measuring device that constitutes a timer. It is the purpose of the stand to control and monitor the administration of several doses during the day. To each injection pen, there is allotted a time of the day in the memory of the device telling when the injection should be taken. When it is the time to administer a dose from the pen, a visual indicator by the pen shows that the dose should be taken from the pen in question. At the same time an acoustic alarm can be given. The removal of the pen is detected by means of a suitable sensor, for example a sensor operating by means of a mechanical switch or on contactless principle, and when the pen is removed for a certain period of time, this is interpreted as an event of administration of the dose. When the event of administration of the dose has been registered in this way, the visual indicator by the pen remains, for a given time, for example until the beginning of the next standby time of the same pen, in a state that shows that the dose has already been taken from the pen. This is indicated advantageously with a colour light that can be easily detected. The indicator for the pen showing that a dose should be taken and the indicator showing that the dose has been taken can be different indicators which are turned “on” and “off”. It is, of course, possible to use physically the same indicator which changes its state, e.g. colour, according to the state of the pen in question. The operating principle is the same for each injection pen to be monitored in the stand. The injection pens can be different in that they contain medicaments which act differently and which should be taken at a certain time of the day. Especially in the treatment of diabetes, the pens may contain different types of insulin.
[0041] In the following the structure of the control device implementing the aforementioned operating principle will be described in more detail. FIG. 1 shows a side-view of a stand for keeping several dosage units 3 , in this case injection pens containing insulin. The stand is a casing, provided with the necessary electronics therein and containing a coupling for an external power source (coupling for a battery charger or a plug to be inserted to a socket). For each injection pen there is a socket 1 to which it can be placed to a vertical position, or, as shown in the figure, to a sloping position. The socket 1 is composed of a tube, which is dimensioned in such a manner that the dosage unit 3 illustrated with broken lines is in the normal position located entirely in the tube, i.e. the end of the same is located inside the inlet opening of the tube so that it cannot be removed from the tube with fingers. The tube is attached to the body casing of the control device, to a recess located in the inclined front wall, i.e. the top wall 9 of the casing. The tube is made of transparent material, for example acrylic plastic, wherein it is easy to see whether there is an injection pen inside the tube.
[0042] In the same wall of the casing from which the tubes protrude, there is also a user interface, i.e. a display and buttons required for operating the device. The function of the display and buttons will be described hereinbelow.
[0043] [0043]FIG. 2 shows a top view of the device. As can be seen in the figure, the device contains tubes for four injection pens. The invention is not, however, restricted to the number of tubes, and thus, it also falls within the scope of the invention that there is only one tube for one injection pen, although the device is best suited for controlling the administration of different types of doses, wherein it is necessary to use at least two different dosage units 3 , and at least two different sockets 1 , respectively, for example when two different types of insulin are used for the treatment of diabetes. When the device contains two or more sockets 1 , they are identical in shape so that a conventional injection pen fits in each socket. The front wall of the container, i.e. the top wall 9 which is slightly inclined, contains a display 5 on which different kind of information can be shown depending on the ways in which the device is programmed. In the normal state the display may only show for example the date and the time. For the treatment of diabetes a separate time has been programmed for each injection pen in the data processing unit of the device. The time measured by the time measuring device of the device is shown on the display in the manner mentioned above, and the data processing unit is arranged to compare the pre-programmed time with the time of the time measuring device. When it is time to administer a dose from the injection pen in question, the data processing unit gives commands to members which control the following functions: the alarm of the device gives a visual alarm by means of a signal light visible by the appropriate injection pen, and possibly an acoustic alarm as well. At the same time the display shifts to a state in which information programmed in the memory of the data processing unit is transmitted thereon, said information relating to the event of administration of that particular dose, for example the size of the dose (in the case of diabetes, units of insulin from the injection pen indicated by the alarm, or another measurement which is used in the injection pen and can be set therein before the injection). Thus, the data processing unit and the time measuring device cooperate in a manner similar to a timer.
[0044] Furthermore, it is possible that alarms relating to other actions can also be programmed in the data processing unit, which alarms are given at fixed times of the day, i.e. when the device gives an alarm, it does not necessarily indicate that a dose must be taken, but it can refer to other measures (meal, exercise, etc.) relating to the treatment of diabetes. The alarm of the device can in this case give a visually and/or acoustically different alarm than the alarm relating to the administration of a dose.
[0045] According to the principle disclosed in the publication WO 99/43283, the entire disclosure of which is incorporated herein by reference, the device also registers the removal of the dosage unit, and thus, the corresponding indicator will continuously indicate that the dose has been taken. This function will be described in more detail hereinbelow. If the dosage unit has not been removed within a fixed period of time after the alarm, the device gives another alarm.
[0046] The device can communicate with an outside supervisor for example by means of landline or wireless communication. Thus, for example a doctor can monitor the treatment, and in the case of a bilateral connection, the doctor can also program the device from a distance. Thus, it is possible to program different kinds of instructions in the data processing unit of the device, such as the sizes of doses, other instructions such as instructions for meals and exercises which can be shown on the display, etc. Furthermore, it is possible to change the administration times (set new alarm times) from a distance. Although the connection is protected as well as possible, to be sure the device contains a security function allowing only a change of particular scale one way or the other in the values relating to the administration of the medicament dose (time of day, size of the dose), i.e. an upper limit is determined for the changes (for example units of insulin and h). A special alarm may be automatically transmitted outside via the data transmission line if the device has not registered an event of administration of the dose within a predetermined time after the first alarm given to the user of the device. It is possible to provide the device with a function by means of which the user can avoid false alarm beforehand by entering information by means of the buttons of the user interface that certain injection will be taken care of in another way. Furthermore, the figure shows an emergency button 6 , which, when pressed continuously for a predetermined period of time, for example 0.5 seconds, sends a special alarm outside. The special alarm may be programmed to be transmitted via the data transmission line directly to a special address, for example to an emergency centre. Furthermore, FIG. 2 shows function buttons 10 , by means of which it is possible to move in the menu shown on the display 5 and confirm that different activities (meal, exercise) have been performed. These confirmations are also registered in the memory and the person supervising the treatment can monitor them via the data transmission line.
[0047] [0047]FIG. 3 shows schematically how the dosage unit 3 located inside the tube is lifted up to the operational position. The lower end of the dosage unit is positioned in the space below the top wall 9 , the tube extending to this space as well. When the pre-programmed time and the time of the time measuring device match, an alarm relating to the event of administration of the dose is given, and in connection with the alarm the data processing unit also gives an actuating command to a lifter 4 located in the lower end of the tube and touching the lower end of the injection pen, said lifter lifting the pen inside the tube so that the opposite end of the pen rises above the inlet opening of the tube. In FIG. 3 the lifter 4 is implemented by means of an eccentric attached to an electrically rotated shaft 8 with a quadratic cross-section. The lifter 4 is of such a type that it does not lock the pen in its place, but the lower end of the pen rests freely on top of said lifter, and the pen can be removed by tilting the container, wherein the pen slides out, or by removing the tube. In a device containing several injection pens the eccentrics are placed on the same shaft 8 at regular angular distances so that they face different directions, and the shaft always revolves a corresponding distance (i.e. in a device with four sockets at distances of 90°) Furthermore, the visual light indicator 2 connected to the dosage unit is placed inside the casing, in the lower end of the tube in such a manner that it directs light from the end of the tube to the wall of the tube. Thus, the tube functions as a light guide and conducts the light emitted by the indicator into view, wherein it can be seen at least in the upper end of the tube as a glowing, ring-like light. The indicator 2 can be composed for example of a series of light-emitting diodes located at the end of the tube. When the event of administration of the dose has been registered, the colour of the light-emitting diodes can change (for example from green to red), or other light-emitting diodes that are placed for this purpose below the tube and emit different kind of light are switched on. Furthermore, a text may appear on the display 5 indicating from which socket 1 (tube) the dosage unit 3 should be taken and the size of the respective dose, and for this purpose, the front wall may contain a letter or a number by each tube.
[0048] When the lifter 4 has lifted the injection pen to the upper position, the removal of the same is detected by means of a sensor, for example with a sensor marked with the reference numeral 7 in FIG. 3, such as a light cell, operating on the contactless principle, and thus the indicator 2 indicates that the dose has been taken and the time (date and time of day) the dose was taken is at the same time registered in the memory of the data processing unit of the device. By means of the above-mentioned bi-directional data transmission connection, the person supervising the treatment, such as a doctor, can monitor the times of administration of the doses. The injection pen must be removed for a predetermined period of time, so that mere lifting of the pen up and lowering it back down right thereafter would not be registered as an event of administration of the dose.
[0049] The lifter 4 can be of another type as well, for example a plunger operating electrically by means of a magnetic coil, or by means of a motor of its own, in which case the lifters of different sockets are not mechanically connected to each other. If it is desired that the injection pen can be removed at other times than the time set for administrating the dose, the lifter 4 can also be arranged to operate manually, for example mechanically by means of a control apparatus, or with a special press button. The tubes surrounding the injection pens may also be easily detachable from the casing, for example they can be screwed off. If the tube is fixed to the body casing by means of a screw thread, the outwards protruding portion of the tube can then be handily adjusted as well. In practice, however, it has been observed that the insulin injection pens of different manufacturers differ from each other very slightly in length, whereas in diameters the variation is greater.
[0050] The function of the lifters 4 is advantageously arranged in such a manner that when the indicator 2 has detected that the dose has been taken, the lifter 4 of the corresponding socket is lowered down immediately or relatively soon after a delay time. This ensures the prevention of double injection, because the pen moves into the lower position after the dose has been taken, and it cannot be easily removed. Thus, in a situation when it is not the time to take the injection, all pens are in the lower position. When the lifter is implemented using eccentrics and a common shaft, the shaft must always, after an event of administration of a dose, revolve to such a position in which none of the eccentrics lifts the pen upwards, i.e. a distance half of the angular distance between two successive eccentrics. Thus, the mechanical solution itself, bringing forth clearly the pens from which a dose is intended to be taken while the other pens lie in their rest position, already ensures the prevention of double injection. Despite of this prevention of double injection provided already by the structure, it is possible to arrange an alarm within a fixed, predetermined precautionary time (for example within 2 hours from the administration), if, however, some kind of an attempt is made to remove the same pen. In the case of a double injection attempt, the alarm of the device receives information from the sensor 7 detecting the removal of the pen, and the alarm can give an acoustically or visually different alarm (warning signal) when compared to the normal alarm relating to the administration of a dose (reminder signal), thus warning of the risk of double injection. Furthermore, to be on the safe side, it is possible to provide the device with a function by means of which the special alarm is transmitted outside via a data transmission line when the device registers an injection from the same pen twice within the precautionary time, i.e. the sensor 7 has detected that within a set time (precautionary time) from the first registered injection, the same pen has been away for a fixed delay time, which is interpreted as a double injection. There are, however, cases in which the diabetic intentionally wishes to take another dose smaller than the normal dose from the same pen within a short period of time, for example due to an extra meal. This would be interpreted as a double injection. Unnecessary alarm can be avoided if it is possible to enter information in the device in which the user indicates that he is intentionally taking an injection from the same pen twice. Thus an alarm is not transmitted within the precautionary time.
[0051] The invention is not limited solely to tubes, but the sockets can be composed of one or several longitudinal supporting elements with another shape, said supporting elements extending in the height direction. It is for example possible to use several rib-like elements around the dosage unit 3 . One supporting element with an open cross-section may also be sufficient for each socket, said supporting element being located in a sloping position in such a manner that the dosage unit 3 rests against the same and said supporting element may thus be shaped on the side of the dosage unit as a curved groove-like structure. In the alternatives where the supporting element does not surround the dosage unit 3 entirely as a tube-shaped element, the dosage unit can be removed without a lifter as well, but also in these cases it is possible to arrange a mechanical lifting movement in conjugation with the time of administering the dose, wherein, in addition to the visual indicator, said dosage unit 3 is at the same time distinguishable from the others. Also in this case the supporting elements can be dimensioned in such a manner that in the normal position the upper ends of the dosage units remain below the upper end of the supporting element, and the lifter 4 lifts the upper end of the dosage unit 3 above the upper end of the element.
[0052] [0052]FIG. 4 shows that all tubes or sockets 1 with another shape do not necessarily have to contain an injection pen, but the device can be programmed for a smaller number of different injection pens. The basic model is a device with four sockets, wherein the maximum number of injection pens is four. The connecting cable by means of which the device can be connected to a plug socket is marked with the reference numeral 11 . In FIG. 4 one of the sockets is missing (a tube or a corresponding supporting element/elements has/have been released) and the hole remaining in the body casing is plugged. One of the sockets is also modified into a special seat for a portable injection pen provided with a control device of its own, containing a sensor detecting the movement relating to the injection (e.g. the movement of the piston or a part connected thereto kinetically). Thus, the seat functions as a charger for the battery of the control device. The control device can be the device presented in the international publication WO99/43283 that can be attached to the injection pen as a separate element and contains timer and alarm functions of its own. When the body casing is designed, such a charger possibility can be taken into account for example in such a manner that one hole in the body casing, in which the lower end of the dosage unit is located in normal use, is equipped with current contacts, for example contacts supplying direct current, which are otherwise covered by the tube fixed to the hole e.g. by means of screwing down, but which are coupled to the conductors of a fitting element attached in the hole to replace the tube, said conductors passing to the charging contacts of the fitting element. Into such a fitting element fixed to the body casing it is now possible to insert a control device accompanying the pen, the contacts of the control device being now connected to the contacts of the fitting element. Another structural possibility is to arrange a hole in the body casing which is originally wider and functioning as a charger and containing current contacts required for the charging in readiness, and the control device can be inserted in the hole. When the aim is to change this section into a conventional socket, a fitting element is inserted therein, containing an attachment point for a tube or another supporting element, or a tube or a corresponding supporting element is already contained therein.
[0053] In the charging by means of the body casing, the control device and the injection pen are attached to each other, wherein they can be easily taken along from the body casing. Naturally, it is also possible to register the placement of the pen and the control device in the charging and release from the charging into the memory of the device, because such a movement can be easily detected and this information can also be read from outside by means of the data transmission line. FIG. 4 shows how among three “operating” sections the one in the middle functions as a charger for the control device of a portable injection pen. In the treatment of diabetes it is thus possible to act in such a manner that the morning insulin is taken at home from the injection pen of the outermost socket, the portable injection pen and the control device are taken along from the charger when going away for the day, and the evening insulin is again taken at home from the other outermost socket. When the body casing is modified, the movements of the lifters 4 are of course programmed to occur according to the locations of those injection pens that can be lifted up. When eccentrics located on the same shaft are used, the shaft 8 can revolve double a distance at the moment of operation, so that it is possible to pass by the empty (plugged) section or the section functioning as a charger. If the diabetic is at home at all times when a dose must be taken, in the place of the portable injection pen and the charger of its control device there is a socket similar to those intended for other injection pens.
[0054] The same principle can be applied for four-injection treatment, wherein the plugged hole seen in the drawing also provides an operative development location. Thus, the order can be such that on the right-hand side there is the socket for the injection pen containing the morning insulin, the following socket is for the portable injection pen for the daytime insulin to be taken before lunch, and it is followed by the socket for the injection pen for insulin to be taken around at 5 p.m., and on the left-hand side there is a socket for the “night insulin” to be taken late in the evening. When necessary, the device can be designed in such a manner that the chronological order of the sockets and charger locations proceeds from left to right. If the diabetic is at home at all times a dose must be taken, in the place of the portable injection pen and the charger of its control device there is a socket similar to those intended for other injection pens.
[0055] [0055]FIG. 5 shows a preferred embodiment of charging the control device of a portable injection pen, which can be applied in the device shown hereinabove in FIG. 4. The charging functions inductively, wherein the table control device contains a primary coil L 1 which is connected to a power source and functions as a charger, and surrounds the charger socket 1 to which the portable injection pen is placed. The injection pen may be fastened into its control device, or the injection pen can also be of the type to which the control device of its own is integrated in such a manner that it cannot be released from the injection pen. The control device on the injection pen is positioned inside the charger socket, and it contains a secondary coil L 2 connected via a rectifier to a rechargeable battery functioning as a power source, said secondary coil being positioned inside the coil in the charger socket 1 , and having charging current induced thereto as a result of the alternating current in the primary coil L 1 of the charger socket. The primary socket L 1 and the secondary socket L 2 may also be positioned in another way with respect to each other in the charging position, so that they are inductively coupled to each other.
[0056] At the same time when the control device of the portable injection pen is set into a charging position, it is possible to transfer information thereto from the table control device, and the table control device may read information contained therein. The data transmission may take place via a separate line, but advantageously charging current is also used for data transmission, wherein the charging current contains components which the control device of the portable injection pen recognizes as data and transfers to the memory. The information contained in the control device of the portable injection pen can be transferred therefrom to the table control device, i.e. it can be “discharged” via the same line by means of which the charging is conducted, for example after the charging, when there is certainly a sufficient amount of power available for data transmission. Combined charging and data transmission can be implemented inductively or with a direct charging current contact. Concerning the principle of inductive charging and simultaneous change of data between the charged device and charger device, reference is made to U.S. Pat. Nos. 6,028,413 and 5,455,466, respectively. The disclosures of these two documents are incorporated herein by reference.
[0057] Exchange of information between the control device of the portable injection pen and the table control device can take place in another wireless manner, for example by means of an infrared connection.
[0058] [0058]FIG. 6 shows the control device 16 , which is incorporated in the portable injection pen especially for prevention of a double injection and whose power source (battery) can be charged by the table control device in the manner described hereinabove. The device is based on the idea that when a dose is taken, the cap 12 protecting the needle must always be removed. In the body of the injection pen 3 , for example at the base of the needle part 13 there is a resonance circuit 15 (a so-called passive tag). An active transmitter-receiver part 14 connected to the power source (rechargeable battery of the control device) that generates a radio field is located in the cap 12 . The principle is similar to the one used in shop control gates, but in a sort of a way in reversed order, i.e. in the normal situation (the passive tag and the active part located close to each other, i.e. the cap 12 on top of the needle 13 ), the resonance circuit 15 is located in the radio field (in which the shop control gate would give an alarm). When the resonance circuit 15 is not located close to the active part 14 , a different kind of radio field is detected by the active part. In this situation, in which shop control gates are in the normal situation, we are dealing with a special case, i.e. the cap 12 has been removed from the top of the needle 13 . When the cap is removed, the control device detects the removal of the cap through the missing resonance circuit. The resonance circuit 15 can be arranged in the cylindrical plastic part located at the base of the needle part 13 , for example by attaching an adhesive tape containing the circuit to the part or embedding the circuit 15 in this part already at the manufacturing stage. It is, for example, possible to produce a ring-like or cylindrical part that fits tightly around the plastic part and is made of an adhesive film containing the circuit. This part can be removed from the plastic part when a needle 13 is changed in the injection pen 3 , or the entire injection pen is replaced. The principle of recognizing an event of administration of a dose is otherwise the same as the one described above. The cap 12 must be removed from the top of the needle 13 for a period of fixed length. In practice, the time is measured in such a manner that to save power the active transmitter-receiver part 14 first checks, for example within short intervals (1 to 2 s), whether the resonance circuit 15 is present, and when a fixed number of successive checking steps have been calculated in which the resonance circuit is missing, the interpretation is made that the injection has been taken. The actual control device 16 containing a transmitter part, a processor, a timer and a power source is a separate piece that can be fixed to a conventional cap 12 of an injection pen 3 , and it contains an indicator 2 . When it is time to take a dose from the pen, the visual indicator 2 indicates that a dose should be taken. At the same time it is possible to give an acoustic alarm. The release of the cap 12 is recognized on the basis of the above-described principle based on the resonance circuit 15 . When the event of administration of the dose has been registered in this way, the visual indicator 2 by the pen remains, for a given time, for example for a set precautionary time (for example 2 to 3 hours), in a state that shows that the dose has already been taken from the pen. This is indicated advantageously with a colour light that can be easily detected. The indicator 2 showing that a dose should be taken and the indicator showing that the dose has been taken can be different indicators which are turned “on” and “off”, for example implemented with LEDs of different colours (for example green: take a dose, red: a dose taken). It is, of course, possible to use physically the same indicator which changes its state, e.g. colour, according to the state of the pen in question. If an attempt is made to take a dose again within the precautionary time, the control device gives an alarm (a special warning signal) on the event of administration of a double injection, for example by means of an acoustic signal (signal tone). The control device does not, however, prevent one from taking a second injection within the precautionary time. When an administration time and a precautionary time of a fixed length after the event of administration (measured with a timer) is not on in the control device, the indicators of the device are in the passive state (for example the visual light-emitting indicator/indicators are turned off). Alternatively, to save the power source it is possible to keep the light/lights in a turned-off state when the dose has been taken appropriately, and turn them on only when the cap is removed for the second time during this precautionary time, wherein the lit light is a warning (an acoustic signal can also be given).
[0059] In its simplest form such double injection warning device in a portable pen can only contain the aforementioned resonance circuit 15 and the active part 14 arranged in the cap 12 , as well as the indicator/indicators 2 , and it only requires such an amount of data processing and time measuring capacity and such a power source that the device is capable of registering the dose as administered. When the device is within a fixed precautionary time in the state “dose taken”, the indicator gives an alarm if the sensors detect the removal of the cap. This precautionary time could, in principle, be set so that it would end only at the time of administration of the next injection, but it is advantageously shorter, so that the pen can be serviced every now and then without causing an alarm.
[0060] The control device 16 can be attached to the existing cap 12 of an injection pen by means of one or several fixing means that can be attached around the cylindrical portion of the cap 12 and are designated at 17 in the figure. Alternatively, the control device 16 can be formed as a bushing that has a cavity wherein the cap 12 can be fitted with a suitable tightness so that the control device 16 surrounds the cap 12 . This general configuration is depicted in FIG. 7.
[0061] [0061]FIG. 7 shows an embodiment where the control device 16 cooperates with the needle 13 without a complementary sensor in the needle part 13 or elsewhere in the injection pen 3 . The control device 16 contains a sensor 14 that acts on capacitive principle, that is, the sensor 14 has two electrodes that form a capacitor. The change of the properties of an RC-circuit being part of the sensor can be detected in the form of a changed natural oscillation frequency. The presence or absence of the needle part 13 or the proximal end of the injection pen body between the electrodes can be detected and the the administration of a dose can be deduced analogously to the previous example of FIG. 6. In fact when any matter is in the vicinity of the capacitive sensor 14 , it affects its capacitance and consequently the properties of the sensor circuit that can be easily detected.
[0062] The capacitive sensor 14 in the cap 12 can be utilized even in a more sophisticated manner. When sensitive enough, it can be used to detect the change of the insulin volume of the insulin container in the injection pen 3 . This requires the measurement before and after the injection in exactly the same position of the cap 12 , that is, while it is over the needle 13 . A sensor detecting a grip by the fingers can be incorporated in the control device 16 in this case, and it can be a sensitive sensor detecting the presence of human fingers through the electrical conductivity of skin, heat by the skin, or pressure applied by the fingers, and solutions known from various control interfaces of a human and a device reacting to just a light touch by a finger can be applied. One example of a sensor film having an efficient response to a pressure is the electromechanical film widely known as EMF. The sensor is designated at 18 in FIG. 7, and it can be placed around the device 16 along its periphery over an area where the device 16 is gripped by fingers when the cap 12 is to be removed. When the sensor 18 of any aforementioned kind detects a grip, it immediately gives a command to the capacitive sensor 14 to perform a measurement. When the removal of the cap 12 has been detected, and the cap 12 thereafter is back on its place, the measurement data just before the cap removal and the measurement data of the normal situation of the cap being back again is compared, and a slight difference of the readings will indicate that the container volume has decreased, i.e. the insulin has flown from the container through the needle. This difference of measurement values is smaller than the difference of the values between the situations where the cap 12 is over the needle 13 on the pen and away from the pen, respectively. This arrangement of combining another suppplementary measurement with the actual detection measurement of the cap removal may be helpful in deciding whether the cap 12 has been just removed for a while and put back, or whether in fact some insulin has been injected. To work in a reliable manner the electrodes of the capacitive sensor 14 in the control device 16 should be close to the body of the injection pen 3 and protected aginst external influences by a surrounding shield so that the the parts of the insulin pen 3 closest to the needle part 13 (insulin container) have the largest influence on the capacitance of the sensor 14 and the changes experienced by the sensor.
[0063] Above the embodiments have been described where the control devices can be fitted to ordinary, usually cylindrical caps of commercially available existing injection pens. It is also possible to produce a special cap, in which the control device is integrated so that it forms an inseparable single unit with the cap. The special cap can be changed in an injection pen to replace a conventional cap at the same time when a resonance circuit is placed at the base of the needle. This specially designed cap can use all sensor embodiments presented hereinabove.
[0064] The control device 16 placed on or integrated in the cap can be placed in the charging socket of the table control device, and the charging and data transmission can be implemented according to the above-described non-contacting and contacting principles.
[0065] Furthermore, when the needle part 13 also has a sensor, such as the circuit 15 discussed above, it is possible to produce separately needles in which the sensor part required by the control device 16 has already been integrated. This sensor part, such as the aforementioned resonance circuit, can be placed in the wider part located at the base of the needle, for example inside this part or on top of the same.
[0066] [0066]FIG. 8 shows how it is possible to use the table control device also for monitoring other kind of treatment related to diabetes. A portable blood sugar measurement device M, which by means of an analysis principle known as such measures the blood sugar content in the blood sample placed therein, can be placed in the control device. The blood sugar measuring device contains information on the measuring moment and the measured blood sugar, and the memory of the same may contain blood sugar information measured at different times. The measured data and measuring times are stored in the memory of the table control device by means of a data transmission connection between the measurement device and the control device, for example by means of interface points based on mechanical contact, and this information can also be transmitted to an outside supervisor via a data transmission line.
[0067] [0067]FIG. 9 shows schematically the data transmission system, according to which the information contained in the table control device “CONSOLE”, including blood sugar measurement information, are read automatically at fixed intervals, preferably once a day, for example at night. According to the way shown in FIG. 8, the table control device can be connected to a so-called robot phone. The robot phone may be integrated in the table control device, wherein it can be implemented with a card containing the necessary electronics. The table control device can also be provided with a GSM card, wherein the data transmission takes place in a wireless manner. The drawing shows how the transmission of information outside from the control device can take place via a public telecommunication network or a wireless data transmission connection in two ways. The first way, marked with “Phase# 1 ” illustrates the above-mentioned alarm cases. The second way, marked with “Phase# 2 ” illustrates at least data transmission outside from the device at fixed intervals (“incoming data”) by means of which at least information on the times of administration of doses and advantageously also on the blood sugar values is transmitted to an outside expert (“Doctor”) automatically at fixed times of the day, preferably at night time. The treatment actions and the results of the same from the previous day (Change in patient's glucose levels) can thus be read by the expert for example on a computer screen first thing in the morning, and on the basis of this data it is possible to use the same line to transmit information back to the table control device (instructions and changes in values, marked with the word “Adjustments”). Thus, this data transmission is preferably bi-directional.
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The invention relates to a portable control device for monitoring the administration of doses by a diabetic. The control device is arranged in conjunction with a portable dosage unit having a body and an injection member designed to deliver the dose to the diabetic and attached to the body of the portable dosage unit. The dosage unit has a removable cap over the injection member. The control device is provided in the cap and is movable together with the cap. The control device comprises a sensor arranged to detect the removal of the cap from over the injection member and connected to an indicator of the control device for showing if the cap has been removed from over the injection member for administering insulin.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention concerns a method to process magnetic resonance diffusion image data, as well as a user interface, a magnetic resonance apparatus, and a non-transitory, computer-readable data storage medium encoded with programming instructions for implementing such a method.
2. Description of the Prior Art
In magnetic resonance diffusion imaging, multiple diffusion images with different diffusion directions and/or diffusion weightings, which are typically characterized by a b-value, are normally acquired. A diffusion coefficient map can then be created from the diffusion images, for example. This is a spatially resolved depiction of apparent diffusion coefficients (ADC). The apparent diffusion coefficient typically describes the average length of a trajectory of a water molecule in tissue. If the length of the trajectory is long, the water molecules can move freely and the apparent diffusion coefficient is large. If the movement of the water molecules is prevented, such as due to a high cell density in compact tissue, which may be due to a tissue variation, the apparent diffusion coefficient is small. The diffusion images and/or the diffusion coefficient map are designated as diffusion image data.
SUMMARY OF THE INVENTION
An object of the invention is to enable a particularly advantageous processing and/or display of magnetic resonance diffusion image data.
A method in accordance with the invention for processing diffusion image data of an examination subject acquired by a magnetic resonance apparatus, includes the following steps: provide diffusion image data to a computer, provide a signal threshold to the computer, and in the computer, calculate a b-value map on the basis of the diffusion image data and the predetermined signal threshold.
The provision of the diffusion image data to the computer can be acquisition of the diffusion image data by a magnetic resonance apparatus. Alternatively or additionally, the provision of the diffusion image data can be a loading of previously acquired diffusion image data into the computer, for example from a database.
The provided diffusion image data typically includes at least two diffusion images, the at least two diffusion images having different diffusion weightings, in particular different b-values. The diffusion weighting is typically dependent on the formation of diffusion gradients that are used during the acquisition of the diffusion images. As noted, the strength of the diffusion weighting is typically described by a b-value, with a higher b-value indicating a stronger diffusion weighting, for example due to a higher amplitude and/or a longer duration of the diffusion gradients. The diffusion images typically include a spatial distribution of magnetic resonance signals acquired with a diffusion weighting, known as diffusion signals. A diffusion image may have no or only a weak diffusion weighting, thus a b-value of nearly zero. The diffusion images can be three-dimensional and then, for example, can include multiple two-dimensional slice images that together form a three-dimensional diffusion image.
The diffusion image data may already include at least one diffusion coefficient map. A diffusion coefficient map typically includes a spatial distribution of diffusion coefficients (namely apparent diffusion coefficients) of the examination subject that are measured by the magnetic resonance apparatus. A calculation of a diffusion coefficient map typically takes place on the basis of the at least two diffusion images. Alternatively, an already-calculated diffusion coefficient map may be loaded directly in the provision of the diffusion image data, such as from a database.
The method according to the invention is based on the insight that diffusion images with special (in particular high) b-values are often relevant to an assessment by an expert personnel. In these diffusion images, for example, compact tissue with a low apparent diffusion coefficient is especially emphasized. However, the b-value used in the acquisition of the diffusion images has a direct influence on the echo time of an acquisition sequence. Higher b-values typically lead to longer echo times. Given the use of higher b-values, the signal-to-noise ratio of the diffusion images therefore typically decreases. Therefore, typically at least two diffusion images with small or medium b-values are used to determine the diffusion coefficient map. However, the b-values of the at least two diffusion images should also be markedly different so that the precision of the determination of the apparent diffusion coefficient is improved. It is typically not known in advance which b-values are necessary for assessment of the diffusion images, for example for clear delimitation of compact or injured tissue, nor it is known in advance for which b-value such tissue can best be differentiated from normal tissue. In order to enable a best possible differentiation, many diffusion images with different b-values must often be acquired, so the measurement time for acquisition of the diffusion images is very high, and it may still occur that a diffusion image with a special b-value that would be of interest has not been acquired. Therefore, in conventional methods for processing diffusion image data, diffusion images are typically extrapolated that have different virtual b-values from the measured b-values. Since the optimal b-value is unknown before the calculation, many diffusion images with virtual b-values must often be calculated, of which only a small part is relevant to expert personnel for the assessment of the diffusion images. This generates unnecessary data in a database and a high workload for expert personnel, who must seek out relevant diffusion images from the large number of diffusion images with the different virtual b-values.
The calculation of the b-value map on the basis of the diffusion image data and the predetermined signal threshold in accordance with the invention is advantageous compared to conventional methods for processing of diffusion image data. The b-value map produced in accordance with the invention advantageously includes a spatial distribution of those b-values for which a diffusion signal measured by the magnetic resonance apparatus has the predetermined signal threshold. Magnetic resonance signals, in particular diffusion signals, typically decrease with increasing b-values. That b-value for which the spatially resolved diffusion signal reaches the predetermined signal threshold and/or falls below the predetermined signal threshold can then be stored in a parameter map (the b-value map). The b-value map advantageously needs to be calculated only once from the predetermined signal threshold and the diffusion image data, in particular of the diffusion coefficient map calculated from the diffusion image data. The calculation of the b-value map thus saves computing time and evaluation time. The b-value map simultaneously offers the versatility of many diffusion images with different diffusion weightings. In particular, the b-value map includes virtual b-values and can thus also be designated as a virtual b-value map. The b-value map is in fact calculated on the basis of diffusion image data that have been acquired with defined b-values. The b-value map is advantageously not limited to these defined b-values, however, but rather includes a broader spectrum of (in particular virtual) b-values and/or additional (in particular virtual) b-values. The b-value map is thus not limited to one b-value. The b-value map thus saves on additional tools to assess diffusion image data. The b-value map also reduces the workload of an expert personnel since he or she only needs to assess one image (the b-value map) instead of possibly many diffusion images. After the calculation of the b-value map, the b-value map can be made available electronically as a data file, for example by display at a display unit, storage in a database, and/or transfer to an additional computer, etc.
In an embodiment, a display of the calculated b-value map takes place. The b-value map can be displayed at a display unit (for example a monitor), in particular in a user interface. The displayed b-value map can then be viewed and/or assessed by a user, in particular an expert personnel. Expert personnel can set parameters for the displayed b-value map via an input unit. For example, the user can modify the slice of the b-value map that is to be displayed and/or the contrast of the b-value map, for example by means of adjusting the signal threshold.
In another embodiment, the display of the calculated b-value map includes a windowing of the calculated b-value map. This allows the user to produce the windowing of the b-value map. For this purpose, the user can select a windowing of the displayed b-value map, for example in order to display specific tissue (in particular compact tissue) with a low apparent diffusion coefficient (and thus a high b-value) with a desired contrast in the b-value map. In particular, low b-values in the b-value map can be masked out to show the compact tissue with a high b-value. This means that the windowing is advantageously set such that tissue with low b-values is shown black in the b-value map, such that compact tissue with a high b-value particularly clearly emerges. For example, the windowing can include the setting of a minimum b-value and a window width for the b-value. All b-values that are smaller than the minimum b-value are then shown as black in the b-value map, for example. All b-values which are greater than the window width added to the minimum b-value are then shown as white in the b-value map. B-values lying in-between are shown in greyscale depending on their formation, for example. Naturally, another method for windowing of the b-value map (for example the adjustment of a window width and a middle point of the window) is also possible. Naturally, a color presentation of the b-value map according to a color palette can also be chosen. A windowing of the displayed b-value map is particularly advantageous because observers (in particular expert personnel) of medical image data (diffusion image data, for example) are accustomed to a windowing of the image data and implement this intuitively. A windowing of the b-value map also advantageously requires no recalculation of the b-value map, and accordingly saves on computing resources. Nevertheless, through the windowing the b-value map can have a particularly advantageous and significant contrast.
In another embodiment, the provision of the signal threshold includes a determination of the signal threshold using the diffusion image data and/or additional magnetic resonance image data. The signal threshold can be calculated using an algorithm. It can therefore be calculated so that the b-value map is displayed with an advantageous contrast, and thus has a clear significance to an observing expert personnel. The automatic calculation of the signal threshold can also represent an advantageous starting point for a later change of the signal threshold which in particular includes a recalculation of the b-value map due to an input by the user in an input unit.
In another embodiment the predetermination of the signal threshold includes an input to the computer by a user via an input unit. The user can thus provide an advantageous signal threshold for calculation of the b-value map. The entry of the signal threshold can be based on a b-value map that is already displayed, in particular with an automatically determined signal threshold. With the input of the signal threshold, the user can modify the b-value map such that the b-value map is displayed to the user at a desired contrast so that an advantageous and particularly simple assessment of the b-value map is possible.
A user interface according to the invention has an image data acquisition unit, a specification unit and a computer, wherein the image data acquisition unit, the specification unit and the computer are designed to execute a method for processing diffusion image data of an examination subject acquired by means of at least one magnetic resonance apparatus, wherein the image data acquisition unit is designed to receive diffusion image data, the specification unit is designed to provide a signal threshold, and the computer is designed for calculation of a b-value map on the basis of the diffusion image data and the predetermined signal threshold.
The image data acquisition unit can be designed for loading the diffusion image data, in particular from a database. The image data acquisition unit can also be designed to receive the diffusion image data from a magnetic resonance apparatus.
Embodiments of the user interface according to the invention are designed analogous to the embodiments of the method according to the invention. According to an embodiment, the user interface thus has a display unit that is designed to display the calculated b-value map. According to another embodiment, the display unit is designed so that, dependent on an entry made by a user via an input unit of the user interface, the display of the calculated b-value includes a windowing of the calculated b-value map. According to another embodiment, the specification unit (in particular a computing module of the specification unit) is designed to implement a determination of the signal threshold using the diffusion image data and/or additional magnetic resonance image data. This step can also be implemented by the computer of the user interface, which includes the specification unit. According to one embodiment, the specification unit comprises an input unit, wherein the provision of the signal threshold includes an input of the signal threshold into the input unit by a user.
The user interface can have additional control components that are necessary and/or advantageous for execution of a method according to the invention. The user interface can also be designed to send control signals to a magnetic resonance apparatus and/or to receive and/or process control signals in order to execute a method according to the invention. Computer programs and additional software can be stored in a memory unit of the user interface, by means of which computer programs and additional software a processor of the user interface automatically controls and/or executes a method workflow of a method according to the invention. The user interface according to the invention thus enables a processing and/or display of diffusion image data that especially saves computing time, is versatile and is significant.
The magnetic resonance apparatus according to the invention has an image data acquisition unit, a specification unit and a computer, wherein the image data acquisition unit, the specification unit and the computer are designed to execute a method to process diffusion image data of an examination subject that are acquired by a data acquisition unit, in which a patient is situated, of the magnetic resonance apparatus, wherein the image data acquisition unit is designed to require diffusion image data, the specification unit is designed to provide a signal threshold, and the computer is designed to calculate a b-value map on the basis of the diffusion image data and the predetermined signal threshold.
In particular, the image data acquisition unit is designed to receive diffusion image data for the data acquisition unit. The image data acquisition unit can also be designed to load the diffusion image data, in particular from a database. Embodiments of the magnetic resonance apparatus according to the invention are designed analogous to the embodiments of the method or of the user interface according to the invention. For this purpose, computer programs and additional software can be stored in a memory unit of the magnetic resonance apparatus, by means of which computer programs and additional software a processor of the magnetic resonance apparatus automatically controls and/or executes a method workflow of a method according to the invention. The magnetic resonance apparatus according to the invention thus enables a processing and/or display of diffusion image data that especially saves computing time, is versatile and is significant.
The present invention also encompasses a non-transitory, computer-readable data storage medium encoded with programming instructions that, when the storage medium is loaded into a computer or processor of a user interface or a magnetic resonance apparatus, cause the interface or the magnetic resonance apparatus to execute any or all embodiments of the method described above. The computer must thereby respectively have the requirements (for example a corresponding working memory, a corresponding graphics card or a corresponding logic unit) so that the respective method steps can be executed efficiently. The control information of the electronically readable data medium is designed to implement a method according to the invention given use of the data medium in a computer of a user interface and/or of a magnetic resonance apparatus. Examples of electronically readable data media are a DVD, a magnetic tape or a USB stick on which is stored electronically readable control information, in particular software (see above). All embodiments according to the invention of the method described in the preceding can be implemented when this control information (software) is read from the data medium and stored in a controller and/or computer of a user interface and/or of a magnetic resonance apparatus.
The advantages of the user interface according to the invention, of the magnetic resonance apparatus according to the invention and of the computer program product according to the invention essentially correspond to the advantages of the method according to the invention are described above. The corresponding functional features of the method are developed by corresponding objective modules, in particular by hardware modules.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 schematically illustrates a magnetic resonance apparatus according to the invention for execution of the method according to the invention.
FIG. 2 is a flowchart of an embodiment of the method according to the invention.
FIG. 3 is a more detailed flowchart of an embodiment of the method according to the invention.
FIG. 4 schematically depicts the dependency of a diffusion signal of a diffusion image on a b-value that was used to acquire the diffusion image, for aqueous tissue and compact tissue.
FIG. 5 depicts six diffusion images acquired from the same examination subject with the same field of view, but with different b-values.
FIG. 6 shows three depictions of a b-value map with different windowings, with the same field of view as in FIG. 5 .
DESCRIPTION OF THE PREFERRED EMBODIMENTS
FIG. 1 shows a magnetic resonance (MR) apparatus 11 according to the invention for execution of the method according to the invention. The magnetic resonance apparatus 11 has a detector unit formed by a magnet unit 13 , with a basic magnet 17 to generate a strong and in particular constant basic magnetic field 18 . In addition to this, the magnetic resonance apparatus 11 has a cylindrical patient accommodation region 14 to accommodate an examined person 15 (in particular a patient 15 ), wherein the patient accommodation region 14 is cylindrically enclosed by the magnet unit 13 in a circumferential direction. The patient 15 can be slid into the patient accommodation region 14 by means of a patient bearing device 16 of the magnetic resonance apparatus 11 . For this purpose, the patient bearing device 16 has a table bed that is arranged so as to be movable within the magnetic resonance apparatus 11 . The magnet unit 13 is externally shielded by a housing 31 of the magnetic resonance apparatus 11 .
The magnet unit 13 furthermore has a gradient coil unit 19 to generate magnetic field gradients that are used for a spatial coding during an imaging. The gradient coil unit 19 is controlled by means of a gradient control unit 28 . Furthermore, the magnet unit 13 has: a radio-frequency (RF) antenna unit 20 which, in the shown case, is designed as a body coil permanently integrated into the magnetic resonance apparatus 11 , and a radio-frequency antenna control unit 29 to excite a polarization that arises in the basic magnetic field 18 generated by the basic magnet 17 . The radio-frequency antenna unit 20 is controlled by the radio-frequency antenna control unit 29 and radiates radio-frequency magnetic resonance sequences into an examination space that is essentially formed by the patient accommodation region 14 . The radio-frequency antenna unit 20 is furthermore designed to receive magnetic resonance signals, in particular from the patient 15 .
To control the basic magnet 17 , the gradient control unit 28 and the radio-frequency antenna control unit 29 , the magnetic resonance apparatus 11 has a computer 24 . The computer 24 centrally controls the magnetic resonance apparatus 11 , for example the implementation of a predetermined imaging gradient echoes. Control information (for example imaging parameters) as well as reconstructed magnetic resonance images can be displayed to an operator at a display unit 25 —for example on at least one monitor—of the magnetic resonance apparatus 11 . In addition to this, the magnetic resonance apparatus 11 has an input unit 26 by means of which information and/or parameters can be input by an operator during a measurement process and/or a display process of image data. The computer 24 can directly pass control commands to the gradient control unit 28 and the radio-frequency antenna control unit 29 . Furthermore, the computer comprises an image data receiving (acceptance) unit 32 and a specification unit 33 . The computer with the image data acquisition unit 32 and the specification unit 33 , the display unit 25 and the input unit 26 form a user interface 34 , which is likewise designed to execute a method according to the invention.
The shown magnetic resonance apparatus 11 can naturally include additional components that magnetic resonance apparatuses conventionally have. The general functioning of a magnetic resonance apparatus 11 is known to those skilled in the art, such that a more detailed description of the additional components is not necessary herein.
FIG. 2 shows a flowchart of an embodiment of the method according to the invention for processing of diffusion image data of a patient 15 that are acquired by the magnetic resonance apparatus 11 . In a first method step 40 , an acquisition of diffusion image data takes place by means of the image data acquisition unit 32 and/or the magnetic resonance apparatus 11 . In a further method step 41 , a provision of a signal threshold takes place by means of the specification unit 33 . In a further method step 42 , a calculation of a b-value map takes place by means of the computer 24 on the basis of the diffusion image data and the provided signal threshold. In a further method step 43 , a display of the calculated b-value map takes place by means of the display unit 25 .
FIG. 3 shows a more detailed workflow diagram of an embodiment of a method according to the invention. The four underlying method steps from FIG. 2 are here provided with sub-steps according to an advantageous embodiment. These sub-steps (described in the following) are hereby to be viewed only as optional and exemplary. The acquisition of the diffusion image data in the first method step 40 includes a first acquisition step 44 in which an acquisition of at least two diffusion images takes place by means of the magnetic resonance apparatus 11 . The at least two diffusion images are thereby acquired with different b-values. One b-value of the two different b-values can thereby also amount to zero, such that the acquisition of a diffusion image takes place without diffusion weighting. In FIG. 5 , six diffusion images 70 , 71 , 72 , 73 , 74 , 75 of an examination subject that are acquired with different b-values are shown with the same field of view, which diffusion images 70 , 71 , 72 , 73 , 74 , 75 are arranged ascending according to the value of the b-value. For example, the second diffusion image 71 was acquired with a higher b-value—and thus with a higher diffusion weighting—than the first diffusion image 70 . The third diffusion image 72 was acquired with a higher b-value than the second diffusion image 71 etc. It can be seen that the signal strength in the diffusion images 70 , 71 , 72 , 73 , 74 , 75 decreases with increasing b-values. At the same time, the signal-to-noise ratio also decreases with increasing b-values, whereby the image quality of the diffusion images 70 , 71 , 72 , 73 , 74 , 75 decreases with increasing b-values. However, in diffusion images 70 , 71 , 72 , 73 , 74 , 75 with higher b-values an exemplary tissue mass 76 , 77 with compact tissue (for example a tumor or tissue affected by a stroke) is clearly emphasized. The tissue mass 77 in fifth diffusion image 74 is thus more clearly demarcated from its environment than the tissue mass 76 in the first diffusion image 70 . An acquisition of diffusion images 70 , 71 , 72 , 73 , 74 , 75 with higher b-values thus leads to an improved contrast between the tissue mass and surrounding tissue given a simultaneous loss of signal-to-noise ratio.
Furthermore, the acquisition of the diffusion image data in the first method step 40 includes a second acquisition step 45 in which a calculation of a diffusion coefficient map takes place by means of the computer 24 (in particular the image data acquisition unit 32 ) on the basis of the at least two acquired diffusion images. The calculation of the diffusion coefficient map from the at least two acquired diffusion images takes place by means of known methods. The diffusion coefficient map is required later for the calculation of the b-value map using said diffusion coefficient map. The diffusion coefficient map and/or the diffusion images hereby represent the diffusion image data which are acquired by the image data acquisition unit 32 in the first method step 40 .
The provision of the signal threshold by means of the specification unit 33 in the further method step 41 includes a first specification step 46 in which a calculation of the signal threshold takes place by means of the computer 24 (in particular the specification unit 33 ) on the basis of the diffusion image data and/or additional image data. An advantageous signal threshold is determined automatically by execution of an algorithm on the basis of the diffusion images and/or diffusion coefficient map acquired in the first method step 40 .
The additional method step 41 includes a second specification step 47 , wherein an input of the signal threshold by a user into the input unit 26 takes place. The user can hereby adapt the signal threshold calculated in the first specification step 46 . This can take place on the basis of a b-value map displayed at the display unit 25 , with the b-value map being recalculated and displayed after adaptation of the signal threshold by the user.
In the further method step 42 , the b-value map is calculated by means of the computer 24 on the basis of the diffusion image data acquired in the further method step 40 and on the basis of the signal threshold provided in the further method step 41 .
The calculation of the b-value map from the diffusion coefficient map is illustrated in the following in a very simple, abstracted formula. The calculation for an image point and/or a voxel of the diffusion coefficient map and the corresponding image point and/or voxel of the b-value map is described. The simplest expression of the relationship between a diffusion signal S in a diffusion image which was acquired given a defined b-value b and an apparent diffusion coefficient ADC is:
S=S 0 *exp(− b *ADC)
wherein S 0 is the value of the diffusion signal that was measured with a b-value of zero or was extrapolated from a b-value of zero. Resolved for b, the relationship is:
b = - 1 ADC * ln ( S S 0 )
If a signal threshold S TH for S is now provided, a b-value b TH can thus be calculated in which a diffusion signal measured by means of the magnetic resonance apparatus has the predetermined signal threshold:
b
TH
=
-
1
ADC
*
ln
(
S
TH
S
0
)
The b-value map then advantageously includes the b-values b TH for each image point and/or a voxel of the diffusion coefficient map. The b-value map thus likewise includes a spatially resolved depiction of the b-values b TH . It is noted again that the described shown method for calculation serves only for illustration, and that an actual method for calculation of the b-value map advantageously takes into account additional terms (for example an additional perfusion in tissue that is present for diffusion and/or other molecule types than water).
However, in the present formula it is already apparent that tissue types with different apparent diffusion coefficients ADC have different b-values in the b-value map. Compact tissue with a small apparent diffusion coefficient ADC T hereby has a large b-value b TH . Tissue types—in particular normal tissue and/or water—with a large apparent diffusion coefficient ADC have a small b-value b TH . This is clarified in the diagram of FIG. 4 . Here the natural logarithm of a diffusion signal S measured in a diffusion image is plotted on a diffusion signal axis 60 over a b-value axis 61 with b-values b with which the diffusion image was acquired. The dependency of the diffusion signal S on the b-value b is shown for two different tissue types. A water curve 64 shows the dependency of the logarithm of the diffusion signal of aqueous tissue on the b-value. A tissue mass curve 66 shows the dependency of the logarithm of the diffusion signal of compact tissue (in particular a tissue mass) on the b-value. Given a b-value of zero—thus given diffusion images which were acquired without diffusion weighting—the water curve 64 and the tissue mass curve 66 have the same diffusion signal, and thus meet at an intersection point 63 . The absolute value of the slope of the water curve 64 (which corresponds to the diffusion coefficient ADC W of aqueous tissue) is hereby greater than the absolute value of the slope of the tissue mass curve 66 (which corresponds to the diffusion coefficient ADC T of compact tissue). If a signal threshold 62 for the diffusion signal is now provided, the water curve 64 reaches the signal threshold 62 at a first b-value 65 , wherein the tissue mass curve 66 reaches the signal threshold 62 at a second b-value 67 . Due to the different diffusion coefficients ADC W of the aqueous tissue and ADC T of the compact tissue (and thus different slopes of the water curve 64 and the tissue mass curve), the first b-value 65 is smaller than the second b-value 67 . The compact tissue thus can be clearly differentiated from aqueous tissue in the b-value map. Naturally, the shown curves 64 , 66 are only exemplary, schematic and in particular idealized, since they ignore perfusion effects, for example.
After calculation of the b-value map, an additional processing of the b-value map can still take place—for example by filtering and/or masking of image noise—to increase the image quality of the b-value map.
The display of the calculated b-value map in the further method step 43 includes a first display step 48 in which the b-value map calculated in the additional method step 42 is displayed at a display unit 25 (in particular a monitor). The b-value map can be shown in a two-dimensional presentation in slice images. The possibility is then provided to the user to select the different slice images for display by means of the input unit 26 . The b-value map can also advantageously be shown in a maximum intensity projection (MIP).
The display of the calculated b-value map in the further method step 43 includes a second display step 49 in which a windowing of the calculated b-value map takes place. The windowing can be implemented by a user by means of the input unit 26 . The displayed b-value map is thereby shown windowed, whereby the contrast between compact tissue and aqueous tissue in the displayed b-value map can be improved, for example.
Shown in FIG. 6 is a b-value map in a first windowing 80 , a second windowing 81 and a third windowing 82 . Each windowing 80 , 81 , 82 hereby shows the same tissue mass 83 , 84 , 85 in a respective different windowed presentation. The field of view and the examination subject of the b-value map of FIG. 6 correspond to the field of view and the examination subject of FIG. 5 . FIG. 6 shows that a distinct contrast between compact tissue of the tissue mass 83 , 84 , 85 and surrounding tissue can be achieved exclusively by means of a windowing of the b-value map. While the tissue mass 83 of the first windowing 80 is just barely set apart from the surrounding tissue, the tissue mass 84 of the second windowing 81 can already be clearly differentiated from the surrounding tissue. The tissue mass 85 of the third windowing 82 is even more clearly prominent. In contrast to the presentation of the tissue mass 76 , 77 in the diffusion images 70 , 71 , 72 , 73 , 74 , 75 of FIG. 5 , the improved contrast between compact tissue and surrounding tissue due to the windowing of the b-value map that is depicted in FIG. 6 leads to no losses in the signal-to-noise ratio. Furthermore, the b-value map includes only one image which must be assessed by expert personnel, in particular by windowing.
The method steps of the method according to the invention that are presented in FIG. 2 and FIG. 3 and illustrated in FIG. 4 and FIG. 6 are executed by the magnetic resonance apparatus 11 , in particular the user interface 34 of the magnetic resonance apparatus 11 . For this, the computer 24 of the magnetic resonance apparatus 11 —in particular the computer 24 of the user interface 34 of the magnetic resonance apparatus 11 —includes necessary software and/or computer programs that are stored in a memory unit of the computer 24 . The software and/or computer programs include program means that are designed to execute the method according to the invention when the computer program and/or the software is executed in the computer 24 by a processor of the magnetic resonance apparatus 11 , in particular a processor of the user interface 34 of the magnetic resonance apparatus 11 .
Although modifications and changes may be suggested by those skilled in the art, it is the intention of the inventors to embody within the patent warranted hereon all changes and modifications as reasonably and properly come within the scope of their contribution to the art.
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In a method, a user interface, a magnetic resonance apparatus, and a storage medium encoded with programming instructions, in order to enable processing and/or display of magnetic resonance diffusion image data, diffusion image data are provided to a computer, a signal threshold are provided to a computer, and a b-value map is calculated by the computer on the basis of the diffusion image data and the predetermined signal threshold.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the benefit of priority under 119(e) of U.S. Provisional Application No. 61/405,975, filed Oct. 22, 2010.
BACKGROUND
[0002] 1. Field
[0003] The embodiments discussed herein relate to a panel mounting system. More specifically, a system of extrusions for attaching panels to a building is described.
[0004] 2. Description of the Related Art
[0005] Generally, a mounting system for mounting metal skin exterior panels on structural members of a building must have four basic characteristics: (1) load carrying capability to support the panels without substantial deformation; (2) adjustability to facilitate attachment of the panels to the structural members; (3) tight sealing to minimize infiltration of wind, rain, snow, hail and the like; and (4) removability to allow removal of any panel and/or seal member without disturbing others. However, it is known that the wall panels are widely used to create a finished, durable, and aesthetic appearance on building walls of all types, as well as for panels for truck bodies, shipping containers, and the like. The panels are typically formed as laminates of outer surface sheets bonded to inner core layer or layers that have structural strength and rigidity, yet are light-weight, flexible under building and environmental stresses, and attractive for the external or interior appearance of building walls.
[0006] The panels are mounted to building walls by various types of mounting devices. For example, one-piece channel-shaped extrusions of metal or rigid plastic are widely used to retain the panels at joints and corners. With conventional extrusion designs, installation proceeds progressively by first installing a corner or terminal extrusion, then a panel, then an “H” (straight, two-sided) extrusion, then another panel, and so on until another corner of termination is reached. Installers must be able to size the panels, position the mounting extrusions, and form joints that are properly aligned and cleanly formed.
[0007] However, conventional mounting systems using extruded devices have been rather inconvenient to use and expensive. With one-piece extrusions, installation proceeds in one direction along a building wall, and caulking the gaps between the panel edges and the extrusions must be done at the time of installation. If the panels are misaligned or a panel becomes damaged, the panels must be removed in sequence in the backward direction. An individual panel cannot be removed out of sequence. The already-installed caulking must be removed or it will detract from the clean appearance of the panels. With one-piece extrusions, the panel fitting and caulking must be done correctly when first installed. Installers may be tempted to leave out the caulking to facilitate panel repair or removal, but this can lead to panel and building failure due to water seepage through the gaps and into the building walls.
[0008] Additionally, extrusions in conventional mounting systems typically include a flange or extension that surrounds or overlaps the outer perimeter of the panel to retain and secure the panel to the building or other body to which the panel is mounted. For example, the outer perimeter of the panels may be inserted into a slot or groove of the extrusion so that one wall of the slot or groove is visible on the exterior of the mounted panel. The walls of the slot may be somewhat flexible and are typically spaced for the thickness of the panel. Another conventional mounting system includes multiple components, where the back of the panel is placed against a first component attached to the wall and then a second component snaps into the first component at a joint between adjacent panels. However, this second component includes an extension that overlaps the outer perimeter of the panel, such that a portion of the mounting system is again visible at the exterior edges of each panel section.
[0009] Thus, conventional mounting systems such as those described above do not provide a clean, planar surface for the exterior faces of the mounted panels because the flange or the extension securing the edge of the panels is raised from the panel edge and may be of a noticeably different color.
[0010] Furthermore, due to the variety of sill flashings, head flashings, and parapet flashings, which are often provided by the various door and window manufacturers, conventional mounting systems are not always compatible with the various flashings and can be troublesome for installers arriving at the jobsite with no directions on how to handle the intersection of two different building materials.
SUMMARY
[0011] One exemplary embodiment of the present invention provides a mounting apparatus for mounting a panel to a structure. The mounting apparatus includes one or more panel extrusions that attaches to a back side of the panel such that the panel extrusions are obscured behind the panel. A connector extrusion secures the panel extrusions to the structure.
[0012] Another exemplary embodiment of the present invention provides a mounting system for mounting panels to a structure. The mounting system includes an air and water barrier layer, a strip of foam tape disposed on the air and water barrier layer, and a panel assembly. The panel assembly includes a panel and one or more panel extrusions attached to a back side of the panel such that the panel extrusions are obscured behind the panel. A connector extrusion secures the panel assembly to the structure. The connector extrusion is disposed on the strip of foam tape to achieve leveling and seals.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings. However, the accompanying drawings and their exemplary depictions do not in any way limit the scope of the inventions embraced by this specification. The scope of the inventions embraced by the specification and drawings are defined by the words of the accompanying claims.
[0014] FIG. 1 is an external perspective view of an installed mounting system according to an exemplary embodiment of the invention;
[0015] FIG. 2 is a perspective view of the back side of a panel assembly according to an exemplary embodiment of the invention;
[0016] FIG. 3 is a perspective view of a cross-section of the mounting system according to an exemplary embodiment of the invention;
[0017] FIG. 4 is a perspective view of a panel extrusion according to an exemplary embodiment of the invention;
[0018] FIG. 5 a is a perspective view of a connector extrusion according to an exemplary embodiment of the invention;
[0019] FIG. 5 b is a perspective view of an end-of-run connector extrusion according to exemplary embodiment of the invention;
[0020] FIG. 6 is a cross-sectional view of two adjacent panel assemblies mounted to a structure according to an exemplary embodiment of the invention;
[0021] FIG. 7 is a cross-sectional view of an end run of a panel assembly mounted to a structure according to an exemplary embodiment of the invention;
[0022] FIG. 8 is a cross-sectional view of a v-groove cut in a panel according to an exemplary embodiment of the invention;
[0023] FIG. 9 is a perspective view of a spring clip according to an exemplary embodiment of the invention;
[0024] FIG. 10 is a perspective view of a spring clip inserted in a panel according to an exemplary embodiment of the invention;
[0025] FIG. 11 is another perspective view of a spring clip inserted in a panel according to an exemplary embodiment of the invention;
[0026] FIG. 12 is a perspective view of an insert strip with a spring clip in each side according to an exemplary embodiment of the invention;
[0027] FIG. 13 is perspective view of an insert strip with multiple spring clips in each side of the insert strip according to an exemplary embodiment of the invention; and
[0028] FIG. 14 is a perspective end view of an insert strip showing the ends of spring clips extending into the panel extrusions according to an exemplary embodiment of the invention.
DETAILED DESCRIPTION
[0029] In the following, the present advancement will be discussed by describing a preferred embodiment with reference to the accompanying drawings. However, those skilled in the art will realize other applications and modifications within the scope of the disclosure as defined in the enclosed claims.
[0030] FIG. 1 is a perspective view of a finished wall 10 with panels 12 mounted using the mounting system described herein. The panels 12 are typically mounted using only three specialized extrusions (not all shown in FIG. 1 ). The panels 12 and insert strips 14 obscure the extrusions so there is a clean look to the finished wall 10 . In one non-limiting embodiment, it is preferable to use a panel having a corrugated core laminated between two metallic sheets (see FIG. 8 ). When properly installed, the mounting system provides at least five seals that trap and drain water to the outside of the structure. The five seals are discussed in detail below.
[0031] FIG. 2 depicts a completed panel assembly 20 from the back side. A panel assembly includes the panel 12 and panel extrusions 30 . The panel extrusions 30 are visible from the back side of the panel assembly 20 , however, after installation, the panel 12 obscures the panel extrusions 30 , as discussed above. Once a panel assembly 20 is installed by securing it to a structure, insert strips 14 are placed adjacent to panel edges to obscure the connector extrusions 40 (see FIG. 3 ).
[0032] FIG. 3 shows a perspective view of the junction between adjacent panel assemblies 20 . For clarity and to avoid obscuring the lines on the figure, the connector extrusion 40 is shown raised in the gutter space between the panel extrusions 30 . When installed, however, the connector extrusion 40 secures the panel extrusions 30 to the structure. As mentioned above, the insert strip 14 is disposed between the two panel extrusions 30 to hide the connector extrusion 40 .
[0033] A perspective view of a panel extrusion 30 is shown in FIG. 4 . The following description of the features of the panel extrusion 30 is discussed in relation to the disposition of the panel extrusion as shown in FIGS. 6 and 7 . The panel extrusion 30 is typically formed as a single extruded piece and then cut according to the required lengths. The panel extrusion 30 includes: an intermediate portion 33 , extensions 34 , a panel-side flange 31 , a structure-side flange 32 , and an insert strip flange 36 .
[0034] When the panel extrusion 30 is installed, the panel-side flange 31 is secured to the panel 12 in the panel assembly 20 , and the structure-side flange 32 is secured to the wall 100 of the structure. Although one of ordinary skill in the art will recognize that other shapes and positions may be used for the flanges 31 and 32 , in the non-limiting embodiment shown in FIGS. 4 , 6 , and 7 , the flanges 31 and 32 are substantially flat and extend from respective extensions 34 in opposite directions. It is preferred that the structure-side flange 32 extends in a direction outward from the panel 12 so as to engage with the connector extrusion 40 and to be secured to the wall 100 . The extensions 34 extend from opposite ends of the intermediate portion 33 in opposite directions, thereby adjoining the flanges 31 and 32 to the intermediate portion 33 .
[0035] The panel extrusion 30 also includes an insert strip holding portion 35 . In one non-limiting embodiment, the insert strip holding portion 35 is a slot having an opening that is approximately the same width or smaller than the thickness of an insert strip 14 . The slot of the insert strip holding portion 35 is delimited by the insert support flange 36 , the extension 34 , and the intermediate portion 33 . In particular, the insert support flange 36 extends from the extension 34 adjacent to the intermediate portion 33 in a direction such that, when the panel extrusion 34 is installed, the insert strip holding portion 35 opens outward so as to receive an insert strip 14 .
[0036] As seen in FIGS. 6 and 7 , the majority of the insert support flange 36 is substantially parallel to the intermediate portion 33 , however, it is understood that one of ordinary skill in the art could alter the position and/or shape of the insert support flange 36 to another angle, so long as the opening of the slot remains substantially the same width or smaller than the thickness of the insert strip 14 . Further, an end portion 37 of the insert support flange 36 may be angled so that it is not co-planar with the majority of the insert support flange 36 . Additionally, it is preferable that the end portion 37 of the insert support flange 36 is angled in a direction away from the intermediate portion 33 , which may ease insertion of the insert strip 14 into the insert strip holding portion 35 .
[0037] Furthermore, the panel extrusion 30 includes a raised ridge 38 that runs the length of the intermediate portion. Depending on the width of the insert strip 14 , the ridge 38 may assist in securing the insert strip 14 to the panel extrusion 30 , as shown in FIG. 7 .
[0038] The following description of the features of the connector extrusion 40 is discussed in relation to the position of the connector extrusion as shown in FIGS. 6 and 7 . There are two versions of the connector extrusion 40 , a connector extrusion 40 having two projection legs 44 , as seen in FIGS. 5 a and 6 , and a connector extrusion 40 having a single projection leg 44 (an end-of-run connector), as seen in FIGS. 5 b and 7 . The two versions, however, are otherwise substantially the same and therefore, the reference numerals used are the same for both versions.
[0039] Like the panel extrusion 30 , the connector extrusion 40 is also typically formed as single extruded piece and then cut according to the required lengths. The connector extrusion 40 includes: a groove 42 and at least one projection leg 44 .
[0040] The groove 42 of the connector extrusion 40 is delimited by side walls 42 a and a junction wall 42 b that adjoins the two side walls 42 a . In a non-limiting embodiment, it is preferred that a lower portion of each of the two side walls 42 a extends past the junction wall 42 b . In the version of the connector extrusion 40 with only one projection leg 44 , the projection leg 44 extends from one of the two side walls 42 a away from the groove 42 . In the version of the connector extrusion 40 with a projection leg 44 extending from each side wall 42 a , the two projection legs 44 extend in opposite directions away from the groove 42 . Preferably, in a non-limiting embodiment, the projection legs 44 are substantially perpendicular to the side walls 42 a from which the projection legs 44 extend.
[0041] As shown in FIGS. 6 and 7 , panel assemblies are mounted to a structure by engaging the structure-side flange 32 of the panel extrusion 30 with the projection leg(s) 44 of the connector extrusion 40 . FIG. 6 shows a cross-sectional view of the junction between two adjacent mounted panel assemblies 20 . As mentioned above, a panel assembly 20 includes the panel 12 that is connected to a panel extrusion 30 . Typically, the panel 12 is prepared from a planar panel that has been cut with a v-groove 50 (see FIG. 8 ) near each side edge and folded at the cut to make a return edge 12 a and form a box shape. The preferred method of cutting the v-groove is described below. The return edge 12 a of the panel 12 is typically 1″ in width, but may be wider or narrower depending on the needs of the particular job. The panel extrusions 30 are correspondingly sized and cut and are typically attached to the inside corners of the box-shaped panel 12 . Preferably, a fastener 24 , such as a screw for example, is used to fasten the panel 12 to the panel extrusion 30 . Additionally, a sealant 22 may be disposed between the panel extrusion 30 and the inside surface of the panel 12 . The sealant 22 is preferably a silicone sealant.
[0042] In another non-limiting embodiment, the mounting system further includes: an air and water barrier layer 102 , and a strip of foam tape 104 . The order of the assembled components is as follows. The air and water barrier layer is typically adhered to the surface of the wall 100 and then the strip of foam tape 104 is adhered to the surface of the air and water barrier layer 102 . The connector extrusion 40 is secured to the strip of foam tape 102 with a fastener 26 and engages the structure-side flange 32 , securing the structure-side flange 32 to the strip of foam tape 102 as well. Thus, the panel assemblies 20 are secured to the wall 100 .
[0043] The assembly shown in FIG. 7 is substantially the same as described with respect to FIG. 6 , however, as mentioned previously, FIG. 7 depicts a single panel extrusion 30 and a connector extrusion 40 with only one projection leg 44 . In addition, the panel insert 14 is secured only on one side by the insert strip holding portion 35 .
[0044] As mentioned above, the complete installed mounting system 10 provides five seals that trap and drain water to the outside of the structure. The five seals are described below with reference to FIG. 6 . The first seal is formed at the contact points of the outer surface of the insert strip 14 with the intermediate portion 33 of the panel extrusion 30 . The second seal is formed at the contact points of the inner surface of the insert strip 14 with the insert support flange 36 over the gutter space, which is between the insert strip 14 and the connector extrusion 40 . The third seal is formed at the contact point between the projection leg 44 of the connector extrusion 40 and the structure side flange 32 of the panel extrusion 30 . The fourth seal is formed between the strip of foam tape 104 and the structure side flange 32 . The fifth seal is formed between the strip of foam tape 104 and the air and water barrier layer 102 . Accordingly, when all of the above components are properly installed, the mounting system has five seals to prevent water from entering the structure to which the panels are mounted.
[0045] FIG. 8 is a cross-sectional view of a v-groove 50 cut in a panel 12 to form the box shape. The v-groove 50 may be formed by any of a variety of ways known to those skilled in the art. In a non-limiting embodiment using a laminated panel 12 , it is preferable that the v-groove 50 pass through one of the outer metallic sheets, all the way through the corrugated core, and then begin to cut away a small amount of the inner surface of the opposing metallic sheet. It is preferred to cut the v-groove 50 in the above-described manner so that the panel 12 bends easier and straighter, and does not leave a mark on and/or penetrate the outer surface of the opposing metallic sheet, which would ruin the panel 12 .
[0046] A spring clip 60 is depicted in FIG. 9 . The spring clip 60 is used to hold in place narrow insert strips, which would otherwise rest so that the insert strip does not entirely cover the intermediate space between adjacent installed panel assemblies 20 . The spring clip 60 is typically formed as a cylindrical thin rod and then bent to the desired shape, discussed herein. Preferably, the spring clip is an elastic metal, however, other elastic materials may be suitable. In one non-limiting embodiment shown in FIGS. 9-13 , the spring clip 60 includes: an arm extension 61 , a first bend 62 , a first extension 63 , a second bend 64 , a second extension 65 , a third bend 66 , an third extension 67 , and a fourth bend 68 .
[0047] The arm extension 61 of the spring clip 60 extends away from the first extension 63 such that the first bend 62 is an angle between approximately 90 and 150 degrees, and preferably approximately 120 degrees. The second bend 64 connects the second extension 65 and the first extension 63 . The second bend 64 forms a loop which allows the first extension 63 and the second extension 65 to be substantially parallel, however the second extension 65 extends from the second bend 64 in a plane that is distinct from the plane along which the first extension 63 extends. The third bend 66 forms a loop which allows the second extension 65 and the third extension 67 to be substantially parallel. Additionally, the third extension 67 may extend from the second bend 64 in substantially the same plane along which the second member 63 extends. The fourth bend 68 , located at the end of the arm extension 61 , prevents the spring clip from digging into the panel once the insert strip is installed.
[0048] FIGS. 10 and 11 show the spring clip 60 inserted into the side of an insert strip in two different positions, such that in the position shown in FIG. 10 , the arm extension 61 extends in a first angled direction and in the position shown in FIG. 11 , the arm extension 61 extends in a second angled direction. Further, in FIG. 10 , the third extension 67 remains against the exterior surface of the insert strip such that only the first and second extensions 63 and 65 are inserted into the core of the insert strip. In FIG. 11 , however, the third extension 67 is inserted into the core of the insert strip beside the first and second extensions 63 and 65 . FIG. 12 further illustrates the positions shown in FIGS. 10 and 11 , as the spring clips 60 a and 60 b are inserted into opposite sides of the same insert strip 14 . Once inserted into the insert strip 14 , the arm extensions 61 typically extend at approximately a 45° angle with respect to the edge of the insert strip 14 where the spring clips 60 a and 60 b are inserted.
[0049] The two different positions of insertion of the spring clips 60 a and 60 b , as shown in FIG. 12 , cause the arm extensions 61 to hold specific positions with respect to the insert strip 14 . Specifically, the arm extension 61 of spring clip 60 a lies in the plane of the panel surface of the insert strip 14 , at a position of 45° from the cut longitudinal edge of the insert strip 14 . The arm extension 61 of spring clip 60 b is positioned 45° away from the plane of the panel surface of the insert strip 14 , and 45° away from the plane of the cut longitudinal edge of the insert strip 14 , which is perpendicular to the plane of the panel surface of the insert strip 14 .
[0050] FIG. 13 shows an insert strip in position to be inserted between panel assemblies 20 . The insert strip in FIG. 13 includes two spring clips 60 on each side.
[0051] As depicted in the cross-sectional view in FIG. 14 , the insert strip 14 is inserted into the junction area between two panel assemblies 20 . The arm extensions 61 of the spring clips 60 extend from the sides of the insert strip 14 and abut the panel extrusion 30 to place the insert strip between the two panel assemblies 20 , thereby concealing the mounted connector extrusion 40 .
[0052] Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
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A mounting apparatus for mounting a panel to a structure. The mounting apparatus includes a panel extrusion that attaches to a back side of the panel such that the panel extrusion is obscured behind the panel in order to show a clean surface look. A connector extrusion secures the panel extrusion to the structure for simple construction.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This utility patent application claims priority to U.S. Provisional Patent Application No. 61/315,939, filed on Mar. 20, 2010, entitled “Pet Door Bug and Debris Blocker,” the benefit of which is claimed under 35 U.S.C. 119, and is further incorporated herein by reference.
FIELD OF THE INVENTION
[0002] The present invention relates generally to pet doors and screen doors and more particularly to blocking the entry of bugs/insects, small animals, dirt, and unwanted extraneous materials entering the gap between a pet door and a screen door.
BACKGROUND
[0003] Panel pet doors for sliding doors are installed in the existing tracks of a sliding door to allow a pet (typically a dog or cat) to enter or exit a home through a pet door.
[0004] An example of a panel pet door is described in the following U.S. patents entitled “Adjustable Pet Door” to E. Alan Lethers: 7363956, 7063123, and 6691483, each of which is hereby incorporated herein by reference in its entirety.
[0005] The panel pet door shown in FIG. 1 , item 3 is often similar in height to the sliding door 1 and is placed in the same sliding rails as the sliding door. The pet door 4 is located near the bottom of the panel pet door 3 providing access for the pet into or out of the home.
[0006] When a panel pet door is installed adjacent to a sliding door, the screen door 2 must be left open the width 5 of the pet door opening to prevent the screen door from blocking the passage of the pet into or out of the home. On a warm day, a sliding door may be opened to allow fresh air to enter the home, and with the screen door only partially closed, a large gap 6 exists between the panel pet door 3 and the partially closed screen door 2 . This gap is often 3 inches wide by approximately 7 feet tall (over 250 square inches) allowing bugs/insects (mosquitoes, flies, lizards, spiders, etc.) and other extraneous materials including leaves and more to enter the home.
[0007] Due to the wide variation in pet doors and sliding door/screen door combinations, there is also a wide variation in the width of the gap between the screen door and the pet door. Double paned sliding glass doors for example, typically result in a larger gap than single paned sliding doors. For this reason, there is a need for a solution that supports easy customization of gap width for each pet door/screen door combination.
[0008] Since an embodiment providing a solution to this gap occurs adjacent to where a person walks in and out of the sliding door, there is a need for a solution that will minimize the risk of injury if the person accidentally bumps into the invention.
BRIEF SUMMARY OF THE INVENTION
[0009] One aspect of this invention addresses the need for blocking the gap between the panel pet door and the partially closed screen door as described above. As a result of this invention, which in one embodiment may act as a barrier, bugs/insects (such as mosquitoes, flies, lizards, spiders, etc.) and leaves, etc. are blocked from entering the home while allowing the sliding door to remain open for the exchange of air into and out of the home. FIG. 2 illustrates one embodiment blocking the gap between the screen door and the panel pet door with a projecting flange 7 , also referred to as a barrier.
[0010] In one embodiment, the barrier 7 is made of a flexible material to give a soft and quiet contact to the screen door when closed and to accommodate variation in the contact of the screen door to the barrier by bending to provide a seal throughout the length of the barrier. In another embodiment, the invention is in a pre-flexed shape so when the screen door is closed and in contact with the invention, the shape bends, but not to the extent that it gives the appearance of bending too far backwards.
[0011] In a further embodiment, stiffening ribs exist on the backside of the projecting flange (the side opposite from where the screen door contacts) to provide additional rigidity for the purpose of reducing waviness.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] The features, objects, and advantages of the present invention will become more apparent from the detailed description set forth below when taken in conjunction with the drawings, in which like reference characters identify correspondingly throughout and wherein:
[0013] FIG. 1 depicts a typical scenario prior to the installation of the invention.
[0014] FIG. 2 depicts a typical panel pet door/sliding door/screen door installation with one embodiment of the projecting flange installed and blocking the gap.
[0015] FIG. 3 depicts a cross-sectional top-down view of one embodiment of the projecting flange as depicted in FIG. 2 .
[0016] FIG. 4 depicts a zoomed in view showing one embodiment of the stopping device.
[0017] FIG. 5 depicts a top-down view of one embodiment of the barrier showing the screen door stopping device as depicted in FIG. 4 .
DETAILED DESCRIPTION OF EXEMPLARY EMBODIMENTS
Disclosure Overview
[0018] As a result of the gap caused by the installation of panel pet doors, there is a need for a solution that blocks this gap. The solution is provided by this invention. FIG. 2 illustrates one embodiment of the invention installed between a panel pet door/sliding door/screen door arrangement so as to block the gap. In one embodiment, a projecting flange is used as a barrier. In a further embodiment, the projecting flange 7 may be constructed of a flexible material to accommodate variation in the contact of the screen door to the invention by bending to provide a continuous seal throughout the length of the invention.
[0019] In yet another embodiment, the projecting flange or barrier may be in a pre-flexed shape so when the screen door is closed and in contact with the invention the shape bends, but not to the extent that it gives the appearance of bending too far backwards. In another embodiment, the base of the projecting flange 7 or barrier (the bottom portion attaching to the panel pet door) provides additional rigidity to minimize flexion, which would otherwise increase undesirable waviness down the length of the invention. Excess waviness provides small openings between the invention and the screen door allowing small bugs/insects or debris to enter.
[0020] In another embodiment, stiffening ribs may be provided on the backside of the projecting flange or barrier (the side opposite from where the screen door contacts) to provide additional rigidity for the purpose of reducing waviness.
[0021] As is known in the industry, the gap size between the screen door and the panel pet door may vary from one door to the next. The projecting flange or barrier 7 may be provided with multiple guide lines of separation, as shown in the embodiment at locations 102 (3 places in this embodiment), for easy customization with scissors, or any other cutting device, to match the reach of the projecting flange to the gap size between a screen door and panel pet door.
[0022] FIG. 3 depicts a cross-sectional top-down view of one embodiment of the invention as depicted in FIG. 2 . As shown in FIG. 3 , one or more ribs (also referred to as ridges) ( 101 a , 101 b , 101 c . . . ) generally referred to as ribs 101 occur on the backside (opposite the side where the screen door contacts the invention) in this embodiment. Three ribs are shown in this embodiment of the invention. These ribs provide additional rigidity to minimize waviness along the length of the invention.
[0023] The base of one embodiment of the invention includes a hollow closed loop 104 , triangular in this embodiment, to provide additional rigidity while keeping the weight to a minimum. The additional rigidity minimizes undesirable waviness, which would otherwise allow bugs/insects and undesirable extraneous material such as leaves to enter through narrow gaps.
[0024] Tests were performed with earlier prototypes, demonstrating a flat cross-sectional shape (instead of curved as shown in the “blade” 105 ) would allow for excessive waviness in some scenarios down the length (perpendicular to the cross section) of the barrier due to manufacturing, shipping or other causes. Increased waviness creates intermittent small openings at location 107 , enabling small bugs/insects to fly into or otherwise enter the home. To correct this small opening problem, the side of one embodiment of the blade of the barrier facing the screen door 2 has a curvature 105 extending to establish contact with the screen door when closed to seal these gaps. The curvature of this embodiment provides additional rigidity, beyond what a flat surface could provide, to minimize waviness, thereby reducing small gap openings. Although a flat cross-sectional shape would be acceptable in some embodiments, it may be less desirable in other embodiments where minimizing waviness is important. To further minimize small gaps, the material of one embodiment is designed with flexibility to provide contact throughout the length despite the inherent waviness resulting from manufacturing, and to minimize the contact sound when closing the screen door to contact the invention. When the screen door is closed, the material of this embodiment flexes to reduce waviness while aligning to form continuous contact with the screen door. In some embodiments, a rigid material would also be acceptable.
[0025] To minimize the risk of injury when accidentally bumping into the invention when a person walks in or out through the sliding door, the flexible material of some embodiments is selected to flex instead of causing injury as a rigid embodiment might.
[0026] In one embodiment, attachment of the projecting flange or barrier 7 to the panel pet door may be performed with dual-sided tape 106 .
[0027] A stopping device, consisting of 201 and 202 in one embodiment, may be inserted into the frame where the sliding screen door slides, to prevent closing the screen door beyond the projecting flange or barrier 7 . In some embodiments, the stopping device may not be required. One embodiment of the stopping device consists of a washer 201 , also referred to as a spacer, made of a material softer than metal, such as nylon, that is installed into the top or bottom rail of the sliding door. In one embodiment of the stopping device, the nylon washer is held in place by inserting a screw 202 through the washer and into the frame where the sliding door slides.
[0028] Reference throughout this document to “one embodiment”, “certain embodiments”, “an embodiment” or similar term means that a particular feature, structure, or characteristic described in connection with the embodiment is included in at least one embodiment of the present invention. Thus, the appearances of such phrases in various places throughout this specification are not necessarily all referring to the same embodiment. Furthermore, the particular features, structures, or characteristics may be combined in any suitable manner on one or more embodiments without limitation.
[0029] While certain exemplary embodiments have been described and shown in the accompanying drawings, it is to be understood that such embodiments are merely illustrative of and not restrictive on the broad invention, and that this invention not be limited to the specific constructions and arrangements shown and described, since various other modifications may occur to those ordinarily skilled in the art. Trademarks and copyrights referred to herein are the property of their respective owners.
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A barrier device preventing access of pests such as mosquitoes, flies, and other small animals as well as debris between a panel pet door and a screen door by providing a seal between the panel pet door and the screen door. The barrier material may have ribs for the purpose of added stiffening or as a guide for adjusting the reach of the barrier. A stopping device may be used to ensure the screen door is closed to a location where good contact is made with the barrier device.
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BACKGROUND OF THE INVENTION
This invention relates to devices for use with bags of food, pet food, potting soil, and other bulk items. More particularly, this invention relates to devices used to close and open these types of bags.
A previous invention, U.S. Pat. No. 6,105,217, “Bag Clamp”, was co-authored by this inventor, and this patent application is a set of improvements to that invention.
As covered in the cited patent application, modern polymer plastic bags are useful containers for bulk foods, bulk pet foods, and other loose, granular or small-sized items. The bags have the drawback that they are difficult to close properly once opened. They usually have smooth or slick surfaces which are difficult to grab with closure devices.
Polymer bags such as those under consideration here are often opened with the intention of closing and then re-opening then at a future time. Secure closure of the bag, to preserve product freshness for example, is necessary as is easy re-opening. Therefore, a bag closure device of this type should securely close the opened bag and be convenient to use to re-open. The previous invention by this inventor accomplished these goals by use of a strong spring to keep the device closed and by distributing the gripping force along the length of the device rather than concentrating it in the center of the device.
There are competing devices in use that also close polymer bags, but they largely fail to close and keep closed heavier bags. The competing devices tend to slip off of the bag surface easily and are much less useful.
In the cited patent, this inventor developed a device that could be made in a variety of sizes while retaining the generic characteristics of the invention. The small versions could be used for potato chip bags, popcorn bags, and the like, while the largest size would be capable of closing and re-opening larger bags of potting soil or pet food. The large device was strong enough to prevent spillage of product if a bag was knocked over, for example.
Opening polymer bags is also a problem, because they are usually tightly sealed to prevent product degradation while on store shelves. A method of quickly and predictably opening such bags is also desirable. Providing such a method prevents bag tearing, destruction of the bag, and spillage of bag contents while making bag closing and re-opening more straight-forward. The cited invention possessed features to aid consumers in opening polymer bags in an easy and safe manner, long with the above-described closure, clamping and reopening features.
INVENTION DISCLOSURE
The present invention is a set of improvements to the cited invention co-authored by this inventor. The additional features are non-obvious and confer additional, valuable, and useful capabilities to the cited invention.
In common with the cited invention, there is a clamp for closing and holding closed a polymer bag, consisting of a pair of opposed clamp members, where these clamp members can be moved from a closed bag clamping position to an open bag receiving position by pressing on them with the hand. A hinge connects the two members and holds them closed with the aid of a spring. There is a sharp blade on the inside of the “top” member held underneath a blade guard and opposite a split anvil. The blade does not extend past the guard in its rest or guard protected position. The blade guard rests movably on one end on a fixed rest and is fixedly attached on the other. The blade guard has a slit down its length that permits the blade to emerge when a thin finger engagable springboard button that it is connected to is pressed by the user gripping the bag clamp.
By pressing the button with a thumb while gripping the device, the blade is pushed through the slot in the guard and can then engage a polymer bag and cut it. When the button is not being pressed, the blade is retracted behind the guard for safety reasons.
The blade itself is improved over the previous invention, possessing increased sharpness and an improved cutting angle for maximum cutting efficiency. This is possible because of the added safety for users conferred by the blade guard.
The anvil of the previous invention is now a split anvil, with two parallel sides between which the blade fits and is guided. These changes to the previous invention are non-obvious safety improvements. The split anvil also holds bag material up to allow the blade to more easily penetrate the bag. When the blade is pressed through the guard, the guard itself is held against the split anvil, and the blade, in an anvil protected position, never contacts the anvil.
There are a set of ribs on the inside of each clamp member, configured so that the rib ridges on opposite sides meet when the clamp is closed. These ribs are designed to aid holding the bag when the clamp is closed. The ribs have an additional effect of stretching the bag material so that the blade can be more effective in cutting. The ribs also distribute the gripping force away from the hinge spring location.
The clip mouth ends also meet (the “lips”), and allow the bag to be drawn through the clip during the cutting process. There is in this improved invention an additional “tooth” in the middle of the bag “lips”. The improved spring is now strong enough to hold larger bags than before.
BRIEF DESCRIPTION OF THE DRAWINGS
The construction and operation of the invention can be readily appreciated from inspection of the drawings that accompany this application, combined with the detailed specification to follow.
FIG. 1 is an overview drawing of the user grasping/cutting a bag with the invention.
FIG. 2 is a perspective view of the invention from the top.
FIG. 3 is a side view of the invention from the grasping end
FIG. 4 is view of the inner surface of the bottom member
FIG. 5 is a view of the inner surface of the top member
FIG. 6 is a side view of the invention looking at the mouth end with the clamp members held open
FIG. 7 is a cross-section diagram of the invention looking at the mouth end
FIG. 8 is a cross section diagram of the invention looking at it from either side
DETAILED DESCRIPTION OF THE INVENTION
The present invention is an improved clamp for safely opening, clamping, and resealing polymer plastic storage bags. As shown in FIG. 2 and FIG. 3 , the improved bag clamp 100 is comprised of an upper clamp member 101 and a lower clamp member 102 that are separated from each other as shown, the separation defining an opening 103 through which a polymer bag can be drawn. The upper 101 and lower 102 members each include a lip 104,105 that guides the polymer bag into the improved bag clamp opening 103 .
The upper and lower clamp members each possess a leading end portion 106,107 for receiving the polymer bag. These end portions terminate in curved receptor edges 108,109 . The outer surface of each of the clamp members 101,102 is smooth.
An open box-like structure 112 , having a slot 113 , is disposed on the inner surface of the lower clamp member 102 . An elongated member 110 , fixedly attached to the inner surface of the upper clamp member, is accepted in the slot 113 for rotational movement within the slot. As shown in FIG. 3 , a spring clip 111 joins the clamp members 101,102 together and biases the mouth ends of the device together. The spring clip 111 possesses a pair of legs that are inserted through the sleeves 117,118 on the inner surfaces of the upper 101 and lower 102 clamp members.
Referring now to FIG. 4 , It will be noted that on the inner surface of the “lower” clamp member 102 , a raised rib 115 is placed parallel to the mouth end of the clamp member 102 . In FIG. 5 , this rib is matched on the “upper” member by a similar rib 116 , disposed such that when the clamp members 101,102 are biased closed by the spring clip 111 , the ribs contact each other.
Referring to FIG. 8 , it can be seen that the clamp members meet at the mouth ends of the clamp members 104,105 and at the internal ribs 115,116 inside the clamp members. The spring pressure holds the polymer bag closed at these points. Note that a blade is not used to help keep a clamped bag closed, unlike in the cited invention, where a blade is continuously pressed against a flat anvil to help grip the bag.
In order to clamp the polymer bag closed, the user begins by grasping the bag with one hand as in FIG. 1 . With the other hand, the user separates the clamp members 101,102 by squeezing the grasping ends of the invention and biasing the clamp 100 to an open bag receiving position. The user then slides the open edges of the invention until the top of the polymer bag abuts the internal structure 112 . The user then relaxes the hand pressure on the grasping ends of the invention and allows the internal spring 111 to bias the clamp to a closed bag clamping position. The pressure of the spring is now applied to the surface of the bag on both sides of the bag by the internal ribs 115,116 and the mouth ends of the clamp members 104,105 .
The polymer bag can be released quickly from the clamp by squeezing the grasping ends of the clamp members while simultaneously removing the bag.
To slice open the polymer bag, the user grasps the clamp grasping ends and squeezes, as in the process to clamp the bag. The user then places the clamp over the bag as if to clamp it, as described above. The user then presses on the springboard button 120 to press the blade 121 and blade guard 123 downward into contact with the bag and push the blade through the bag, where it stops between the guides of the split anvil 122 .
The leading edges of the mouth end of the clamp 106,107 , the edges away from the springboard button, have a radiused corner 108,109 to help guide the clamp over seams in the polymer bag. The user then draws the clamp across the bag top in the direction of the other edge of the bag while keeping continuous pressure on the springboard button 120 . When the bag is completely open, the springboard button 120 is released and the blade retracts behind the blade guard 123 for safety.
It is evident that there are additional embodiments and applications of the improved bag clamp invention which are not disclosed in this detailed description, but which would clearly fall with the scope of said invention. This specification is intended to illustrate and clarify the nature of this invention and not limit its scope.
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An improved bag clamp and bag cutter is presented that is a non-obvious increase in capability over this inventor's previous bag clamp/cutter invention. The improved clamp possesses a stronger spring, an improved cutting blade with safety guard, a springboard button for pressing the blade firmly against a bag surface, and other improvements.
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This application claims the benefit of U.S. Provisional Patent Application Ser. No. 60/442,089, filed Jan. 23, 2003.
The present invention is directed to certain pharmaceutically acceptable salts of sertraline:
and pharmaceutical compositions thereof, wherein said salts are selected from the group consisting of the p-toluenesulfonic acid salt, the fumaric acid salt, the benzenesulfonic acid salt, the benzoic acid salt, the L-tartaric acid salt and the (−)-camphor-10-sulfonic acid salt.
The compound, sertraline, or (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthylenamine, is a therapeutically potent selective serotonin reuptake inhibitor. This compound is useful for the treatment of a number of diseases, disorders and conditions associated with the central nervous system and the modulation of serotonin receptors.
Sertraline is commercially sold as its hydrochloride salt. U.S. Pat. No. 4,536,518 describes the synthesis of certain cis-4-phenyl-1,2,3,4-tetrahydronaphthalenamine derivatives, including sertraline and generally recites pharmaceutically acceptable salts of these compounds. U.S. Pat. No. 5,248,699 describes several polymorphs of sertraline hydrochloride. The foregoing applications, owned in common with the present application and incorporated herein by reference in their entirety, generically recite pharmaceutically acceptable acid addition salts for the compounds referred to therein.
The salts of the present invention exhibit properties, including those of solid-state stability and compatibility with certain drug product formulation excipients, that render them preferable in comparison to the free base and other known salts of sertraline.
SUMMARY OF THE INVENTION
The present invention is directed to pharmaceutically acceptable salts of sertraline:
wherein said salts are selected from the group consisting of the p-toluenesulfonic acid salt, the fumaric acid salt, the benzenesulfonic acid salt, the benzoic acid salt, the L-tartaric acid salt and the (−)-camphor-10-sulfonic acid salt.
In one preferred embodiment of the invention, the pharmaceutically acceptable salt is the p-toluenesulfonic acid salt and hydrates thereof. The p-toluenesulfonic acid salt of sertraline is characterized by the principal x-ray diffraction pattern peaks expressed in terms of 2θ and d-spacings (also referred to as d-value) measured with copper radiation (within the margins of error indicated):
Angle 2θ (±0.2)
d-value (Å) (±0.2)
6.5
13.6
16.1
5.5
16.6
5.3
20.0
4.4
23.7
3.8
24.0
3.7
25.8
3.5
28.5
3.1
The sertraline p-toluenesulfonic acid salt crystal is characterized in that it generally forms plates. The sertraline p-toluenesulfonic acid salt is further characterized in having an onset of melting transition/decomposition point at about 260° C. as measured by differential scanning calorimetry. Further, the sertraline p-toluenesulfonic acid salt of the invention is also characterized in having an aqueous solubility of 0.4 mg/ml and a pH of 4.1 in aqueous solution. In addition, the sertraline p-toluenesulfonic acid salt has a hygroscopicity of approximately 0.1% at 90% relative humidity.
In another preferred embodiment of the invention, the pharmaceutically acceptable salt is the fumaric acid salt. The fumaric acid salt of sertraline is characterized by the principal x-ray diffraction pattern peaks expressed in terms of 2θ and d-spacings as measured with copper radiation (within the margins of error indicated):
Angle 2θ (±0.2)
d-value (Å) (±0.2)
13.9
6.4
15.5
5.7
18.3
4.8
19.1
4.6
20.8
4.3
23.0
3.9
23.4
3.8
27.4
3.2
The sertraline fumaric acid salt is further characterized in having an onset of melting transition at about 187° C. as measured by differential scanning calorimetry. Further, the sertraline fumaric acid salt of the invention is also characterized in having an aqueous solubility of 2.8 mg/ml and a pH of 3.4 in aqueous solution. In addition, the sertraline fumaric acid salt has a hygroscopicity of approximately 0.3% at 90% relative humidity.
In another preferred embodiment of the invention, the pharmaceutically acceptable salt is the benzenesulfonic acid salt. The benzenesulfonic acid salt of sertraline is characterized by the principal x-ray diffraction pattern peaks expressed in terms of 2θ and d-spacings as measured with copper radiation (within the margins of error indicated):
Angle 2θ (±0.2)
d-value (Å) (±0.2)
7.5
11.9
15.1
5.9
22.4
4.0
22.9
3.9
23.4
3.8
24.4
3.6
24.8
3.6
27.9
3.2
The sertraline benzenesulfonic acid salt crystal is characterized in that it generally forms needles. The sertraline benzenesulfonic acid salt is further characterized in having a solid-solid transition at about 185° C. and an onset of melting transition point at about 230° C. as measured by differential scanning calorimetry. Further, the sertraline benzenesulfonic acid salt of the invention is also characterized in having an aqueous solubility of 0.9 mg/ml and a pH of 4.6 in aqueous solution. In addition, the sertraline benzenesulfonic acid salt has a hygroscopicity of approximately 0.3% at 90% relative humidity.
In a preferred embodiment of the invention, the pharmaceutically acceptable salt is the benzoic acid salt. The benzoic acid salt of sertraline is characterized by the principal x-ray diffraction pattern peaks expressed in terms of 2θ and d-spacings as measured with copper radiation (within the margins of error indicated):
Angle 2θ (±0.2)
d-value (Å) (±0.2)
14.9
5.9
16.1
5.5
18.0
4.9
18.5
4.8
19.3
4.6
23.6
4.4
25.0
3.6
25.2
3.5
The sertraline benzoic acid salt is further characterized in having an onset of melting transition point at about 154° C. as measured by differential scanning calorimetry. Further, the sertraline benzoic acid salt of the invention is also characterized in having an aqueous solubility of 0.52 mg/ml and a native pH of 5.2 in aqueous solution. In addition, the sertraline benzoic acid salt has a hygroscopicity of approximately 0.1% at 100% relative humidity.
In a preferred embodiment of the invention, the pharmaceutically acceptable salt is the L-tartaric acid salt. The L-tartaric acid salt of sertraline is characterized by the principal x-ray diffraction pattern peaks expressed in terms of 2θ and d-spacings as measured with copper radiation (within the margins of error indicated):
Angle 2θ (±0.2)
d-value (Å) (±0.2)
13.7
6.5
15.0
5.9
16.7
5.3
18.4
4.8
20.5
4.3
22.1
4.0
22.9
3.9
24.5
3.6
The sertraline L-tartaric acid salt is further characterized in having an onset of melting transition/decomposition point at about 184° C. as measured by differential scanning calorimetry. Further, the sertraline L-tartaric acid salt of the invention is also characterized in having an aqueous solubility of 4.8 mg/ml and a pH of 3.0 in aqueous solution. In addition, the sertraline L-tartaric acid salt has a hygroscopicity of less than 0.1% at 100% relative humidity.
In a preferred embodiment of the invention, the pharmaceutically acceptable salt is the (−)-camphor-10-sulfonic acid salt. The (−)-camphor-10-sulfonic acid salt of sertraline is characterized by the principal x-ray diffraction pattern peaks expressed in terms of 2θ and d-spacings as measured with copper radiation (within the margins of error indicated):
Angle 2θ (±0.2)
d-value (Å) (±0.2)
5.6
15.8
13.1
6.8
14.6
6.1
15.8
5.6
18.2
4.9
19.9
4.5
21.7
4.1
22.6
3.9
The sertraline (−)-camphor-10-sulfonic acid salt is further characterized in having an onset of melting transition/decomposition point at about 265° C. as measured by differential scanning calorimetry. Further, the sertraline (−)-camphor-10-sulfonic acid salt of the invention is also characterized in having an aqueous solubility of 1.5 mg/ml and a native pH of 4.6 in aqueous solution. In addition, the sertraline, (−)-camphor-10-sulfonic acid salt has a hygroscopicity of approximately 0.4% at 100% relative humidity.
Another embodiment of the invention relates to a pharmaceutical composition comprising a salt of sertraline selected from the p-toluenesulfonic acid salt, the fumaric acid salt, the benzenesulfonic acid salt, the benzoic acid salt, the L-tartaric acid salt and the (−)-camphor-10-sulfonic acid salt; a pharmaceutically acceptable carrier or excipient, for use in the treatment in a mammal a disease, disorder or condition selected from the group consisting of aggression disorders; anxiety disorders (e.g., panic attack, agoraphobia, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder and acute stress disorder); cognitive disorders selected from the group consisting of amnestic disorders (e.g., amnestic disorders due to a general medical condition, substance-induced persisting amnestic disorder and amnestic disorders not otherwise specified), deliriums (e.g., deliriums due to a general medical condition, substance-induced delirium and delirium not otherwise specified), dementias (e.g., dementia of the Alzheimer's type, vascular dementia, dementia due to a general medical condition (e.g., AIDS-, Parkinson's-, head trauma-, and Huntington's-induced dementias), substance-induced persisting dementia, dementia due to multiple etiologies, and dementia not otherwise specified) and cognitive disorders not otherwise specified; depression disorders; emesis; epilepsy; food-related behavioral disorders, including anorexia nervosa and bulimia; headache disorders selected from the group consisting of migraine, cluster and vascular headaches; learning disorders, including attention deficit disorder and attention deficit-hyperactivity disorder; obesity; ocular disorders; platelet aggregation disorders; psychotic conditions selected from the group consisting of schizophrenia (e.g., paranoid-type, disorganized-type, catatonic-type, undifferentiated-type and residual-type), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorders due to a general medical condition and psychotic disorders not otherwise specified; sleep disorders selected from the group consisting of primary sleep disorders (e.g., parasomnias and dyssomnias), sleep disorders related to another mental disorder (including, without limitation, mood and anxiety disorders), sleep disorders due to a general medical condition and sleep disorders not otherwise specified; sexual behavior disorders; substance-abuse disorders selected from the group consisting of alcohol-related disorders, including alcohol-use disorders (e.g., dependence and abuse disorders) and alcohol-induced disorders (e.g., intoxication, withdrawal, intoxication delirium, withdrawal delirium, persisting dementia, persisting amnestic, mood, anxiety, sexual dysfunction, sleep and not otherwise specified disorders), amphetamine-related disorders, including amphetamine-use disorders (e.g., dependence and abuse disorders) and amphetamine-induced disorders (e.g., intoxication, withdrawal, intoxication delirium, psychotic, mood, anxiety, sexual dysfunction, sleep and not otherwise-specified disorders), caffeine-related disorders, such as intoxication, induced-anxiety disorder, induced-sleep disorder and disorders not otherwise specified; cannabis-related disorders, including cannabis-use disorders (e.g., abuse and dependence disorders) and cannabis-induced disorders (e.g., intoxication, intoxication delirium, psychotic, anxiety and not otherwise specified disorders), cocaine-related disorders, including cocaine-use disorders (e.g., dependence and abuse disorders) and cocaine-induced disorders (e.g., intoxication, withdrawal, intoxication delirium, psychotic, mood, anxiety, sexual dysfunction, sleep and not otherwise specified disorders), hallucinogen-related disorders, including hallucinogen-use disorders (e.g., dependence and abuse disorders) and hallucinogen-induced disorders (e.g., intoxication, persisting perception, intoxication delirium, psychotic, mood, anxiety and not otherwise specified disorders), inhalant-related disorders, including inhalant-use disorders (e.g., dependence and abuse disorders) and inhalant-induced disorders (e.g., intoxication, intoxication delirium, persisting dementia, psychotic, mood, anxiety and not otherwise specified disorders), nicotine-related disorders, such as dependence, withdrawal and not otherwise specified disorders, opioid related disorders, including opioid-use disorders (e.g., dependence and abuse disorders) and opioid-induced disorders (e.g., intoxication, withdrawal, intoxication delirium, psychotic, mood, sexual dysfunction, sleep and not otherwise-specified disorders), phencyclidine-related disorders, including phencyclidine-use disorders (e.g., dependence and abuse disorders) and phencyclidine-induced disorders (e.g., intoxication, intoxication delirium, psychotic, mood, anxiety and not otherwise-specified disorders), sedative-, hypnotic- or anxiolytic-related disorders, including sedative-use disorders (e.g., dependence and abuse disorders) and sedative-induced disorders (e.g., intoxication, withdrawal, intoxication delirium, withdrawal delirium, persisting dementia, persisting amnestic, psychotic, mood, anxiety, sexual dysfunction, sleep and not otherwise specified disorders), polysubstance-related disorder, other substance dependence and abuse disorders, and other substance-induced disorders (e.g., intoxication, withdrawal, delirium, persisting dementia, persisting amnestic, psychotic, mood, anxiety, sexual dysfunction, sleep and not otherwise specified disorders); and vision disorders, including glaucoma.
The present invention further relates to a method of treating in a mammal a disease, disorder or condition selected from the group consisting of aggression disorders; anxiety disorders (e.g., panic attack, agoraphobia, panic disorder with or without agoraphobia, agoraphobia without history of panic disorder, specific phobia, social phobia, obsessive-compulsive disorder, post-traumatic stress disorder and acute stress disorder); cognitive disorders selected from the group consisting of amnestic disorders (e.g., amnestic disorders due to a general medical condition, substance-induced persisting amnestic disorder and amnestic disorders not otherwise specified), deliriums (e.g., deliriums due to a general medical condition, substance-induced delirium and delirium not otherwise specified), dementias (e.g., dementia of the Alzheimer's type, vascular dementia, dementia due to a general medical condition (e.g., AIDS-, Parkinson's-, head trauma-, and Huntington's-induced dementias), substance-induced persisting dementia, dementia due to multiple etiologies, and dementia not otherwise specified) and cognitive disorders not otherwise specified; depression disorders; emesis; epilepsy; food-related behavioral disorders, including anorexia nervosa and bulimia; headache disorders selected from the group consisting of migraine, cluster and vascular headaches; learning disorders, including attention deficit disorder and attention deficit/hyperactivity disorder; obesity; ocular disorders; platelet aggregation disorders; psychotic conditions selected from the group consisting of schizophrenia (e.g., paranoid-type, disorganized-type, catatonic-type, undifferentiated-type and residual-type), schizophreniform disorder, schizoaffective disorder, delusional disorder, brief psychotic disorder, shared psychotic disorder, psychotic disorders due to a general medical condition and psychotic disorders not otherwise specified; sleep disorders selected from the group consisting of primary sleep disorders (e.g., parasomnias and dyssomnias), sleep disorders related to another mental disorder (including, without limitation, mood and anxiety disorders), sleep disorders due to a general medical condition and sleep disorders not otherwise specified; sexual behavior disorders; substance-abuse disorders selected from the group consisting of alcohol-related disorders, including alcohol-use disorders (e.g., dependence and abuse disorders) and alcohol-induced disorders (e.g., intoxication, withdrawal, intoxication delirium, withdrawal delirium, persisting dementia, persisting amnestic, mood, anxiety, sexual dysfunction, sleep and not otherwise specified disorders), amphetamine-related disorders, including amphetamine-use disorders (e.g., dependence and abuse disorders) and amphetamine-induced disorders (e.g., intoxication, withdrawal, intoxication delirium, psychotic, mood, anxiety, sexual dysfunction, sleep and not otherwise-specified disorders), caffeine-related disorders, such as intoxication, induced-anxiety disorder, induced-sleep disorder and disorders not otherwise specified; cannabis-related disorders, including cannabis-use disorders (e.g., abuse and dependence disorders) and cannabis-induced disorders (e.g., intoxication, intoxication delirium, psychotic, anxiety and not otherwise specified disorders), cocaine-related disorders, including cocaine-use disorders (e.g., dependence and abuse disorders) and cocaine-induced disorders (e.g., intoxication, withdrawal, intoxication delirium, psychotic, mood, anxiety, sexual dysfunction, sleep and not otherwise specified disorders), hallucinogen-related disorders, including hallucinogen-use disorders (e.g., dependence and abuse disorders) and hallucinogen-induced disorders (e.g., intoxication, persisting perception, intoxication delirium, psychotic, mood, anxiety and not otherwise specified disorders), inhalant-related disorders, including inhalant-use disorders (e.g., dependence and abuse disorders) and inhalant-induced disorders (e.g., intoxication, intoxication delirium, persisting dementia, psychotic, mood, anxiety and not otherwise specified disorders), nicotine-related disorders, such as dependence, withdrawal and not otherwise specified disorders, opioid related disorders, including opioid-use disorders (e.g., dependence and abuse disorders) and opioid-induced disorders (e.g., intoxication, withdrawal, intoxication delirium, psychotic, mood, sexual dysfunction, sleep and not otherwise-specified disorders), phencyclidine-related disorders, including phencyclidine-use disorders (e.g., dependence and abuse disorders) and phencyclidine-induced disorders (e.g., intoxication, intoxication delirium, psychotic, mood, anxiety and not otherwise-specified disorders), sedative-, hypnotic- or anxiolytic-related disorders, including sedative-use disorders (e.g., dependence and abuse disorders) and sedative-induced disorders (e.g., intoxication, withdrawal, intoxication delirium, withdrawal delirium, persisting dementia, persisting amnestic, psychotic, mood, anxiety, sexual dysfunction, sleep and not otherwise specified disorders), polysubstance-related disorder, other substance dependence and abuse disorders, and other substance-induced disorders (e.g., intoxication, withdrawal, delirium, persisting dementia, persisting amnestic, psychotic, mood, anxiety, sexual dysfunction, sleep and not otherwise specified disorders); and vision disorders, including glaucoma; comprising administering to a subject in need thereof a therapeutically effective amount of a salt of sertraline selected from the group consisting of the p-toluenesulfonic acid salt, the fumaric acid salt, the benzenesulfonic acid salt, the benzoic acid salt, the L-tartaric acid salt and the (−)-camphor-10-sulfonic acid salt.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is the observed powder X-ray diffraction pattern of the p-toluenesulfonic acid salt of sertraline (y axis is linear counts per second; X in degrees 2 theta).
FIG. 1B is the observed powder X-ray diffraction of the fumaric acid salt of sertraline (y axis is linear counts per second; X in degrees 2 theta).
FIG. 1C is the observed powder X-ray diffraction pattern of the benzenesulfonic acid salt of sertraline (y axis is linear counts per second; X in degrees 2 theta).
FIG. 1D is the observed powder X-ray diffraction of the benzoic acid salt of sertraline (y axis is linear counts per second; X in degrees 2 theta).
FIG. 1E is the observed powder X-ray diffraction pattern of the L-tartaric acid salt of sertraline (y axis is linear counts per second; X in degrees 2 theta).
FIG. 1F is the observed powder X-ray diffraction of the (−)-camphor-10-sulfonic acid salt of sertraline (y axis is linear counts per second; X in degrees 2 theta).
FIG. 2A is the differential scanning calorimetric trace of the p-toluenesulfonic acid salt of sertraline.
FIG. 2B is the differential scanning calorimetric trace of the fumaric acid salt of sertraline.
FIG. 2C is the differential scanning calorimetric trace of the benzenesulfonic acid salt of sertraline.
FIG. 2D is the differential scanning calorimetric trace of the benzoic acid salt of sertraline.
FIG. 2E is the differential scanning calorimetric trace of the L-tartaric acid salt of sertraline.
FIG. 2F is the differential scanning calorimetric trace of the (−)-camphor-10-sulfonic acid salt of sertraline.
DETAILED DESCRIPTION OF THE INVENTION
Sertraline is a selective serotonin reuptake inhibitor useful in the treatment of a number of central nervous system diseases, disorders and conditions. The commercial form of sertraline is its hydrochloride salt sold under the trademark Zoloft®.
Sertraline, including its hydrochloride salt and stable polymorph, and methods of preparing the same, are disclosed in U.S. Pat. Nos. 4,536,518 and 5,248,699. Further methods of preparing sertraline are set forth in U.S. Pat. Nos. 4,777,288; 4,839,104; 4,855,500; 5,463,126; 5,442,116; 5,082,970; 5,466,880; 5,196,607; 5,750,794; 5,288,916; and 6,323,500; as well as in the following published patent applications: International PCT Patent Publication No. WO 99/57089; European Patent Publication Nos. EP 997 535 A1 and EP 1 059 287 A1; and U.S. Patent Publication No. 2001-0044142 A1. All of the foregoing patents and patent publications are hereby incorporated by reference.
The particular pharmaceutically acceptable salts of sertraline of the present invention are only slightly hygroscopic, have high aqueous solubility and high melting points. These characteristics combined with their relative inertness towards common excipients used in pharmaceutical formulations make them highly suitable for pharmaceutical formulation use. In addition, the particular pharmaceutically acceptable salts of the present invention exhibit good solid state stability under accelerated conditions.
Although in general other acid addition salts of sertraline are all crystalline, those salts are in several cases hygroscopic or have unstable crystal forms as to render them poor candidates for pharmaceutical formulation use.
Preparation of the sertraline salts of the invention is carried out ordinarily by dissolving the sertraline free base in a suitable solvent, preferably a (C 1 –C 6 )alkyl ester or ketone, more preferably ethyl acetate or acetone, most preferably ethyl acetate, then adding in the acid to be added to the-sertraline free base. The particular acid, i.e., any of p-toluenesulfonic acid, fumaric acid, benzenesulfonic acid, benzoic acid, L-tartaric acid or (−)-camphor-10-sulfonic acid, may be added in solid form to the solution of free base or as a solution in a suitable solvent, preferably in a solvent as listed immediately above, in a preferred 1:1 free base:acid ratio. The mixture is then allowed to stir for several hours to several days. The product salt is then isolated by filtering the reaction mixture, washing the isolated salt in a suitable solvent, and then drying the resultant salt product, preferably in a vacuum oven at a temperature between 25 and 40° C. for approximately 24 to 48 hours. The final product salt is ordinarily harvested in approximately 90 to 100% yield.
Differential Scanning Calorimetry
The solid state thermal behavior of the salts of the invention were investigated by differential scanning calorimetry (DSC). The DSC thermograms were obtained on a Mettler Toledo DSC 821 e (STAR e System). Generally, samples between 1 and 10 mg were prepared in crimped aluminum pans with a small pinhole. The measurements were run at a heating rate of 5° C. per minute in the range of 30 to 300° C.
As seen in FIG. 2A , the p-toluenesulfonic acid salt of sertraline exhibits an onset of melt transition at about 260° C. As seen in FIG. 2B , the fumaric acid salt of sertraline exhibits an onset of melt transition at about 187° C. As seen in FIG. 2C , the benzenesulfonic acid salt of sertraline exhibits an onset of melt transition at about 229° C. As seen in FIG. 2D , the benzoic acid salt of sertraline exhibits an onset of melt transition at about 154° C. As seen in FIG. 2E , the L-tartaric acid salt of sertraline exhibits an onset of melt transition at about 184 ° C. As seen in FIG. 2F , the (−)-camphor-10-sulfonic acid salt of sertraline exhibits an onset of melt transition at about 265 ° C. One of skill in the art will however note that in DSC measurement there is a certain degree of variability in actual measured onset and peak temperatures which occur depending on rate of heating, crystal shape and purity, and other measurement parameters.
Powder X-ray Diffraction Patterns
The power x-ray diffraction patterns for the pharmaceutically acceptable salts of the invention were collected using a Bruker D5000 diffractometer (Bruker AXS, Madison, Wis.) equipped with copper radiation CuK α , fixed slits (1.0, 1.0, 0.6 mm), and a Kevex solid state detector. Data was collected from 3.0 to 40.0 degrees in two theta (2θ) using a step size of 0.04 degrees and a step time of 1.0 seconds.
The x-ray powder diffraction patterns of each of the following salts of sertraline: the p-toluenesulfonic acid salt, the fumaric acid salt, the benzenesulfonic acid salt, the benzoic acid salt, the L-tartaric acid salt and the (−)-camphor-10-sulfonic acid salt, were conducted with a copper anode with wavelength 1 at 1.54056 and wavelength 2 at 1.54439 (relative intensity: 0.500). The range for 2θ was between 3.0 to 40.0 degrees with a step size of 0.04 degrees, a step time of 1.00 second, a smoothing width of 0.300 and a threshold of 1.0.
The diffraction peaks at diffraction angles (2θ) in a measured powder X-ray diffraction analysis for the p-toluenesulfonic acid salt of sertraline are shown in Table I. The relative intensities, however, may change depending on the crystal size and morphology. The actual measured powder diffractogram is displayed in FIG. 1A .
TABLE I
Powder X-ray Diffraction Pattern for the p-Toluenesulfonic
Acid Salt of Sertraline with Intensities and Peak
Locations of Diffraction Lines.
Angle 2θ
d-value (Å)
I
(±0.2)
(±0.2)
(rel. %)
6.5
13.6
76.7
10.0
8.9
29.2
12.1
7.3
29.9
13.1
6.8
13.2
14.2
6.2
11.6
16.1
5.5
60.2
16.6
5.3
100.0
17.5
5.1
33.3
18.0
4.9
23.0
18.4
4.8
20.0
19.6
4.5
12.8
20.0
4.4
37.9
20.4
4.3
28.9
20.8
4.3
18.6
21.0
4.2
15.7
21.5
4.1
15.2
22.2
4.0
20.0
22.4
4.0
24.7
22.8
3.9
13.6
23.7
3.8
36.6
24.0
3.7
35.1
24.4
3.7
18.3
24.9
3.6
27.8
25.8
3.5
48.0
26.3
3.4
9.7
27.1
3.3
6.8
27.7
3.2
8.9
28.5
3.1
51.3
30.0
3.0
10.5
31.5
2.8
14.2
31.7
2.8
14.0
32.5
2.8
5.4
33.1
2.7
6.4
33.9
2.6
9.1
34.7
2.6
6.8
35.7
2.5
5.3
36.6
2.5
6.4
36.9
2.4
8.4
38.1
2.4
5.4
39.2
2.3
8.0
Table II sets forth the 2θ, d-spacings and relative intensities and peak locations for the powder x-ray diffraction pattern representative for the p-toluenesulfonic acid salt of sertraline. The numbers as listed are computer-generated.
TABLE II
Powder X-ray Diffraction Intensities and Peak Locations
Representative of the p-Toluenesulfonic Acid Salt of Sertraline.
Angle 2θ (±0.2)
d-value (Å) (±0.2)
I (rel. %)
6.5
13.6
76.7
16.1
5.5
60.2
16.6
5.3
100.0
20.0
4.4
37.9
23.7
3.8
36.6
24.0
3.7
35.1
25.8
3.5
48.0
28.5
3.1
51.3
The diffraction peaks at diffraction angles (2θ) in a measured powder X-ray diffraction analysis for the fumaric acid salt of sertraline are shown in Table III. Again, the relative intensities, however, may change depending on the crystal size and morphology. The actual measured powder diffractogram is displayed in FIG. 1B .
TABLE III
Powder X-ray Diffraction Pattern for the Fumaric
Acid Salt of Sertraline with Intensities and Peak
Locations of Diffraction Lines.
Angle 2θ
d-value (Å)
I
(±0.2)
(±0.2)
(rel. %)
4.5
19.4
9.2
9.1
9.7
11.8
10.4
8.5
4.8
11.4
7.8
6.6
12.5
7.1
11.0
13.9
6.4
54.2
14.8
6.0
14.7
15.5
5.7
100.0
16.1
5.5
25.8
16.9
5.2
14.9
17.3
5.1
11.4
18.0
4.9
11.1
18.3
4.8
26.8
18.6
4.8
19.0
19.2
4.6
41.4
20.4
4.4
24.6
20.8
4.3
27.9
21.1
4.2
25.1
22.1
4.0
25.0
22.4
4.0
24.3
23.0
3.9
78.8
23.4
3.8
39.0
23.9
3.7
33.3
25.0
3.6
24.2
25.3
3.5
22.4
25.9
3.4
21.4
27.4
3.2
40.2
28.6
3.1
16.6
28.8
3.1
22.1
29.9
3.0
14.0
31.9
2.8
14.0
32.4
2.8
16.9
33.1
2.7
12.1
38.0
2.4
9.8
38.3
2.3
9.3
Table IV sets forth the 2θ, d-spacings and relative intensities and peak locations for the powder x-ray diffraction pattern representative for the fumaric acid salt of sertraline. The numbers as listed are computer-generated.
TABLE IV
Powder X-ray Diffraction Intensities and Peak Locations
Representative of the Fumaric Acid Salt of Sertraline.
Angle 2θ (±0.2)
d-value (Å) (±0.2)
I (rel. %)
13.9
6.4
54.2
15.5
5.7
100.0
18.3
4.8
26.8
19.1
4.6
41.4
20.8
4.3
27.9
23.0
3.9
78.8
23.4
3.8
39.0
27.4
3.2
40.2
The diffraction peaks at diffraction angles (2θ) in a measured powder X-ray diffraction analysis for the benzenesulfonic acid salt of sertraline are shown in Table V. Again, the relative intensities, however, may change depending on the crystal size and morphology. The actual measured powder diffractogram is displayed in FIG. 1C .
TABLE V
Powder X-ray Diffraction Pattern for the Benzenesulfonic
Acid Salt of Sertraline with Intensities and Peak
Locations of Diffraction Lines.
Angle 2θ
d-value (Å)
I
(±0.2)
(±0.2)
(rel. %)
7.5
11.9
40.6
8.9
10.0
10.5
12.7
7.0
28.5
13.0
6.8
4.7
13.6
6.5
35.1
13.8
6.4
6.3
15.1
5.9
79.3
16.2
5.5
11.8
16.7
5.3
13.6
17.2
5.2
8.7
17.9
5.0
18.5
18.2
4.9
22.3
19.8
4.5
100.0
20.6
4.3
36.3
22.4
4.0
42.4
22.9
3.9
66.4
23.4
3.8
41.9
24.0
3.7
5.8
24.4
3.6
38.3
24.8
3.6
38.2
25.5
3.5
6.2
26.2
3.4
6.7
26.9
3.3
6.3
27.4
3.3
5.8
27.6
3.2
15.4
27.9
3.2
32.9
28.3
3.1
14.9
28.9
3.1
8.0
29.1
3.1
10.1
29.8
3.0
6.4
30.3
2.9
8.6
30.6
2.9
18.3
31.1
2.9
11.3
32.1
2.8
7.3
32.5
2.8
11.2
32.8
2.7
13.1
33.0
2.7
8.7
33.6
2.7
4.2
34.1
2.6
8.8
34.6
2.6
5.4
35.3
2.5
7.4
36.1
2.5
12.8
36.3
2.5
8.2
36.6
2.5
5.5
37.7
2.4
7.5
38.1
2.4
5.9
38.4
2.3
4.1
39.2
2.3
7.4
39.5
2.3
10.1
Table VI sets forth the 2θ, d-spacings and relative intensities and peak locations for the powder x-ray diffraction pattern representative for the benzenesulfonic acid salt of sertraline. The numbers as listed are computer-generated.
TABLE VI
Powder X-ray Diffraction Intensities and Peak Locations
Representative of the Benzenesulfonic Acid Salt of Sertraline.
Angle 2θ (±0.2)
d-value (Å) (±0.2)
I (rel. %)
7.5
11.9
40.6
15.1
5.9
79.3
22.4
4.0
42.4
22.9
3.9
66.4
23.4
3.8
41.9
24.4
3.6
38.3
24.8
3.6
38.2
27.9
3.2
32.9
The diffraction peaks at diffraction angles (2θ) in a measured powder X-ray diffraction analysis for the benzoic acid salt of sertraline are shown in Table VII. Again, the relative intensities, however, may change depending on the crystal size and morphology. The actual measured powder diffractogram is displayed in FIG. 1D .
TABLE VII
Powder X-ray Diffraction Pattern for the Benzoic
Acid Salt of Sertraline with Intensities and Peak
Locations of Diffraction Lines.
Angle 2θ
d-value (Å)
I
(±0.2)
(±0.2)
(rel. %)
8.0
11.0
6.7
10.1
8.8
4.7
11.7
7.5
12.0
13.2
6.7
23.4
13.6
6.5
16.2
14.9
5.9
47.3
16.1
5.5
100.0
16.7
5.3
12.7
18.0
4.9
46.0
18.5
4.8
33.7
19.3
4.6
32.6
20.3
4.4
9.0
21.1
4.2
28.2
21.7
4.1
17.9
22.4
4.0
13.4
22.7
3.9
13.9
23.2
3.8
31.8
23.6
3.8
40.0
24.2
3.7
11.3
25.0
3.6
39.5
25.2
3.5
37.4
25.7
3.5
10.7
26.1
3.4
20.9
26.6
3.3
50.0
27.2
3.3
22.9
28.0
3.2
6.9
28.5
3.1
7.1
29.0
3.1
8.7
30.1
3.0
7.6
30.5
2.9
19.3
31.8
2.8
15.3
32.4
2.8
15.4
34.2
2.6
13.6
34.5
2.6
10.3
36.4
2.5
6.9
37.0
2.4
7.0
37.4
2.4
7.7
38.0
2.4
5.9
39.6
2.3
5.5
Table VIII sets forth the 2θ, d-spacings and relative intensities and peak locations for the powder x-ray diffraction pattern representative for the benzoic acid salt of sertraline. The numbers as listed are computer-generated.
TABLE VIII
Powder X-ray Diffraction Intensities and Peak Locations
Representative of the Benzoic Acid Salt of Sertraline
Angle 2θ (±0.2)
d-value (Å) (±0.2)
I (rel. %)
14.9
5.9
47.3
16.1
5.5
100.0
18.0
4.9
46.0
18.5
4.8
33.7
19.3
4.6
32.6
23.6
3.8
40.0
25.0
3.6
39.5
25.2
3.5
37.4
The diffraction peaks at diffraction angles (2θ) in a measured powder X-ray diffraction analysis for the L-tartaric acid salt of sertraline are shown in Table IX. Again, the relative intensities, however, may change depending on the crystal size and morphology. The actual measured powder diffractogram is displayed in FIG. 1B .
TABLE IX
Powder X-ray Diffraction Pattern for the L-Tartaric
Acid Salt of Sertraline with Intensities and
Peak Locations of Diffraction Lines.
Angle 2θ
d-value (Å)
I
(±0.2)
(±0.2)
(rel. %)
4.1
21.7
20.0
8.2
10.8
17.8
10.0
8.8
9.5
10.4
8.5
3.5
11.3
7.8
10.8
12.2
7.2
24.0
13.7
6.5
55.0
15.0
5.9
100.0
16.4
5.4
26.9
16.7
5.3
45.7
17.1
5.2
11.4
17.4
5.1
14.7
18.4
4.8
31.2
19.0
4.7
8.4
20.2
4.4
14.7
20.5
4.3
68.1
20.9
4.2
10.0
22.1
4.0
38.5
22.9
3.9
54.9
23.9
3.7
22.1
24.5
3.6
42.8
25.6
3.5
5.8
26.2
3.4
29.0
26.6
3.4
23.1
27.1
3.3
6.3
27.5
3.2
11.7
28.9
3.1
9.2
29.9
3.0
15.8
30.5
2.9
14.4
31.4
2.8
14.2
32.0
2.8
15.7
32.4
2.8
11.4
32.9
2.7
14.6
33.5
2.7
9.2
34.7
2.6
9.0
35.8
2.5
5.0
36.7
2.4
7.0
37.3
2.4
6.1
37.9
2.4
10.2
39.0
2.3
8.4
Table X sets forth the 2θ, d-spacings and relative intensities and peak locations for the powder x-ray diffraction pattern representative for the L-tartaric acid salt of sertraline. The numbers as listed are computer-generated.
TABLE X
Powder X-ray Diffraction Intensities and Peak Locations
Representative of the L-Tartaric Acid Salt of Sertraline.
Angle 2θ (±0.2)
d-value (Å) (±0.2)
I (rel. %)
13.7
6.5
55.0
15.0
5.9
100.0
16.7
5.3
45.7
18.4
4.8
31.2
20.5
4.3
68.1
22.1
4.0
38.5
22.9
3.9
54.9
24.5
3.6
42.8
The diffraction peaks at diffraction angles (2θ) in a measured powder X-ray diffraction analysis for the (−)-camphor-10-sulfonic acid salt of sertraline are shown in Table XI. Again, the relative intensities, however, may change depending on the crystal size and morphology. The actual measured powder diffractogram is displayed in FIG. 1B .
TABLE XI
Powder X-ray Diffraction Pattern for the (−)-
Camphor-10-sulfonic acid Salt of Sertraline with
Intensities and Peak Locations of Diffraction Lines.
Angle 2θ
d-value (Å)
I
(±0.2)
(±0.2)
(rel. %)
5.6
15.8
100.0
7.2
12.2
9.8
9.4
9.4
11.1
11.2
7.9
11.2
12.3
7.2
5.0
13.1
6.8
53.2
13.4
6.6
8.2
13.7
6.4
13.6
14.6
6.1
48.3
15.1
5.9
23.9
15.9
5.6
92.4
16.9
5.2
14.3
17.2
5.1
19.3
17.6
5.0
23.4
17.7
5.0
19.0
18.2
5.9
28.9
19.2
4.6
14.2
19.5
4.5
16.8
19.9
4.5
39.0
20.6
4.3
16.8
20.8
4.3
10.4
21.4
4.1
21.1
21.7
4.1
45.8
22.1
4.0
17.9
22.6
3.9
29.8
23.0
3.9
28.5
23.5
3.8
20.3
24.0
3.7
17.3
24.4
3.6
11.4
24.8
3.6
20.5
26.3
3.4
10.7
26.8
3.3
12.0
27.1
3.3
10.7
28.3
3.1
12.1
29.0
3.1
7.9
30.4
2.9
9.5
30.8
2.9
9.4
31.8
2.8
7.7
32.2
2.8
7.4
32.7
2.7
7.4
33.8
2.6
8.1
34.2
2.6
9.4
35.4
2.5
6.8
36.0
2.5
6.5
38.7
2.3
7.1
39.6
2.3
7.1
39.8
2.3
6.7
Table XII sets forth the 2θ, d-spacings and relative intensities and peak locations for the powder x-ray diffraction pattern representative for the (−)-camphor-10-sulfonic acid salt of sertraline. The numbers as listed are computer-generated.
TABLE IV
Powder X-ray Diffraction Intensities and Peak Locations
Representative of the (−)-Camphor-10-sulfonic
Acid Salt of Sertraline.
Angle 2θ (±0.2)
d-value (Å) (±0.2)
I (rel. %)
5.6
15.8
100.0
13.1
6.8
53.2
14.6
6.1
48.3
15.8
5.6
92.4
18.2
4.9
28.9
19.9
4.5
39.0
21.7
4.1
45.8
22.6
3.9
29.8
The pharmaceutically acceptable sertraline salts of the invention, including the p-toluenesulfonic acid salt, the fumaric acid salt, the benzenesulfonic acid salt, the benzoic acid salt, the L-tartaric acid salt and the (−)-camphor-10-sulfonic acid salt (hereafter “the active salts”), can be administered via either the oral, transdermal (e., through the use of a patch), intranasal, sublingual, rectal, parenteral or topical routes. Transdermal and oral administration are preferred. The active salt is, most desirably, administered in dosages ranging from about 0.01 mg up to about 1500 mg per day, preferably from about 0.1 to about 300 mg per day in single or divided doses, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen. However, a dosage level that is in the range of about 0.001 mg to about 10 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the weight and condition of the persons being treated and their individual responses to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval during which such administration is carried out. In some instances, dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effects, provided that such larger doses are first divided into several small doses for administration throughout the day.
The active salts of the invention can be administered alone or in combination with pharmaceutically acceptable carriers or diluents by any of the several routes previously indicated. More particularly, the active salt can be administered in a wide variety of different dosage forms, e.g., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, transdermal patches, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents. In addition, oral pharmaceutical compositions can be suitably sweetened and/or flavored. In general, the active salt is present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
For oral administration, tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc can be used for tabletting purposes. Solid compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar, as well as high molecular weight polyethylene glycols. When aqueous suspensions and/or elixirs are desired for oral administration the active salt may be combined with various sweetening or flavoring agents, coloring matter and, if so desired, emulsifying and/or suspending agents, together with such diluents as water, ethanol, propylene glycol, glycerin and various combinations thereof.
For parenteral administration, a solution of an active salt in either sesame or peanut oil or in aqueous propylene glycol can be employed. The aqueous solutions should be suitably buffered (preferably pH greater than 8), if necessary, and the liquid diluent first rendered isotonic. These aqueous solutions are suitable for intravenous injection purposes. The oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
It is also possible to administer the active salts topically and this can be done by way of creams, a patch, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
The following examples illustrate the methods and compounds of the present invention. It will be understood, however, that the invention is not limited to the specific Examples.
EXAMPLE 1
P-Toluenesulfonic Acid Salt of Sertraline
A 50 ml flask was charged with the free base sertraline (300 mg; 0.98 mmol) and ethyl acetate (5 ml). The mixture was filtered to remove any specks and fibers present. To the clarified solution was added tosic acid monohydrate (186 mg., 0.98 mmol, 1.0 equiv.) dissolved in ethyl acetate (5 ml) and stirred at room temperature overnight. The product was isolated by filtration, washed with cold ethyl acetate and dried at 20 to 30° C. under vacuum for about 24 hours. The identity of the title compound was verified by powder x-ray diffraction. Yield: 463 mg (0.96 mmol; 99%) Elem. Anal. Obs'd: C 60.33%, H 5.32%, N 3.02%, S 6.94%; Calc'd C 60.25%, H 5.27%, N 2.93%, S 6.70%.
EXAMPLE 2
Fumaric Acid Salt of Sertraline
A 50 ml flask was charged with the free base sertraline (300 mg; 0.98 mmol) and ethyl acetate (5 ml). The mixture was filtered to remove any specks and fibers present. To the clarified solution was added fumaric acid (114 mg., 0.98 mmol, 1.0 equiv.) dissolved in ethyl acetate (5 ml). The mixture was stirred over 48 hours and the final slurry of white precipitate was isolated by filtration, washed with ethyl acetate and dried at 45° C. under vacuum for about 24 hours. Yield 397 mg (0.94 mmol; 96%). The identity of the title compound was verified by powder x-ray diffraction. Elem. Anal. Obs'd: C 59.77%, H 5.16%, N 3.34%; Calc'd C 59.73%, H 5.01%, N 3.32%.
EXAMPLE 3
Benzenesulfonic Acid Salt of Sertraline
A 50 ml flask was charged with the free base sertraline (300 g; 0.98 mmol) and ethyl acetate (5 ml). The mixture was filtered to remove any specks and fibers present. To the clarified solution was added benzenesulfonic acid (155 g., 0.98 mmol, 1.0 equiv.) dissolved in ethyl acetate. The mixture was stirred at overnight at room temperature allowing crystallization to occur. The product was isolated by filtration, washed with ethyl acetate and dried at 20 to 30° C. under vacuum for about 24 hours. The identity of the title compound was verified by powder x-ray diffraction. Yield: 399 mg (0.86 mmol; 88%). Elem. Anal. Obs'd: C 59.56%, H 4.85%, N 3.01%, S 7.26%; Calc'd C 59.49%, H 4.99%, N 3.02%, S 6.90%.
EXAMPLE 4
Benzoic Acid Salt of Sertraline
A 50 ml flask was charged with the free base sertraline (153.3 mg; 0.50 mmol) and ethyl acetate (5 ml). The mixture was filtered to remove any specks and fibers present. To the clarified solution was added with a benzoic acid (62 mg., 0.51 mmol, 1.0 equiv.) dissolved in acetone (5 ml). The mixture was stirred at room temperature for 48 hours. The product was isolated by filtration, washed with acetone and dried at 20 to 30° C. under vacuum for about 24 hours. The identity of the title compound was verified by powder x-ray diffraction. Elem. Anal. Obs'd: C 67.33%, H 5.56%, N 3.21%; Calc'd C 67.30%, H 5.41%, N 3.27%.
EXAMPLE 5
L-Tartaric Acid Salt of Sertraline
A 50 ml flask was charged with the free base sertraline (300 mg; 0.98 mmol) and ethyl acetate (5 ml). The mixture was filtered to remove any specks and fibers present. To the clarified solution was added L-tartaric acid (147 mg., 0.98 mmol, 1.0 equiv.) dissolved in ethyl acetate (5 ml). The mixture was stirred at overnight and the product was isolated by filtration, washed with ethyl acetate and dried at 20 to 30° C. under vacuum for about 24 hours. The identity of the title compound was verified by powder x-ray diffraction. Yield: 439 mg (0.96 mmol; 98%) Elem. Anal. Obs'd: C 55.23%, H 5.07%, N 3.06%; Calc'd C 55.27%, H 5.08%, N 3.07%.
EXAMPLE 6
(−)-Camphor-10-sulfonic Acid Salt of Sertraline
A 50 ml flask was charged with the free base sertraline (300 mg; 0.98 mmol) and ethyl acetate (5 ml). The mixture was filtered to remove any specks and fibers present. To the clarified solution was added a solution of (−)-camphor-10-sulfonic acid (228 mg., 0.98 mmol, 1.0 equiv.) dissolved in ethyl acetate (5 ml) over heat. The resultant crystal slurry was allowed cooled to room temperature and stirred for about 4 hours. The product was isolated by filtration, washed with ethyl acetate and dried at 45° C. under vacuum for about 48 hours. The identity of the title compound was verified by powder x-ray diffraction. Yield: 508 mg (0.94 mmol; 96%) Elem. Anal. Obs'd: C 60.28%, H 6.22%, N 2.61%, S 6.19%; Theor. C 60.22%, H 6.18%, N 2.60%, S 5.95%.
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The present invention is directed to certain pharmaceutically acceptable salts of the therapeutically potent selective serotonin reuptake inhibitor, sertraline:
and pharmaceutical compositions thereof, wherein said salts are selected from the group consisting of the p-toluenesulfonic acid salt, the fumaric acid salt, the benzenesulfonic acid salt, the benzoic acid salt, the L-tartaric acid salt and the (−)-camphor-10-sulfonic acid salt.
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RELATED APPLICATION(S)
This application claims priority under 35 U.S.C. §119 (e) of Korean Patent Application No. 10-2005-0132706 filed Dec. 28, 2005, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
The present invention relates to a capacitor and a method for manufacturing the same.
BACKGROUND OF THE INVENTION
A merged memory logic (MML) device is an integrated device that incorporates a memory cell array, such as a dynamic random access memory (DRAM), and an analog or a peripheral circuit into a single chip. Since multimedia functions have been enhanced by the introduction of the MML, it is possible to efficiently achieve integration and high-speed of semiconductor devices.
Development is underway for manufacturing a capacitor having high capacitance for an analog circuit in which high-speed operation is needed. There are two main types of capacitors used in analog circuits. They are polysilicon/insulator/polysilicon (PIP) type capacitors and metal/insulator/metal (MIM) type capacitors. In general, because conductive polysilicon is used for the upper and lower electrodes of a PIP type capacitor, a natural oxide forms due to an oxidation occurring at the interface between the upper/lower electrode and a dielectric thin layer. Because of the natural oxide formation, the conventional PIP capacitor has a defect that lowers its capacitance.
In addition, the capacitance decreases due to a depletion region formed on a polysilicon layer. Thus, there is a disadvantage in that the PIP capacitor is not suitable for high-speed and high-frequency operations. To overcome these disadvantages, a metal-insulator-silicon (MIS) or a metal-insulator-metal (MIM) is used. The MIM type capacitor is generally used for high performance semiconductor devices because it has low resistivity and does not cause parasitic capacitance derived from the depletion.
Hereinafter, a related art capacitor will be described with reference to the accompanying drawings.
FIG. 1 is a sectional view of showing a structure of a MIM capacitor according to the related art.
As shown in FIG. 1 , a capacitor according to the related art includes a first interlayer dielectric 10 having the first contact hole formed on a substrate. A Metal-Insulator-Metal (MIM) type capacitor is formed at an upper portion of the first interlayer dielectric 10 . The MIM type capacitor includes a first conductive layer 11 , a first insulating layer 13 , and a second conductive layer 14 , which are sequentially deposited at an upper portion of the first interlayer dielectric 10 . Here, a second interlayer dielectric 15 is formed on an entire surface of the substrate including the MIM type capacitor. The first conductive layer 11 , functioning as a lower electrode of the capacitor, is connected to a third conductive layer 17 a formed on the second interlayer dielectric 15 through a first plug 16 , which is formed in a second contact hole.
In addition, the second conductive layer 14 , functioning as an upper electrode of the capacitor, is connected to a fourth conductive layer 17 b formed on the second interlayer dielectric 15 through a second plug 20 , which is formed in a third contact hole
In the capacitor according to the related art, a first conductive layer 11 , a first insulating layer 13 , and a second conductive layer 14 are flatly constructed of layers in horizontal planes. In order to increase the capacitance through increasing the surface area of the electrodes, the related art capacitor is expanded along the horizontal plane.
Accordingly, in the capacitor according to the related art, there is a limit to increasing the length and width of a capacitor with a defined area.
BRIEF SUMMARY
Accordingly, embodiments of the present invention are directed to a capacitor and a method for manufacturing the same that substantially obviates one or more problems due to limitations and/or disadvantages of the related art.
Accordingly, it is an object of embodiments of the present invention to provide a capacitor capable of being formed in a vertical plane without an additional mask process or deposition process and a method of manufacturing the same.
Additional advantages, objects, and features of the invention will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be earned from practice of the invention. The objectives and other advantages of the invention may be realized and attained by the structure particularly pointed out in the written description and claims hereof as well as the appended drawings.
To achieve these objects and other advantages and in accordance with the purpose of the invention, as embodied and broadly described herein, there is provided a capacitor comprising: a first conductive line formed on a substrate; a first interlayer dielectric having a first via hole formed at an upper portion of the first conductive line, and a second and third via hole pair formed at one region of the substrate; a first barrier metal layer and a contact plug formed in the first via hole; a first capacitor electrode formed in the second via hole; and a second capacitor electrode formed in the third via hole, wherein the first and second capacitor electrodes and the first interlayer dielectric disposed between the first and second capacitor electrodes form a vertically constructed capacitor.
In another aspect of the present invention, there is provided a method for manufacturing a capacitor comprising: forming a first conductive line on a substrate; forming a first interlayer dielectric on the substrate including the first conductive line; forming a first via hole through the first interlayer dielectric at an upper portion of the first conductive line, and forming a second and third via hole pair being adjacent to each other through the first interlayer dielectric at a region of the substrate; forming a first barrier metal layer and a contact plug in the first via hole; and forming first and second capacitor electrodes in the second and third via holes, respectively.
It is to be understood that both the foregoing general description and the following detailed description of the present invention are exemplary and explanatory and are intended to provide further explanation of the invention as claimed.
BRIEF DESCRIPTION OF THE DRAWINGS
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this application, illustrate embodiment(s) of the invention and together with the description serve to explain the principle of the invention. In the drawings:
FIG. 1 is a view for showing a structure of a capacitor according to the related art;
FIG. 2 is a view showing a capacitor and a peripheral metal layer thereof according to an embodiment of the present invention;
FIG. 3 is a cross-sectional view for showing a structure of a capacitor according to an embodiment of the present invention; and
FIGS. 4 through 8 are cross-sectional views for illustrating a method for manufacturing the capacitor according to an embodiment of the present invention.
DETAILED DESCRIPTION OF THE INVENTION
Reference will now be made in detail to the preferred embodiments of the present invention, examples of which are illustrated in the accompanying drawings. Wherever possible, the same reference numbers will be used throughout the drawings to refer to the same or like parts.
Hereinafter, a method for manufacturing a semiconductor device according to an embodiment of the present invention will be described with reference to the accompanying drawings.
In the description of an embodiment of the present invention, when something is formed “on” each layer, the “on” includes the concepts of “directly and indirectly”.
FIG. 2 is a view showing a capacitor and a peripheral metal layer thereof according to an embodiment of the present invention. FIG. 3 is a cross-sectional view for showing a structure of a capacitor according to an embodiment of the present invention.
As shown in FIGS. 2 and 3 , a capacitor according to an embodiment of the present invention includes a plurality of first conductive lines 41 a , 41 b , 41 c , and 41 d and a first interlayer dielectric 42 . The plurality of first conductive lines 41 a , 41 b , 41 c , and 41 d can be formed on a semiconductor substrate 40 . The first interlayer dielectric 42 can be formed on the semiconductor substrate 40 including on the plurality of first conductive lines 41 a , 41 b , 41 c , and 41 d .
As shown in FIG. 5A , first via holes 43 a can be formed through the first interlayer dielectric 42 at the first conductive lines 41 a , 41 b , 41 c , and 41 d . Second and third via holes 43 b and 43 c , and fourth and fifth via holes 43 d and 43 e can be formed through the first interlayer dielectric 42 at one region of a semiconductor substrate 40 in pairs of two adjacent via holes.
As shown in FIG. 5B , a conductive ion can be implanted in the semiconductor substrate 40 below the second and third via holes 43 b and 43 c , and fourth and fifth via holes 43 d and 43 e .
Although two pairs of via holes are descried in this embodiment, the present invention is not limited thereto. That is, more pairs of via holes can be formed.
Referring again to FIGS. 2 and 3 , a first barrier metal layer 44 a and a contact plug 45 a can be formed in the first via holes 43 a , which are formed on the first conductive lines 41 a , 41 b , 41 c , and 41 d . First and second capacitor electrodes 46 a and 46 b can be formed in the second and third via holes 43 b and 43 c , and are made of the barrier metal layer and the contact plug formation material. Third and fourth capacitor electrodes 46 c and 46 d are also formed in the fourth and fifth via holes 43 d and 43 e , and are made of the barrier metal layer and the contact plug formation material.
First and second dielectric layers 42 a and 42 b remain between the first and second capacitor electrodes 46 a and 46 b , and between the third and fourth capacitor electrodes 46 c and 46 d .
That is, a Metal-Insulator-Metal (MIM) type first capacitor 50 a of a vertical construction is composed of the first and second capacitor electrodes 46 a and 46 b and the first capacitor dielectric layer 42 a disposed between the first and second capacitor electrodes 46 a and 46 b . In addition, a MIM type second capacitor 50 b of a vertical construction is composed of the third and fourth capacitor electrodes 46 c and 46 d and the second capacitor dielectric layer 42 b disposed between the third and fourth capacitor electrodes 46 c and 46 d .
A second conductive line 51 a can be connected to the first barrier metal layer 44 a and the contact plug 45 a , which are formed in the first via holes 43 a . Conductive pads 51 b , 51 c , 51 d , and 51 e can be formed at upper portions of the first and second capacitor electrodes 46 a and 46 b , and the third and fourth capacitor electrodes 46 c and 46 d , respectively.
As describe above, the first and second capacitor electrodes can be formed in pairs of via holes. One vertical capacitor is composed of the first and second capacitor electrode and a first interlayer dielectric remaining between the first and second capacitor electrodes.
The following is a description of a method for manufacturing a capacitor according to an embodiment of the present invention having a construction illustrated above.
FIGS. 4 through 8 are cross-sectional views for describing a method for manufacturing a capacitor according to an embodiment of the present invention.
Referring to FIG. 4 , a first conductive layer can be deposited on a semiconductor substrate 40 . Then, a first photoresist layer (not shown) can be coated on the first conductive layer, and selectively patterned.
Next, the first conductive layer can be etched using the patterned first photoresist layer as a mask to form first conductive lines 41 a , 41 b , 41 c , and 41 d .
Then, referring to FIG. 5A . a first interlayer dielectric 42 can be deposited on the semiconductor substrate 40 including the first conductive lines 41 a , 41 b . 41 c , and 41 d . A second photoresist layer can be coated on the substrate and patterned to expose the first conductive lines 41 a , 41 b , 41 c , and 41 d and a region of the semiconductor substrate 40 . First via holes 43 a to contact the first conductive lines 41 a , 41 b , 41 c , and 41 d , and a pair of second and third via holes 43 b and 43 c and a pair of fourth and fifth via holes 43 d and 43 e to contact a region of the semiconductor substrate 40 that can be formed using the patterned second photoresist layer as a mask.
As shown in FIG. 5B , a conductive ion can be implanted in the semiconductor substrate 40 disposed at lower portions of the second and third via holes 43 b and 43 e , and fourth and fifth via holes 43 d and 43 e .
Although only two pairs of via holes have been described, the present invention is not limited thereto. That is, more via holes can be formed.
Referring to FIG. 6 , a first barrier metal layer 44 and a second conductive layer 45 can be formed on the first interlayer dielectric 42 including the first to fifth via holes 43 a , 43 b , 43 c , 43 d , and 43 d . Here, the second conductive layer 45 can form a plug. In a specific embodiment, the second conductive layer can be formed of tungsten.
Then, as shown in FIG. 7 , the first barrier metal layer 44 and the second conductive layer 45 can be planarized by a chemical mechanical polishing process to expose the first interlayer dielectric 42 .
Accordingly, a first barrier metal layer 44 a and a contact plug 45 a are formed in the first via holes 43 a at upper portions of the first conductive lines 41 a , 41 b , 41 c , and 41 d . First and second capacitor electrodes 46 a and 46 b are formed in the second and third via holes 43 b and 43 c , respectively, and are composed of the barrier metal layer and a contact plug formed of the second conductive layer. In the same manner, third and fourth capacitor electrodes 46 c and 46 d are formed in the fourth and fifth via holes 43 d and 43 e , respectively, and are composed of the barrier metal layer and a contact plug formed of the second conductive layer.
Moreover, the first dielectric layer 42 between each via hole pair functions as first and second capacitor dielectric layers 42 a and 42 b between the first and second capacitor electrodes 46 a and 46 b , and between the third and fourth capacitor electrodes 46 c and 46 d , respectively.
That is, a MIM type first capacitor 50 a of a vertical construction can be composed of the first and second capacitor electrodes 46 a and 46 b , and the first capacitor dielectric layer 42 a formed therebetween. Further, a MIM type second capacitor 50 b of a vertical construction can be composed of the third and fourth capacitor electrodes 46 c and 46 d and the second capacitor dielectric layer 42 b formed therebetween.
Next, referring to FIG. 8 , a third conductive layer can be deposited on the first interlayer dielectric 42 , and a third photoresist layer can be coated and patterned thereon. Then, the third conductive layer can be selectively etched using the patterned third photoresist layer as a mask to form a second conductive line 5 l a on the first barrier metal layer 44 a and the contact plug 45 a formed in the first via holes 43 a and conductive pads 51 b , 51 c , 51 d , and 51 e at upper portions of each of the first and second capacitor electrodes 46 a and 46 b , and third and fourth capacitor electrodes 46 c and 46 d .
Through the aforementioned process, first and second capacitor electrodes are formed in a pair of via holes. The first and second capacitor electrodes can form one vertical capacitor with an interlayer dielectric between the first and second capacitor electrodes.
As is clear from the forgoing description, in the capacitor and the method for manufacturing the same according to embodiments of the present invention, the present invention can provide a capacitor of a vertical construction during a formation of a via hole and a formation of a barrier metal layer and a contact hole in the via hole without an additional mask
It should be understood that the examples and embodiments described herein are for illustrative purposes only and that various modifications or changes in light thereof will be suggested to persons skilled in the art and are to be included within the spirit and purview of this application.
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A capacitor capable of being formed in a vertical plane without an additional mask process and/or deposition process and a method of manufacturing the same are provided. The capacitor includes: a first conductive line formed on a substrate; a first interlayer dielectric including a first via hole formed at an upper portion of the first conductive line, and a second and third via hole pair formed at a region of the substrate; a first barrier metal layer and a contact plug formed in the first via hole; and first and second capacitor electrodes formed in the second and third via holes, respectively. The first and second capacitor electrodes and the first interlayer dielectric disposed between the first and second capacitor electrodes form a vertically constructed capacitor.
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TECHNICAL FIELD
[0001] This disclosure relates to wireless communication systems. In particular, this disclosure relates to determining when to wake up a processor in a mobile station.
BACKGROUND
[0002] Continual development and rapid improvement in wireless communications systems have placed increased demands on manufactures of mobile stations (e.g. pagers, cell phones, smartphones, and other wireless devices) to operate with improved performance, in part to reduce power consumption and extend battery life. One way to save power is to place the mobile station's application processor into a “sleep mode” (i.e., power-saving mode), which reduces battery consumption while the processor is in sleep mode. For example, when a user stops interacting with a mobile station, the mobile station can take advantage of the inactivity by placing the processors that ordinarily handle the user interactions into a power-saving sleep mode.
[0003] Wireless devices depend on wireless signals for communication, and the mobile station monitors the status of these wireless signals, for example by determining a Received Signal Strength Indicator (RSSI). When the mobile station is on the threshold of coverage (e.g., when a low signal level is received at the mobile station), the processors may be kept “awake” as the mobile station toggles between an “in-service” condition and a “not-in-service” condition. Toggling between conditions may occur because each time the mobile station detects signal coverage, it reports an in-service condition to a processor.
[0004] Reporting an in-service condition to the processor may wake-up the processor so that it may perform tasks such as background data transmission. However, because the mobile station is on the threshold of coverage, the mobile station may not be able to reliably transmit background data over the wireless link. Even though the mobile station cannot reliably perform background data transmission, the processor is nonetheless kept awake while the mobile station toggles between an in-service condition and a not-in-service condition. Thus, while the mobile station toggles between the in-service condition and the not-in-service condition, the mobile station is not able to take advantage of the processor's power-saving sleep mode.
BRIEF DESCRIPTION OF THE DRAWINGS
[0005] The system may be better understood with reference to the following drawings and description. In the figures, like reference numerals designate corresponding parts throughout the different views.
[0006] FIG. 1 shows a block diagram of an exemplary mobile station that may perform wake-up suppression.
[0007] FIG. 2 shows an exemplary flow diagram of the processing that wake-up suppression logic may implement.
[0008] FIG. 4 is another example of the logic that wake-up suppression logic may implement.
[0009] FIG. 3 shows an example of the various thresholds that the wake-up suppression logic may implement.
[0010] FIG. 5 shows exemplary measurements of the received signal strength indicator (RSSI) over time, leading to reporting of an in-service condition.
[0011] FIG. 6 shows exemplary measurements of RSSI over time, leading to a delayed-reporting timer elapsing and reporting an in-service condition.
DETAILED DESCRIPTION
[0012] FIG. 1 shows an example of a mobile station 100 . The mobile station can be a wireless communications device, such as a pager, cell phone, smartphone, notebook, tablet computer, or other wireless capable of wireless communications. In one implementation, the mobile station 100 includes processor 108 , a transceiver 102 , a user interface 120 , and memory 110 . The processor 108 may control the operation of the mobile station 100 by responding to user inputs from the user interface 120 , operating the transceiver 102 , reading or writing information to or from the memory 110 , transmitting data, receiving data, and/or processing data related to performing such tasks. In some implementations, the processor 108 may be a single processor, while in other implementations, the processor 108 may be multiple processors that are physically separate and/or logically separate. For example, the processor 108 may include an application processor 104 and a modem processor 106 . The application processor 104 may, as examples, perform processing related to the user interface, user applications, and/or data networking functions. The modem processor 106 may, as examples, perform processing related to controlling the transceiver 102 and determining the received signal strength. The division of processing tasks between the processor 108 and application processor 104 need not be rigid, and either processor may be configured to perform any particular functionality depending on the implementation.
[0013] Still referring to FIG. 1 , the transceiver 102 can wirelessly transmit and receive voice and data using a wireless communication protocol or standard, such as GSM, CDMA, IEEE 802.11, WIMAX, WCDMA, UMTS, or other protocol or standard. As noted above, the processor 108 can communicate with the transceiver 102 to wirelessly send and receive data. The transceiver 102 may also obtain or determine the received signal strength of a signal received from the wireless communication network and report the received signal strength to the processor 108 . The processor 108 can use the memory 110 to store the value of the received signal strength as a parameter or variable in memory as indicated by the received signal strength indicator 116 . In addition, processor 108 can use the memory 110 to store wake-up suppression logic 112 , wake-up suppression parameters 114 , and an out-of-service indicator 118 .
[0014] The application processor 104 and/or modem processor 106 may operate in a power-saving mode (or “sleep mode”). In the sleep mode, either processor may perform few functions, perform them more slowly, power down certain section of the processor, or otherwise operate in a reduced functionality mode. The reduced functionality mode may use less power and extend the battery life of mobile station 100 . For example, the application processor 104 may enter sleep mode based on a determination that sleep mode is appropriate because a user has stopped interacting with the user interface 120 , because no background data processing is scheduled, and/or because data networking functions are no longer possible or desired. Once the user beings interacting with the user interface 120 , background data processing is scheduled, or data networking functions are possible or desired, the application processor 104 may exit sleep mode and “wake up.” In some implementations, certain information received by the application processor 104 may cause it to wake up. When the application processor 104 receives an in-service condition indicating that a wireless link is available for background data transmission, the application processor 104 may wake up in order to send or receive background data over the wireless link. As explained further below, it may be advantageous to delay sending the in-service condition to the application processor so that the application processor 104 can remain asleep until a sufficiently reliable signal is received by the transceiver 102 .
[0015] The wireless link may be used to wirelessly transmit and/or receive voice or data at the mobile station 100 . An in-service condition may indicate that a wireless link for data transmission may be available between the transceiver 102 and a base station. An out-of-service condition may indicate that a wireless link may not be available between the transceiver 102 and a base station, the mobile station 100 is not registered with a network, and/or the wireless link is unreliable for transmitting data over the wireless link. The processor 108 may determine the out-of-service condition based on parameters such as data transmission error rate, the status of the physical layer resources of the wireless link, and/or the received signal strength. The out-of-service condition may be stored as an out-of-service indicator 118 in memory 110 .
[0016] The mobile station 100 may register with a network. Registering with a network allows assignment of physical layer resources of the wireless link to be used for voice and/or data traffic. After the mobile station 100 registers with the network, the mobile station 100 can monitor the assigned physical layer resources to determine if data can be transmitted. If the mobile station 100 successfully registers with the network and background data can be transmitted, the modem processor 106 may report an in-service condition. The in-service condition can be determined based on the received signal strength at the transceiver 102 .
[0017] The modem processor 106 may store the received signal strength in memory 110 as the received signal strength indicator (RSSI) 116 . The modem processor 106 may update the RSSI 116 according to a predetermined schedule. For example, the modem processor 106 may update the RSSI 116 every second, every ten seconds, every three minutes, or any other predetermined rate. If the RSSI 116 is above the in-service condition threshold and the mobile station 100 is registered with the network, then the modem processor 106 can report an in-service condition to the application processor 104 . If the RSSI 116 is below the in-service condition threshold or the mobile station 100 is not registered with the network, the modem processor may not report an in-service condition to the application processor 104 . In some situations, the RSSI 116 may fluctuate between levels that would ordinarily cause toggling between reporting an in-service condition and a not-in-service condition. Each time the modem processor 106 reports an in-service condition to the application processor 104 , the application processor 106 may wake up so that the application processor 104 may transmit background data over the wireless link. However, if the RSSI 116 is fluctuating between in-service and not-in-service levels, the application processor 104 would ordinarily remain awake each time it receives a service message indicating in-service condition. Receiving rapidly changing service messages may preclude the application processor 106 from obtaining the benefits of sleep mode, even though the application processor 106 is effectively unable to transmit background data.
[0018] In other implementations, the modem processor 106 may employ other logic and other thresholds for determining whether to report an in-service condition to the application processor 104 . The modem processor 106 can use wake-up suppression logic (WSL) 112 along with WSL parameters 114 for determining whether to report an in-service condition to the application processor 104 after the mobile station 100 successfully registers with the network. If the WSL 112 determines that an in-service condition has been met and the mobile station 100 is successfully registered with a network, the processor 106 may report an in-service condition to the application processor 104 . If the WSL 112 determines that an in-service condition has not been met or that the mobile station 100 is not successfully registered with a network, the processor 106 may not report an in-service condition to the application processor 104 .
[0019] The WSL 112 can provide certain benefits, particularly when the mobile station 100 is in a low-signal coverage area that causes toggling between a not-in-service condition and an in-service condition or while the mobile station 100 is near the edge of a coverage area. In cases where the mobile station 100 toggles between a not-in-service condition and an in-service condition, the modem processor 106 may employ the WSL 112 in order to delay reporting of an in-service condition to the application processor 104 . The WSL 112 can employ multiple thresholds in order to determine whether to report an in-service condition to the application processor 104 . Referring to FIG. 4 , its shows multiple thresholds that the WSL 112 can utilize: a timer-starting threshold 402 , a delayed-reporting threshold 404 , and a timer-reset threshold 406 . Each of these thresholds are described in detail below, with reference to various implementations as illustrated in FIG. 2 and FIG. 3 . Each of these thresholds may be stored as one of the WSL parameters 114 in the memory 110 . The modem processor 106 may set the WSL parameters 114 to certain values that are desirable for level of signal for which the wake-up suppression is active. For example, the timer-starting threshold may be set to an RSSI value of −92 dBm, the delayed-reporting threshold may be set to an RSSI value of −96 dBm, and the timer-reset threshold may be set to an RSSI value of −100 dBm.
[0020] Referring to FIG. 2 and block diagram 200 , in one implementation, the WSL 112 can start in at ( 202 ) where the WSL 112 monitors the RSSI 116 . At ( 204 ), if the WSL 112 determines that the RSSI 116 is greater than the timer-starting threshold 402 ( FIG. 4 ), the WSL 112 , through the modem processor 106 , reports an in-service condition to the application processor 104 . On the other hand, if the WSL 112 determines that the RSSI 116 is less than a timer-starting threshold 402 , the WSL 112 continues to ( 206 ) and determines whether the delayed-reporting timer has already been started. If the delayed-reporting timer has not been started, the WSL 112 starts a delayed-reporting timer ( 208 ). If the delayed-reporting timer has already been started, the WSL 112 increments the delayed-reporting timer ( 210 ). Continuing to ( 212 ), if the delayed-reporting timer has elapsed, the WSL 112 , through the modem processor 106 , reports an in-service condition to the application processor 104 . If the delayed-reporting timer has not elapsed, the WSL 112 , through the modem processor 106 , determines whether to continue the process again at ( 214 ). The delayed-reporting timer may be based on elapsed time, number of measurements, or both. The modem processor 106 may set the delayed-reporting timer to a certain value that is desirable for the wake-up suppression duration. For example, in one implementation, the delayed-reporting timer may elapse after three minutes. In another implementation, the delayed-reporting timer may elapse after ten consecutive RSSI measurements above the delayed-reporting threshold.
[0021] FIG. 6 helps illustrate the implementation of the WSL 112 described above. FIG. 6 is a plot of RSSI values on the y-axis as a function of time on the x-axis. Referring to the left-most portion of the graph, the RSSI values are below the timer-starting threshold 402 . As indicated, for example, by RSSI value 606 , the delayed-reporting timer is started because the RSSI values are below the timer starting threshold 402 . The WSL 112 will suppress reporting of an in-service condition to the application processor 104 until the delayed-reporting timer elapses. Once the delayed reporting timer elapses, as indicated at RSSI value 610 , the WSL 112 will report an in-service condition to the application processor 104 .
[0022] Referring now to FIG. 3 , flow diagram 300 is another implementation of the WSL 122 and includes some of the same logic as indicated in FIG. 2 , ( 202 )-( 216 ), which operate as described above. However, as indicated in flow diagram 300 , the WSL 112 may include logic in addition to those shown in FIG. 2 . For example, if the WSL 112 determines that a delayed-reporting timer has not elapsed ( 212 ), the WSL 112 determines at ( 320 ) whether the RSSI is above a delayed-reporting threshold 404 . If the RSSI is above the delayed-reporting threshold 404 for ten consecutive values, the WSL 112 , through the modem processor 106 , reports at ( 216 ) an in-service condition to the application processor 104 , even though the delayed-reporting timer may not have elapsed. If the RSSI is below the delayed-reporting threshold 404 , the WSL 112 determines at ( 322 ) whether the RSSI is less than a timer-reset threshold 406 . If the RSSI is less than the timer-reset threshold 406 for five consecutive values, then the WSL 112 resets the delayed-reporting timer ( 324 ) and determines whether to continue the processes again at ( 214 ). Otherwise, the WSL 112 does not reset the delayed-reporting timer and then WSL 112 determines whether to continue the process again at ( 214 ).
[0023] FIG. 4 helps illustrate the implementation of the WSL 112 described above. FIG. 3 shows waiting region 410 , delayed-reporting region 420 , and delayed-reset region 430 . The waiting region 410 is defined by the area below the timer-starting threshold 402 . The delayed-reporting region 420 is defined by the area above the delayed-reporting threshold 404 . The delayed-reset region is defined by the area below the timer-reset threshold 406 . The y-axis of FIG. 3 represents RSSI values. When RSSI values are within waiting region 410 , the WSL 112 will suppress the in-service condition until the delayed-reporting timer elapses or another event occurs that causes the WSL 112 to report an in-service condition. As one example of an event that may cause the WSL 112 to report an in-service condition, the WSL 112 may report an in-service condition if ten consecutive measurements be within the delayed-reporting region 420 . Further, the delayed-reporting timer may be reset by certain events. For example, if five consecutive RSSI values are within the delayed-reset region 430 , the WSL 112 may reset the delayed-reporting timer.
[0024] FIG. 5 also helps illustrate the implementation of the WSL 112 described above. FIG. 5 is a plot of RSSI values on the y-axis as a function of time on the x-axis. Starting at the left-most portion of the graph and continuing towards to right, RSSI values are measured over time. At RSSI value 504 , the RSSI has fallen below the timer-starting threshold 402 . Because RSSI value 504 is below the timer-starting threshold 402 , the WSL 112 starts or increments the delayed-reporting timer. (Referring to FIG. 2 , this is the transition from 206 to 208 or 210 .) Accordingly, the WSL 112 may suppress reporting an in-service condition until the delayed reporting timer elapses. Continuing further along the plot of RSSI values in FIG. 5 , RSSI value 506 is below the timer-reset threshold 406 . Because five consecutive RSSI values were below the timer-reset threshold 406 , the WSL 112 resets the delayed-reporting timer (Referring to FIG. 3 , this is the transition from 322 to 324 ). Continuing further along the plot of RSSI values in FIG. 5 , the WSL 112 increments the delayed-reporting timer while the RSSI values remain below the timer-starting threshold 402 . However, because the delayed-reporting timer has not elapsed between RSSI value 508 and RSSI value 510 , the WSL 112 does not report an in-service condition. Instead, once ten consecutive RSSI values are above the delayed-reporting threshold 404 , the WSL 112 reports an in-service condition, as is shown at RSSI value 510 .
[0025] FIG. 6 also helps illustrate the implementation of the WSL 112 described above. FIG. 6 is a plot of RSSI values on the y-axis as a function of time on the x-axis. Starting at RSSI value 606 and continuing to the right along the plot of RSSI values, the WSL 112 increments the delayed-reporting timer while the RSSI values remain below the timer-starting threshold 402 . At RSSI value 610 , however, the delayed-reporting timer elapses and the WSL 112 reports an in-service condition. This is in contrast to FIG. 5 , where ten consecutive RSSI values were above the delayed-reporting threshold 404 . Referring again to FIG. 6 , ten consecutive RSSI values are not above the delayed-reporting threshold 404 . Thus, the WSL 112 does not report an in-service condition until the delayed-reporting timer elapses at RSSI value 610 .
[0026] Certain events may cause the modem processor 106 to report immediately the service condition to the application processor 104 , regardless of the operational state of the WSL 112 . When certain events occur, it may no longer be beneficial or desirable for the WSL 112 to suppress reporting of the in service condition. For example, the processor 108 may stop executing the WSL 112 if the out-of-service indicator 118 indicates that a wireless link for data transmission is not available, the mobile station 100 is not registered with a network, and/or the wireless link is unreliable for transmitting data. The processor 108 may resume the WSL 112 once the out-of-service indicator 118 indicates that a wireless link for data transmission may be available, the mobile station is registered with the network, and/or the wireless link is more reliable for transmitting data. As another example, if the application processor 106 is no longer in sleep mode, the modem processor 106 may stop executing the WSL 112 and/or stop suppressing reporting of the in-service condition to the application processor 104 . As described above, the user may interact with the user interface 120 , which may cause the application processor 104 to exit sleep mode. Additionally, the modem processor 106 may determine that a paging indication (e.g., a voice call, SMS, or data packet is designated for the mobile station 100 ) was received by the transceiver 102 from the base station. In order to respond the paging indication, the modem processor 106 may wake up the application processor.
[0027] Using the WSL 112 , the application processor 106 is able to remain in sleep mode for a longer period of time, especially in cases where background data transmission may not be reliable and the application processor 106 may be prematurely awoken while the modem processor 104 toggles between an in-service condition and a not-in-service condition. Because the WSL 112 can suppress reporting of the in-service condition, the application processor 106 remains in sleep mode for a longer period of time, the mobile station 100 can reduce power consumption and extend battery life, even when the mobile station 100 in an area with unreliable coverage.
[0028] The methods, devices, and logic described above may be implemented in many different ways in many different combinations of hardware, software or both hardware and software. For example, all or parts of the system may include circuitry in a controller, a microprocessor, or an application specific integrated circuit (ASIC), or may be implemented with discrete logic or components, or a combination of other types of analog or digital circuitry, combined on a single integrated circuit or distributed among multiple integrated circuits. All or part of the logic described above may be implemented as instructions for execution by a processor, controller, or other processing device and may be stored in a tangible or non-transitory machine-readable or computer-readable medium such as flash memory, random access memory (RAM) or read only memory (ROM), erasable programmable read only memory (EPROM) or other machine-readable medium such as a compact disc read only memory (CDROM), or magnetic or optical disk. Thus, a product, such as a computer program product, may include a storage medium and computer readable instructions stored on the medium, which when executed in an mobile station, computer system, or other device, cause the device to perform operations according to any of the description above.
[0029] The processing capability of the system may be distributed among multiple system components, such as among multiple processors and memories, optionally including multiple distributed processing systems. As examples, the application processor and the modem processor may be physically separate processors in different packages, may be distinct processors on the same die or in the same package, or may be implemented as a single processor that executes instructions to perform the processing described above for the modem processor and the application processor. Parameters, databases, and other data structures may be separately stored and managed, may be incorporated into a single memory or database, may be logically and physically organized in many different ways, and may implemented in many ways, including data structures such as linked lists, hash tables, or implicit storage mechanisms. Programs may be parts (e.g., subroutines) of a single program, separate programs, distributed across several memories and processors, or implemented in many different ways, such as in a library, such as a shared library (e.g., a dynamic link library (DLL)). The DLL, for example, may store code that performs any of the system processing described above. While various embodiments of the invention have been described, it will be apparent to those of ordinary skill in the art that many more embodiments and implementations are possible within the scope of the invention. Accordingly, the invention is not to be restricted except in light of the attached claims and their equivalents.
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A method and device that intelligently suppresses reporting of an “in-service” condition to the application processor in a mobile station when the mobile station experiences low received signal strength. When the mobile station's application processor is in a power-saving mode, an in-service condition is not reported to the application processor until certain conditions are met. Delayed reporting of the in-service condition will help prevent a toggling effect (or “ping-pong”) of reporting an in-service condition immediately followed by a not-in-service condition. Because the application processor can remain asleep until a sufficiently reliable received signal is available, suppressing reporting of the in-service condition helps prevent unnecessarily waking-up the application processor, and thereby reduces battery consumption.
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FIELD OF INVENTION
The present invention relates to specific compositions made by alkoxylation of crude guerbet alcohol mixtures that contain between 15% and 50% lower molecular weight alkoxylated alcohols. The lower molecular weight alcohols are the raw material alcohols used to make the guerbet. Compositions containing this specific bi-modal distribution have unique emulsification properties.
BACKGROUND OF THE INVENTION
Guerbet alcohols have been known for over 100 years now. Marcel Guerbet pioneered the basic chemistry in the 1890s. It has allowed for the synthesis of a regiospecific beta branched hydrophobe which introduces high purity, branching into the molecule. Guerbet Alcohols, the oldest and best-understood material in the class of compounds, have been known since the 1890's when Marcel Guerbet 1 first synthesized these materials. The reaction sequence, which bears his name, is related to the Aldol Reaction and occurs at high temperatures under catalytic conditions.
The product is an alcohol with twice the molecular weight of the reactant alcohol minus a mole of water. The reaction proceeds by a number of sequential steps. These steps are (a) oxidation of alcohol to aldehyde, (b) Aldol condensation after proton extraction, (c) dehydration of the Aldol product, and (d) hydrogenation of the allylic aldehyde. The reaction takes place without catalyst, but it is strongly catalyzed by addition of hydrogen transfer catalysts. At low temperatures 130-140° C. the rate-limiting step is the oxidation process (i.e. formation of the aldehyde). At somewhat higher temperatures 160-180° C. the rate-limiting step is the Aldol Condensation. At even higher temperatures other degradative reactions occur and can become dominant.
Many catalysts have been described in the literature as effective for the preparation of Guerbet Alcohols. These include, nickel, lead salts (U.S. Pat. No. 3,119,880), Oxides of copper, lead, zinc, chromium, molybdenum, tungsten, and manganese (U.S. Pat. No. 3,558,716). Later US patents (U.S. Pat. No. 3,979,466) include palladium compounds and silver compounds (U.S. Pat. No. 3,864,407). There are advantages and disadvantages for each type.
The Cannizzaro Reaction is a major side reaction and is described as the disproportionation of two molecules of an aldehyde brought about by the action of sodium or potassium hydroxide to yield the corresponding alcohol and acid. On a practical level, it results in a product that is both difficult to purify and has undesired products present. The ability to capitalize upon the Guerbet reaction and develop useful cost effective derivatives has resulted eluded scientists for many years.
A major problem with the currently used Guerbet products is the fact that they are sold as very high purity products, requiring elaborate clean up processes and post treatments to make products that find applications mostly in cosmetic products. Guerbet alcohols undergo a series of post reaction steps that (a) remove unreacted alcohol (vacuum stripping), (b) remove unsaturation (hydrogenation), (c) remove Cannizzaro soap (filtration) and (d) remove color/odor bodies. These operations add to the cost of the product and make the utility impractical. All inventions covering Guerbet alcohols and their derivatives were made using highly purified materials, which not only limited the usefulness due to costs, but also as will become apparent by this disclosure, resulted in mono-modal surfactants that lack the highly efficient emulsification properties that result when using lower purity products. By lower purity products is meant those products in which unreacted raw material alcohol is left in the mixture and subsequently co-alkoxylated to give bi-modal surfactants, having unique emulsification properties.
Most commonly alcohols of natural origin, which are straight chain, even-carbon, primary alcohols are used for the production of Guerbet alcohols. Guerbet alcohols are beta branched primary alcohols. Oxo alcohols can also be used, but the reaction rate and conversions are reduced.
We have surprisingly found that upon alkoxylation of a low purity guerbet alcohol, a bi-modal alkoxylate occurs having outstanding emulsification properties. These emulsifiers are outstanding when used with crude petroleum and other non-polar compounds.
The Invention
Objective of the Current Invention
It is an objective of the present invention to provide unique bi-modal alkoxylated emulsifiers. These bi-modal emulsifiers are made up of between 50 and 90% by weight of a guerbet alcohol alkoxylate and between 10% and 50% by weight non-guerbet starting alcohol alkoxylate.
It is another objective of the present invention to provide a process for making emulsions using the unique bi-modal alkoxylated emulsifiers of the present invention.
SUMMARY OF THE INVENTION
The current invention is aimed at a bi-modal alkoxylated emulsifier made by the alkoxylation of a partially reacted crude guerbet alcohol. We have surprisingly found that when the guerbet reaction is carried out to between 50% and 75% many important, heretofore unrecognized benefits occur. The first is that the Cannizzaro reaction is almost nil, second the formation of higher molecular weight species likewise is almost nil, thirdly the reaction time is significantly reduced, yields are increased and most importantly when the resulting composition is alkoxylated with ethylene oxide, propylene oxide and mixtures thereof, unique very efficient bi-modal emulsifiers result.
DETAILED DESCRIPTION OF THE INVENTION
The current invention relates to a bi-modal emulsifier composition, which comprises:
(a) between 10% and 50% by weight of an emulsifier which conforms to the following structure:
CH 3 (CH 2 ) n− O—(CH 2 CH 2 O) a (CH 2 CH(CH 3 )O) b —(CH 2 CH 2 O) c —H
wherein;
n is an integer ranging from 5 to 19;
a, b, and c are independently each integers ranging from 0 to 20, with the proviso that a+b+c be greater than 5;
and
(b) between 90% and 50% of an emulsifier which conforms to the following structure:
wherein;
y is an integer ranging from 5 to 19, and is equal to n;
x is an integer ranging from 3 to 17 with the proviso that x=y+2
a, b, and c are independently each integers ranging from 0 to 20, with the proviso that a+b+c be greater than 5.
Another aspect of the invention is drawn to a process for making an emulsion, which comprises mixing;
(1) between 1% and 50% by weight of a water insoluble oil,
(2) between 98% and 35% water
and
(3) between 1% and 15% by weight of bi-modal emulsifier compositions, which comprises:
(a) between 10% and 50% by weight of an emulsifier which conforms to the following structure:
CH 3 (CH 2 ) n− O—(CH 2 CH 2 O) a (CH 2 CH(CH 3 )O) b —(CH 2 CH 2 O) c —H
wherein;
n is an integer ranging from 5 to 19;
a, b, and c are independently each integers ranging from 0 to 20, with the proviso that a+b+c be greater than 5;
and
(b) between 90% and 50% of an emulsifier which conforms to the following structure:
wherein;
y is an integer ranging from 5 to 19, and is equal to n;
x is an integer ranging from 3 to 17 with the proviso that x=y+2
a, b, and c are independently each integers ranging from 0 to 20, with the proviso that a+b+c be greater than 5.
The various proviso listed above are a direct result of the fact that the alcohol undergoing the Aldol condensation is the exact same alcohol that makes up the non-guerbet portion of the composition. Clearly, the non-guerbet alcohol has a much lower molecular weight than the guerbet alcohol (half the molecular weight+18). When this bi-modal mixture is alkoxylated as a mixture, the result is an emulsifier pair with outstanding emulsification properties due in part to the bi-modal composition.
Preferred Embodiments
In a preferred embodiment n is 5, x is 3 and y is 5.
In a preferred embodiment n is 9, x is 7 and y is 9.
In a preferred embodiment n is 7, x is 5 and y is 7.
In a preferred embodiment n is 11, x is 9 and y is 11.
In a preferred embodiment n is 19, x is 17 and y is 19.
In a preferred embodiment a+c ranges from 10-40.
In a preferred embodiment b ranges from 1 to 20.
In a preferred embodiment a+c ranges from 10-40 and b ranges from 1 to 20.
EXAMPLES OF BI-MODAL GUERBET ALCOHOLS
Example #1-5
To 967 grams of decyl alcohol in a suitable reaction flask, add 30.0 grams of sodium hydroxide and 2.0 grams of nickel, under good agitation. Heat material to between 230 and 250° C. The water generated from the reaction will be removed. Reaction progress is followed by GLC analysis. Samples were taken at different points in the reaction as shown below:
Example
CH 3 (CH 2 ) 9 OH
1
50.0%
50.0%
2
60.2%
39.8%
3
74.6%
24.4%
4
85.0%
15.0%
5
90.0%
10.0%
Example #6-10
To 1000 grams of octyl alcohol in a suitable reaction flask, add 30.0 grams of potassium carbonate and 1.0 grams of nickel, under good agitation. Heat material to 220 to 240 C. The water generated from the reaction is distilled off. Reaction progress is followed by GLC analysis. Samples were taken at different points in the reaction as shown below:
Example
CH 3 (CH 2 ) 7 OH
6
50.0%
50.0%
7
60.0%
40.0%
8
75.0%
25.0%
9
85.0%
15.0%
10
90.0%
10.0%
Example #11-15
To 1000 grams of lauryl alcohol in a suitable reaction flask, add 30.0 grams of potassium carbonate and 1.0 grams of nickel, under good agitation. Heat material to 220 to 240° C. The water generated from the reaction will be distilled off. Reaction progress is followed by GLC analysis. Samples were taken at different points in the reaction as shown below:
Example
CH 3 (CH 2 ) 11 OH
11
50.0%
50.0%
12
60.0%
40.0%
13
75.0%
25.0%
14
85.0%
15.0%
15
90.0%
10.0%
Example #16-20
To 1000 grams of C-20 alcohol in a suitable reaction flask, add 30.0 grams of potassium carbonate and 1.0 grams of nickel, under good agitation. Heat material to 220 to 240° C. The water generated from the reaction is distilled off. Reaction progress is followed by GLC analysis. Samples were taken at different points in the reaction as shown below:
Example
CH 3 (CH 2 ) 19 OH
16
50.0%
50.0%
17
60.0%
40.0%
18
75.0%
25.0%
19
85.0%
15.0%
20
90.0%
10.0%
Example #21-25
To 1000 grams of hexyl alcohol in a suitable reaction flask, add 30.0 grams of potassium carbonate and 1.0 grams of nickel, under good agitation. Heat material to 220 to 240° C. The water generated from the reaction will be distilled off. Reaction progress is followed by GLC analysis. The product is a mixture of 2-butyl-octanol and hexyl alcohol. Samples were taken at different points in the reaction as shown below:
Example
CH 3 (CH 2 ) 5 OH
21
50.0%
50.0%
22
60.0%
40.0%
23
75.0%
25.0%
24
85.0%
15.0%
25
90.0%
10.0%
EXAMPLES OF BI-MODAL GUERBET ALKOXYLATES
To the specified amount of the specified bi-modal guerbet is added 0.2% KOH based upon the total number of grams added (including ethylene oxide, propylene oxide and bimodal guerbet). The reaction is Apply nitrogen sparge through dump valve and charge Begin heating and allow to mix 15-20 minutes. Apply full vacuum and strip for 30-40 minutes at 220-240 F. Break vacuum with ethylene oxide and react at 290-300 F. and 45 psig. After all of the first ethylene oxide has been added, add propylene oxide. After the propylene oxide has been added add the last portion of ethylene oxide has been added. Hold at 290-300 F. for 1 hour.
Bimodal
Alcohol
Ethylene
Propylene
Ethylene
Example
Example
Grams
Oxide (1)
Oxide
Oxide (2)
26
1
341
659
0
0
27
2
355
645
0
0
28
3
372
628
0
0
29
4
387
613
0
0
30
5
392
608
0
0
31
6
564
436
0
0
32
7
580
420
0
0
33
8
597
403
0
0
34
9
612
388
0
0
35
10
618
382
0
0
36
11
297
703
0
0
37
12
310
690
0
0
38
13
328
672
0
0
39
14
340
660
0
0
40
15
344
656
0
0
41
16
438
440
590
440
42
17
466
44
59
440
43
18
542
440
590
0
44
19
536
600
400
600
45
20
550
0
590
0
46
21
144
0
400
0
47
22
152
0
400
200
48
23
165
0
59
440
49
24
169
880
1180
880
50
25
176
880
0
880
APPLICATIONS EXAMPLES
The molecular weight of the alcohol for reaction purposes is calculated by 56110/Observed Hydroxyl Value=Calculated Molecular Weight
Example
Observed Hydroxyl Value
Calculated MW
1
246.0
228
2
231.6
242
3
215.1
261
4
202.6
277
5
197.5
284
6
301.6
186
7
284.5
197
8
262.2
214
9
247.2
227
10
243.1
231
11
207.3
270
12
195.6
287
13
179.5
312
14
170.6
329
15
166.4
337
16
128.0
438
17
120.1
466
18
389.6
542
19
368.2
536
20
102.0
550
21
389.6
144
22
368.2
152
23
340.0
165
24
331.6
169
25
315.6
177
HLB
HLB, the so-called Hydrophile—Lipophile Balance, is the ratio of oil soluble and water-soluble portions of a molecule. The system was originally developed for ethoxylated products. Listed in Table 1 are some approximations for the HLB value for surfactants as a function of their solubility in water. Values are assigned based upon that table to form a one-dimensional scale, ranging from 0 to 20.
The HLB system, in it's most basic form, allows for the calculation of HLB using the following formulation: HLB = % Hydrophile by weight of molecule 5
One can predict the approximate HLB needed to emulsify a given material and make more intelligent estimates of which surfactant or combinations of surfactants are appropriate to a given application. When blends are used the HLB can be estimated by using a weighted average of the surfactants used in the blend.
HLB Needed to Emulsify
Oil
HLB Needed
Cottonseed oil
6
Petrolatum
7
Chlorinated paraffin
8
Beeswax
9
Mineral spirits
10
Butyl Stearate
11
Lanolin
12
Orthodichlorobenzene
13
Nonylphenol
14
Benzene
15
Acid, Lauric
16
Acid, Oleic
17
By using the oil specified and making an emulsion of it, one can calculate the emulsifier's HLB. The knowledge of what HLB is required to emulsify a particular oil allows one to experimentally determine the HLB of an unknown surfactant. Using this information above, a comparison of the calculated and observed HLB can be achieved. The bimodal emulsifier was blended with an oil of known Required HLB. The oils, or oil blends, were chosen based on their required HLB as compared to our calculated HLB values for the compounds. Initially, three emulsions of different HLB's were prepared at the calculated HLB value, one unit above, and one unit below. If the emulsions did not perform well, more emulsions were prepared until the emulsion performed well. Their performances were based on how milky and stable they were, relative to the other emulsions prepared in the series for that particular compound. The tested concentrations of water: oil: surfactant were 56%: 40%: 4%, respectively. Some of the oils we used include limonene, mineral spirits, paraffin oil, isopropyl myristate, isostearic acid, and oleic acid. The method is believed to be accurate to +/−1 HLB unit.
We have observed that by using bimodal guerbet emulsifiers of the present invention, not only are the values of the HLB shifted to the lower range, but the emulsion made using these kinds of emulsifiers are far more stable than with non-bimodal surfactants.
Example
Calculated HLB
Observed HLB
1
13.2
11.3
2
12.9
10.6
3
12.6
9.5
4
12.2
8.9
5
12.1
7.9
6
8.7
7.0
7
8.4
6.6
8
8.1
5.0
9
7.8
4.5
10
7.6
4.0
11
14.0
8.3
12
13.8
7.6
13
13.4
6.6
14
13.2
5.9
15
13.0
5.6
While the illustrative embodiments of the invention have been described with particularity, it will be understood that various other modifications will be apparent to and can be readily made by those skilled in the art without departing from the spirit and scope of the invention. Accordingly, it is not intended that the scope of the claims appended hereto be limited to the examples and descriptions set forth hereinabove but rather that the claims be construed as encompassing all the features of patentable novelty which reside in the present invention, including all features which would be treated as equivalents thereof by those skilled in the art to which the invention pertains.
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The present invention relates to specific compositions made by alkoxylation of crude guerbet alcohol mixtures that contain between 15% and 50% lower molecular weight alkoxylated alcohols. The lower molecular weight alcohols are the raw material alcohols used to make the guerbet. Compositions containing this specific bi-modal distribution have unique emulsification properties.
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BACKGROUND OF THE INVENTION
Sealing and labeling of containers is a highly developed art. There are many instances where the sealing and labeling procedure is designed to prevent tampering of the container prior to the time of use. In the medical supply field as well as in the food packaging field it is often quite important that the integrity of the containers be maintained until the proper time. Of prime concern is the danger of damage and contamination of deterioration of the contents. By combining a labeling function with a tamper indicating function, two important aspects of packaging can be attained.
Two examples of the variety of different types of tamper-proof labels which are presently in use are depicted in U.S. Pat. No. 3,088,830 to Graham and U.S. Pat. No. 3,702,511 to Miller. From these patents it is quite apparent that tamper-proof labels are highly desirable. Accordingly, it is naturally advantageous to provide improvements in labels where the positive locking action of the label is assured and where it is virtually impossible to remove the label without damaging the container. Furthermore, the label should permit opening of the package and breaking of the label at the desired time in a quick, neat and efficient manner.
SUMMARY OF THE INVENTION
With the above background in mind, it is among the primary objectives of the present invention to provide a tamper-proof label for a container such as a plastic tube of separable components where the label can be heat sealed in place so as to be mechanically interlocked with the material of the container. The label is designed so that it cannot be removed without damaging the the container itself and when the container is opened the label will cleanly and neatly separate thereby controlling the area of rupture and providing a neat and sanitary appearance to the opened container. By being mechanically interlocked with the container, positive evidence of tampering is assured as well as maintenance of sterility status. The structure is more inexpensive and efficient to apply and utilize since it need only be applied to a portion of the circumference of a tubular member in use. Naturally, the mechanical interlock provides increased strength at the joint. The label is particularly useful in application on thermoplastic containers where the heat and pressure applied during the heat seal can cause the plastic to flow and engage in a mechanical interlock with the exposed surface of the label.
In summary, a tamper-proof label is provided which is adapted to be applied to joined surfaces of a member and heat sealed in place. A base sheet adapted to bear identifying indicia is provided with cuts in at least one location with the cuts being spaced so as to be located on each side of adjoining surfaces of a member to which the label is applied. The cuts permit material of the member of flow therethrough and over the exposed surface of the label when predetermined heat and pressure is applied after the label has been placed on a member thereby mechanically locking the label in position.
With the above objectives in mind, reference is had to the attached drawing.
BRIEF DESCRIPTION OF THE DRAWING
In the drawing:
FIG. 1 is a fragmentary side elevation view of a container with a label of the invention being applied thereto;
FIG. 2 is a fragmentary side elevation view of a container with a label of the invention mounted thereon; and
FIG. 3 is an enlarged fragmentary sectional view thereof taken along the plane of line 3--3 of FIG. 2.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
Label 20 is a rectangularly shaped member which is designed for application to a structure to be sealed such as a syringe cartridge as depicted in FIGS. 1-3. The syringe cartridge 22 is of a typical design having an upper half 24 and a lower half 26. The halves meet at a common joining point 28 so as to seal an item such as a syringe inside of container 22. Common materials for container 22 include thermoplastic material such as polyethylene and polypropylene.
Label 20 is designed to accommodate indicia thereon for labeling of the container and to cover the joint line 28 of the two container halves to seal the container and prevent opening of the container without initial removal or breaking of the label. Any tampering with container 22 prior to the time of use would be evidenced by damage to label 20 which engages the separation line 28 for the container halves.
Label 20 is constructed of a material such as paper which is adapted to have indicia applied to one side thereof for identification of the container contents and to receive a well known conventional type of pressure sensitive adhesive backing 30 on the other side for initial engagement with the container when the label is applied. Label 20 is depicted as rectangular in configuration and naturally it may assume other configurations as long as it is of sufficient size to extend both above and below the joint line 28 and be applied to both container half 24 and container half 26. It is not necessary that the label 20 extend around the entire circumference of the container. It may cover only a portion of the container surface as depicted in the drawings.
Label 20 is provided with a plurality of cuts such as die cuts or prescores 32 on its surface with the cuts 32 being divided into two groups. One group is positioned on the label so that when the label is applied to a container they will be on one side of joint line 28 and the other group positioned so that they will be on the other side of joint line 28 thereby providing cuts 32 in alignment with each container half 24 and container half 26. While the cuts may take any reasonable configuration it has been found acceptable to use diagonal cuts as depicted.
In use, container 22 is filled with the desired object such as a medical instrument and the two halves 24 and 26 are brought into engagement to form joint line 28. Label 20 with cuts 32 therein and adhesive 30 on one side thereof is then applied to the container with the adhesive 30 engaging with the surface of container 22 so as to initially hold label 20 in position. Label 20 is positioned so that a portion including one group of cuts 32 is in engagement with container half 24 and the remaining portion of label 20 with a second group of cuts 32 is in engagement with container half 26. In this manner, label 20 extends on both sides of joint line 28 as well as covering a portion of joint line 28.
An appropriate heat sealing mechanism is then employed on the label so that heat and pressure applied by the heat sealing mechanism causes the material of container 20, which is a material such as thermoplastic, to soften and flow. Partial containment by label 20 forces the softened plastic to flow into the slits or cuts 32 in label 20 and flow over the surface of the label so as to form a mechanical lock with the fibers and surface of the label. This condition is best depicted in FIG. 3 of the drawing where material 34 has passed through slit 32 and has extended onto the upper surface of label 20 so as to mechanically retain label 20 in position against container 22. Label 20 is thereby sealed to the container 22 and cannot be removed without tearing and this provides evidence of tampering. Should an attempt be made to open the container, it can only be accomplished by damage to label 20 in view of the mechanical interlock between the container and the label. In fact, any relative movement of the plastic parts of any substance would also show as a rupture of the label 20. It should be kept in mind that it is desirable to have cuts 32 of larger size than the area of the tool which is utilized in making the heat seal. The heat seal can be applied in the prescored area by use of a conventional heat sealing tool for application of heat and pressure. The heat sealed bond also adds strength to the joint because the label itself creates a resistance to removal. In fact, where a label of this type has been applied to a 1cc. syringe in a conventional container, the result has been an additional resistance to rupture of approximately 21/2 lbs. in tension for a paper label 3/8 in. wide. The paper employed for the label is of a conventional type and the pressure sensitive adhesive is also conventional well known product. It should also be kept in mind that the surface of the label to which the adhesive 30 is not applied should be of the type which is adapted to bear and display appropriate indicia.
In general, the label of the present invention provides positive evidence of tampering to thereby maintain sterility status for a common type of medical instrument such as a syringe being stored in a container. Furthermore, the label can be constructed of a conventional label stock with no additional structure other than the cuts being employed to utilize the label as a tamper-proof device. Furthermore, the present structure permits the label to be assembled to only a portion of the circumference of a structure such as a container thereby eliminating the necessity of a wrap-around design thereby reducing cost and simplifying application of the label. The strength of the joint is increased enhancing the possibility of bulk packaging of self-contained syringes without failure due to shield fall-off. The area of rupture when the container is opened is controlled resulting in a neat and sanitary appearance when the contents are to be utilized. Finally, heat sealing the label eliminates the necessity for special adhesives when plastic materials of unusual nature are employed. In this manner, the label is considerably more versatile in that a tailor-made adhesive is not required for each different type of plastic utilized for each different type of container.
Thus, the several aforenoted objects and advantages are most effectively attained. Although several somewhat preferred embodiments have been disclosed and described in detail herein, it should be understood that this invention is in no sense limited thereby and its scope is to be determined by that of the appended claims.
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A tamper-proof label adapted to be applied to joined surfaces of a member and heat sealed in place. A label includes a sheet adapted to bear identifying indicia with the sheet being cut in at least one location and the cuts being spaced so that they are located on each side of adjoining surfaces of the member to which the label is applied. The cuts permit material of the member to flow therethrough and over the exposed surface of the label when a predetermined amount of heat and pressure is applied so as to mechanically lock the label in position.
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CROSS-REFERENCE TO RELATED APPLICATION
[0001] This application claims priority to and is a non-provisional of Indian Provisional Application No. 3665/DEL/2013, filed on Dec. 16, 2013, which application is incorporated by reference herein in its entirety.
FIELD OF THE INVENTION
[0002] The present invention relates to N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamides as anticancer agents and process for the preparation thereof. The present invention particularly relates to N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamides of formula 1.
[0000]
R 1 =H, 4-F, 4-Cl, 4-Br, 4-OMe, 3-F, 2,4-diOMe, 2,5-diOMe, 3,5-diOMe, 3,4,5-triOMe, 4-ClBn
R 2 =3-OPh, 4-F, 4-Cl, 4-Br, 4-OMe, 3,5-diOMe
BACKGROUND OF THE INVENTION
[0005] Small molecules which affect the tubulin polymerization have attracted much attention in chemistry, biology, and particularly in medicine fields for the past few years. One of the recognized targets in cancer research is represented by microtubules (Tubulin as a Target for Anticancer Drugs: Agents which Interact with the Mitotic Spindle. Jordan, A.; Hadfield, J. A.; Lawrence, N. J.; McGown, A. T. Med. Res. Rev. 1998, 18, 259-296.). Microtubule-targeting agents (taxanes and vinca alkaloids) have played a crucial role in the treatment of diverse human cancers (Microtubules as a Target for Anticancer Drugs. Jordan, M. A.; Wilson, L. Nat. Rev. Cancer 2004, 4, 253-265). However, they have certain limitations in their clinical utility, such as drug resistance, high systemic toxicity, complex syntheses, and isolation procedure. Therefore, identification of new molecules with tubulin binding mechanism is attractive for the discovery and development of novel anticancer agents.
[0006] E7010, (Novel sulfonamides as potential, systemically active antitumor agents. Yoshino, H.; Ueda, N.; Niijima, J.; Sugumi, H.; Kotake, Y.; Koyanagi, N.; Yoshimatsu, K.; Asada, M.; Watanabe, T.; Nagasu, T. J. Med. Chem. 1992, 35, 2496-2497) a sulphonamide exhibits good antitumor activity by inhibiting tubulin polymerization, (In vivo tumor growth inhibition produced by a novel sulfonamide, E7010, against rodent and human tumors Koyanagi, N.; Nagasu, T.; Fujita, F.; Watanabe, T.; Tsukahara, K.; Funahashi, Y.; Fujita, M.; Taguchi, Yoshino, H.; Kitoh, K. Cancer Res. 1994, 54, 1702-1706.), which causes cell cycle arrest and apoptosis in M phase (Yokoi, A.; Kuromitsu, J.; Kawai, T.; Nagasu, T.; Sugi, N. H.; Yoshimatsu, K.; Yoshino, H.; Owa, T. Mol. Cancer. Ther. 2002, 1, 275-286; Mechanism of action of E7010, an orally active sulfonamide antitumor agent: inhibition of mitosis by binding to the colchicine site of tubulin. Yoshimatsu, K.; Yamaguchi, A.; Yoshino, H.; Koyanagi, N.; Kitoh, K. Cancer Res. 1997, 57, 3208-3213.).
[0000]
[0000] 1,2,3-triazole moieties have displayed a broad range of biological properties such as antifungal, anti-allergic, antibacterial, anti-HIV, anticonvulsant, anti-inflammatory and antitubercular activities. Particularly, these triazoles exhibited anticancer activity (Synthesis and anticancer activity of chalcone-pyrrolobenzodiazepine conjugates linked via 1,2,3-triazole ring side-armed with alkane spacers. Kamal, A.; Prabhakar, S.; Ramaiah, M. J.; Reddy, P. V.; Reddy, C. R.; Mallareddy, A.; Shankaraiah, N.; Reddy, T. L. N.; Pushpavalli, S. N. C. V. L.; Bhadra, M. P. Eur. J. Med. Chem. 2011, 46, 3820-3831; Stefely et al. have described a limited number of 1,3-oxazole triazoles which have a limited scope of determining the antitumor activity of these of these compounds. N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide as a new scaffold that provides rapid access to antimicrotubule agents: Synthesis and evaluation of antiproliferative activity against select cancer cell Lines. Stefely, J. A.; Palchaudhuri, R.; Miller, P. A.; Peterson, R. J.; Moraski, G. C.; Hergenrother, P. J.; Miller, M. J. J. Med. Chem. 2010, 53, 3389-3395). Accordingly, there is a need of more potent antitumor agents which is solved by the present invention.
OBJECTIVES OF THE INVENTION
[0007] The main objective of the present invention is to provide novel N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide analogues 1a-k to 6a-k useful as antitumor agents.
[0008] Yet another object of the present invention is to provide a process for the preparation of novel N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide derivatives.
SUMMARY OF THE INVENTION
[0009] The present invention provides a compound of formula 1,
[0000]
[0000] wherein R1 is optionally selected form the group comprising of hydrogen, halogen or ether and R2 is optionally selected from the group comprising of halogen or ether.
[0010] Also, the present invention provides a process for preparation of the compounds of formula 1.
DETAILED DESCRIPTION OF THE INVENTION
[0011] Accordingly, the present invention provides a compound of formula 1,
[0000]
[0000] wherein R1 is optionally selected from the group comprising of hydrogen, halogen or ether and R2 is optionally selected from the group comprising of halogen or ether.
[0012] In an embodiment of the present invention, halogen group of R1 is selected from the group consisting of chlorine, bromine or fluorine.
[0013] In another embodiment of the present invention, ether group of R1 is selected from the group consisting of methoxy, dimethoxy or trimethoxy ether.
[0014] In one embodiment of the present invention, halogen group of R2 is selected from the group consisting of chlorine, bromine or fluorine.
[0015] In another embodiment of the present invention, ether group of R2 is selected from the group consisting of methoxy, dimethoxy, trimethoxy, or phenoxy ether.
[0016] In yet another embodiment of the present invention wherein the representative compounds comprising:
N-((1-(3-Phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(phenylamino)nicotinamide (1a) 2-(4-Fluorophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol4-yl) methyl)nicotinamide (1b) 2-(4-Chlorophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (1c) 2-(4-Bromophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (1d) 2-(4-Methoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (1e) 2-(3-Fluorophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (1f) 2-(2,4-Dimethoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (1g) 2-(2,5-Dimethoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (1h) 2-(3,5-Dimethoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (1i) N-((1-(3-Phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,4,5-trimethoxyphenylamino) nicotinamide (1j) 2-(4-Chlorobenzylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (1k) N-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(phenylamino)nicotinamide (2a) N-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-fluorophenyl)amino) nicotinamide (2b) 2-((4-Chlorophenyl)amino)-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (2c) 2-((4-Bromophenyl)amino)-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (2d) N-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-methoxyphenyl)amino) nicotinamide (2e) N-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3-fluorophenyl)amino) nicotinamide (2f) 2-((2,4-Dimethoxyphenyl)amino)-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (2g) 2-((2,5-Dimethoxyphenyl)amino)-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (2h) 2-((3,5-Dimethoxyphenyl)amino)-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (2i) N-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3,4,5-trimethoxyphenyl)amino) nicotinamide (2j) 2-(4-Chlorobenzylamino)-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (2k) N-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(phenylamino)nicotinamide (3a) N-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-fluorophenyl)amino) nicotinamide (3b) N-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-chlorophenyl)amino) nicotinamide (3c) 2-((4-Bromophenyl)amino)-N-((1-(4-chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (3d) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-methoxyphenyl)amino) nicotinamide (3e) N-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3-fluorophenyl)amino) nicotinamide (3f) N-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((2,4-dimethoxyphenyl)amino) nicotinamide (3g) N-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((2,5-dimethoxyphenyl)amino) nicotinamide (3h) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3,5-dimethoxyphenyl)amino) nicotinamide (3i) N-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3,4,5-trimethoxyphenyl)amino) nicotinamide (3j) N-((1-(4-Chlorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-chlorobenzyl)amino) nicotinamide (3k) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(phenylamino)nicotinamide (4a) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-fluorophenyl)amino) nicotinamide (4b) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-chlorophenyl)amino) nicotinamide (4c) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-bromophenyl)amino) nicotinamide (4d) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-methoxyphenyl)amino) nicotinamide (4e) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3-fluorophenyl)amino) nicotinamide (4f) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((2,4-dimethoxyphenyl)amino) nicotinamide (4g) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((2,5-dimethoxyphenyl)amino) nicotinamide (4h) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3,5-dimethoxyphenyl)amino) nicotinamide (4i) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3,4,5-trimethoxyphenyl)amino) nicotinamide (4j) N-((1-(4-Bromobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-chlorobenzyl)amino) nicotinamide (4k) N-((1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(phenylamino)nicotinamide (5a) 2-((4-Fluorophenyl)amino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (5b) 2-((4-Chlorophenyl)amino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (5c) 2-((4-Bromophenyl)amino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (5d) N-((1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-methoxyphenyl)amino) nicotinamide (5e) 2-((3-Fluorophenyl)amino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (5f) 2-((2,4-Dimethoxyphenyl)amino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (5g) 2-((2,5-Dimethoxyphenyl)amino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (5h) 2-((3,5-Dimethoxyphenyl)amino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (5i) N-((1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3,4,5-trimethoxyphenyl)amino) nicotinamide (5j) N-((1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3,4,5-trimethoxyphenyl)amino) nicotinamide (5k) N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(phenylamino)nicotinamide (6a) N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-fluorophenyl)amino) nicotinamide (6b) 2-((4-Chlorophenyl)amino)-N-((1-(3,5-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (6c) 2-((4-Bromophenyl)amino)-N-((1-(3,5-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (6d) N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((4-methoxyphenyl)amino) nicotinamide (6e) N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3-fluorophenyl)amino) nicotinamide (6f) N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((2,4-dimethoxyphenyl)amino)nicotinamide (6g) N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((2,5-dimethoxyphenyl)amino) nicotinamide (6h) N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3,5-dimethoxyphenyl)amino) nicotinamide (6i) N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-((3,4,5-trimethoxyphenyl)amino) nicotinamide (6j) 2-((4-Chlorobenzyl)amino)-N-((1-(3,5-dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (6k).
[0083] In still another embodiment of the present invention, wherein the structural formula of the representative compounds comprising:
[0000]
[0084] In one more embodiment of the present invention, the compounds of formula 1 is useful as antitumour agents.
[0085] Accordingly, the present invention also provides a process for preparation of compounds of formula 1, wherein the process steps comprising:
[0000] i. reacting compound of formula 8 with compound of formula 9a-k in ethylene glycol at a temperature ranging between 130-140° C. for the a time period ranging between 5-6 hr to obtain substituted nicotinamide of formula 10 a-k,
[0000]
[0000] ii. reacting substituted nicotinamide of formula 10a-k as obtained in step (i) with substituted azides of formula 12a-k in a mixture of water and tert-butyl alcohol in the ratio of 2:1 followed by sequential addition of sodium ascorbate and copper sulphate at a temperature ranging between 25-30° C. for a time period ranging between 10-12 h to obtain compound of formula 1,
[0000]
[0086] In an embodiment of the present invention wherein the compound 9 used in step (i) is selected from the group consisting of aniline, 4-fluoroaniline, 4-bromoaniline, 4 methoxyaniline, 3-fluoroaniline, 2,4-dimethoxyaniline, 2,5-dimethoxyaniline, 3,5-dimethoxyaniline, 3,4,5-trimethoxyaniline and (4-chlorophenyl)methanamine.
[0087] In another embodiment of the present invention wherein the substituted nicotinamide of formula 10 a-k used in step (ii) is selected from the group consisting of 2-(phenylamino)-N-(prop-2-ynyl)nicotinamide, 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide, 2-(4-chlorophenylamino)-N-(prop-2-ynyl)nicotinamide, 2-(4-bromophenylamino)-N-(prop-2-ynyl)nicotinamide, 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide, 2-(3-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide, 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide, 2-(2,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide, 2-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide, N-(prop-2-ynyl)-2-(3,4,5-trimethoxyphenylamino)nicotinamide and 2-(4-chlorobenzylamino)-N-(prop-2-ynyl)nicotinamide.
[0088] In yet another embodiment of the present invention, wherein the substituted benzylazide of formula 12 a-k used in step (ii) is selected from the group consisting of 1-(azidomethyl)-3-phenoxybenzene, 1-(azidomethyl)-4-fluorobenzene, 1-(azidomethyl)-4-chlorobenzene, 1-(azidomethyl)-4-bromobenzene, 1-(azidomethyl)-4-methoxybenzene and 1-(azidomethyl)-3,5-dimethoxybenzene.
[0089] The precursor substituted anilines (9a-k) and substituted benzyl alcohols are commercially available and the N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl) arylamides of formulae 1a-k to 6a-k have been prepared as illustrated in the Scheme.
[0090] i) To the solution of 2-choronicotinic acid (5 g, 31.84 mmol) in dry DCM under nitrogen, Oxalyl chloride (38.21 mmol) and catalytic amount of N,N-dimethylformamide were added carefully with stirring. The reaction was stirred for 3 hr. The solution was concentrated under vacuum to yield 2-chloronicotinyl chloride as solid which was used for next reaction without purification.
[0091] Acid chloride (4.5 g, 25.56 mmol) was dissolved in dry DCM, cooled to 0° C., propargylamine hydrochloride (30.61 mmol) and triethylamine (76.68 mmol) were added. The reaction was warmed to room temperature. After stirring overnight, the reaction mixture was diluted with water and extracted with DCM. The organic layer was separated, washed with aq. NaHCO 3 and brine dried with Na 2 SO 4 and concentrated in vacuum to give 8.
[0092] ii) 2-Chloro-N-(prop-2-ynyl)nicotinamide (8, 1.03 mmol) was dissolved in ethylene glycol, and treated with an appropriate aniline (9, 1.03 mmol). The reaction mixture was heated to 120-130° C. for 6 h. After the reaction was completed, the reaction mixture was diluted with water and extracted with ethylacetate. The combined extracts were dried with Na 2 SO 4 and concentrated. the crude was purified by column chromatography to give pure product 10a-k as solid.
[0093] Procedure for triazole formation:
[0094] To a solution of corresponding aminonicotinamides (1 equivalent) and corresponding benzylazides (1 equivalent) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.1 equivalents) and copper (II) sulphate (0.05 equivalents) were added sequentially. The reaction was stirred at room temperature for 10-12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography by ethyl acetate/petroleum ether to afford pure product.
[0095] All the N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl) arylamide derivatives were synthesized and purified by column chromatography using different solvents like ethyl acetate, hexane.
[0096] These new analogues of N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamides have shown promising anticancer activity in various cancer cell lines.
[0000]
EXAMPLES
[0097] The following examples are given by way of illustration of the working of the invention in actual practice and therefore should not be construed to limit the scope of present invention.
[0098] Compounds 12a-k are prepared by using the synthesis described in J. Med. Chem. 2010, 53, 3389-3395.
Example 1
N-((1-(3-Phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(phenylamino)nicotinamide(1a)
[0099] Compound 8 (194 mg, 1 mmol) and aniline (9a, 93 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(phenylamino)-N-(prop-2-ynyl)nicotinamide 10a as pure product. To a solution of 2-(phenylamino)-N-(prop-2-ynyl)nicotinamide (10a, 150 mg, 0.59 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 147 mg, 0.65 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product as solid (210 mg, 74%); mp: 124-126° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.51 (s, 1H), 8.25 (dd, J=2.2, 1.5 Hz, 1H), 7.84 (dd, J=2.2, 1.5 Hz, 1H), 7.80 (brs, 1H), 7.66-7.60 (m, 3H), 7.33-7.25 (m, 4H), 7.08 (t, J=7.5 Hz, 1H), 7.00-6.90 (m, 7H), 6.61-6.59 (m, 1H), 5.45 (s, 2H), 4.62 ppm (d, J=5.2 Hz, 2H); MS (ESI m/z): 477 [M+H] + . Yield: 74%
Example 2
2-(4-Fluorophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol4-yl)methyl)nicotinamide (1b)
[0100] Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 138 mg, 0.61 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1b (220 mg 80%); mp: 160-162° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.36 (s, 1H), 8.25 (dd, J=3.0, 1.5 Hz, 1H), 7.59 (m, 2H), 7.54 (s, 1H), 7.35-7.28 (m, 3H), 7.22 (brs, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.03-6.94 (m, 7H), 6.67-6.63 (m, 1H), 5.45 (s, 2H), 4.64 ppm (d, J=6.0 Hz, 1H); MS (ESI m/z): 495 [M+H] + . Yield: 80%
Example 3
2-(4-Chlorophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (1c)
[0101] Compound 8 (194 mg, 1 mmol) and 4-chloroaniline (9c, 127 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-chlorophenylamino)-N-(prop-2-ynyl)nicotinamide 10c as pure product. To a solution of 2-(4-chlorophenylamino)-N-(prop-2-ynyl)nicotinamide (10c 150 mg, 0.52 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12c, 130 mg, 0.57 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1c (204 mg 76%); mp: 127-129° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.51 (s, 1H), 8.25 (dd, J=2.2, 1.5 Hz, 1H), 7.84 (dd, J=2.2, 1.5 Hz, 1H), 7.80 (brs, 1H), 7.61-7.58 (m, 3H), 7.35-7.23 (m, 4H), 7.08 (t, J=7.5 Hz, 1H), 6.98-6.91 (m, 7H), 6.67-6.63 (m, 1H), 5.45 (s, 2H), 4.62 (d, J=5.2 Hz, 2H); MS (ESI m/z): 511 [M+H] + . Yield: 76%
Example 4
2-(4-Bromophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (1d)
[0102] Compound 8 (194 mg, 1 mmol) and 4-bromoaniline (9d, 172 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-bromophenylamino)-N-(prop-2-ynyl)nicotinamide 10d as pure product. To a solution of 2-(4-bromophenylamino)-N-(prop-2-ynyl)nicotinamide (10d, 150 mg, 0.45 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 112 mg, 0.5 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1d (220 mg 80%); mp: 160-162° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.36 (s, 1H), 8.25 (dd, J=3.0, 1.5 Hz, 1H), 7.59 (m, 2H), 7.54 (s, 1H), 7.35-7.28 (m, 3H), 7.22 (brs, 1H), 7.11 (t, J=7.5 Hz, 1H), 7.03-6.94 (m, 7H), 6.67-6.63 (m, 1H), 5.45 (s, 2H), 4.64 ppm (d, J=6.0 Hz, 1H); MS (ESI m/z): 555 [M+H] + . Yield: 80%
Example 5
2-(4-Methoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (1e)
[0103] Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 132 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1f (202 mg, 75%); mp: 95-98° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.32 (s, 1H), 8.18 (dd, J=3.0, 1.5 Hz, 1H), 7.80 (dd, J=3.0, 1.5 Hz, 2H), 7.59 (s, 1H), 7.49 (d, J=8.3 Hz, 2H), 7.33-7.27 (m, 3H), 7.07 (t, J=7.5 Hz, 1H), 6.96-6.90 (m, 5H), 6.85-6.79 (m, 2H), 6.54-6.50 (m, 1H), 5.45 (s, 2H), 4.60 (d, J=5.2 Hz, 2H) 3.78 (s, 3H); MS (ESI m/z): 507 [M+H] + . Yield: 75%
Example 6
2-(3-Fluorophenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (1f)
[0104] Compound 8 (194 mg, 1 mmol) and 3-fluoroaniline (9f, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(3-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10f as pure product. To a solution of 2-(3-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10f, 150 mg, 0.55 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 86 mg, 0.61 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1e (220 mg, 80%); mp: 130-132° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.62 (s, 1H), 8.31 (dd, J=3.0, 1.7 Hz, 1H), 7.83 (dd, J=3.0, 1.7 Hz, 1H), 7.78-7.73 (m, 1H), 7.59-7.53 (m, 2H), 7.36-7.18 (m, 3H), 7.12 (t, J=7.5 Hz, 1H), 6.99-6.91 (m, 5H), 6.71-6.66 (m, 2H), 5.48 (s, 2H), 4.66 ppm (d, J=5.6 Hz, 2H); MS (ESI m/z): 495 [M+H] + . Yield: 80%
Example 7
2-(2,4-Dimethoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (1g)
[0105] Compound 8 (194 mg, 1 mmol) and 2,4-dimethoxyaniline (9 g, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10g as pure product. To a solution of 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10 g, 150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.004 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1g (201 mg, 78%); mp: 127-129° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.30 (s, 1H), 8.25-8.21 (m, 2H), 7.73 (d, J=7.5 Hz 1H), 7.56 (s, 1H), 7.35-7.28 (m, 3H), 7.11 (t, J=7.5 Hz, 1H), 6.99-6.90 (m, 5H), 6.59-6.47 (m, 3H), 5.45 (s, 2H), 4.67 (d, J=5.2 Hz, 2H), 3.87 (s, 6H), 3.79 ppm (s, 3H); MS (ESI m/z): 537 [M+H] + . Yield: 78%
Example 8
2-(2,5-Dimethoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (1h)
[0106] Compound 8 (194 mg, 1 mmol) and 2,5-dimethoxyaniline (9h, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10h as pure product. To a solution of 2-(2,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10h, 150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1h (201 mg, 78%); mp: 154-156° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.71 (s, 1H), 8.34 (d, J=2.2 Hz, 1H), 8.32 (dd, J=3.0, 1.5 Hz, 1H), 7.76 (dd, J=2.2, 1.5 Hz, 1H), 7.54 (s, 2H), 7.32 (d, J=7.5 Hz, 2H), 7.28 (d, J=2.2 Hz, 1H), 7.18-7.06 (m, 2H), 6.97-6.84 (m, 5H), 6.76 (d, J=8.3 Hz 1H), 6.66-6.62 (m, 1H), 6.42-6.38 (m, 1H) 6.40 (dd, J=3.0 Hz, 1H), 5.45 (s, 2H), 4.66 (d, J=5.2 Hz, 2H), 3.90 (s, 3H), 3.79 (s, 3H); MS (ESI m/z): 537 [M+H] + . Yield: 78%
Example 9
2-(3,5-Dimethoxyphenylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)nicotinamide (1i)
[0107] Compound 8 (194 mg, 1 mmol) and 3,5-dimethoxyaniline (91,153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10i as pure product. To a solution of 2-(3,5-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (101,150 mg, 0.48 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 119 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1i (201 mg, 78%); mp: 123-125° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.55 (s, 1H), 8.27 (dd, J=2.2, 1.5 Hz, 1H), 7.82 (dd, J=2.2, 1.5 Hz, 1H), 7.72 (t, J=6.0 Hz, 1H), 7.58 (s, 1H), 7.33-7.28 (m, 1H), 7.08 (t, J=7.5 Hz, 1H), 6.97-6.90 (m, 7H), 6.62-6.58 (m, 1H), 6.08 (t, J=2.2 Hz 1H), 5.46 (s, 2H), 4.61 (d, J=5.2 Hz, 2H), 3.80 ppm (s, 6H); MS (ESI m/z): 537 [M+H] + Yield: 78%
Example 10
N-((1-(3-Phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(3,4,5-trimethoxyphenylamino) nicotinamide (1j)
[0108] Compound 8 (194 mg, 1 mmol) and 3,4,5-trimethoxyaniline (9j, 183 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain N-(prop-2-ynyl)-2-(3,4,5-trimethoxyphenylamino)nicotinamide 10j as pure product. To a solution of N-(prop-2-ynyl)-2-(3,4,5-trimethoxyphenylamino)nicotinamide (10j, 150 mg, 0.41 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 102 mg, 0.45 mmol), in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.004 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1j (186 mg, 75%); mp: 142-144° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.42 (s, 1H), 8.27 (d, J=7.5, Hz, 1H), 7.85 (d, J=7.5 Hz 2H), 7.75 (brs, 1H), 7.60 (s, 1H), 7.39-7.27 (m, 3H), 7.11 (t, J=7.5 Hz, 1H), 6.99-6.83 (m, 7H), 6.65 (m, 1H), 5.47 (s, 2H), 4.66 (d, J=5.28 Hz, 2H), 3.85 (s, 6H), 3.81 ppm (s, 3H); MS (ESI m/z): 567 [M+H] + . Yield: 75%
Example 11
2-(4-Chlorobenzylamino)-N-((1-(3-phenoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (1k)
[0109] Compound 8 (194 mg, 1 mmol) and 4-(4-chlorobenzyl)aniline (9k, 217 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-chlorobenzylamino)-N-(prop-2-ynyl)nicotinamide 10k as pure product. To a solution of 2-(4-chlorobenzylamino)-N-(prop-2-ynyl)nicotinamide (10k, 150 mg, 0.50 mmol) and 1-(azidomethyl)-3-phenoxybenzene (12a, 124 mg, 0.55 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 1k (184 mg, 60%); mp: 209-211° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 8.45 (t, J=5.2 Hz, 1H), 8.14-8.11 (m, 1H), 7.63 (d, J=7.5 Hz, 1H), 7.50 (brs, 1H), 7.45 (s, 1H), 7.27-7.13 (m, 7H), 7.02 (t, J=7.5 Hz, 1H), 6.90-6.80 (m, 5H), 6.36-6.32 (m, 1H), 5.33 (s, 2H), 4.60 (d, J=5.2 Hz, 2H), 4.49 ppm (d, J=6.0 Hz, 2H); MS (ESI m/z): 525 [M+H] + . Yield: 60%.
Example 12
N-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-fluorophenylamino) nicotinamide (2b)
[0110] Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-4-fluorobenzene (12b, 91 mg, 0.61 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 2b (187 mg, 80%); mp: 197-199° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.61 (s, 1H), 8.63 (brs, 1H), 8.24 (dd, J=4.4, 1.4 Hz, 1H), 7.98 (dd, J=, 8.0, 1.8 Hz, 1H), 7.64 (s, 1H), 7.63-7.58 (m, 2H), 7.41 (s, 1H), 7.23 (s, 1H), 6.98 (t, J=8.4 Hz, 2H), 6.88 (t J=8.4 Hz, 2H), 6.69-6.65 (m, 1H), 5.44 (s, 2H), 4.63 (d, J=5.5 Hz, 2H), 3.78 (s, 3H); MS (ESI m/z): 421 [M+H] + . Yield: 80%
Example 13
N-((1-(4-Fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-methoxyphenylamino)nicotinamide (2e)
[0111] Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-4-fluorobenzene (12b, 88 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 2e (173 mg, 75%); mp: 169-171° C.; 1 H NMR (500 MHz, CDCl 3 ) δ 10.26 (s, 1H), 8.23 (dd, J=4.0, 1.5 Hz, 1H), 7.74 (dd, J=8.0, 1.5 Hz, 1H), 7.50 (d, J=9.0 Hz, 1H), 7.29-7.24 (m, 4H), 7.06 (t, J=9.0 Hz, 2H), 6.83 (d, J=9.0 Hz, 2H), 6.59-6.50 (m, 1H), 5.47 (s, 2H), 4.64 (d, J=5.2 Hz, 2H), 3.78 (s, 3H); MS (ESI m/z): 433 [M+H] + . Yield: 75%
Example 14
2-(2,4-Dimethoxyphenylamino)-N-((1-(4-fluorobenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (2g)
[0112] Compound 8 (194 mg, 1 mmol) and 2,4-dimethoxyaniline (9 g, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10g as pure product. To a solution of 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10 g, 150 mg, 0.48 mmol) and 1-(azidomethyl)-4-fluorobenzene (12b, 79 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 2g (167 mg, 70%); mp: 146-148° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.33 (s, 1H), 8.25 (dd, J=7.5, 1.5 Hz, 1H), 7.72 (dd, J=7.5, 1.5 Hz, 1H), 7.53 (s, 1H), 7.28-7.23 (m, 3H), 7.18-7.13 (m, 1H), 7.03 (t, J=8.3 Hz, 2H), 6.58-6.54 (m, 1H), 6.46 (s, 2H), 5.45 (s, 2H), 4.64 (d, J=5.2 Hz, 2H), 3.90 (s, 3H), 3.79 (s, 3H); MS (ESI m/z): 463 [M+H] + . Yield: 70%
Example 15
2-(4-Fluorophenylamino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (5b)
[0113] Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-4-methoxybenzene (12c, 99 mg, 0.61 mmol)) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 5b (192 mg, 80%); mp: 201-204° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.57 (s, 1H), 8.45 (brs, 1H), 8.25 (dd, J=4.7, 1.4 Hz, 1H), 7.94 (dd, J=7.7, 1.4 Hz, 1H), 7.62-7.57 (m, 3H), 7.41 (s, 1H), 7.23 (s, 1H), 6.98 (t, J=8.4 Hz, 2H), 6.88 (t J=8.4 Hz, 2H), 6.69-6.65 (m, 1H), 5.44 (s, 2H), 4.63 (d, J=5.5 Hz, 2H), 3.78 (s, 3H); MS (ESI m/z): 433 [M+H] + . Yield: 80%
Example 16
N-((1-(4-Methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-methoxyphenylamino) nicotinamide (5e)
[0114] Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-4-methoxybenzene (12c, 95 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 5e (189 mg, 80%); %); 1 H NMR (300 MHz, CDCl 3 ) δ 10.31 (s, 1H), 8.19 (dd, J=4.9, 1.7 Hz, 1H), 7.7.81 (dd, J=7.7, 1.7 Hz, 2H), 7.52-7.48 (m, 3H), 7.25-7.19 (m, 2H), 6.85-6.81 (m, 4H), 6.55-6.51 (m, 1H), 5.42 (s, 2H), 4.55 (d, J=5.4 Hz, 2H), 3.78 (s, 3H), 3.77 ppm (s, 3H); yield 80%
Example 17
2-(2,4-Dimethoxyphenylamino)-N-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl) nicotinamide (5g)
[0115] Compound 8 (194 mg, 1 mmol) and 2,4-dimethoxyaniline (9e, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10g as pure product. To a solution of 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10 g, 150 mg, 0.48 mmol) and 1-(azidomethyl)-4-methoxybenzene (12c, 86 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 10 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 5g (180 mg, 79%); mp: 178-180° C.; 1 H NMR (500 MHz, CDCl 3 ) δ 10.30 (s, 1H), 8.23 (m, 2H), 7.74 (dd, J=6.0, 2.0 Hz, 2H), 7.51 (s, 1H), 7.34 (brs, 1H), 7.20 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 6.56-6.48 (m, 3H), 5.45 (s, 2H), 4.64 (d, J=6.0 Hz, 2H), 3.87 (s, 3H), 3.79 (s, 3H), 3.79 (s, 3H); MS (ESI m/z): 475 [M+H] + . Yield: 79%
Example 18
N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-fluorophenylamino)nicotinamide (6b)
[0116] Compound 8 (194 mg, 1 mmol) and 4-fluoroaniline (9b, 111 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide 10b as pure product. To a solution of from 2-(4-fluorophenylamino)-N-(prop-2-ynyl)nicotinamide (10b, 150 mg, 0.55 mmol) and 1-(azidomethyl)-3,5-dimethoxybenzene (12d, 116 mg, 0.61 mmol)) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 6b (182 mg, 71%); mp: 209-211° C.; mp: 140-142° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.32 (s, 1H), 8.19 (dd, J=3.0, 1.5 Hz, 1H), 7.81 (dd, J=3.0, 1.5 Hz, 2H), 7.52-7.47 (m, 3H), 7.20 (d, J=9.0 Hz, 2H), 6.83 (t, J=7.5 Hz, 4H), 6.55-6.51 (m, 1H), 5.41 (s, 2H), 4.58 (d, J=4.5 Hz, 2H), 3.78 (s, 3H), 3.77 (s, 3H); MS (ESI m/z): 463 [M+H] + Yield: 71%
Example 19
N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(4-methoxyphenylamino) nicotinamide (6e)
[0117] Compound 8 (194 mg, 1 mmol) and 4-methoxyaniline (9e, 123 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10e as pure product. To a solution of 2-(4-methoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10e, 150 mg, 0.53 mmol) and 1-(azidomethyl)-3,5-dimethoxybenzene (12d, 102 mg, 0.58 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 11 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 6e (197 mg, 78%); mp: 147-149° C.; 1 H NMR (300 MHz, CDCl 3 ) δ 10.17 (s, 1H), 8.24 (dd, J=4.9, 1.7 Hz, 1H), 7.55-7.48 (dd, J=7.7, 1.7 Hz, 1H), 7.17 (t, J=5.0 Hz, 1H), 6.87 (d, J=8.8 Hz, 2H), 6.62-6.57 (m, 1H), 6.42-6.39 (m, 3H), 5.42 (s, 2H), 4.66 (d, J=5.4 Hz, 2H), 3.79 (s, 3H), 3.75 ppm (s, 6H) MS (ESI m/z): 475 [M+H] + . Yield: 78%
Example 20
N-((1-(3,5-Dimethoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)-2-(2,4-dimethoxyphenyl amino)nicotinamide (6g)
[0118] Compound 8 (194 mg, 1 mmol) and 2,4-dimethoxyaniline (9e, 153 mg, 1 mmol) were taken in ethylene glycol and heated at 140° C. for 6 h. Then the reaction mixture was cooled and extracted with ethyl acetate from the aqueous layer and concentrated in vacuum. The compound was further purified by column chromatography using 60-120 silica gel to obtain 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide 10g as pure product. To a solution of 2-(2,4-dimethoxyphenylamino)-N-(prop-2-ynyl)nicotinamide (10 g, 150 mg, 0.48 mmol) and 1-(azidomethyl)-3,5-dimethoxybenzene (12d, 102 mg, 0.53 mmol) in 2:1 mixture of water and tert-butyl alcohol, sodium ascorbate (0.06 mmol) and copper (II) sulphate (0.005 mmol) were added sequentially. The reaction was stirred at room temperature for 12 h, TLC analysis indicated completion of reaction. The reaction mixture was concentrated under vacuum and extracted with EtOAc to give crude product. The crude was purified by column chromatography to afford pure product 6e (175 mg, 72%); mp: 147-149° C.; 1 H NMR (500 MHz, CDCl 3 ) δ 10.36 (s, 1H), 8.25 (dd, J=5.0, 3.0 Hz, 1H), 7.73 (dd, J=7.0 Hz, 1H), 7.53 (s, 1H), 7.15 (brs, 1H), 6.58-6.54 (m, 1H), 6.47-6.43 (m, 2H), 6.36 (s, 3H), 5.41 (s, 2H), 4.66 (d, J=5.2 Hz, 2H), 3.91 (s, 3H), 3.80 (s, 3H), 3.74 ppm (s, 6H) MS (ESI m/z): 505 [M+H] + . Yield: 72%
[0119] The compounds of present invention are obtained and the yield of compound of FORMULA 1 is ranging between 60-81%.
[0120] Examples for the preparation of compounds 2a, 2c, 2d, 2f, 2h, 2i, 2j, 2k, 3a-k, 4a-k, 5a, 5c, 5d, 5f, 5h, 5i, 5k, 6a, 6c, 6d, 6f, 6h, 6i, 6j and 6k.
[0000]
Compound
Method of
no
Starting materials
preparation
2a
2-(phenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1a.
4-fluorobenzene
2c
2-(4-chlorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and
in 1c.
1-(azidomethyl)-4-fluorobenzene.
2d
2-(4-bromophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1d.
4-fluorobenzene.
2f
2-(3-fluorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1f.
4-fluorobenzene
2h
2-(2,5-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1h.
(azidomethyl)-4-fluorobenzene
2i
2-(3,5-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1i.
(azidomethyl)-4-fluorobenzene
2j
N-(prop-2-ynyl)-2-(3,4,5-
As described in
trimethoxyphenylamino)nicotinamide
1j.
and 1-(azidomethyl)-4-fluorobenzene
2k
2-(4-chlorobenzylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1k.
4-fluorobenzene
3a
2-(phenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1a.
4-chlorobenzene
3b
2-(4-fluorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1b.
4-chlorobenzene.
3c
2-(4-chlorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1c.
4-chlorobenzene
3d
2-(4-bromophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1d.
4-chlorobenzene
3e
2-(4-methoxyphenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1e.
4-chlorobenzene
3f
2-(3-fluorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1f.
4-chlorobenzene
3g
2-(2,4-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1g.
(azidomethyl)-4-chlorobenzene
3h
2-(2,5-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1h.
(azidomethyl)-4-chlorobenzene
3i
2-(3,5-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1i.
(azidomethyl)-4-chlorobenzene
3j
N-(prop-2-ynyl)-2-(3,4,5-
As described
trimethoxyphenylamino)nicotinamide
in 1j.
and 1-(azidomethyl)-4-chlorobenzene
3k
2-(4-chlorobenzylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1k.
4-chlorobenzene.
4a
2-(phenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1a.
4-bromobenzene
4b
2-(4-fluorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1b.
4-bromobenzene
4c
2-(4-chlorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1c.
4-bromobenzene
4d
2-(4-bromophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1d.
4-bromobenzene
4e
2-(4-methoxyphenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1e.
4-bromobenzene
4f
2-(3-fluorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1f.
4-bromobenzene
4g
2-(2,4-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1g.
(azidomethyl)-4-bromobenzene
4h
2-(2,5-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1h.
(azidomethyl)-4-bromobenzene
4i
2-(3,5-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1i.
(azidomethyl)-4-bromobenzene
4j
N-(prop-2-ynyl)-2-(3,4,5-
As described
trimethoxyphenylamino)nicotinamide
in 1j.
and 1-(azidomethyl)-4-bromobenzene
4k
2-(4-chlorobenzylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1k.
4-bromobenzene
5a
2-(phenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1a.
4-methoxybenzene
5c
2-(4-chlorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1c.
4-methoxybenzene
5d
2-(4-bromophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1d.
4-methoxybenzene
5f
2-(3-fluorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1f.
4-methoxybenzene
5h
2-(2,5-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1h.
(azidomethyl)-4-methoxybenzene
5i
2-(3,5-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1i.
(azidomethyl)-4-methoxybenzene
5j
N-(prop-2-ynyl)-2-(3,4,5-
As described
trimethoxyphenylamino)nicotinamide
in 1j.
and 1-(azidomethyl)-4-methoxybenzene
5k
2-(4-chlorobenzylamino)-N-(prop-2-
As described
ynyl)nicotinamide and and 1-
in 1k.
(azidomethyl)-4-methoxybenzene
6a
2-(phenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1a.
3,5-dimethoxybenzene
6c
2-(4-chlorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1c.
3,5-dimethoxybenzene
6d
2-(4-bromophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1d.
3,5-dimethoxybenzene
6f
2-(3-fluorophenylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1f.
3,5-dimethoxybenzene
6h
2-(2,5-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1h
(azidomethyl)-3,5-dimethoxybenzene
6i
2-(3,5-dimethoxyphenylamino)-N-(prop-
As described
2-ynyl)nicotinamide and 1-
in 1i.
(azidomethyl)-3,5-dimethoxybenzene
6j
N-(prop-2-ynyl)-2-(3,4,5-
As described
trimethoxyphenylamino)nicotinamide
in 1j.
and 1-(azidomethyl)-3,5-
dimethoxybenzene
6k
2-(4-chlorobenzylamino)-N-(prop-2-
As described
ynyl)nicotinamide and 1-(azidomethyl)-
in 1k.
3,5-dimethoxybenzene
Biological Activity:
[0121] The in vitro anticancer activity studies for these N-((1-benzyl-1H-1,2,3-triazol-4-yl) methyl) arylamide analogues were carried out at the National Cancer Institute, USA.
Anticancer Activity
[0122] The N-((1-benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamide analogues have been tested at NCl, USA, against sixty human tumor cell lines derived from nine cancer types (leukemia, non-small cell lung cancer, colon cancer, CNS cancer, melanoma cancer, ovarian cancer, renal cancer, prostate cancer and breast cancer). For these compounds results are expressed as growth inhibition (GI 50 ) values as per NCl protocol. The anticancer activity data of compounds 1a, 1b, 1e, 1g, 1i and 1k are shown in Table 2.
[0000]
TABLE 2
Cytotoxicity of compounds 1a, 1b, 1e, 1g, 1i and 1k
in sixty cancer cell lines
Cancer panel/
GI 50
Cell lines
1a
1b
1e
1g
1i
1k
Leukemia
CCRF-CEM
3.34
NT
3.80
1.20
4.19
3.05
HL-60(TB)
3.74
NT
2.66
2.21
3.97
3.39
K-562
3.69
NT
3.48
0.75
5.05
3.24
MOLT-4
3.74
NT
2.91
3.65
4.85
3.28
RPMI-8226
3.61
NT
4.84
3.03
5.25
3.12
SR
2.56
—
—
—
—
3.31
Non-small-cell-lung
A549/ATCC
4.81
6.11
3.44
4.15
4.02
3.21
EKVX
5.18
25.3
4.16
5.09
6.33
3.65
HOP-62
5.58
60.2
5.07
12.7
6.31
5.69
HOP-92
—
10.7
5.67
—
4.67
4.23
NCI-H226
3.24
38.6
3.92
2.24
9.82
3.66
NCI-H23
3.73
29.9
3.45
2.24
6.22
—
NCI-H322M
—
5.29
5.24
NT
6.15
—
NCI-H460
2.85
5.25
3.52
3.05
3.98
2.85
NCI-H522
2.11
10.8
2.13
1.82
3.31
2.18
Colon
COLO 205
2.79
6.22
2.86
2.14
4.12
2.18
HCC-2998
3.70
NT
2.53
3.33
9.60
4.17
HCT-116
3.40
5.02
4.17
3.08
4.34
3.18
HCT-15
3.81
—
3.93
2.89
3.89
3.39
HT29
3.65
5.60
3.66
3.26
3.88
2.96
KM12
3.63
5.61
3.43
1.65
3.84
3.62
SW-620
3.97
6.58
3.86
2.12
3.88
4.04
CNS
SF-268
3.22
2.1
4.59
3.88
5.43
4.82
SF-295
3.69
5.66
2.94
0.56
4.06
2.80
SF-539
3.10
15.1
2.79
2.65
4.39
2.24
SNB-19
3.27
20.7
3.55
3.33
9.64
3.91
SNB-75
1.94
3.81
3.09
3.41
3.98
2.02
U251
3.61
7.12
3.91
3.60
4.58
2.66
Melanoma
LOX IMVI
4.54
61.3
3.60
3.01
5.10
3.90
MALME-3M
NT
15.1
3.80
4.07
5.81
5.69
M14
2.86
13.7
3.15
2.13
4.80
2.49
MDA-MB-435
2.65
2.79
1.71
0.25
2.23
2.33
SK-MEL-2
6.05
34.2
3.66
7.67
6.69
4.44
SK-MEL-28
4.93
7.98
3.88
2.60
4.14
2.95
SK-MEL-5
3.89
4.48
2.90
0.72
3.11
2.53
UACC-257
1.42
6.87
4.82
NT
4.86
3.83
UACC-62
3.02
6.51
3.13
1.43
3.86
2.08
Ovarian
IGROV1
30.7
5.89
NT
5.96
NT
9.03
OVCAR-3
17.7
2.98
3.69
1.54
3.69
3.48
OVCAR-4
23.4
5.19
5.42
5.11
5.42
3.37
OVCAR-5
NT
4.23
100
8.34
100
5.62
OVCAR-8
7.44
3.72
5.96
4.10
5.96
3.63
NCI/ADR-RES
14.0
2.12
3.21
2.12
3.21
2.86
SK-OV-3
5.94
3.11
4.33
2.59
4.33
3.32
Renal
786-0
23.2
5.59
6.73
4.06
6.73
—
A498
13.7
2.35
4.18
1.01
4.18
2.12
ACHN
11.05
4.79
6.90
4.83
6.90
4.03
CAKI-1
64.2
3.41
6.30
1.71
6.30
4.36
SN12C
52.9
4.75
7.41
1.71
7.41
3.44
TK-10
24.5
4.59
5.16
3.14
5.16
3.70
UO-31
86.3
3.00
5.25
8.06
5.25
3.00
RXF 393
5.69
2.59
3.77
7.83
3.77
2.19
Prostate
PC-3
20.4
3.86
4.74
0.62
4.74
2.96
DU-145
8.58
3.76
1.05
3.37
1.05
4.00
Breast
MCF7
—
—
—
0.65
—
2.99
MDA-MB-31/ATCC
14.5
3.09
5.35
5.54
5.35
2.29
HS 578T
30.9
5.90
NT
2.94
NT
2.72
BT-549
45.5
4.58
7.16
3.51
7.16
2.72
T-47D
21.4
4.03
4.68
4.28
4.68
3.20
MDA-MB-468
51.7
2.32
2.42
1.46
2.42
3.44
[0123] All the compounds showed enhanced antitumor activity in tested cell lines. In the present investigation, an attempt has been made, in view of the biological importance of both 2-anilino nicotinyl structure and 1,2,3-triazoles group. The resulting compounds 1a, 1b, 1c, 1d, 1f, 1g, 1i, 1k, 6b and 6g were found to be more potent with IC 50 values ranging from 1.25-3.98 and 0.74-2.51 μM and compared with E7010 IC 50 values 4.45 and 9.06 μM against A549 and MCF-7 cell lines respectively ( Chem MedChem 2012, 7, 680-693). Introduction of triazole group on 2-anilino nicotinyl moiety resulted that there is enhancement of biological activity of representative compounds (1a, 1b, 1c, 1d, 1f, 1g, 1i, 1k, 6b and 6g) compare with E7010. Biological data of representative compounds has been provided in Table 1.
(Novel sulfonamides as potential, systemically active antitumor agents. Yoshino, H.; Ueda, N.; Niijima, J.; Sugumi, H.; Kotake, Y.; Koyanagi, N.; Yoshimatsu, K.; Asada, M.; Watanabe, T.; Nagasu, T. J. Med. Chem. 1992, 35, 2496-2497)
[0000]
TABLE 3
IC 50 (μM) values of compounds and E7010
Compound no
A549
MCF-7
1a
1.54
1.65
1b
1.69
1.65
1c
3.98
2.51
1d
1.90
0.97
1f
1.90
1.78
1g
1.57
0.74
1i
1.93
0.93
1k
1.79
2.51
6b
1.25
1.0
6g
1.31
1.17
E7010
4.45
9.06
Significance of the Work Carried Out
[0125] A compound of formula 1 that has been synthesized exhibited significant cytotoxic activity against different human tumour cell lines.
Advantages of the Invention
[0126] 1. The present invention provides N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamides as potential antitumor agents.
[0127] 2. It also provides a process for the preparation of novel N-((1-Benzyl-1H-1,2,3-triazol-4-yl)methyl)arylamides.
|
The present invention provides a compound of general formula 1, useful as potential anticancer agents against human cancer cell lines and process for the preparation thereof.
R 1 =H, 4-F, 4-Cl, 4-Br, 4-OMe, 3-F, 2,4-diOMe, 2,5-diOMe, 3,5-diOMe, 3,4,5-triOMe, 4-ClBn
R 2 =3-OPh, 4-F, 4-Cl, 4-Br, 4-OMe, 3,5-diOMe
| 2
|
BACKGROUND OF THE INVENTION
The present invention relates to new derivatives of the antibiotics collectively defined as LL-F28249. These antibiotics preferably are produced by the fermentation of the microorganism Streptomyces cyaneogriseus subsp. noncyaneogenus, deposited in NRRL under deposit accession no. 15773. The LL-F28249 compounds and the method for their production are disclosed in European Patent Application Publication No. 170,006, incorporated herein by reference.
The present invention further relates to methods and compositions for preventing, treating or controlling helmintic, ectoparasitic, insect, acarid, and nematode infections and infestations in warm-blooded animals and agricultural crops by administering thereto prophylactically, therapeutically or pharmaceutically effective amount of the present Δ 23 -LL-F28249 agents (compounds), mixtures thereof or the pharmaceutically and pharmacologically-acceptable salts thereof.
These infections not only cause devastating effects to animals but also seriously effect the economics of farmers in raising meat-producing animals such as swine, sheep, cattle, goats, rabbits and poultry. Further, such infections are a source of great concern for companion animals such as horses, dogs and cats. Therefore, effective methods for the treatment and prevention of these diseases constantly are being sought.
SUMMARY OF THE INVENTION
The present invention provides novel derivatives of the compounds designated LL-F28249 and represented by the following structural formula,
______________________________________ ##STR1## ##STR2##Component R.sub.1 R.sub.2 R.sub.3 R.sub.4______________________________________LL-F28249α CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.3LL-F28249β CH.sub.3 H CH.sub.3 CH.sub.3LL-F28249γ CH.sub.3 CH.sub.3 CH.sub.3 CH.sub.3LL-F28249ε CH(CH.sub.3).sub.2 H H CH.sub.3LL-F28249δ CH.sub.2 CH.sub.3 H CH.sub.3 CH.sub.3LL-F28249θ CH(CH.sub.3).sub.2 H CH.sub.3 CH.sub.2 CH.sub.3LL-F28249 CH(CH.sub.3).sub.2 H CH.sub.2 CH.sub.3 CH.sub.3LL-F28249λ CH(CH.sub.3).sub.2 CH.sub.3 CH.sub.3 CH.sub.3______________________________________
The compounds of the present invention are represented by structural formula (I), ##STR3## wherein R 1 is methyl, ethyl or isopropyl; R 2 is hydrogen or methyl; R 3 is hydrogen, methyl or ethyl; R 4 is methyl or ethyl; and the pharmaceutically and pharmacologically acceptable salts thereof.
The compounds of the present invention are useful anthelmintics, ectoparasiticides, insecticides, acaricides and nematicides in treating, preventing or controlling such diseases in warm-blooded animals, such as poultry, cattle, sheep, swine, rabbits, horses, dogs, cats and human beings, and agricultural crops.
Although these diseases have been recognized for years and therapies exist for the treatment and prevention of the diseases, the present invention provides novel compounds in the search for effective such therapy. For instance, U.S. Application for Letter patent Ser. Nos. 907,186; 907,187; 907,188; 907,259; 907,281 and 907,284 of Asato and Asato et al, filed concurrently herewith and incorporated herein by reference thereof, provide novel compounds for such uses.
U.S. Pat. No. 3,950,360, Aoki et al, Apr. 13, 1976, discloses certain antibiotic substances obtained by culturing a Streptomyces microorganism, said compounds being useful as insecticides and acaricides. Further, an entire series of U.S. patents relates to certain compounds produced by the fermentation of Streptomyces avermitilis (U.S. Pat. No. 4,171,314, Chabala et al, Oct. 16, 1979; U.S. Pat. No. 4,199,569, Chabala et al, Apr. 22, 1980; U.S. Pat. No. 4,206,205, Mrozik et al, June 3, 1980; U.S. Pat. No. 4,310,519, Albers-Schonberg, Jan. 12, 1982; U.S. Pat. No. 4,333,925, Buhs et al, June 8, 1982). U.S. Pat. No. 4,423,209, Mrozik, Dec. 27, 1983 relates to the process of converting some of these less desirable components to more preferred ones. British Patent Application 2166436A of Ward et al relates to antibiotics also.
The present compounds or the pharmaceutically and pharmacologically-acceptable salts thereof exhibit excellent and effective treatment and/or prevention of these serious diseases of warm-blooded animals.
It is an object of the present invention, therefore, to provide novel Δ 23 -compounds of the LL-F28249 series of compounds.
It is a further object of the present invention to provide novel methods for the treatment, prevention or control of helmintic ectoparasitic, insect, acarid and nematode infections and infestations in warm-blooded animals and agricultural crops.
It also is an object of the present invention to provide novel compositions to effectively control, prevent or treat said diseases in warm-blooded animals.
These and further objects will become apparent by the below-provided detailed description of the invention.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the invention are represented by structural formula (I), ##STR4## wherein R 1 is methyl, ethyl or isopropyl; R 2 is hydrogen or methyl; R 3 is hydrogen, methyl or ethyl; R 4 is methyl or ethyl; and the pharmaceutically and pharmacologically acceptable salts thereof.
Preferably, R 1 is isopropyl; R 2 is hydrogen or methyl; R 3 is methyl; and R 4 is methyl. Most preferred compound includes RI as isopropyl, R 2 as hydrogen, R 3 as methyl and R 4 as methyl.
The Δ 23 -LL-F28249 derivatives of the present invention are prepared by eliminating the 23-hydroxyl group and introducing a double bond at the 23-24 position.
The process involves oxidation of the 5-hydroxyl group of the appropriate LL-F28249 compound with activated MnO 2 in ether at room temperature (about 25° C.) to afford the 5-oxo-LL-F28249 compound. This is followed by reacting the 5-oxo-LL-F28249 compound with dialkylaminosulfur trifluoride in an inert solvent, such as dimethoxyethane, at a temperature of about -50° C. to -5° C. and then reducing the 5-oxo group with NaBH 4 in methanol or ethanol at room temperature (25° C.) to yield the 5-hydroxy-LL-F28249 components containing a double bond at the thermodynamically more stable 23-24 position (Δ 23 ).
The LL-F28249 compounds with a 5-methoxy group (LL-F28249γ and λ) are directly reacted with dialkylaminosulfur trifluoride to yield Δ 23 -LL-F28249γ and λ, respectively.
The compounds of the present invention are useful as anthelmintics, ectoparasiticides, insecticides, acaricides and nematicides.
The disease or group of diseases described generally as helminthiasis is due to infection of an animal host with parasitic worms known as helminths. Helminthiasis is a prevalent and serious economic problem in domesticated animals such as swine, sheep, horses, cattle, goats, dogs, cats and poultry. Among the helminths, the group of worms described as nematodes causes widespread and often times serious infection in various species of animals. The most common genera of nematodes infecting the animals referred to above are Haemonchus, Trichostrongylus, Ostertagia, Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia, Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis, Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris and Parascaris. Certain of these, such as Nematodirus, Cooperia, and Oesophagostomum primarily attack the intestinal tract, while others, such as Haemonchus and Ostertagia, are most prevalent in the stomach. Still others, such as Dictyocaulus, are found in the lungs. However, other parasites may be located in other tissues and organs of the body such as the heart and blood vessels, subcutaneous and lymphatic tissue and the like. The parasitic infections known as helminthiases lead to anemia, malnutrition, weakness, weight loss, severe damage to the walls of the intestinal tract and other tissues and organs, and, if left untreated, may result in death of the infected host. The Δ 23 -LL-F28249 compound derivatives of the present invention unexpectedly have high activity against these parasites. Additionally, the compounds of this invention also are active against Dirofilaria in dogs, Nematospiroides, Syphacia, Aspiculuris in rodents, arthropod ectoparasites such as ticks, mites, lice, fleas, blowfly, of animals and birds, the ectoparasite Lucilia sp. of sheep, biting insects and migrating dipterous larvae such as Hypoderma sp. in cattle, Gastrophilus in horses and Cuterebra sp. in rodents.
The compounds of the present invention also are useful in treating, preventing or controlling parasites (collectively includes ecto and/or endoparasites) which infect human beings, as well. The most common genera of parasites of the gastrointestinal tract of man are Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella, Capillaria, Trichuris, and Enterobius. Other medically important genera of parasites which are found in the blood or other tissues and organs outside the gastrointestinal tract are the filiarial worms such as Wuchereria, Brugia, Onchocerca and Loa, Dracunculus and extra-intestinal stages of the intestinal worms Strongyloides and Trichinella. The present compounds also are of value against arthropods parasitizing man, biting insects and other dipterous pests causing annoyance to man.
These compounds further are active against household pests such as the cockroach, Blattella sp., clothes moth, Tineola sp., carpet beetle Attagenus sp. and the housefly Musca domestica.
Insect pests of stored grains such as Tribolium sp., Tenebrio sp., and of agricultural plants such as spider mites (Tetranychus sp.), aphids (Acyrthiosiphon sp.), southern army worms, tobacco budworms, boll weevils migratory orthopterans, such as locusts and immature stages of insects living on plant tissue are controlled by the present compounds, as well as the control of soil nematodes and plant parasites such as Meloidogyne sp.
The compounds of the present invention may be administered orally or parenterally for animal and human usage, while they may be formulated in liquid or solid form for agricultural use. Oral administrations may take the form of a unit dosage form such as a capsule, bolus or tablet, or as a liquid drench where used as an anthelmintic for animals.
The animal drench is normally a solution, suspension or dispersion of the active compound, usually in water, together with a suspending agent such as bentonite and a wetting agent or like excipient. Generally, the drenches also contain an antifoaming agent. Drench formulations generally contain about 0.001% to 0.5%, by weight, of the active compound. Preferred drench formulations contain about 0.01% to 0.1% by weight.
Capsules and boluses comprise the active ingredient admixed with a carrier vehicle such as starch, talc, magnesium stearate or di-calcium phosphate.
Where it is desired to administer the Δ 23 -LL-F28249 derivatives in a dry, solid unit dosage form, capsules, boluses or tablets containing the desired amount of active compound usually are employed. These dosage forms are prepared by intimately and uniformly mixing the active ingredient with suitable finely divided diluents, fillers, disintegrating agents and/or binders such as starch, lactose, talc, magnesium stearate, vegetable gums and the like. Such unit dosage formulations may be varied widely with respect to their total weight and content of the active compound depending upon factors such as the type of host animal to be treated, the severity and type of infection and the weight of the host.
When the active compound is to be administered via an animal feedstuff, it is intimately dispersed in the feed or used as a top dressing or in the form of pellets which may then be added to the finished feed or optionally fed separately. Alternatively, the active compounds of the invention may be administered to animals parenterally such as by intraruminal, intramuscular, intratracheal or subcutaneous injection. In such- an event, the active compound is dissolved or dispersed in a liquid carrier vehicle.
For parenteral administration, the active compound is suitably admixed with an acceptable vehicle, preferably a vegetable oil such as peanut oil, cotton seed oil or the like. Other parenteral vehicles such as organic preparations using solketal, glycerol formal and aqueous parenteral formulation also are used. The active LL-F28249 compound derivative or derivatives are dissolved or suspended in the parenteral formulation for administration. Such formulations generally contain about 0.005% to 5%, by weight, of the active compound.
Although the compounds of the present invention are primarily used in the treatment, prevention or control of helminthiasis, they also are useful in the prevention, treatment or control of diseases caused by other parasites (collectively both ecto and/or endoparasites). For example, arthropod parasites such as ticks, lice, fleas, mites and other biting insects in domesticated animals and poultry are controlled by the present compounds. These compounds also are effective in treatment of parasitic diseases which occur in other animals including human beings. The optimum amount to be employed will, of course, depend upon the particular compound employed, the species of animal to be treated and the type and severity of parasitic infection or infestation. Generally, the amount useful in oral administration of these novel compounds is about 0.001 mg to 10 mg per kg of animal body weight, such total dose being given at one time or in divided doses over a relatively short period of time (1-5 days). The preferred compounds of the invention give excellent control of such parasites in animals by administering about 0.025 mg to 3 mg per kg of animal body weight in a single dose. Repeat treatments are given as required to combat re-infections and are dependent upon the species of parasite and the husbandry techniques being employed. The techniques for administering these materials to animals are known to those skilled in the veterinary field.
When the compounds described herein are administered as a component of animals' feed or dissolved or suspended in the drinking water, compositions are provided in which the active compound or compounds are intimately dispersed in an inert carrier or diluent. An inert carrier is one that will not react with the active component and that will be administered safely to animals. Preferably, a carrier for feed administration is one that is, or may be, an ingredient of the animal ration.
Suitable compositions include feed premixes or supplements in which the active compound is present in relatively large amounts wherein said feed premixes or supplements are suitable for direct feeding to the animal or for addition to the feed either directly or after an intermediate dilution or blending step.
Typical carriers or diluents suitable for such compositions include distillers' dried grains, corn meal, citrus meal, fermentation residues, ground oyster shells, wheat shorts, molasses solubles, corn cob meal, edible bean mill feed, soya grits, crushed limestone and the like. The active compounds are intimately dispersed throughout the carrier by methods such as grinding, stirring, milling or tumbling. Compositions containing about 0.005% to 2.0%, by weight, of the active compound are particularly suitable as feed premixes.
Feed supplements, which are fed directly to the animal, contain about 0.0002% to 0.3%, by weight, of the active compounds. Such supplements are added to the animal feed in an amount to give the finished feed the concentration of active compound desired for the treatment and control of parasitic diseases. Although the desired concentration of active compound will vary depending upon the factors previously mentioned as well as upon the particular derivative employed, the compounds of this invention are usually fed at concentrations of about 0.00001% to 0.02% in the feed in order to achieve the desired antiparasitic result.
The compounds of this invention also are useful in combating agricultural pests that inflict damage upon growing or stored crops. The present compounds are applied, using known techniques such as sprays, dusts, emulsions and the like, to the growing or stored crops to effect protection from agricultural pests.
The present invention is illustrated by the following examples which are illustrative of said invention and not limitative thereof.
EXAMPLE I Δ 23 -5-oxo-LL-F28249α
In 1.5 mL of dry dimethoxyethane, 0.2168 g of 5-oxo-LL-F28249 is dissolved. Under N 2 atmosphere and at -6° C., 0.1148 g of diethylaminosulfur trifluoride is added dropwise. After stirring for 15 minutes, the mixture is poured into an ice-H 2 O mixture and stirred for 0.5 hours. The aqueous mixture is extracted with CH 2 Cl 2 several times, and the combined extracts are dried (MgSO 4 ) and evaporated to dryness. The residual gum is purified by chromatography on silica gel using 20:1 CH 2 Cl 2 /EtOAc on preparative plates to afford Δ 23 -5-oxo-LL-F28249α that is characterized by mass spectrometry and NMR spectroscopy.
EXAMPLE 2 Δ 23 -LL-F28249α
In 3 mL of MeOH containing 0.04 g of Δ 23 -5-oxo-LL-F28249α, 3.6 mg of NaBH 4 is added at room temperature. After 5 minutes, the mixture is evaporated to dryness and chromatographed on a silica gel preparative plate using CH 2 Cl 2 /EtOAc (20:1) to afford 0.0258 g of the title compound that is identified by mass spectrometry and NMR spectroscopy.
EXAMPLE 3
5-Oxo-LL-F28249α
In 15 mL of anhydrous Et 2 O, 3.5 g of activated MnO 2 is stirred under N 2 atmosphere, and 0.5 g of LL-F28249α is added in one portion. After stirring for 4 hours at room temperature (about 25° C.), the mixture is filtered through diatomaceous earth, and the filter cake is washed with Et 2 O. The filtrate is evaporated to dryness to afford the title compound (0.23 g) that is characterized by mass spectrometry and NMR spectroscopy.
EXAMPLES 4 AND 5 Δ 23 -LL-F28249γ
The title compound is prepared by reacting LL-F28249γ with diethylaminosulfur trifluoride by the method of Example 1 and identified by mass spectrometry and NMR spectroscopy.
Similarly, Δ 23 -LL-F28249γ is prepared.
EXAMPLES 6-10
Using the procedures described in Example 3, the following 23-oxo-compounds are prepared:
______________________________________ ##STR5## (I)R.sub.1 R.sub.3 R.sub.4______________________________________CH.sub.3 CH.sub.3 CH.sub.3CH(CH.sub.3).sub.2 H CH.sub.3CH.sub.2 CH.sub.3 CH.sub.3 CH.sub.3CH(CH.sub.3).sub.2 CH.sub.3 CH.sub.2 CH.sub.3CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.3 CH.sub.3______________________________________
EXAMPLES 11-15
Using the procedures described in Examples 1 and 2, the following 23-oxo-compounds are prepared:
______________________________________ ##STR6## (I)R.sub.1 R.sub.3 R.sub.4______________________________________CH.sub.3 CH.sub.3 CH.sub.3CH(CH.sub.3).sub.2 H CH.sub.3CH.sub.2 CH.sub.3 CH.sub.3 CH.sub.3CH(CH.sub.3).sub.2 CH.sub.3 CH.sub.2 CH.sub.3CH(CH.sub.3).sub.2 CH.sub.2 CH.sub.3 CH.sub.3______________________________________
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The present invention relates to novel derivatives of LL-F28249 compounds wherein the 23-hydroxy group is eliminated to introduce a double bond at the 23,24 position. These resulting derivatives are Δ 23 -LL-F28249 compounds. These LL-F28249 precursor compounds preferably are derived via a controlled microbiological fermentation of Streptomyces cyaneogriseus subsp. noncyanogenus having deposit accession number NRRL 15773. The novel derivatives of the present invention possess activity as anthelmintic, ectoparasitic, insecticidal, acaricidal and nematicidal agents. They also are useful in areas of human and animal health and in agricultural crops.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a §371 National Stage Application of PCT/EP2009/063930 filed Oct. 22, 2009, which claims priority to DE 10 2008 052 680.0 filed Oct. 22, 2008and U.S. Provisional Application No 61/175,556 filed May 5, 2009.
FIELD OF THE INVENTION
The invention concerns an adjustment device for adjusting the position of a screw that is able to move a part of a surgical instrument, a surgical positioning unit supporting surgical guide means, such as drill guides and cutting planes, and a method for the adjustment of surgical guide means.
BACKGROUND OF THE INVENTION
During transpedicular instrumentation of vertebral column segments, the insertion of surgical implant close to sensible structures requires a very high degree of precision. For protection of nerves in proximity and blood vessels a high number of control X-ray images is acquired causing an increased irradiation. Despite multiplanar X-ray control there is a relatively high rate of misplaced implants caused by the difficulty of deducing 3D information from the acquired images and by the freehand drilling. According to a meta analysis by Kosmospoulos and Schizas [1] taking into account 130 ex- and in-vivo studies regarding accuracy of pedicle screw placements there is a variance of 0%-72% (median 10%) of implantation failure rate using conventional technique.
For better control of implantation and in order to avoid perforations, a multitude of computer assisted navigation and robotic systems especially in the domain of spine surgery have been developed and commercialized by research laboratories and by the industry. For spine surgery, especially in minimally invasive procedures, most computer assisted surgery systems use medical images for input patient data. From a methodological point of view these systems can be classified by the image modality (preoperative Computer Tomography (CT), intraoperative 2D, respectively 3D, fluoroscopy) and by the registration method of transfer of the planning into the operating site (navigated or robotically). Depending on the underlying principle, the surgical workflow as well as the advantages and disadvantages resulting from the respective boundary conditions change with respect to the conventional technique.
Generally speaking, computer assisted systems could prove in the framework of clinical studies, that the failure implantation rate of pedicle screws can be reduced significantly to 0%-28% (Median 5%) with respect to conventional approach [1] . Additionally, Grützner et al. [2] demonstrated in the framework of a clinical study, that by use of fluoroscopic navigation systems (2D or 3D) the irradiation dose could be reduced by up to 40% respectively 70%. Especially the Operating Room staff took advantage from this reduction besides the patient, the former being exposed to such irradiation on a daily basis during such interventions.
This positive tendency is not valid for CT based systems though, for which the overall irradiation balance for the patient is disadvantageous with respect to the conventional approach because of the navigation data set that needs to be acquired additionally to the diagnosis CT data set [3] . Additionally there are supplemental costs for the CT data such that a CT based planning is only justifiable in the case where the structures to be treated show large deformations.
The necessary detail accuracy of the data sets is with few concessions also provided with intra operative 3D imaging or 3D Fluoroscopy. These systems (e.g. Siemens Arcadis Orbic) allow the navigation within multiplanar reconstructions but with reduced quality and especially with a reduced scan volume (approximatively 12 cm×12 cm×12 cm) with respect to pre operative CT data sets. A major advantage of the intraoperative 3D imaging however is, that the datasets are acquired intra operatively just before the implantation and that the registration can be done automatically. Thanks to this, the probability of anatomic alteration (e.g in the case of traumatological interventions) between the preoperative CT scan and the Operating Room as well as registration errors can be minimized. This is also potentially reflected when comparing the position failure rates of such systems (4%-9% CT based [4]-[7] , under 1% 3D fluoroscopy [8]-[9] ).
There are several advantages and disadvantages of the CT based and the 2D and 3D fluoroscopic navigation systems that are being discussed controversial in the literature. In more detail these issues are:
Operating Room time compared to the conventional approach The invasiveness necessary for the intervention (size/type of incision, attachment of reference basis to the bone, etc.) Problems with the clinical and surgical workflow being modified in a different way Purchase cost and additional cost per intervention
An important limiting factor of navigation based systems is the necessary tracking system (mostly optical tracking) by which the registration (alignment of the planning data with the patient anatomy) as well as the positioning and alignment of the implantation instruments is performed. On the one hand the intra operative flexibility is greatly reduced by the “line of sight” problem and the limited work space, on the other hand the achievable accuracy is limited for example because of markers being soiled by blood or the temperature sensibility of the sensor system. Furthermore there is the problem of free hand positioning of the instruments (drills, drill guides, cutting jigs) which causes the results being heavily dependent on the dexterity of the surgeon besides exact planning. There is no controversy that the expenses for navigation bases systems are significant when compared with the conventional approach. The necessary purchase of a tracking system (costs between 10000 and 40000 ) is in the centre of focus here. There are additional costs for the different instruments (interfaces for the trackers on the instruments and guides, calibration tools, etc.) that are customized to the respective tracking based navigation system and for the costs for single use items necessary for each surgery (i.e. 500 -1000 ).
A system being used for spine surgery in a clinical setting that does not require a tracking system neither for registration (automatic image based registration) nor for instrument alignment, is the semi active robotic assistance system SpineAssist® (Mazor Surgical Technologies, Caesarea, Israel) [10] , also disclosed in WO 03/1009768. The system is attached to a reference basis that itself is attached dorsally to several segments of the vertebral column. This allows a robotically alignment of a drill guide in the direction of pedicle screw placement. After planning controlled alignment the robot is being switched off and the surgeon performs the drilling through the positioned drill guide. The system is based on pre operative CT data sets with the known advantages and disadvantages (except for the problems with registration). The alignment or so called registration between planning CT data set and the patient anatomy is carried out in a pure image based way by using biplanar fluoroscopic data sets (so-called “fluoromerge”) [11] and calibration fiducials being integrated in the reference basis.
The Robodoc (see U.S. Pat. No. 5,806,518) is another robotic system that is used for surgical applications for hip and knee. Despite the advantages which result from the different functional principles described above with respect to tracking based free hand navigation one can summarizes the limitations of the system on the basis of the problems that are discussed generally in conjunction with robotic assisted surgery:
Purchase costs (e.g. SpineAssist® approx. 120.000 ) plus additional costs per case. Safety related methodological efforts (e.g. redundant safety architecture), since active components are in touch with the patient. The operative and technological effort for maintaining sterility of the semi active robotic system (cable based system with six motor-encoder units). The application specific design (work space) of the robotic system comprising a specific kinematics with therefore designed electronics and drive unit which do not allow a universal application for different medical problems.
Furthermore there are different approaches originating in stereotactic neurosurgery. These systems allow the adjustment of a trajectory (e.g. to target a certain area in the brain) based on a 3D image data set (e.g. CT data set). The coordinate system of the stereotaxy frame is aligned with the planning image data set either by a direct unambiguous link to the reference frame of the CT-gantry, or by taking advantage of the visibility of certain parts of the stereotactic frame in the image data set. For a patent on this topic see for example U.S. Pat. No. 4,706,665, which describes a purely passive positioning system. Some axis of the articulated stereotactic frames can be driven electrically such that it becomes similar to a robotic system (see US 2007/0055389). The alignment of the stereotactic frame (respectively of the robot) can also be performed with positioning sensor technology as described in EP 0 728 446. WO 01/78015 and especially WO 02/37935 describes a system, where based on multiplanar X-ray images a planning for an osteotomy (bone cut) or respectively an osteosynthesis (alignment of two bone fragments) is generated with computer assistance and then realised with a mechanical device. More precisely the computer system calculates the necessary adjustment parameters for realising the plan, which is then adjusted accordingly by the surgeon. But those systems require robotics device to make it fast and accurate or they require manual adjustment of several screws which is slow and prone to human errors.
In those applications where patient images are used as input data, one objective of the invention is to provide a solution that does not require a navigation system or a robotics system but that is fast and easy to adjust accurately guides and instruments.
For applications outside of spine surgery, it is possible to assist the surgeon by a computer-assisted surgery system without using medical images. This refers to navigation systems. In those cases, using a navigation system with an optical or magnetic tracking system makes sense since it generates 3D data instead of medical images. Such data are used for optimal positioning of instruments. In navigation systems, trackers are attached to patient anatomical structures such as bone for example, but also to instruments such as cutting and drilling guides. However, the precise adjustment of cutting guides or drilling guides with navigation systems is usually done manually, using the navigation system as a visual control, or using adjustment guides with screws that are time consuming and cumbersome, and they may require additional fixations.
Many devices used in conjunction with navigation systems use screws to adjust and finely tune the position of a surgical instrument. For instance, in U.S. Pat. No. 6,712,824, Millar uses a mechanism with three screws to adjust a cutting plane guide for knee surgery, but the screws must be adjusted manually which takes time. Similar principles can be found in EP 1 444 957 by Cusick, or US 2006/0235290 by Gabriel. Moreover the mechanical architecture is serial and it does not lock automatically to a given position when the screws are not turned, it is therefore necessary to use additional pins in the bone to fix the guide.
More complex architectures are using more than three screws in order to adjust cutting blocks. For instance, in EP 1 669 033, Lavallee uses a navigation system to adjust the position of several screws of a femoral cutting block but this process is not easy and it takes a long time.
The tracking technology of navigation systems can take multiple forms. It includes, but is not limited to optical active technology, with active infrared Light Emitting Diodes (LEDs) on trackers, optical passive technology (with passive retro-reflective markers on trackers), mechanical passive arms with encoders, accelerometers and gyrometers, or magnetic technology. Those tracking technologies are known as prior art of navigation systems for surgery. In this type of applications which does not use medical images, it is therefore necessary to propose adjustments devices and methods to make fast, easy and precise positioning of surgical instruments using a navigation system.
Referring to FIG. 1 , the instrument 1 is any surgical instrument that has the following characteristics:
[A] The instrument 1 has a tracker 10 attached thereon so that it is tracked by the navigation system 2 . The navigation system 2 comprises a camera 20 and a control unit 21 such as a computer with a screen. [B] The instrument 1 is rigidly fixed to a solid 3 that is also tracked by the navigation system 2 . [C] The instrument has a fixed part 11 which is fixed to the solid 3 and a mobile part 12 which is mobile with respect to the fixed part 11 . [D] The position of the fixed part 11 with respect to the mobile part 12 can be adjusted by screws 13 . The number of screws is independent of the invention.
A tracker 30 is attached to the bone 3 or directly to the fixed part 11 of the instrument. It is used as a reference for collecting data points and surfaces with the navigation system. The target of cutting plane position is defined in a coordinate system attached to tracker 30 .
A screwdriver 7 is used to adjust the instrument position with respect to the solid 3 in a target position. The target position of the instrument is supposed to be selected by the surgeon or set to default values with respect to anatomical landmarks digitized with the navigation system. The target position is represented by a geometric relationship M 0 between the fixed part 11 of the instrument and its mobile part 12 . By trivial calibration, the target position can be represented equivalently to a geometric relationship M 1 between a tracker attached to the mobile part and a tracker attached to the fixed part or to the solid.
The problem is for the user to move several screws 13 independently to move the mobile part 12 until the geometric relationship between the mobile part tracker 10 and the solid tracker 30 matches M 1 within a very low tolerance limit such as for instance 0.5 mm and 0.2°.
The manual adjustment of individual screws 13 takes a long time and it is difficult to converge towards a solution.
To help this process, for any initial position of the screws 13 and mobile part 12 , the control unit 21 of the navigation system 2 can calculate the necessary screw differential adjustments DSi, for each screw 13 i (where i is from 1 to N and N is the number of screws), which is necessary to bring the mobile part 12 to the target position. This is an easy calculation that only requires knowing the geometry of the screw placements with respect to the mobile and fixed parts and that is specific to each geometry. In a first step, the display of the navigation system can simply show the adjustments necessary DSi on each screw to the user such that the user follows the indications on the screen. While the screws 13 are manually adjusted, the values DSi are recalculated in real-time by the navigation system and the user can adjust the various screws accordingly.
However, this process remains long and complicated.
The present invention thus aims at providing an adjustment process that is short and simple in order to save intraoperative time and reduce the risk of failure, and an adjustment device suited for such a process.
SUMMARY OF INVENTION
This is achieved by a device for adjusting the position of a screw that is able to move a part of a surgical instrument, said device comprising:
a stem comprising a tip suited to the head of the screw, a actuated system for driving said stem in rotation,
characterised in that it comprises communication means to communicate with a control unit, such that the control unit transmits to the actuated system the number of turns to apply to the stem to reach the target position of the screw.
The control unit is included in a navigation system or is connected to a medical imaging system.
Advantageously, the device comprises detection means for identifying which screw the tip of the device is in contact with, wherein the communication means of the device are able to transmit said identification information to the control unit.
According to a first embodiment of the invention, said detection means comprise a sliding stem able to slide inside the stem and a position sensor adapted to measure the displacement of the sliding stem with respect to the tip of the device.
According to a second embodiment, said detection means comprise electrical connectors arranged at the tip of the device and an ohmmeter.
According to a third embodiment, the detection means comprise a “Hall effect” sensor arranged in the tip of the device.
According to a fourth embodiment, said detection means comprise an optical sensor, a first optical fiber and a second optical fiber, the first and second optical fibers being arranged inside the stem so as to respectively light the cavity of the screw head and bring the reflected light to said optical sensor.
According to a fifth embodiment, said detection means comprises a tracker rigidly attached to the device.
Another object of the invention is a surgical system for alignment of surgical guide means with respect to a solid, said system comprising:
a positioning unit comprising a fixed part that is fixed with respect to the solid and a mobile part supporting the surgical guide means, the position of said mobile part being adjustable with respect to the fixed part by screws, a referencing unit for detecting the position of the positioning unit with respect to a target position of the surgical guide means, a control unit for computing the target position of screws,
said system being characterised in that it comprises a device as described above for adjusting the positions of the screws.
The surgical guide means are generally drill guides or cutting blocks.
In one embodiment of the invention, the control unit is connected to an imaging system and the referencing unit comprises calibration markers that are detectable by the imaging system.
The referencing unit can be removably attached to an attachment unit rigidly fixed to the solid.
In another embodiment, the control unit is included in a navigation system and the referencing unit comprises a first reference element attached to the solid or to the fixed part of the positioning unit, that generates a first three-dimensional reference tracker, which is independently registered in the navigation system and a second reference element applied to the mobile part of the positioning unit that needs to be adjusted, that generates a second three-dimensional reference tracker, which is independently registered in the navigation system.
The position of the mobile part of the positioning unit is adjusted to a target defined by use of the navigation system, and the control unit determines the number of turns of the screws necessary to reach the target.
Advantageously, the system comprises means for indicating to the user which screw must be turned and how many turns must be applied to each screw to reach the target
The system may also comprise a ruler on the positioning unit and/or on the adjustment device to adjust each screw.
In one preferred application of the invention, the system comprises an attachment unit for attachment to the spine of a patient, a referencing unit attached to the attachment unit and a positioning unit attached to the attachment unit and/or to the referencing unit, the positioning unit comprising four screws for adjusting the position and/or orientation of a drill guide.
In another preferred application of the invention, the system comprises an attachment unit for attachment to the femoral head of a patient, a referencing unit attached to the attachment unit and a positioning unit attached to the attachment unit and/or to the referencing unit, the positioning unit comprising four screws for adjusting the position and/or orientation of a drill guide.
In application of the invention to knee surgery, the positioning unit comprises a fixed part for attachment to the tibia or to the femur of a patient, a mobile part supporting a cutting plane and three screws for adjusting the position of the cutting plane with respect to the fixed part.
In another advantageous embodiment of the invention, the positioning unit is a spacer comprising two parallel plates and a screw for adjusting the distance between the plates.
The invention relates generally to surgical systems for alignment of surgical guides or instruments with respect to a well defined target (e.g. a planned cutting plane or a planned drilling bore in an object such as a bone).
Such surgical systems comprise:
a positioning unit, comprising a fixed part which is fixed with respect to the operated structure or object such as a bone, a mobile part supporting the surgical guide; the position of the mobile part with respect to the fixed part can be adjusted by screws. a referencing unit, which function is to allow the determination of the position of the positioning unit with respect to the target; depending on the method involved, the referencing unit can comprise calibration markers that can be detected by an imaging system, or, when a navigation system is used, the referencing unit comprises trackers attached to the fixed part (or directly to the object) and to the mobile part.
An adjustment device that will be described in detail below allows an automated adjustment of the screws to the target position.
The adjustment device is driven by a control unit that is linked (wired or wireless) to the imaging system or to the navigation system, the control unit being able, taking into account the position of the positioning unit and of the target, to compute the number of turns to apply to each screw to reach the target.
In some cases, the fixed part of the positioning unit can be fixed directly to the object, e.g. by pins, or indirectly, the fixed part being thus fixed to an attachment unit which is itself rigidly fixed to the object.
More generally, the adjustment device is adapted for adjusting the position of any screw that is able to move a part of a surgical instrument.
Not only fixed positions (poses) count for a fixed spatial relationship, but all determinable or known relationships, from which the poses of the positioning unit and the referencing unit are determinable.
A positioning unit of the herein mentioned type is used for the spatial positioning (adjustment) of surgical guiding means. The referencing unit is used for determining the location of the positioning unit by means of 2D or 3D image data. The fixed spatial relationship between the referencing unit and the positioning unit can be discontinued temporarily. This can be used in particular for cleaning or adjustment of the positioning unit. Furthermore the temporary disconnection can have the advantage that the positioning unit is not attached to the patient in order to avoid having cumbersome components within proximity of the patient when using the positioning unit. For performing the surgical act (e.g. drilling in the spine) the spatial relationship is established again.
Using calibration markers included in a referencing unit, the position of the referencing unit with respect to images (or accordingly the orientation or accordingly the pose, whereas these analogies are valid for the remainder) can be determined. Several methods are known to calibrate the geometry of an imaging device and correct distortion of images at the same time.
For instance, in [ 11 ], calibration markers of a specific referencing unit are automatically detected by a computer that digitizes fluoroscopic 2D images and the known spatial arrangement of the individual markers makes it possible to compute a perspective matrix between coordinates of points in a coordinate system attached to the image and coordinates of points in a coordinate system attached to the referencing unit. In the case of 3D fluoroscopic images, standard point to point registration techniques can be used to match the markers detected in images with a known model of the spatial arrangement of those markers [12 ]. Hereby the calibration markers can have various types or shapes or arrangements, such as spheres, crosses, or Z-shaped structures like in standard stereotactic frames or registration features [13] for example. Based on these shapes and structures, an unambiguous determination of the position of the referencing unit can be carried out.
In a preferred embodiment the referencing unit is fixed to the fixed part of the positioning unit, and the position of the positioning unit is determined with respect to the medical images on which the target is defined.
For instance, in the case of 2D fluoroscopic images, the referencing unit contains at least 5 markers (usually 10 or 20) whose accurate positions are known by manufacturing in the coordinate system of the fixed part of the positioning unit to which it is attached in a reproducible manner. Standard x-ray image calibration techniques based on perspective matrices are used to register the image coordinate system with a coordinate system attached to the fixed part of the positioning unit. If necessary, an image distortion correction is performed at the same time by using the marker geometry as a reference or by using a secondary set of calibration markers arranged in a plane roughly parallel to the image plane. Those methods are well described in the literature. With at least 2D fluoroscopic x-ray images, it is possible to define a 3D surgical tool position or trajectory. The instance of a linear trajectory is taken. If the user defines a target trajectory on those x-ray images using a computer and a user interface, the target trajectory is therefore reconstructed in 3D in the coordinate system of the fixed part of the positioning unit. The mobile part position derives from the fixed part by the lengths of the screws. The kinematic model of the positioning device makes it possible to compute the position of the surgical guide from a series of screw length values. It is therefore necessary to invert the kinematic model to calculate the value of each screw such that the surgical guide will coincide with the target. Inverting a kinematic model is usually performed by using simple geometric rules for a parallel architecture and it depends on each specific mechanical design. This uses standard techniques developed for robotic control.
Hereby a defined adjustment of the mobile part of the positioning unit can be realised, which can be in particular based on a dataset defined in the computer.
By the fact that the positioning unit does not contain any active electrical components, electrical components cannot constitute a risk directly at the patient. Active electrical components comprise all components with an electric current flowing through them. Contrary to active components, passive components can be present with no risk, they are less cumbersome device, and they are less expensive.
In one embodiment of the invention, the positioning unit can have surgical guide means which comprise in particular drill guides or cutting jigs in such an advantageous way that the surgical guiding means can be moved or positioned in a defined way by the positioning unit using a plurality of screws.
In another embodiment of the invention, the surgical positioning unit can include an attachment unit, which allows to be attached to the anatomy. Hereby the positioning unit can be attached or detached to/from the attachment unit in an advantageous way. This can increase the versatility of the system. Furthermore it can be advantageous, that the adjustment is not done on the patient directly.
In a preferred embodiment of the invention, the referencing unit can be a part of the surgical guide means and/or of the positioning unit and/or of the attachment unit. It is hereby preferred, that the referencing unit is a part of the attachment unit, since the attachment unit emerges directly near the anatomical structure, which causes the referencing unit to be realised close to the anatomical structure. This can increase the quality and the success of the surgery.
If the referencing unit is attached to the positioning unit, the position of the positioning unit can be determined advantageously directly and hence a zero balance, which defines the start position for adjustment of the positioning unit, is determined. When realizing the referencing unit as a part of the surgical guide means it is especially advantageously that the surgical guide means can be coded separately. This coding can also be done for the positioning unit and the attachment unit with the markers.
In the case where calibration markers are set on the mobile part of the positioning unit only and there is no referencing unit on the fixed part nor on the attachment part, then it is necessary to know the previous values of each screw length to compute the necessary screw length values to reach the target. Such knowledge can be acquired by the user who enters data in the computer of the control unit or by using a ruler in the adjustment unit that measures screw lengths when it is in contact with the positioning unit.
In another embodiment of the invention, the calibration markers can be primarily be manufactured with X-ray visible and/or MRI visible material. Hereby the calibration markers can be localised advantageously using X-ray or MRI imaging methods, thus allowing determining the position of the referencing unit.
In another embodiment of the invention, the calibration markers can be primarily manufactured with X-ray invisible and/or MRI invisible material. Hereby the calibration markers can be localised advantageously with a higher contrast with respect to the other parts of the positioning unit. Furthermore the determination of the calibration markers can become easier.
In order to obtain a detailed image data set, the computer can straighten the image data and correct for image distortion. Therefore the computer can determine the relative positions of the different calibration markers between each other and hence establish the correction parameters accordingly.
In another embodiment of the invention, the referencing unit can feature several referencing units. Each referencing unit can carry out the position determination based imaging method analogue to the function of the referencing unit. Hereby several positions for the surgery guide means can be determined with one or several images in an advantageously way, such that these positions can be determined independently. Hence it is especially realisable that in case of several fractures or damages at different places at the spine, an intervention is carried out with one data set that has been acquired with an imaging system.
In another embodiment of the invention the positioning unit can be attached in a defined way at different locations on the attachment unit. Hereby the workspace can be increased in an advantageous way.
In another embodiment of the invention, the positioning unit can encompass means for angle detection. Hereby the position and/or the orientation of the positioning unit can be determined especially in an advantageous way. This can increase the safety for the patient.
In another preferred embodiment of the invention, the positioning unit can feature a readable scale or ruler. This allows increasing the safety for the patient, since the surgeon can verify the data.
In another embodiment of the invention, the positioning unit can be designed in a modular way. Hereby the positioning unit can be advantageously assembled in a reduced workspace, since the positioning unit can be made of parts/modules of different sizes thanks to the modularity.
Furthermore, the task can be achieved by a surgical positioning system, whereas the surgical positioning system comprises a surgical positioning unit according to the former description and an adjustment device. The adjustment device can be in particular designed as a wireless screwdriver. Furthermore the adjustment device is used for adjusting the positioning unit. By acting of the adjustment device on a screw of the positioning unit, the positioning unit can be designed to be adjustable.
Advantageously the adjustment of the positioning unit can be controlled by the user thanks to the adjustment device. Hereby the speed of the adjustment can be carried out depending on the pressure. As soon as the target position of the screw has been reached, the adjustment for this screw can be stopped.
In another embodiment of the invention, the adjustment device can act on the positioning unit in a coded way. Acting in a coded way shall mean that acting or correspondingly activating the screw can only occur if the coding allows it. Hereby a wrong activating or a wrong order while adjusting the screws can be avoided.
Hereby especially a signalisation for the user can be achieved by the coding, in particular if the correct actuator element is activated. This can be especially displayed by LED or display. Additionally the display could show the advancement of the adjustment that means for instance the number of remaining revolutions or turns of the screws.
In a further embodiment of the invention, the coding or identification of screws can be implemented electrically and/or mechanically and/or optically. Hereby especially the electrical coding can be realized by RFID chip or resistor coding implemented with defined areas of materials with different conductivity. The mechanical coding comprises different attachments on the adjustment device, whereas the attachments mechanically coded can be associated to certain screws. This corresponds to the key-lock system.
Furthermore the mechanical codings can have different surface designs or different hexagonal cavities. The coding can be in particular designed in such a way that several features are captured simultaneously for identification. The redundant coding can have the advantage, that the possibility of a wrong coding is minimized (e.g. in case of pollution of the coding, a wrong mechanical depth or a wrong resistance could be measured).
In another embodiment of the invention the adjustment can be carried out relatively to a stationary not moving part. Hereby it can be determined in a advantageous way, how many (partly) revolutions a screw has been turned relatively to a defined angle
The optical codings could be colour differences or barcodes or areas scanned by a laser which once read can be associated to a screw.
In order to determine the position of the screws, the screws can comprise another coding, whereby a relative adjustment is feasible. In particular this can be performed in such a way that next to a screw a boring is placed with an angle ALPHA. Hereby the screw can complete several entire revolutions and/or a partial revolution with respect to the zero angle (ALPHA).
In order to achieve surgical security and a higher quality of the intervention, the coding can be designed in a redundant way. This can be accomplished in particular by two coding systems (e.g. optical and electrical).
In another embodiment of the invention, the surgical positioning system can comprise a computer, whereby there is a software running on the computer, whereby the software displays the image data and an operator defines or determines accordingly a position for the surgical guide means and the software determines screw parameters for the positioning unit with respect to the referencing unit. These screw parameters can be transferred to the adjustment device which thus can position the screws of the positioning unit.
Hereby the operator can exactly determine the position of the trajectory that constitutes a target to reach. Furthermore the data that were determined can be stored electronically for quality assurance. Not only the surgeon who takes responsibility for the intervention is considered as the operator as a single person but it can also be a team of persons being involved in the surgery and where each person only realizes a certain sub task. Meant are those persons that are involved in the success of the here described activities, steps and features.
Furthermore the task is achieved by a method for aligning of surgical guide means, whereby the former described surgical positioning system is used and whereby the method comprises the following steps:
Attaching the surgical positioning unit to the anatomy in particular by clamping and/or tightening with screws of the attachment unit to the spine or an anatomical structure. Performing the medical imaging, in particular establishing multiplanar X-ray images and/or establishing of a volumetric data set, whereas at least parts of the referencing unit as well as of the bone to be treated are imaged Transferring of the dataset to the computer and determination of the pose of the surgical guide means by the operator and determining the position of the referencing unit and a set of corresponding screw parameters for the positioning unit.
By attaching the surgical positioning unit to the anatomy, a rigid basis for parts of the positioning unit can be established.
By the fact that parts of the referencing unit and parts of the treated bones are available in the computer thanks to the imaging, the operator can determine the optimal trajectory for his intervention and these data can be used for computing the positioning unit. Furthermore the computer can perform hereby the referencing automatically.
The last described step can be performed also in another advantageous order. Thereby the transfer of the data set is done first, then the determination of the pose (position) of the referencing unit by the computer, subsequently a definition of the desired pose (position) of the surgical guide means and at last the determination of a set of corresponding screw parameters by the computer.
In a further embodiment of the method, the step of connecting the surgical positioning unit to the anatomy can comprise the following further steps: attaching the attachment unit to the anatomy, attaching the referencing unit to the attachment unit and attaching the positioning unit to the referencing unit and/or to the attachment unit, whereas the last step can also be carried out later in the course of the method. By this further step of connecting the surgical positioning unit to the anatomy can be advantageously further divided and hence the quality of the surgery can be increased. Hereby, the adjustment of the positioning unit can be performed advantageously not at the patient directly.
In a further embodiment of the method, the method can comprise the step of transferring the screw parameters to the adjustment device. Hereby the screw parameters can be advantageously stored in the adjustment device.
In a further embodiment of the method, the method can comprise the step of adjusting the positioning unit by the adjustment device. Hereby, errors occurring during transmission of the position data for the surgical guide means can be reduced. Preferably the data can be transferred in the computer connected to the positioning unit. The adjustment device can subsequently adjust the positioning unit accordingly. Hereby the adjustment device can preferably designed mobile in order to move it to the positioning unit.
In order to carry out an exact adjustment, the screws can be turned first into one direction until bedstop and then moved in the other direction until reaching the target parameter.
In order to gain good access to a concerned bony structure, exposing of the necessary bony structures can be done prior of attaching the surgical positioning unit to the anatomy. Exposing of the necessary bony structures can be advantageously be performed by the surgeon.
Preferably, the method can comprise the following steps in the following preferred order:
The referencing unit is attached for the imaging methods The referencing unit is removed. The parameters are determined by the computer The positioning unit is adjusted The positioning unit is attached to the attachment unit
In a preferable embodiment, the adjustment device identifies the screw to which it is attached by the coding of the screw before the adjustment of said screw.
The expert can according to requirements of the intervention modify this preferred order without altering the scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
In the following the invention is further explained by examples of different embodiments, in reference to the following figures, wherein:
FIG. 1 is a sequential view showing a conventional screwdriver positioned into the screws of a surgical instrument.
FIGS. 2A and 2B show the adjustment device according to the invention.
FIG. 3A is a partial sectional view of the device stem, device tip, and instrument screws, where the auto-detection of the screw is done by a mechanical solution.
FIG. 3B is a view of the screw head adapted to recognize the tip of the adjustment device.
FIG. 4 is a partial sectional view of the device stem, device tip, and instrument screws, where the auto-detection of the screw is done by an electrical solution.
FIG. 5 is a partial sectional view of the device stem, device tip, and instrument screws, where the auto-detection of the screw is done by a magnetic solution.
FIG. 6 is a partial sectional view of the device stem, device tip, and instrument screws, where the auto-detection of the screw is done by an optical solution.
FIG. 7 is a sequential view of the adjustment device, the navigation system, and the instrument, where the auto-detection of the screw is done by a tracking solution.
FIG. 8 illustrates a cutting slot which is adjusted by three screws with respect with the fixed part fixed to the tibial bone.
FIG. 9 illustrates an embodiment of the fixed part used in spine surgery.
FIG. 10 illustrated the attachment of a referencing unit to the fixed part of FIG. 9 .
FIG. 11 is a view of the mobile part supporting a drill guide for spine surgery that is adjustable by four screws.
FIG. 12 is a view of the adjustment device operated with the mobile part of FIG. 11 .
FIG. 13 illustrates x-ray images of the planned drill axis in a vertebra.
FIG. 14 shows an embodiment of the fixed part adapted for hip surgery.
FIG. 15 is an x-ray image of the fixed part, a referencing unit fixed thereon
FIG. 16 is a positioning unit supporting a drill guide for hip surgery.
FIG. 17 shows another embodiment of a fixed part suited for hip surgery.
FIG. 18 is a surgical procedure flow diagram, showing how the surgeon is supposed to interact with the navigation system to adjust the desired instrument position.
DETAILED DESCRIPTION OF THE INVENTION
Adjustment Device
As represented on FIG. 2 , the adjustment device 4 according to the invention is an actuated screwdriver that comprises a body or handle 40 , a stem 41 , a tip 42 , an optional button 43 that is activated by the user, and an encapsulated battery that brings enough power to rotate the screwdriver.
In a preferred embodiment, the actuation of the screwdriver is done by a motor. In a preferred embodiment the motor is a brushless motor which directly provides feedback on number of turns performed using its internal coding system. But alternatively many other solutions of actuators can be used to rotate a screw, such as piezoelectric actuators. The screw can be replaced by any non reversible linear motion mechanism, such as hydraulic or pneumatic mechanism, and the actuator can be any device that provides a linear motion of said mechanism.
As better seen on FIG. 3A , the stem 41 is rotating with respect to the device body 40 thanks to a rolling system 44 . The rotation is controlled by a motorized system 45 . It must be noted that the devices illustrated on FIGS. 4 to 7 also comprise said rolling and motorized systems, although these features are not shown on these figures.
The device is controlled by the control unit 21 of the navigation system or by the control unit of the imaging system, depending on the way the position of the instrument is determined. The controlled parameters are: turn direction, number of turns, turn speed, turn acceleration and stop. The number of turns and the direction are parameters given by the computer and transmitted through the wireless protocol to the device.
The device communicates with the computer through a wireless protocol, such as Wifi or Bluetooth or ZigBee. In one preferred embodiment, the wireless communication is based on the Bluetooth communication protocol. Optionally, the communication can be also performed by standard wires with a standard wire and communication protocol such as USB, Ethernet, IEEE 1394, RS232, or a proprietary wire and communication protocol, and in that case the power supply is also brought by a cable.
In a simple embodiment of the invention, the computer display indicates to the user the screw in which the screwdriver must be placed. When the user has placed the screwdriver in the head of the screw indicated on the screen, the user presses a button and the screwdriver moves the screw to the target position. The operation is repeated for each screw. If the user misses one screw the computer display shows which screw must be readjusted until the final position of the guide matches the target. For instance, the screw that has the most important number of turns to be accomplished is suggested to the user. Or the screw are always adjusted in the same order, starting by screw 1 , then 2 , until screw N and the process is iterated by skipping screws that already reached the target position with a predefined limit.
Depending on the kinematic structure (e.g. containing singularities) some screws will have to be adjusted more than once in a defined order.
In the case of the adjustment of a drill guide (see FIGS. 11 , 12 , 16 ), the calculated data are transferred to the device 4 . Using a RFID identifier, a single screw (corresponding to one degree of freedom) can now be adjusted in a defined way with the adjustment device in the positioning unit. Once all degrees of freedom are adjusted this way, the drill guide 15 is aligned optimally to a target defined on images and a defined drilling can be carried out.
FIG. 2B shows additionally a possible type of coding. Using the identifiers 46 the correct device 4 or the corresponding correct stem 41 and tip 42 for the device 4 can be determined. This stem 41 engages in the screw head 130 . The tip 42 engages into the screw head cavity 131 which comprises a mechanical resistor element 133 . The coding is established by the shape of the screw head cavity 131 (see FIG. 3B ).
The term screwdriver is used without loss of generality. It means an external mechanism to turn a screw in a given direction. It is also possible to use several mechanisms to grab the screw head by friction or pressure only when a go button is pushed so that the screw cannot be turned manually when the device comes in contact with the screw head, which eliminates parasite motions of the screw.
It is also possible to design a motorized screwdriver such that the handle contains only the stator part and the screw head contains the rotor part, or vice versa. In such mechanism, the handle of the screwdriver can be purely made of coils and it is easily covered by a sterile drape since it has no turning part. In this case, the screw head is a set of miniature coils.
There exist many other adjustment devices principles that can be used to turn the screw with a handy device.
Automatic Detection of the Screw ID
Advantageously, the adjustment device comprises detection means for determining the identification (or code) of the screw the tip is in contact with. Depending on the various embodiments disclosed below, each screw possesses within the navigation system identification (ID) means to distinguish it from the others.
In one preferred embodiment, illustrated on FIG. 3 , the adjustment device detects which screw the tip is in contact with by a mechanical solution. To that end, a thin rigid mechanical stem 50 is sliding inside the device stem 41 . By using the rigid mechanical link between the stem 50 , the body 54 , and the position cursor 51 , the contact between the sliding stem 50 and the screw's head cavity 131 determines the value of the position sensor 52 . When the tip is not inserted into the screw's head 130 , a spring 53 places the position sensor 52 at its default position. When the tip is in the screw's head 130 , the position sensor 52 measures the depth d of the screw's head cavity 131 . This depth is measured and transmitted to the control unit of the navigation system 2 by the wireless communication. Each screw's head cavity 131 has a different depth d, so that the position sensor delivers a different value for each screw, allowing the control unit of the navigation system to know which screw the device is about to activate.
In another embodiment, illustrated on FIG. 4 , the adjustment device detects which screw the tip is in contact with by an electrical solution. In this case, a resistance 60 is inserted into the screw's head 130 linked by two electrical wires 61 , 62 respectively to two connectors 63 , 64 that are on the bottom surface of the screw's head. In the device stem and tip are inserted two electrical wires 65 , 66 that are respectively connected to two connectors 67 and 68 that are on the extremity of the device tip. When the tip is in the screw's head 130 , the connectors 63 and 67 are in contact, as well as the connectors 64 and 68 . It allows the device to measure the tension thanks to an ohmmeter 69 . This tension is measured and transmitted to the control unit of the navigation system by the wireless communication. Each screw's head has a different resistance value r, so that the ohmmeter 69 delivers a different value for each screw, allowing the control unit of the navigation system to know which screw the device is about to activate.
In another embodiment, shown on FIG. 5 , the adjustment device detects which screw the tip is in contact with by a magnetic solution. A magnet 70 is inserted into the screw's head 130 . A “Hall effect” sensor 71 is inserted into the device tip that delivers a tension that is dependent of the distance between the magnet 70 and the sensor 71 . This tension is measured and transmitted to the control unit of the navigation system by the wireless communication. Each screw's head has the same magnet but inserted at a different depth d, so that the sensor 71 delivers a different tension for each screw, allowing the control unit of the navigation system to know which screw the device is about to activate.
In another embodiment, illustrated on FIG. 6 , the adjustment device detects which screw the tip is in contact with by an optical solution. To that end, a cavity 131 is inserted into the screw's head 130 . The bottom 132 of the cavity 131 is painted with a uniform color or with a pattern such as a bar code. A first optical fiber 80 carries light 81 from the device stem to the cavity 131 , in order to light the cavity 131 . A second optical fiber 81 carries the light 83 from the cavity to the device stem and then to an optical sensor such as a micro camera (not shown). The image delivered by the second optical fiber 82 is transmitted to the control unit of the navigation system by the wireless communication. Each bottom 132 of screw's head cavity 131 has a different color or different pattern, allowing the control unit of the navigation system to know which screw the device is about to activate.
In another embodiment, shown on FIG. 7 , the adjustment device detects which screw the tip is in contact with by a tracking solution. A tracker 90 is rigidly fixed to the device 4 . One knows by design the device tip position in the device tracker 90 coordinates system. One knows by design the screw's head position in the instrument tracker 10 coordinates system. Then, once the device tip is inserted into a screw's head, the control unit of the navigation system 2 can determine which screw's head the device tip is inserted in, allowing the control unit of the navigation system to know which screw the device is about to activate. If the accuracy of the navigation system is not sufficient, it can be compensated by adding a simple mechanical contact sensor that detects that the tip is in contact with the screw head.
In another embodiment (not illustrated here), the adjustment device detects which screw the tip is in contact with by a software solution: before the device activation, the navigation system records the position of the Instrument, called the initial position. When the user presses the activation button, the device turns as first step the stem in a constant known direction (e.g. clockwise). The navigation system then tracks the movement of the mobile part of the instrument. By taking into account the design of the screw, the design of the Instrument, the given rotation direction and the number of turns that were applied, one can determine the unique screw that brought the instrument to this current position. Then, once the screw ID is determined by this first stem actuation, the device can then rotate the stem in the correct rotation direction with the correct number of turns to reach the target position.
In all that precedes the control unit of the navigation can be replaced by the control unit of the imaging system, if a medical imaging system is used instead of a navigation system to define the target of the positioning unit.
Surgical Procedure Flow Diagram (with Navigation)
In the example where a navigation system is used, the surgical procedure flow diagram for adjusting the position of a cutting plane as shown on FIG. 8 is composed of steps [A], [B], [C], [D] and [E] that are described in FIG. 18 .
[A] The control unit 21 computes the current position of the mobile part 12 of the positioning unit with respect to the solid 3 thanks to the instrument tracker 10 , the solid tracker 30 , and the localizer system. [B] If the current position is the target position then the procedure exits. [C] If the target position is not reached, then for each screw 13 i , where i is equal to 1, 2 or 3, the computer computes the unique number of turns Ti that needs to be applied on 13 i , so that the mobile part 12 reaches the target position. Ti is positive if the rotation direction is clockwise and negative if the rotation direction is counter-clockwise. For that computation, the computers needs to know the target position of the instrument, which is selected by the surgeon, the screws parameters (diameter, thread length, thread thickness), which are known by design, the screws positions on the Instrument, which are known by design. [D] The navigation system instructs the user which screw needs to be activated:
i. In one preferred embodiment, the user is instructed to place the device tip 42 on a given screw's head. The computer displays on the screen which screw's head the device tip 42 must be placed on. In one preferred embodiment, each screw's head has a unique color, and the computer displays the color of the screw on the screen. In another embodiment, each screw's head is labeled with a unique number (such as 1, 2, 3), and the computer displays the number of the screw on the screen. In another embodiment, each screw's head is labeled with a unique letter (such as A, B, C), and the computer displays the letter of the screw on the screen. Screws can be also differentiated simply by their position on the instrument or by their shape. The user needs to follow the screws order displayed by the computer.
ii. In another preferred embodiment, the user is instructed to place the device tip 42 on a given screw's head. Each screw's head has a unique characteristic such as color, or number, or letter as detailed in (i). The computer computes on which screw's head the device tip 42 must be placed on. The information is then transferred from the computer to the device by the wireless communication protocol. The device then instructs the user by displaying the information on itself, preferably on the top of the handle of the screwdriver. It can be by lighting some colored LEDs if screws are identified by a color, by lighting a letter if screws are identified by a letter, or by lighting a number if screws are identified by a number. The user needs to follow the screws order displayed by the computer or displayed on the handle of the screwdriver.
iii. In another preferred embodiment, the user is not instructed to place the device tip 42 on a particular screw's head. The user can independently choose any screw's head, whatever the order is. The device detects when the tip is in contact or not of the screw's head, and detects which screw it is in contact with, and communicates the screw ID to the navigation system by the wireless communication protocol such that the adjustment necessary for that particular screw is known. Alternatively, these parameters can be first stored in the driver.
[E] Then the user presses the button 43 to activate the adjustment device. If the device is used with automated detection of contact and identification of screw head, pressing a button is not necessary and the device is activated automatically. The device stem 41 then turns the given number of turns Ti that was determined by the computer to reach the target position of the instrument. Once the device stem 41 has turned the desired number of turns Ti, the stem rotation stops, instructing the user that the target position for the screw 13 i has been reached. Optionally, the navigation system 2 can check that the mobile part 12 has reached the desired position for that particular screw and if it is not the case, send an updated command to the screwdriver to add more portions of turn in order to adjust it accordingly and this process can be repeated until the position of the mobile part 12 has reached the desired position within a given arbitrary accuracy such as 0.2 mm for instance, which is done like a standard servoing mechanism. Then the instrument position is updated and the process goes to step [A] for setting other screws to the desired positions. The global process is iterated until all screws have reached their desired position such that the mobile part is now in its final target position for all desired degrees of freedom.
To reach a target screw position, there exist many possible methods to control the motors in order to optimize the speed of the process:
A first method consists in measuring the position of the mobile part before the screw has reached its final position using the navigation system and iterating the command on the motors that take into account the measured position and the target position. Standard control commands can be used to optimize the speed and convergence of such process, for instance using well known Proportional Integral Derivative (PID) commands. Another method consists in turning the motor in the right direction with an increasing speed and then decreasing speed when the motors reach the expected position and finally stopping the motor when it is very low speed so that the measurement taken with the navigation system can be done with averaging and the time delay to stop the device is compliant because of low speed. There exists many additional ways of optimizing the command by using the measurements of the final position of the mobile part using navigation system or by using the measurements of the motor controller that often provide the number of turns performed by the motor, with a division of such number by mechanical reduction. It is also possible to combine both measurements in real time in order to optimize and stabilize the convergence towards the target position.
In some situations, the relationship between the screws is not independent, and it is therefore necessary to adjust some screws before adjusting other screws and coming back to the first screws to be able to reach the desired target. The system can easily predict those situations and optimize the paths between those maneuvers to limit the number of iterations.
Parallel Architectures
In a preferred embodiment, the positioning unit that is used in conjunction with (a) a navigation system or (b) a referencing unit and medical images uses a parallel mechanical architecture instead of a serial architecture.
The advantage of a parallel architecture is the stiffness of the positioning unit such that the mobile part on which the guide or instrument is mounted has a stable relationship with respect to the anatomical structure for any position of the screws that activate individual degrees of freedom of the parallel architecture.
A drawback of a parallel architecture is that it is usually difficult to adjust the screws manually and individually to reach a desired global position because each screw influences all parameters of the global position. Degrees of freedom are strongly correlated together.
However, using the adjustment device which positions automatically the screws to a defined position determined by the computer eliminates this drawback and only the advantageous aspects of this architecture remain.
Manual Adjustment
In a backup mode of functioning, the computer of the control unit simply displays to the user the number of turns to be applied on each screw.
In a preferred embodiment, a ruler can be attached permanently or temporary to each screw to make it possible the adjustment of each screw without the adjustment device. The ruler can be integrated to the positioning unit (see FIG. 16 ) or can be provided directly on the screwdriver.
EXAMPLE 1
Spine Surgery with Medical Imaging
According to a first advantageous embodiment of the invention, illustrated on FIGS. 9-12 , the adjustment device can be utilized in spine surgery performed with medical imaging.
FIG. 9 shows a detail of a spine 3 with several vertebral bones.
An attachment unit 11 ′, which can be seen on side and upper views, is an percutaneous support having a general H shape for supporting a positioning unit for a drill guide (not shown here).
The pins 31 are used for attachment of the attachment unit 11 ′ to the spine 3 .
Thanks to the flanges 32 , different positions for the attachment of the positioning unit and/or the referencing unit (not shown here) are possible.
At the same time the flanges 32 can be used as X-ray visible markers.
Optionally, four screws 33 are used as an additional stabilization for support on the skin, whereas the screws 33 can be likewise designed as markers.
FIG. 10 depicts an attachment unit 11 ′ in different views.
The top view shows a referencing unit 34 that is attached orthogonally to the fixed part 11 .
This orthogonal referencing unit 34 comprises among others also squared markers 32 .
In the top and middle views it can be seen positioning points which are designed as markers 32 .
The bottom view illustrates a x-ray image which shows the spine 3 and markers 32 .
FIG. 11 shows a surgical positioning unit which is located at spine 3 .
The attachment unit 11 ′ with the referencing unit 34 including the corresponding markers is flange mounted to the vertebrae via pins 31 .
The fixed part 11 of the positioning unit is mounted on the referencing unit 34 (not shown here).
The actuator elements of the positioning unit are four screws 13 that can adjust the mobile part 12 and thus the drill guide 15 in a defined way.
The mechanism uses two pairs of screws 13 .
A lower pair of screws 13 at fixed level Z 1 moves a ball and socket joint 12 in a small plane to a defined target (X 1 , Y 1 ) in a limited range that constitutes a first small two-degrees of freedom parallel architecture.
An upper pair of screws 13 at fixed level Z 2 moves a ball and socket joint 12 in a small plane to a defined target (X 2 , Y 2 ) in a limited range that constitutes a second small two-degrees of freedom parallel architecture.
The upper and lower pairs of screws 13 are connected on their basis and constitute a four-degrees of freedom positioning unit.
The drill guide 15 is passing through the two points (X 1 , Y 1 , Z 1 ) and (X 2 , Y 2 , Z 2 ) which define a linear trajectory. Acting on (X 1 , Y 1 ) with the first pair of screws and on (X 2 , Y 2 ) using the second pair of screws makes it possible to reach any linear target in a limited range.
To that end x-ray images are acquired for the entity shown in FIG. 11 and transferred to the computer.
Based on the markers determination, the position of the drill guide 15 can be determined.
For this the positioning unit (in zero position), the drill guide 15 , the attachment unit 11 ′ including referencing unit 34 with markers 32 and the displayed parts of the spine 3 have defined positions to each other.
In the present embodiment the operator has positioned the positioning unit already at the patient in such a way that the drill guide 15 must be modified only slightly.
Using the x-ray images available in the computer and the corresponding coordinates the operator determines the trajectory of the boring in the vertebra.
The computer computes the adjustments of the drill guide 15 using the coordinates such that the extension of the drill guide 15 coincides with the planned boring in the vertebrae.
As shown on FIG. 12 , the adjustment device 4 is then operated to turn the screws 13 by the appropriate number of turns.
FIG. 13 shows an x-ray image of the attachment unit 11 ′ and the planned drilling bore 16 .
EXAMPLE 2
Hip Resurfacing Surgery with Medical Imaging
A second advantageous embodiment of the invention, illustrated on FIGS. 14-17 , the adjustment device can be utilized in hip surgery performed with medical imaging.
For the use of the surgical instrument the positioning unit must be attached to the object being operated (here, the femoral head).
As one can see from FIGS. 14 and 15 , this is achieved by a clamp mechanism which is implemented by the attachment unit 11 ′. The attachment unit 11 ′ is flange mounted to the femoral head 3 of the bone, such that there is an essentially rigid connection.
As one can deduce from the x-ray image in FIG. 14 , the referencing unit 34 is flange mounted to the attachment unit 11 ′. The referencing unit 34 comprises additionally x-ray visible markers 32 , whereby two x-ray images (e.g. lateral view and frontal view) allow determining the coordinates in space.
There are further functions that can be implemented via the markers 32 in particular the flange mounting of a unit with screws. For that purpose a boring for example can act as an essentially x-ray invisible material. With this boring a flange mounting is possible with screws.
With the computer program shown in FIG. 15 , the operator can define the exact trajectory of a boring 16 inside the bone or correspondingly in the femoral head 3 .
Thanks to the coordinates of the referencing unit 34 , which is designed as attachment unit at the same time, and the planned boring 16 , the computer which hosts the software program can determine the adjustment of surgical guide means (not shown here) using the mobile part (not shown here).
FIG. 16 shows a positioning unit 17 which comprises four degrees of freedom of adjustment for adjusting the surgical guide means (which is here a drill guide 15 ).
Such a positioning unit 17 has a scale used to target positions in a defined manner that were computed before by the computer.
The positioning unit 17 comprises a fixed part 11 that can be attached to the attachment unit, and a mobile part 12 that supports the drill guide 15 .
The positioning unit 17 also comprises an upper plate 170 and a lower plate 171 and is provided with screws 13 that are able to move the mobile part 12 with respect to the fixed part 11 , thereby modifying the position and orientation of the drill guide 15 .
In order to guaranty high accuracy, all four adjustments for the different degrees of freedom are reset to 0.
FIG. 16 depicts the positioning unit 17 with the attachment unit 11 ′ as a detachable unit (modular design) which is hence directly flange mountable to the bone.
A further embodiment of the attachment unit 11 ′ is shown in FIG. 17 .
A collar 110 embraces a femoral head 3 and is locked with three screws 111 .
Additionally the collar 110 comprises markers 32 for determination of the coordinates.
Using the attachments 112 the positioning unit can be connected to the attachment unit 11 ′.
EXAMPLE 3
Knee Surgery with a Navigation System
In another preferred embodiment, illustrated on FIGS. 7 and 8 , the surgical application is the total replacement of the knee joint; the solid 3 is the patient's tibia or the basis of the instrument fixed to the tibia, and the tracker 30 , rigidly fixed to the bone, allows the navigation system 2 to track the tibia; the instrument 1 is a cutting block on which a cutting plane 14 must be aligned with the desired target plane selected by the surgeon; the instrument mobile part position is adjustable by three screws; the position of the three screws determine a unique position of the cutting block with respect to the fixed part 11 .
The cutting plane position is defined by a slope angle, a varus/valgus angle, and a cut thickness with respect to the tibia.
The target position is entered into the navigation system by the surgeon or set to default values with respect to anatomical landmarks digitized by the surgeon with the navigation system.
The goal of the device is then to adjust the position of the cutting block to the target position.
In one preferred embodiment, the surgical application is the total replacement of the knee joint; the solid 3 is the patient's femur or the basis of the instrument fixed to the femur, and the solid tracker 30 , rigidly fixed to the bone, allows the navigation system 2 to track the femur; the instrument 1 is a cutting block on which a cutting plane 14 must be aligned with the desired target plane selected by the surgeon; the instrument mobile part position is adjustable by three screws 13 ; the position of the three screws determine a unique position of the cutting block with respect to the fixed part 11 .
The plane position is defined by a slope angle, a varus/valgus angle, and a cut thickness with respect to the femur.
The target position is entered into the navigation system by the surgeon or set to default values with respect to anatomical landmarks digitized by the surgeon with the navigation system.
The goal of the device 4 is then to adjust the position of the cutting block in the target position.
EXAMPLE 4
Spacer Adjustment
In another preferred embodiment, not illustrated, the positioning unit is simply an adjustable spacer or distracter between two bones. A screw mechanism is used to move apart two parallel plates that generate a distance between two bones for ligament balancing check and optimization.
For example, one plate is positioned in contact with the tibia and the other one is positioned in contact with the femur, and the distance between the plates is adjusted by one screw.
Alternatively, 2 pairs of plates are located on the external and on the internal parts of the knee, thus being adjusted by two screws.
For adjusting quickly and precisely the spacer to a desired value, the actuated screwdriver is placed in the screw head and the number of turns is applied to obtain the desired distance.
It must be noted that the referencing method (navigation or medical imaging) is independent from the surgical instrument and application. Indeed, although knee surgery has been described with reference to a navigation system whereas hip resurfacing and spine surgery have been described with reference to an imaging system, the skilled person could practice knee surgery with an appropriate imaging system and hip resurfacing or spine surgery with a appropriate trackers of a navigation system.
REFERENCES
[1] Kosmopoulos V, Schizas C., Pedicle screw placement accuracy: a meta-analysis, Spine. 2007; 32(3): E111-20
[2] P. A. Grützner, A. Hebecker, H. Waelti, B. Vock, L.-P. Nolte, A. Wentzensen, Klinische Studie zur registrierungsfreien 3D-Navigation mit dem mobilen C-Bogen SIREMOBIL Iso-C 3D, Electromed. 2003; 71(1):58-67
[3] Schaeren S, Roth J, Dick W. Effective in vivo radiation dose with image reconstruction controlled pedicle instrumentation vs. CT based navigation, Orthopäde, 2002 April; 31(4):392-6
[4] P. Merloz, J. Tonetti, L. Pittet, M. Coulomb, S. Lavallee, J. Troccaz, P. Cinquin, P. Sautot, Computer assisted spine surgery: a clinical report, Comput Aided Surg. 1999; 3:297-305
[5] T. Laine, T. Lund, M. Ylikoski, J. Lohikoski, D. Schlenzka, Accuracy of pedicle screw insertion with and with-out computer assistance, European Spine Journal, 2000; 9(3):235-240
[6] L. P. Amiot, K. Lang, M. Putzier, H. Zippel, H. Labelle, Comparative results between conventional and computer-assisted pedicle screw installation in the thoracic, lumbar, and sacral spine. Spine. 2000; 25:606-614
[7] Sukovich W, Brink-Danan S, Hardenbrook M. Miniature robotic guidance for pedicle screw placement in poste-rior spinal fusion: early clinical experience with the SpineAssist. Int J Med Robot. 2006 June; 2(2):114-22],
[8] P. A. Grützner, A. Hebecker, H. Waelti, B. Vock, L.-P. Nolte, A. Wentzensen, Klinische Studie zur registrierungsfreien 3D-Navigation mit dem mobilen C-Bogen SIREMOBIL Iso-C 3D. Electromed. 2003; 71(1):58-67;
[9] Wendl K, von Recum J, Wentzensen A, Grützner P A. Iso-C (3D-assisted) navigated implantation of pedicle screws in thoracic lumbar vertebrae. Unfallchirurg. 2003 November; 106(11):907-13
[10] Sukovich W, Brink-Danan S, Hardenbrook M. Miniature robotic guidance for pedicle screw placement in posterior spinal fusion: early clinical experience with the SpineAssist. Int J Med Robot. 2006 June; 2(2):114-22
[11] Hamadeh A, Lavallée S, Cinquin P. Automated 3-dimensional computed tomographic and fluoroscopic image registration. Comput Aided Surg. 1998; 3: 11-19
[12] Horn, B. K. P.: Closed-form solution of absolute orientation using unit quaternions. Journal of Optical Society of America A. (1987), Vol. 4, p. 629
[13] Susil, R. C.; Anderson, J. H.; Taylor, R. H.: A Single Image Registration Method for CT Guided Interventions. Medical Image Computing and Computer-Assisted Intervention. MICCAI'99. Springer (1999), p. 798-808
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The invention concerns a device for adjusting the position of a screw ( 13 ) that is able to move a part of a surgical instrument, said device ( 4 ) comprising: —a stem ( 41 ) comprising a tip ( 42 ) suited to the head ( 130 ) of the screw ( 13 ), —an actuated system ( 45 ) for driving said stem ( 41 ) in rotation, —communication means to communicate with a control unit ( 21 ), such that the control unit ( 21 ) transmits to the actuated system ( 45 ) the number of turns to apply to the stem ( 41 ) to reach the target position of the screw ( 13 ). The invention also concerns a surgical system for alignment of surgical guide means ( 14, 15 ), comprising: —a positioning unit comprising a fixed part ( 11 ) and a mobile part ( 12 ) supporting the surgical guide means ( 14, 15 ), the position of said mobile part ( 12 ) being adjustable with respect to the fixed part ( 11 ) by screws ( 13 ), —a referencing unit for detecting the position of the positioning unit with respect to a target position of the surgical guide means, —a control unit ( 21 ) for computing the target position of screws ( 13 ), —said device ( 4 ) for adjusting the positions of the screws ( 13 ).
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to an ink tank system using a replaceable ink tank for supplying ink to a print head of an ink jet printer for ejecting ink drops to printing sheets. The present invention also relates to a replaceable ink tank used in the ink tank system.
2. Description of the Related Art
A piezo-ink jet system is known in which a small amount of ink is momentarily pressurized using a piezoelectric element to eject ink droplets to the printing sheet. A bubble ink jet system is also known in which a small amount of ink is momentarily heated to generate bubbles and ink drops are ejected toward printing sheets by the action of the pressure of expanding bubbles.
In the printing mode of jetting ink drops, liquid ink is stored in a tank (ink tank), and ink is supplied to a printer head from the tank. Here, for example, when a large-sized poster is print-outputted or in another case of a large printing sheet, ink consumption is large. Accordingly, it is proposed that the ink tank be designed to be replaceable.
For example, a system is proposed in which an air pump is provided on the side of a printer body and pressurized air is fed into an ink tank from the air pump to force-feed ink to a printer head. In this system, a connector needs to be disposed between the printer main body and the ink tank, by which an air supply channel for feeding the pressurized air to the ink tank and an ink supply channel for supplying ink from the ink tank to the print head of the printer unit can be disconnected.
In the ink-jet printing system, since an ink drop jetting port of the print head is remarkably small, a slight dust contaminated in ink may clog the jetting port of the nozzle, thereby causing failure. Although the ink tank containing a quantity of ink is delivered to a user in a sealed condition, dust may enter the tank together with air especially from a pressurized air supply system when the user exchanges the ink tank for a new one.
To solve the problem, it is assumed that an air filter is provided in an air supply channel of the tank so that air surely passes through the air filter before entering the tank. In this case, however, while the ink tank is transported, the ink in the tank adheres to the air filter and solidifies. Therefore, there raises a problem that resistance increases when air passes through the air filter and the ink cannot be smoothly force-fed to the printer body.
SUMMARY OF THE INVENTION
The present invention has been accomplished in consideration of the circumstances above, and an object thereof is to provide a printer ink tank system in which an air filter is disposed in an air supply channel of an ink tank to prevent dust from entering the ink tank together with air and in which ink is prevented from adhering to the air filter to keep the smooth force-feeding of ink to a print head of the printer.
To attain this and other objects, the present invention provides an ink tank system for supplying ink to a print head of an ink jet printer from a replaceable ink tank by pressurizing inside of the ink tank with pressurized air, comprising:
an air supply channel disposed with the ink tank for feeding the pressurized air supplied from a printer unit into the ink tank, the air supply channel having an auxiliary seal for closing the channel and, at an upstream side of the auxiliary seal, being branched to a main air supply channel and an auxiliary channel, an air filter being disposed in the main air supply channel;
an ink supply channel disposed with the ink tank;
an air inlet disposed on an upstream terminal end of said main air supply channel and having a first main seal for hermetically sealing the air inlet;
an ink outlet disposed on a downstream terminal end of said ink supply channel of the ink tank and having a second main seal for hermetically sealing the ink outlet;
a seal release port disposed on a terminal end of said auxiliary channel;
a first hollow needle disposed on the side of the printer unit and being engageable with said air inlet to advance into the air inlet to hermetically penetrate the first main seal, said first hollow needle supplying the pressurized air into the ink tank via said air supply channel;
a second hollow needle disposed on the side of the printer unit and being engageable with said ink outlet to advance into the ink outlet to hermetically penetrate the second main seal, said second hollow needle receiving the ink stored the ink tank to feed the ink to the print head; and
a seal releasing protrusion disposed on the side of printer unit and advancing into said seal release port to break sealing of said auxiliary seal, said first hollow needle, said second hollow needle and said seal releasing protrusion being extended parallel with one another.
When the ink tank is mounted on the printer unit, the first and second hollow needles are hermetically passed through the first and second main seals, respectively, and the seal releasing protrusion is advanced into said seal release port to open said auxiliary seal. Accordingly, the pressurized air supplied via the first hollow needle is passed through the air filter in the main air supply channel and the opened auxiliary seal in the air supply channel and fed into the ink tank, and the ink in the pressurized ink tank is force-fed toward the print head via the second hollow needle.
Here, the auxiliary seal can be constituted of a film which is broken by a pin pushed and moved by the seal releasing protrusion to open the air supply channel at the time the tank is mounted. Moreover, on the side of the ink tank, an air inlet port and an ink outlet port are arranged parallel on opposite sides of the seal release port. It is preferable that the seal release port be protruded ahead of the air inlet port and the ink outlet port in a direction in which the tank is mounted, so that the air inlet port and ink outlet port can be protected from obstacles while the tank is transported.
When the ink tank is unused, the auxiliary seal is interposed between the inside of the ink tank and the air filter in the air supply channel, so that the ink stored in the ink tank is prevented from adhering to the air filter. Therefore, the ink is prevented from making wet or dirty the air filter, to avoid deterioration of the filtering function of the air filter while the ink tank is transported. Possible obstruction to the ink feeding can be eliminated.
When the ink tank is mounted on the printer unit, the first hollow needle (also referred to an air supply pin, hereinafter) and the second hollow needle (also referred to an ink receiving pin, hereinafter) both on the side of the printer engage the air inlet port and the ink outlet port both on the side of the ink tank, respectively, and hit and break the respective main seals in these ports. Simultaneously, the seal releasing protrusion opens the auxiliary seal. Therefore, the pressurized air is supplied from the printer unit through the air supply pin, the air inlet port, the air filter and the air supply channel, and fed into the ink tank. As a result, the ink stored in the ink tank is flown through the ink outlet port and the ink receiving pin, and force-fed to the printer unit.
DESCRIPTION OF THE DRAWINGS
FIG. 1 is a side view diagrammatically showing a printer employing an ink tank system according to an embodiment of the present invention;
FIG. 2 is a perspective view illustrating an inner arrangement of main parts of the printer and an ink supply line of the embodiment;
FIG. 3 is a perspective view showing the ink tank mounted on an ink tank mounting section as seen from a backside of the printer;
FIG. 4 is a perspective view showing the ink tank of the embodiment; and
FIG. 5 is a sectional view showing a structure of a connector head of the ink tank of the embodiment.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
In FIG. 1, a reference numeral 10 denotes a printer unit which is housed in a longitudinal case 12, and a top surface of the case 12 forms a lid 14 which is able to be opened upward. The case 12 is supported by a pair of opposite legs 16. A roll 20 with a printing sheet 18 wound therearound is held horizontally in width direction of the case 12 at the back downside of the case 12. The printing sheet 18 is guided from the roll 20 into the case 12, and printed in the case 12. The printing sheet 18 is used as a poster or the like, its width is broad, and the maximum width of about 54 inches is used.
The printing sheet 18 is guided by a guide roller 22 to a gap between a pair of upper and lower guide plates 24 and 26, further held between a pair of upper and lower feed rollers 28 and 30, and fed toward a front face of the case 12. While the printing sheet 18 is rested on a platen 32, printing is performed by a printer head 34 which moves along the top surface of the printing sheet 18 in the width direction (transverse direction). Additionally, the platen 32 has multiple small holes on its top surface, and the small holes are sucked to a negative pressure by an evacuate fan 36. Therefore, the printing sheet 18 is sucked onto a surface of the platen 32 by a suction pressure acting on the small holes, and fixedly adheres to the surface of the platen 32.
The printer head 34 is of a piezo-ink jet system in which a piezoelectric element pressurizes a small amount of ink to eject ink droplets to the printing sheet 18, and four color ejection nozzles of cyan, magenta, yellow and black are arranged in width direction of the printing sheet 18. The printer head 34 moves along the top surface of the printing sheet 18 held by the platen 32 in the width direction to perform printing.
The printing sheet 18 is passed under the printer head 34, fed between a pair of upper and lower sheet rollers 38, 40, to be discharged from the printer section, further passed between a pair of upper and lower guide plates 42, 44, and guided downward by a guide plate 46. The printing sheet 18 is placed into a large-sized basket-like tray 48 which is attached between the pair of opposite legs 16.
Moreover, a cutter 50 is disposed close to one edge of the printing sheet 18 between the guide plates 42, 44 and the guide plate 46. The cutter 50 cuts the printed printing sheet while moving from the left end to the right in the width direction of the sheet 18. Additionally, since the printing sheet 18 has a broad width (about 54 inches at maximum), its cut portion hangs downward while the cutter 50 is moving, and its uncut portion is wrinkled. A clear cutting is thus impossible. To solve the problem, in the embodiment, an end of the cut printing sheet is pressed and fixed by a pressing lever 52 from above on the cutting start side of the cutter 50. When the cutter 50 reaches the terminal end of the printing sheet 18, the pressing lever 52 raises to release the printing sheet 18. Therefore, since the right and left ends of the cut printing sheet 18 drop substantially simultaneously, printed sheets are orderly collected on the tray 48 without being wrinkled.
An ink tank unit 60 will next be described. As shown in FIG. 2, the ink tank unit 60 is disposed on the rear face of the case 12 and, as shown in FIG. 3, includes four ink tanks 62 which can be detachably mounted from rear (only two are shown in FIG. 3). The four ink tanks 62 contain inks of four colors corresponding to the four color ejecting nozzles of the print head 34, i.e., inks of cyan, magenta, yellow and black, respectively. Since connector sections for connecting the ink tanks 62 and the printer unit 10 have the same structure, one of the connector sections will be described.
The ink tank 62 has a substantial square pole configuration extended back and forth, and includes an ink injection cap 64 and a connector head 66 on its top surface (refer to FIG. 4). The connector head 66 has a seal release port 68 protruded horizontally in a longitudinal direction of the ink tank 62, and an air inlet or port 70 and an ink outlet or port 72 which are arranged parallel on opposite sides of the seal release port 68. The central seal release port 68 is protruded ahead of the air inlet port 70 and ink outlet port 72 (FIGS. 4 and 5).
As shown in FIG. 5, a main seal 74 is provided within the ink outlet 72, and a pipe 76 as an ink supply channel is further connected to the ink outlet 72. The pipe 76 is extended to and communicated with the vicinity of a bottom inside the ink tank 62. Additionally, the pipe 76 is passed through a wall of the ink tank 62, but it is natural that the passed portion is hermetically sealed between an outer peripheral face of the pipe 76 and a hole inner face of the ink tank 62.
A main seal 78 is provided within the air inlet 70, the air inlet 70 is connected to an air supply channel 80 via the main seal 78, and the air supply channel 80 is connected to and communicated with an upper air chamber 82 inside the tank 62. The main seals 74 and 78 are formed, for example, of thick soft rubber plates, so that needle-like ink receiving pin 96 and pressurized air supply pin 94 can easily penetrate the respective seals with maintaining the hermetical sealing condition between the inside of the tank 62 and open air of the outside of the tank 62.
The air supply channel 80 is branched to a main air supply channel 80A and an auxiliary channel 80B, as shown in FIG. 5. The main channel 80A communicates with the air inlet 70 through an air filter 88. The auxiliary channel extends to and communicates with the seal release port 68. At the downstream side from the position branching the main and auxiliary channels 80A, 80B, a auxiliary seal 86 formed of a thin film is interposed in the air supply channel 80.
A piston-like pin 84 is slidably inserted in the seal release port 68 and a tip end of the pin 84 is opposed to the auxiliary seal 86. When broken by the pin 84, the auxiliary seal 86 loses its sealing properties, so that opposite sides of the auxiliary seal 86 of the air supply channel 80 are interconnected. The air filter 88 is attached inside a main channel 80A between the auxiliary seal 86 and the main seal 78 of the air inlet 70. Moreover, an O ring 90 is engaged to the pin 84 to prevent the air supply channel 80 from being connected to the atmosphere via the seal release port 68.
On the other hand, on the side of the printer body 10, a seal releasing protrusion 92, and a first hollow needle, i.e., the pressurized air supply pin 94 and a second hollow needle, i.e., the ink receiving pin 96 positioned on opposite sides of the protrusion 92 are extended opposite to the connector head 66 of each ink tank 62. These pin 92, 94, 96 can advance into and engage with the seal release port 68, the air inlet 70 and the ink supply outlet 72, respectively, when the ink tank 62 is mounted onto a mounting section 98 (FIG. 3). Additionally, in FIG. 2, numeral 100 denotes a drain tank for collecting waste ink which have been ejected for cleaning of the each jetting nozzle of the print head 34.
With such construction, before the ink tank 62 is mounted onto the mounting section 98, the air inlet 70 and the ink supply outlet 72 are sealed by the main seals 78 and 74, respectively, and the seal release port 68 is also sealed by the O ring 90. Therefore, the ink tank 62 is completely shielded from the atmosphere. Additionally, since the auxiliary seal 86 is interposed between the air filter 88 disposed in the main channel 80A and the inside of the ink tank 62, there is no possibility that the ink in the ink tank 62 adheres to the air filter 88.
When the ink tank 62 is mounted onto the mounting section 98, the air supply pin 94 and the ink receiving pin 96 break and advance into the main seals 78 and 74, while the protrusion 92 pushes the slidable pin 84 inside the seal release port 68. As a result, when the pin 84 breaks the auxiliary seal 86, the air inlet 70 is connected to the air chamber 82 inside the ink tank 62. Pressurized air of a constant pressure (about 1.3 kg/cm 2 ) is supplied to the air supply pin 94 from an air pump (not shown) disposed on the side of the printer unit 10 to pressurize the air chamber 82 of the ink tank 62. Therefore, the ink is force-fed to the ink receiving pin 96 via the pipe 76. The ink receiving pin 96 is connected to the printer head 34 by a pipe 102, so that ink is supplied to each ink jetting nozzle.
Recesses 104 shown in FIG. 5 are formed in the left and right side faces of the ink tank 62. A stopper 106 formed of a metal leaf spring disposed on the mounting section 98 of the printer unit 10 is engaged with the recesses 104, so that the ink tank 62 is fixed in a predetermined position.
In the embodiment the ink outlet 72 and the air inlet 70 on the opposite sides of the seal release port 68 are positioned behind the seal release port 68, the ink supply outlet or port 72 and the air inlet or port 70 can be prevented from being damaged or dust can be prevented from adhering to the ports while the ink tank 62 is transported.
As aforementioned, in the present invention, when the ink tank is mounted, the seal releasing pin protruded on the printer unit opens the auxiliary seal for sealing between the air filter in the air supply channel and the air chamber in the ink tank. Therefore, when the ink tank is not mounted yet, ink can be prevented from adhering to the air filter by sealing between the inside of the ink tank and the air filter with the auxiliary seal. Moreover, after the ink tank is mounted, the pressurized air is passed through the air filter and fed into the ink tank, no dust, therefore, enters the ink tank together with the pressurized air, and there is no possibility that the clogging of the printer head causes printing failure.
Since the auxiliary seal is automatically opened when the ink tank is mounted, operation is simplified. Different from a system in which the auxiliary seal is opened by a manually operated lever or the like, incorrect operation of the lever does not occur. The auxiliary seal used herein is preferably constituted in such a manner that the film disposed in the air supply channel is broken by the slidable pin pushed by the seal releasing protrusion on the side of the printer unit.
Moreover, when the seal release port is disposed parallel between and adjacent to the air inlet or port and the ink supply outlet or port on the side of the ink tank, and the seal release port is protruded ahead of the other air and ink ports, no obstacles easily abut on the air and ink ports while the ink tank is transported. Therefore, the air and ink ports can be prevented from becoming dirty or damaged.
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There is provided an ink tank system for supplying ink to a print head of an ink jet printer from a replaceable ink tank by pressurizing inside of the ink tank with pressurized air. By disposing an air filter in an air supply channel of the ink tank, dust is prevented from entering the ink tank together with air, and the ink is prevented from adhering to the air filter, thereby keeping smooth ink force-feeding. At the time the ink tank is mounted, a seal releasing pin protruded on the side of a printer unit opens an auxiliary seal for sealing between the air filter in the air supply channel and an air chamber of the ink tank. After the ink tank is mounted, the pressurized air is passed through the air filter and fed into the ink tank. A replaceable ink tank used in the system is also provided.
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BACKGROUND
[0001] Rotary earth drills are commonly used in drilling operations, especially for drilling holes and conducting subsurface soil testing. These drills utilize drill bits to cut away soil and rock which is then removed from the drilling area up the shaft. Frequently, drill bits break, or lose their edge with age and use, and when they cease to be effective in removing soil or rock, the drilling operation must be stopped, the drill removed and the bits replaced. Therefore, it is desirable to utilize drill bits that retain their edge for the longest possible duration to reduce the occurrence of bit replacement.
[0002] Additionally, after drill bits have been used in drilling operations, it is often difficult to remove them from the heads. This is especially true because it is desirable to perform replacements on site, which is typically in a remote area with limited resources. Some mounting methods have been used that simplify replacement, but result in an increased incident of drill bits coming detached from the head during drilling operations.
[0003] Accordingly, a continuing search has been directed to the development of tools that are more rugged and durable that need to be replaced less frequently, drill earth with greater efficiency, and that can be replaced easily on site, when necessary.
SUMMARY
[0004] The present invention is directed to a rotary earth auger that utilizes drill bit assemblies to which both blades and finger bits are attached. The configuration and arrangement of the bits improves cutting efficiency, increases wear life and reduces the likelihood of the bits breaking during operation.
[0005] The individual drill bit assemblies have a self-locking hook configuration and are retained on the auger head by means of a unique sandwich mechanism to reduce incidents of the drill bit assembly becoming detached from the auger during drilling operations. Additionally, the drill bit assemblies are attached to the auger using an attachment method that resists rusting when the drill is in use, which makes the drill bit assemblies easier to remove from the drill when it is necessary to replace the bits.
[0006] The invention is a hollow auger head assembly for penetrating geological formations, comprising a hollow auger head configured such that it can be secured to a conventional auger used for drilling, and at least two drill bit assemblies secured to the hollow auger head. Each drill bit assembly comprises a drill bit body having a means of attachment, at least one finger bit secured to the underside of the drill bit body, and at least one blade secured to the front edge of the drill bit body.
[0007] The foregoing has outlined rather broadly the features and technical advantages of the present invention in order that the detailed description of the invention that follows may be better understood. Additional features and advantages of the invention will be described hereinafter which form the subject of the claims of the invention. It should be appreciated by those skilled in the art that the conception and the specific embodiment disclosed may be readily utilized as a basis for modifying or designing other structures for carrying out the same purposes of the present invention. It should also be realized by those skilled in the art that such equivalent constructions do not depart from the spirit and scope of the invention as set forth in the appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0008] For a more complete understanding of the present invention, and the advantages thereof, reference is now made to the following descriptions taken in conjunction with the accompanying drawings, in which:
[0009] [0009]FIG. 1 is a bottom elevation view of a hollow auger head assembly embodying features of the present invention;
[0010] [0010]FIG. 2 is a partially exploded view showing assembly of the parts of a hollow auger head assembly of the present invention;
[0011] [0011]FIG. 3 is a partially exploded view showing assembly of the parts of a hollow auger head of the present invention;
[0012] [0012]FIG. 4 is a view of the underside of a drill bit assembly of the present invention; and
[0013] [0013]FIG. 5 is a detailed view of a drill bit assembly of the present invention.
DETAILED DESCRIPTION
[0014] In the discussion of the FIGURES the same reference numerals will be used throughout to refer to the same or similar components. In the interest of conciseness, various other components known to the art, such as drilling components and the like have not been shown or discussed. Numerous specific details are set forth to provide a thorough understanding of the present invention. However, it will be obvious to those skilled in the art that the present invention may be practiced without such specific details.
[0015] Referring to FIG. 1 of the drawings, the reference numeral 100 generally designates the hollow auger head assembly of the present invention. The assembly 100 includes a hollow auger head 10 , and one or more drill bit assemblies 50 .
[0016] [0016]FIG. 2 shows the assembly of the parts that comprise the hollow auger head assembly 100 of the present invention. Each drill bit assembly 50 is secured to the hollow auger head 10 . In a preferred embodiment of the present invention, the securing method comprises a rust-resistant bolt 2 and a rust-resistant nut 4 , made of a material such as stainless steel. It will be obvious to those skilled in the art that the securing method can be other than a nut 4 and bolt 2 ; however, it is desirable to use a securing method that will keep the pieces securely together during use. Similarly, while the securing method can be made of any material, it is desirable to use materials that resist rusting so the drill bit assembly 50 can be easily detached from the hollow auger head assembly 100 after it has been in use in subterranean conditions.
[0017] [0017]FIG. 3 shows the parts of the hollow auger head assembly 100 . The hollow auger head 10 comes in various sizes that correspond with standard size augers used in drilling operations so the hollow auger head assembly 100 can be used with standard drilling equipment. The number of drill bit assemblies 50 that will be used in a particular hollow auger head assembly 100 depends on, among other things, the size of the auger being used. Typically, at least two drill bit assemblies 50 are used on a hollow auger head assembly 100 .
[0018] The hollow auger head 10 consists of an auger pin 12 to which two or more brackets, or sets of brackets 20 , have been cast, or welded, soldered, or otherwise secured, depending on the number of drill bit assemblies 50 that will be used on that hollow auger head assembly 100 . The sets of brackets 20 are positioned equidistant from each other around the circumference of the auger pin 12 . The auger pin 12 is configured with through-material holes 13 and keyway grooves 14 such that it can be connected with conventional augers, and an auger key will fit into a keyway 14 on the auger pin 12 .
[0019] In a preferred embodiment of the present invention, a set of brackets 20 is used to secure each drill bit assembly 50 to the auger pin 12 . Each bracket set 20 consists of a top bracket 22 , a lower bracket 24 and a back bracket 26 , each of which is cast, or soldered or welded to the auger pin 12 along one side such that a gap exists between the top bracket 22 and lower bracket 24 of a size such that the drill bit assembly 50 can be inserted between the top bracket 22 and lower bracket 24 . By positioning the drill bit assembly 50 between a top bracket 22 and a lower bracket 24 , the drill bit assembly 50 is given greater security and is therefore less likely to break or become disconnected during use.
[0020] The drill bit assembly 50 is inserted into the gap between the top bracket 22 and lower bracket 24 and the holes in the brackets 22 , 24 and drill bit assembly 50 are aligned. In a preferred embodiment, a bolt 2 is inserted through the holes in the brackets 22 , 24 and drill bit assembly 50 , and secured with a nut 4 .
[0021] When the drill bit assembly 50 is properly positioned between the upper bracket 22 and lower bracket 24 , the rear edge of the drill bit assembly 50 should be close to the back bracket 26 . The back bracket 26 provides lateral stability for the drill bit assembly 50 when the hollow auger head assembly 100 is in use. This reduces the likelihood of the drill bit assembly 50 moving relative to the brackets such that the bolt 2 could become loose, or be subject to shear pressure such that it would break.
[0022] As shown in FIG. 2, the top bracket 22 has a front edge that has a sinusoidal shape comprising a protruding finger 21 and a recessed curved slot 23 . The front edge of the top bracket 22 forms an interlock with the mirror image sinusoidal shape of the upper edge of the drill bit assembly 50 . The finger 21 on the top bracket 22 fits snugly into the receptacle on 51 on the drill bit assembly 50 , while the finger 53 on the drill bit assembly 50 fits into the receptacle 23 on the top bracket 22 . Even if the bolt 2 were to become loose or break, this self-locking interlock would help ensure the drill bit assembly 50 stayed securely positioned in the top bracket 22 .
[0023] [0023]FIG. 2 also shows the positioning of the bracket sets 20 on the hollow auger head 10 , relative to the auger pin 12 and each other. The positioning of the bracket sets 20 , and as a result the drill bit assemblies 50 , on the hollow auger head 10 relative to each other is an important consideration in the functionality of the hollow auger head assembly 100 . The arrangement of the drill bit assemblies 50 on the hollow auger head assembly 100 is such that the finger bit or bits 60 on a drill bit assembly 50 loosens material and feeds it to the blade 56 on the next drill bit assembly 50 on the auger head assembly 100 for further processing. Proper positioning of the drill bracket sets 20 on the hollow auger head 10 ensures that the drill bit assemblies 50 are properly positioned so that the loosened material is delivered to the blade 56 of the next drill bit head assembly 50 in an efficient manner.
[0024] In alternative arrangements of the present invention, a different number of brackets can be used to secure the drill bit assembly 50 to the hollow auger head 10 . Similarly, brackets of a different shape can be used to secure the drill bit assembly 50 to the auger pin 12 .
[0025] The underside of a drill bit assembly 50 is shown in detail in FIG. 4. The hole 52 for securing the drill bit assembly 50 to the bracket set 20 can be clearly seen. The drill bit assembly 50 shown has one conical finger bit 60 on the underside. However, depending on the particular configuration of the auger head assembly 100 being used, more than one finger bit 60 can be used. The finger bits 60 are designed so that when they are mounted on the drill bit assembly 50 , the cutting edge of the finger bit 60 has a negative rake, or angle, relative to the movement of the hollow auger head assembly 100 .
[0026] Because the cutting portion of the finger bit 60 contacts the geological material which it is drilling into at a negative angle, the cutting edge of the finger bit 60 is protected from excessive wear and cracking that would reduce the life of the finger bit 60 . The negative angle relative to the geological material also reduces the impact between the finger bit 60 and the geological material, which reduces the wear on the finger bit 60 and the likelihood of damage to the finger bit 60 .
[0027] Additionally, a layer of high-quality, wear-resistant metal, such as tungsten carbide or carbide coated metals may be bonded to at least the cutting edge of the finger bit 60 to increase the life of the finger bit 60 . The layer of wear-resistant material may be secured to the finger bit 60 by means such as brazing or use of a bonding material, which bonds the finger bit 60 and wear-resistant materials together when heated.
[0028] In alternate arrangements of the hollow auger head assembly 100 , finger bits 60 that are of a shape other than conical can also be used. The shape, number and position of the finger bits 60 used depends on the exact configuration and intended usage for the hollow auger head assembly 100 .
[0029] [0029]FIG. 5 shows a detailed view of a drill bit assembly 50 of the present invention. The drill bit assembly 50 comprises a drill bit body 54 , one or more finger bits 60 , and a blade 56 secured along the front of the drill bit body. A hole 52 has been cut, reamed or drilled through the drill bit body 54 to allow insertion of a fastening mechanism so the drill bit assembly 50 can be secured to a bracket set 20 .
[0030] The drill bit body 54 is shaped to have an inward facing receptacle 51 and a finger 53 along the top of the drill bit body 54 . The finger 53 on the drill bit body 54 fits snugly into the receptacle 23 on the top bracket 22 of the hollow auger head 10 , while a finger 21 on the top bracket 22 fits snugly into the receptacle on 51 on the drill bit body 54 . The drill bit body 54 has a downward slope 55 from the receptacle 51 and finger 53 to the front edge of the drill bit body 54 where the blade 56 is secured. This slope 55 is useful in channeling processed geological material away from the blade 56 and up and out the auger.
[0031] The blade 56 is comprised of one or more pieces of hardened, wear-resistant material secured along the front edge or edges of the drill bit body 54 . The blade 56 is usually made of wear-resistant metal, such as tungsten carbide or carbide coated metals which may be secured to the drill bit by means such as brazing or use of a bonding material which bonds the drill bit body 54 and blade 56 together when heated. The material can be sharpened as needed, and will retain the sharpened edge for an extended period of time. In some configurations of the drill bit assembly 50 , hardened material is also placed along the front slope 55 of the drill bit body 54 . In some configurations of the drill bit assembly 50 , hardened material is also placed along the outer edge of the drill bit body 54 for cutting and processing of geological materials which come in contact with that edge of the drill bit assembly 50 . The exact position and number of pieces of material on the drill bit body 54 depends on the specific arrangement and use of the hollow auger head assembly 100 .
[0032] In operation, the hollow auger head assembly 100 is secured to an auger and used to drill into geological formations. The drill bit assemblies 50 are positioned around the hollow auger head 10 an appropriate distance from each other and in a proper alignment relative to each other. As the auger is rotated, the finger bits 60 on the drill bit assemblies 50 break up the geological material with which they come in contact. The negative angle of each finger bit 60 is such that the geological material it has broken up is fed back and up to the blade 56 of the next drill bit assembly 50 on the hollow auger head assembly 100 . That blade 56 , further processes and breaks up the geological material, and then feeds it up over the front slope 55 of the drill bit assembly 50 , and subsequently up the auger and out of the drilling area.
[0033] Because a finger bit 60 on a drill bit assembly 50 feeds the blade 56 of the next drill bit assembly 50 on the hollow auger head assembly 100 , positioning of the drill bit assemblies 50 on the hollow auger head assembly 100 relative to each other is critical. Further, the combination of finger bits 60 and blades 56 in a single assembly increases efficiency of breaking up and moving away of geological materials in the drilling operation.
[0034] It is understood that the present invention can take many forms and embodiments. Accordingly, several variations may be made in the foregoing without departing from the spirit or the scope of the invention. For example, the position, shape and number of finger bits 60 on a drill bit assembly can be varied. As another example, pieces of hardened material can be attached to the outside edge of the drill bit assembly by a variety of methods. These pieces of hardened material can assist in the breaking up of the geological formation being processed. The position, shape and number of pieces of hardened material can vary, and still be within the scope of the present invention. Yet another example is the number of pieces, shape and size of the pieces of hardened material affixed to the front of the drill bit assembly, which can be varied, but still fall within the scope of the present invention.
[0035] Having thus described the present invention by reference to certain of its preferred embodiments, it is noted that the embodiments disclosed are illustrative rather than limiting in nature and that a wide range of variations, modifications, changes, and substitutions are contemplated in the foregoing disclosure and, in some instances, some features of the present invention may be employed without a corresponding use of the other features. Many such variations and modifications may be considered obvious and desirable by those skilled in the art based upon a review of the foregoing description of preferred embodiments. Accordingly, it is appropriate that the appended claims be construed broadly and in a manner consistent with the scope of the invention.
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A hollow auger head assembly for penetrating geological formations that utilizes drill bit assemblies to which both blades and finger bits are attached. The method of securing the individual drill bit assemblies to the auger head reduces incidents of the drill bit assembly becoming detached from the auger head during drilling operations. Additionally, a rust-resistant attachment mechanism is used attach the drill bit assemblies to the auger head, which makes the drill bit assemblies easier to remove and replace. The configuration and arrangement of the bits improves cutting efficiency, increases wear life and reduces the likelihood of the bits breaking during operation.
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FIELD OF THE INVENTION
The present invention relates to supercavitating projectiles in general, and, more particularly, to control surfaces for supercavitating projectiles.
BACKGROUND OF THE INVENTION
A supercavitating underwater projectile can achieve speeds of 150 knots, and, therefore, it is especially useful in naval applications. A supercavitating underwater projectile achieves these speeds because it comprises a special tip on its nose known as a “cavitator.” As the projectile travels through the water, the cavitator contacts the water in such as way as to create many small air bubbles. The small air bubbles then coalesce into one big air bubble that is large enough to completely encompass the projectile. The effect is that the projectile is traveling inside a giant air bubble that is itself moving through the water.
FIG. 1 depicts a side view of the salient components of supercavitating projectile 100 as known in the prior art inside cavity 103 . Supercavitating projectile 100 comprises projectile body 101 and four prism-shaped fins 102 - 1 , 102 - 2 , 102 - 3 , and 102 - 4 (not shown), which are equally spaced around body 101 , and cavitator 103 .
As projectile 100 travels through the water, there is a tendency for projectile 100 to swerve or fishtail, and the purpose of fins 102 - 1 through 102 - 4 is to keep projectile 100 completely inside air cavity 104 . This minimizes the amount of projectile 100 which touches the water, which enables projectile 100 to go fast.
SUMMARY OF THE INVENTION
One disadvantage of supercavitating underwater projectiles in the prior art is that the prism-shaped fins tend to penetrate the air-water boundary of the air cavity, which increases the water drag on the projectile. Another disadvantage is that the position of the fins is fixed and does not adjust to changes in the shape of the cavity that are caused by changes in the speed of the projectile.
The present invention enables a supercavitating underwater projectile to stay within the air cavity without some of the costs and disadvantages for doing so in the prior art. For example, the illustrative embodiment provides bumpers which are roughly shaped like skis that face towards the air-water boundary of the air cavity. When the projectile fishtails and one or more of the bumpers come into contact with the air-water boundary, the water imparts torque and a rebounding force to push the projectile completely back into the air cavity. Furthermore, because the bumpers are shaped roughly like skis and not like knives, the bumpers do not penetrate the water or create unnecessary water drag.
Furthermore, the illustrative embodiment comprises an actuator for changing the positioning of the bumpers based on the speed of the projectile and a cavity-shape model.
The illustrative embodiment comprises: a projectile body capable of creating a air cavity inside water, wherein the air cavity is defined by a air-water boundary; and a first ski-shaped bumper connected to the projectile body, wherein the bottom of the first ski-shaped bumper faces the air-water boundary of the air cavity.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 depicts a side view of the salient components of supercavitating projectile 100 as known in the prior art inside cavity 103 .
FIGS. 2A and 2B depict left side and front views, respectively, of the salient components of supercavitating projectile 200 in accordance with the illustrative embodiment.
FIGS. 3A and 3B depicts left side and front views, respectively of the salient components of supercavitating projectile 200 with respect to elliptic paraboloid 301 and frustum 302 of elliptic paraboloid 301 .
FIG. 4 depicts a cut-away view, along line A-A in FIG. 2B , of the salient components of supercavitating projectile 200 .
FIG. 5 depicts longitudinal axis 501 of supercavitating projectile 200 and line 502 , which is perpendicular to longitudinal axis 501 .
DETAILED DESCRIPTION
FIGS. 2A and 2B depict left side and front views, respectively, of the salient components of supercavitating projectile 200 in accordance with the illustrative embodiment. FIGS. 3A and 3B depicts left side and front views, respectively of the salient components of supercavitating projectile 200 with respect to elliptic paraboloid 301 and frustum 302 of elliptic paraboloid 301 . FIG. 4 depicts a cut-away view, along line A-A in FIG. 2B , of the salient components of supercavitating projectile 200 . FIG. 5 depicts longitudinal axis 501 of supercavitating projectile 200 and line 502 , which is perpendicular to longitudinal axis 501 .
Supercavitating projectile 200 comprises: projectile body 201 , bumpers 202 - 1 through 202 - 4 , bumper struts, 203 - 1 through 203 - 4 , cavitator 204 , sensor 401 , controller 402 , and actuator 403 .
Although supercavitating projectile 200 comprises four bumpers and four struts, it will be clear to those skilled in the art, after reading this disclosure, how to make and use alternative embodiments of the present invention which comprise any number of bumpers and struts.
Projectile body 201 is a non-explosive, propelled object, such as a bullet, for imparting kinetic energy to a target. It will be clear to those skilled in the art, after reading this disclosure, how to make and use alternative embodiments of the present invention in which projectile body 201 is an explosive object. Furthermore, it will be clear to those skilled in the art, after reading this disclosure, how to make and use alternative embodiments of the present invention in which projectile body 201 is a self-propelled object, such as a missile, rocket, or torpedo.
Bumper 202 - i , wherein iε{1, 2, 3, 4}, is a ski-shaped structure for keeping projectile body 201 within air cavity 205 and minimize the projectiles yaw angle relative to its trajectory. The purpose of bumper 202 - i is to generate torque and rebounding forces when projectile body 201 fishtails and bumper 202 - i contacts the air-water boundary of air cavity 205 .
The sum of the outer surfaces of bumpers 202 - 1 through 202 - 4 are shaped so as to suggest a frustum 302 of elliptic paraboloid 301 , as depicted in FIGS. 3A and 3B , which frustum is designed to conform to the shape of air cavity 205 . The vertex of the elliptical paraboloid is coincident with cavitator 204 . It will be clear to those skilled in the art, after reading this disclosure, how to make and use alternative embodiments of the present invention in which the bumpers suggest another shape, such as for example, and without limitation, a frustum of a conic section, a box, a pyramid, sphere, or polyhedron. The parabolic shape of bumper 202 - i is intended to present a low-drag surface to the air-water boundary of air cavity 204 , in contrast to the high-drag surface of the bumpers in the prior art. In accordance with the illustrative embodiment, the shape and orientation of bumper 202 - i is such that bumper 202 - i has more surface area facing in parallel with line 502 than perpendicularly to the line (i.e., in parallel with line 503 ) as depicted in FIG. 5 .
Strut 203 - i is a rigid member that structurally connects bumper 202 - i to actuator 403 within projectile body 201 . It will be clear to those skilled in the art, how to make and use strut 203 - i.
Cavitator 204 is a tip, as is well-known in the prior art, on the nose of projectile body 201 that contacts the water in front of supercavitating projectile 200 in such as way as to create many small air bubbles. The small air bubbles then coalesce into one big air bubble that is large enough to completely encompass the supercavitating projectile 200 . It will be clear to those skilled in the art how to make and use cavitator 204 .
Sensor 401 is a mechanism for detecting the speed of supercavitating projectile 200 through the water and for transmitting an indication of that speed to controller 402 . It will be clear to those skilled in the art how to make and use controller 402 .
Controller 402 is electronics for estimating the shape of air cavity 205 based on the speed measurement from sensor 401 and for controlling actuator 403 to position bumpers 202 - 1 through 202 - 4 so that they are in the correct position with respect to the air-water boundary of air cavity 204 . To do this, controller 402 uses a cavity-shape model based on the speed with which supercavitating projectile 200 is moving through the water. For example, when controller 402 determines that air cavity 205 is expanding, controller 402 directs actuator 403 to extend bumpers 202 - 1 through 202 - 4 , but when controller 402 determines that air cavity 205 is contracting, controller 402 directs actuator 403 to retract bumpers 202 - 1 through 204 - 4 .
Actuator 403 is a mechanism for extending and retracting bumpers 202 - 1 through 202 - 4 under the direction of controller 402 . It will be clear to those skilled in the art how to make and use actuator 204 .
It is to be understood that the disclosure teaches just one example of the illustrative embodiment and that many variations of the invention can easily be devised by those skilled in the art after reading this disclosure and that the scope of the present invention is to be determined by the following claims.
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The illustrative embodiment provides bumpers which are roughly shaped like skis that face towards the air-water boundary of the air cavity. When the projectile fishtails and one or more of the bumpers come into contact with the air-water boundary, the water imparts torque and a rebounding force to push the projectile completely back into the air cavity. Furthermore, because the bumpers are shaped roughly like skis and not like knives, the bumpers do not penetrate the water or create unnecessary water drag.
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CROSS REFERENCES TO RELATED APPLICATIONS
The present application claims priority under 35 U.S.C. §119 to Japanese Patent Application No. 2014-060025, filed Mar. 24, 2014, entitled “FUEL-LEVEL SENSING APPARATUS.” The contents of this application are incorporated herein by reference in their entirety.
BACKGROUND
1. Field
The present application relates to a fuel-level measuring apparatus that measures the fuel level in a fuel tank installed in a vehicle.
2. Description of the Related Art
In a vehicle that uses gasoline or light oil as fuel, it is necessary to indicate the fuel level in a fuel tank so that the driver can know when the tank needs to be refilled and how far the car can drive.
A known fuel-level measuring apparatus that measures the fuel level in a fuel tank is disclosed in, for example, Japanese Unexamined Patent Application Publication No. 2013-50410. The apparatus disclosed therein includes a float provided in a fuel tank, the float moving up and down with the surface level of the fuel, and, by making a float arm of the float slide over a resistor plate and converting the surface level into an electric potential difference, the apparatus measures the height of the surface and indicates the fuel level calculated from the height of the surface to a driver.
However, the technique disclosed in Japanese Unexamined Patent Application Publication No. 2013-50410 has the following problems: because the fuel-level measuring apparatus, such as the float, is disposed in the fuel tank, the capacity of the fuel tank decreases by an amount corresponding to the volume of the fuel-level measuring apparatus; because the fuel-level measuring apparatus needs to be disposed in the fuel tank, the shape of the fuel tank is restricted and cannot be thin or complicated; and, because the surface level of the fuel in the tank changes significantly depending on the orientation and driving conditions of the vehicle, it is impossible to measure the accurate fuel level.
SUMMARY
The present application provides a fuel-level measuring apparatus that can ensure a sufficient capacity of a fuel tank, can accurately measure the fuel level in the fuel tank regardless of the orientation and driving conditions of a vehicle, and can measure the fuel level even when the fuel tank has a thin or complicated shape.
According to a first aspect of the embodiment, a fuel-level measuring apparatus that measures the level of fuel in a vehicle fuel tank disposed below a floor panel of a vehicle includes: a tank band that secures the fuel tank to a body of the vehicle; and a strain gauge attached to the tank band. The fuel level is obtained from strain in the tank band detected by the strain gauge.
According to a second aspect of the embodiment, the tank band is attached along a bottom surface of the fuel tank, an elastic member is disposed between the bottom surface of the fuel tank and a top surface (a first surface) of the tank band, and the strain gauge is attached to a surface of the tank band, at a position immediately below the fuel tank and where the elastic member is not disposed.
According to a third aspect of the embodiment, the tank band has a substantially hat shape in section taken in the longitudinal direction thereof and includes edge portions at both ends in the width direction and a projecting portion projecting toward the fuel tank further than the edge portions. The strain gauge is attached to one of the edge portions in the width direction of the tank band.
According to a fourth aspect of the embodiment, the tank band has a substantially hat shape in section taken in the longitudinal direction thereof and includes edge portions at both ends in the width direction and a projecting portion projecting toward the fuel tank further than the edge portions. The strain gauge is attached to a middle portion of the projecting portion in the longitudinal direction.
According to the first aspect of the embodiment, the fuel tank is disposed below the floor panel, and the tank band for securing the fuel tank to the body receives the total weight of the fuel tank and the fuel in the tank. The strain gauge attached to the tank band detects the strain in the tank band caused by the total weight, and the fuel level in the vehicle fuel tank can be obtained from the detected signal. In this configuration, because the fuel-level measuring apparatus does not need to be disposed in the fuel tank, the fuel tank may have a sufficient capacity. Furthermore, because the design flexibility of the fuel tank increases, the fuel level can be obtained even in fuel tanks incapable of accommodating the fuel-level measuring apparatus, such as those having a thin or complicated shape. Furthermore, because the fuel level is obtained not from the surface level, which is likely to be influenced by the orientation and driving conditions of the vehicle, but from the strain caused by the weight, which is less likely to be influenced by the orientation and driving conditions of the vehicle, the fuel level can be obtained regardless of the orientation and driving conditions of the vehicle.
According to the second aspect of the embodiment, the tank band is attached along the bottom surface of the fuel tank, an elastic member is disposed between the bottom surface of the fuel tank and the top surface of the tank band, and the strain gauge is attached to the side edge surface (a second surface) of the tank band, at a position immediately below the fuel tank and where the elastic member is not disposed. Because the elastic member disposed between the fuel tank and the tank band serves as a cushioning member, the elastic member can reliably receive the load applied to the tank band and appropriately support the fuel tank. In particular, because the fuel tank does not move away from the tank band and is kept supported by the tank band even when a large load is applied thereto, such as when the vehicle drives over a bump, the strain in the tank band caused by the load applied by the fuel tank can be constantly measured with the strain gauge attached thereto, and the fuel level can be obtained.
According to the third aspect of the embodiment, the tank band has a substantially hat shape in section taken in the longitudinal direction thereof and includes edge portions at both ends in the width direction and a projecting portion projecting toward the fuel tank further than the edge portions. The strain gauge is attached to one of the edge portions in the width direction of the tank band. Thus, the elastic member and the strain gauge can be efficiently disposed on the tank band. Furthermore, because the strain gauge is disposed on the surface of the tank band adjacent to the fuel tank, there is less possibility of an object, such as a stone on a road, hitting the strain gauge while the vehicle is driving, and hence, it is possible to protect the strain gauge.
According to the fourth aspect of the embodiment, the tank band has a substantially hat shape in section taken in the longitudinal direction thereof and includes edge portions at both ends in the width direction and a projecting portion provided therebetween and projecting toward the fuel tank further than the edge portions. The strain gauge is attached to a middle portion of the projecting portion in the longitudinal direction. Because this portion is more sensitive to a change in load due to an increase or decrease in fuel level in the fuel tank than the other portions, an obvious change in load occurs in this part. Hence, the strain gauge attached to this part can detect an obvious change in strain in the tank band due to an increase or decrease in fuel level, compared with a strain gauge attached to another part, making it possible to obtain the fuel level.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1A is a sectional view of a configuration in which a fuel tank provided with a fuel level measuring apparatus according to one embodiment of the present application is disposed below a floor panel, as viewed from the center of the vehicle's width; and FIG. 1B is a plan view of a tank band.
FIG. 2 is a sectional view taken along line II-II in FIG. 1A .
FIG. 3 is an enlarged view of portion III indicated in FIG. 2 .
FIG. 4 is an enlarged sectional view of the vicinity of a strain gauge attached to a middle portion, in the longitudinal direction, of a projecting portion of the tank band shown in FIG. 1 .
FIG. 5 is a graph showing the relationship between the fuel level and the stress.
FIG. 6 is a sectional view of another type of fuel tank provided with a fuel level measuring apparatus according to the embodiment of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
An embodiment of the present application will be described with reference to the attached drawings. Embodiment
First, the configuration of the present application will be described with reference to FIGS. 1 to 3 . In these drawings, “Fr” denotes the front side, “Rr” denotes the rear side, “Le” denotes the left side, and “Ri” denotes the right side of a vehicle 10 . FIG. 1A is a sectional view of a configuration in which a fuel tank 20 of the present application is disposed below a floor panel 11 a, as viewed from the center of the vehicle's width, and FIG. 1B is a plan view of a tank band 30 that is used to secure the fuel tank 20 to a body 11 . The fuel tank 20 is disposed below the floor panel 11 a of the body 11 of the vehicle 10 , such as a passenger car, a bus, or a truck. Cushioning members 12 formed of rubber, flexible resin, or the like are disposed between the floor panel 11 a and the fuel tank 20 . The body 11 includes cross members 13 extending below the floor panel 11 a. The fuel tank 20 is supported by two tank bands 30 , whose ends are fixed to the cross members 13 of the body of the vehicle 10 . Each of the tank bands 30 is formed in an elongated shape having its longitudinal direction and certain width in its width direction perpendicular to the longitudinal direction.
The fuel tank 20 is formed as a single component of synthetic resin. Alternatively, the fuel tank 20 may be formed by joining an upper tank portion, which is formed of a steel plate or synthetic resin, and a lower tank portion, which is also formed of a steel plate or synthetic resin, at flanges provided along the outer circumference thereof, by using adhesive or a bolt and nut.
The fuel tank 20 has, in a bottom surface 20 a thereof, two (right and left) tank-band fitting grooves 21 to which the two (right and left) tank bands 30 , extending in the front-rear direction of the vehicle 10 , are fitted. Furthermore, a fuel supply pipe 22 through which fuel is supplied from a fuel supply port (not shown) of the vehicle 10 to the fuel tank 20 ; an air-bleeding pipe 23 ; and a fuel supply pipe 24 through which the fuel is supplied from the fuel tank 20 to an engine (not shown) by means of a fuel pump (not shown) are provided in the top surface of the fuel tank 20 .
The right and left tank bands 30 are formed of bent steel plates, and each tank band 30 has a projecting portion 31 that is provided at a middle portion, in the longitudinal direction, of the top surface (the surface facing the fuel tank 20 ) so as to extend over the entire length, as viewed in section taken in the longitudinal direction of the tank bands 30 . The tank band also has edge portions 32 formed on both sides of the projecting portion 31 . In other words, the tank bands 30 have a substantially hat shape in sectional view.
Each projecting portion 31 includes, in the longitudinal direction of the tank band 30 , a horizontal portion 31 a extending in the front-rear direction of the vehicle 10 ; a front attaching portion 31 c formed on the front side of the horizontal portion 31 a; a front slope portion 31 b formed between the horizontal portion 31 a and the front attaching portion 31 c; a rear attaching portion 31 e formed on the rear side of the horizontal portion 31 a ; and a rear slope portion 31 d formed between the horizontal portion 31 a and the rear attaching portion 31 e.
An elastic member 33 formed of rubber, flexible resin, or the like is bonded, with adhesive, to a portion of the projecting portion 31 , the portion including the entire horizontal portion 31 a and the top surfaces, near the horizontal portion 31 a, of the front slope portion 31 b and rear slope portion 31 d.
The fuel tank 20 is disposed at a predetermined position below the floor panel 11 a, and the top surfaces of the elastic members 33 on the right and left tank bands 30 are fitted to the right and left tank-band fitting grooves 21 . The right and left tank bands 30 each have one front attachment hole in the front attaching portion 31 c and one rear attachment hole in the rear attaching portion 31 e . Support bolts 34 are inserted into the attachment holes, and screw portions of the support bolts 34 are made to pass through holes provided in the cross members 13 of the body 11 of the vehicle 10 . Then, the support bolts 34 are fastened with tank-attaching nuts 35 . In this way, the fuel tank 20 disposed below the floor panel 11 a is fixed to the body 11 and supported by the right and left tank bands 30 .
The fuel tank 20 may be entirely or partially (i.e., only at the bottom surface 20 a ) covered with a metal or resin cover, with a rubber or flexible resin layer therebetween, for protection from stones etc. In such a case, grooves to which the right and left tank bands are fitted are provided in the bottom surface of the cover, so that they serve the same function as the tank-band fitting grooves 21 in the fuel tank 20 .
A strain gauge 41 is attached to the side edge 32 of the projecting portion 31 of one of the right and left tank bands 30 , at the middle (center) position in the longitudinal direction. Although one strain gauge 41 is enough, more than one strain gauge 41 may be provided in case of fault or damage. Furthermore, the strain gauge 41 may be attached to the back surface of the edge 32 .
The strain gauge 41 is bonded to the edge 32 of the tank band 30 with adhesive such that the longitudinal directions of the strain gauge 41 and tank band 30 are parallel to each other. The top surface of the strain gauge 41 may be covered with a protection member formed of rubber, resin, or the like.
A gauge lead wire extending from the strain gauge 41 is connected to a strain-level measuring device 42 that detects the strain in the tank bands 30 and is formed of a power supply circuit, a bridge circuit, and an amplifier. The strain-level measuring device 42 is installed somewhere in the vehicle 10 , but not on the fuel tank 20 .
The strain-level measuring device 42 is connected to a processing device 43 that calculates the weight of the fuel 45 from the strain in the tank bands 30 and, moreover, calculates the level of the fuel 45 from the weight of the fuel 45 . The processing device 43 is installed somewhere in the vehicle 10 , but not on the fuel tank 20 .
The processing device 43 is disposed in an instrument panel provided at a driver's seat to indicate the results obtained by the processing device 43 and is connected to a fuel gauge 44 that indicates, using a needle or a bar graph, the level of the fuel 45 in the form of ratio to the capacity of the fuel tank 20 (i.e., from a full state to an empty state).
As described above, the fuel-level measuring apparatus 40 of the present application includes the tank bands 30 , the strain gauge 41 , the strain-level measuring device 42 , the processing device 43 , and the fuel gauge 44 .
Next, a method of how the fuel-level measuring apparatus 40 calculates the level of the fuel 45 in the fuel tank 20 from the strain in the tank bands 30 detected by the strain gauge 41 will be described.
Many metals experience expansion or contraction, which is minimal mechanical change, when a force is applied thereto (such expansion and contraction are generally called “strain”). The strain changes the electrical resistance of the metal. The strain gauge 41 and the strain-level measuring device 42 to which the strain gauge 41 is connected are sensors that detect, as an electric signal, the “strain” caused by a force applied to the metal. The strain and the electrical resistance are proportional to each other by a constant called “resistance change rate”, and the resistance change rate is determined by a passive component. Hence, the force (i.e., load) causing the strain can be obtained by multiplying the detected strain by the resistance change rate of the passive component of the strain gauge 41 . The present application provides a fuel-level detecting apparatus that obtains the level of the fuel 45 in the fuel tank 20 by detecting, with the strain gauge 41 , the strain in the tank bands 30 that support the fuel tank 20 .
Fuel is supplied from the fuel supply port (not shown) in the vehicle 10 to the fuel tank 20 through the fuel supply pipe 22 . The fuel supplied to the fuel tank 20 is supplied to the engine (not shown) through the fuel supply pipe 24 by the fuel pump (not shown).
When the level of the fuel 45 in the fuel tank 20 is increased by supplying fuel, the total weight of the fuel tank 20 (i.e., the sum of the weight of the fuel tank 20 and the weight of the fuel 45 ) increases. On the other hand, when the level of the fuel 45 is decreased by the engine consuming the fuel during driving, the total weight of the fuel tank 20 decreases. In short, the total weight of the fuel tank 20 increases or decreases in proportion to an increase or decrease in level of the fuel 45 .
Because the fuel tank 20 supported by the tank bands 30 at the bottom surface 20 a thereof is disposed below the floor panel 11 a of the vehicle 10 and is fixed to the body 11 , the tank bands 30 are subjected to the total weight of the fuel tank 20 . Hence, the strain due to the load (i.e., the total weight of the fuel tank 20 ) occurs in the tank bands 30 . A material of the tank bands 30 may be selected from any types including resins, metals and the like as known in the art, which have proper strain characteristics to allow the strain gauge 41 mechanically connected to the bands to convert the strain of the tank bands to electric signals, in responding to the total weight of the fuel tank 20 .
When the load applied to the tank bands 30 increases as the level of the fuel 45 in the fuel tank 20 increases, the surfaces of the tank bands 30 adjacent to the fuel tank 20 expand at the projecting portions 31 and the periphery thereof and contract at the front slope portions 31 b and rear slope portions 31 c of the projecting portions 31 .
For verification, three strain gauges were attached to the tank band 30 supporting the fuel tank 20 , as shown in the plan view in FIG. 1B , and the values detected by the strain gauges while the fuel was supplied were recorded and compared. The stresses (MPa) corresponding to the level of the fuel 45 (L) detected by a first strain gauge ( 41 a ) (see FIG. 4 ) attached to a middle portion of the projecting portion 31 in the longitudinal direction, a second strain gauge ( 41 b ) attached to an edge of the front slope portion 31 b of the tank band 30 , and a third strain gauge ( 41 c ) attached to an edge of the rear slope portion 31 d of the tank band 30 are plotted on the graph in FIG. 5 . As shown in FIG. 5 , in each strain gauge, the detected stress increases (or decreases in the case of minus) linearly as the fuel level increases. Thus, there is a linear relationship between the fuel level and the stress. Meanwhile, the stress detected by the first strain gauge was about three to five times those detected by the second and third strain gauges for the same level of the fuel 45 . This shows that the first strain gauge ( 41 a ) can detect the stress applied to the tank band due to an increase in the level of the fuel 45 in a greater magnitude than the other strain gauges. Accordingly, it may be considered that the strain gauge ( 41 a ) attached to the middle portion of the projecting portion 31 of the tank band 30 in the longitudinal direction can most precisely detect the level of the fuel 45 .
Hence, the strain gauge 41 attached to the edge 32 of the tank band 30 and the strain gauge 41 a attached to the middle portion of the projecting portion 31 of the tank band 30 in the longitudinal direction detect the strain (expansion) in the tank band 30 when the load applied to the tank band 30 increases as the level of the fuel 45 increases and detect a decrease in strain due to the expanded tank band 30 returning to the original state when the load applied to the tank band 30 decreases as the level of the fuel 45 decreases.
The strain gauge 41 detects the strain occurring in the tank band 30 as an electric signal and transmits the electric signal.
The strain-level measuring device 42 calculates the strain in the tank bands 30 from the electric signal received from the strain gauge 41 and sends data about the strain level to the processing device 43 .
The processing device 43 calculates the level of the fuel 45 from the strain data received from the strain-level measuring device 42 , using a predetermined arithmetic expression, a map, or the like.
When the fuel tank 20 is filled with the fuel 45 to the limit of its capacity, the total weight of the fuel tank 20 is equal to the sum of the weight of the fuel tank 20 and the weight of the fuel 45 that fills the fuel tank 20 to the limit of its capacity, and at this time, the load applied to the tank bands 30 is maximum. The level of the fuel 45 calculated by the processing device 43 from the electric signal generated by the strain occurring at this time is regarded as the limit of the capacity of the fuel tank 20 , and at this time, the needle of the fuel gauge 44 points to “F”, indicating a full tank.
Furthermore, when the level of the fuel 45 in the fuel tank 20 is zero, the total weight of the fuel tank 20 is equal to the weight of the fuel tank 20 , and at this time, the load applied to the tank bands 30 is minimum. The level of the fuel 45 calculated by the processing device 43 from the electric signal generated by the strain occurring at this time is regarded as zero, and at this time, the needle of the fuel gauge 44 points to “E”, indicating “empty tank”.
The fuel gauge 44 indicates the level of the fuel 45 , which is provided by the processing device 43 , in the form of ratio to the capacity of the fuel tank 20 (i.e., full, ¾ full, ½ full, ¼ full, and empty), using a scale and needle, a bar graph, or the like.
The present application is suitable for various types of vehicle including cars, such as passenger cars, freight cars, and buses, and diesel electric locomotives that use gasoline or light oil as fuel and have a fuel tank disposed and fixed below the floor panel of the vehicle.
FIG. 6 is a schematic view of another type of fuel tank provided with a fuel level measuring device according to the embodiment of the present invention as shown above. This fuel tank 200 has an elastic or flexible (expandable and retractable) body the inside of which is filled with a fuel. The tank body 200 is configured to expand to charge the fuel inside and shrink to discharge the fuel therefrom, responding to the change of the remaining amount (level) of fuel. The fuel tank body 200 secures the tank body to a vehicle body (not shown). As shown in FIG. 6 , a tank band 300 may be provided to support and hold the body of the tank 200 in a manner similar to FIG. 1 . A strain gauge 410 may typically be attached to the tank band 300 at a middle position thereof in the longitudinal direction. However, the position of the gauge 410 is not limited and may be selected from any other places as shown in FIGS. 1-4 . Any aspects and features discussed for the tank band and the gauge in the present application may be applied to this type of fuel tank.
As shown above, the fuel level measuring apparatus according to embodiments of the present invention can be mounted to the outside of the tank body by utilizing a tank band or any such supporting structure designed to hold the tank body, without a necessity of a float or other level detecting devices provided typically inside the tank body. Accordingly, this feature of the invention allows even any types of fuel tanks to easily measure the fuel level, with the tank band and the strain gauge according to the present invention, even in a case where they have no space or a limited space inside the tank for detecting the level of fuel.
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A fuel-level measuring apparatus measures the level of fuel in a vehicle fuel tank. The apparatus can ensure a sufficient capacity of the fuel tank and sense the fuel level even when the fuel tank has a thin or complicated shape. A fuel-level measuring apparatus that senses the level of fuel in a vehicle fuel tank disposed below a floor panel of a vehicle includes a tank band that secures the fuel tank to a body of the vehicle, and a strain gauge attached to the tank band. The fuel level can be obtained from strain in the tank band detected by the strain gauge.
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FIELD OF THE INVENTION
[0001] This invention relates to vehicle lamp assemblies and, in particular, to a novel method for hermetically sealing lamp assemblies having an adjustable reflector.
BACKGROUND OF THE INVENTION
[0002] Generally, vehicles, especially automobiles, are equipped with a wide variety of lights serving many different purposes. These purposes include dashboard lighting, interior overhead lighting, exterior lighting, trunk lighting and under-hood lighting, to name only a few. An even wider variety of lighting needs are presented by boats, air planes and other vehicles. Typical light assemblies include a housing with a lens and an opening in the housing for access to a lamp inside the housing.
[0003] In many applications, an adjustable reflector is mounted within the housing. With this type of lamp assembly, the housing is mounted securely to the vehicle, and the reflector position is adjusted within the housing to modify the direction of the beam of light emitted by the light assembly. Access to the rear portion of the reflector is provided by an opening in the housing. This allows for replacement of the lamp which is mounted to the reflector. Accordingly, the opening in the housing is substantially aligned with the rear of the reflector for easy access to the lamp.
[0004] The above described arrangement, while very useful in allowing for replacement of the lamp, increases the susceptibility of the light assembly to degraded performance due to the introduction of water, dirt or other debris into the lamp assembly. Accordingly, it is known to provide a sealing member between the light assembly housing and the reflector. Because the reflector is moveable, any such sealing member must be capable of allowing relative motion between the housing and the boot. One approach to providing a sealing member is to use flexible material. One such material is Ethylene Propylene Diene Monomer (EPDM) rubber.
[0005] EPDM possesses a number of desired characteristics. EPDM is capable of withstanding wide temperature variations without cracking or deteriorating. EPDM also offers high tensile strength, extreme elongation capabilities to several times its original size, and is generally compatible with other materials used in light assemblies. In a typical light assembly using EPDM, the rubber is mechanically or chemically sealed to the light housing in order to provide a hermetic seal.
[0006] The need for mechanical or chemical sealing in the light assembly process disadvantageously results in additional manufacturing steps and material. Every step in the assembly process adds time, complexity and expense to the manufacturing process. Thus, a reduction in the number of steps needed to accomplish assembly has a direct impact on lowering the manufacturing time and costs of the light assemblies. Furthermore, there are additional costs associated with stocking the increased number of parts or materials used in mechanically or chemically sealing EPDM. Thus, a reduction in the parts or material used to seal the light assemblies has a direct impact on lowering the manufacturing time and costs of the light assemblies.
[0007] Similarly, the manufacturing cost of the light assemblies has a direct impact on the overall cost of a vehicle. Thus, as the process of manufacturing the light assemblies is simplified, the cost of manufacturing can be reduced as increased manufacturing efficiency is realized.
[0008] Throughout the above processes, quality is an important consideration. The seal between the reflectors and the light assembly housings must be sufficiently robust that the performance of the light assemblies is not degraded by mishandling during manufacture, shipment and vehicle assembly processes. Furthermore, depending on the application, light assemblies must function reliably under severe operational conditions such as severe shock and vibration, a wide range of temperature, and exposure to water, oil and dirt.
[0009] It is desirable, therefore, to provide a hermetically sealed light assembly that does not require additional parts or materials. It is further desired that the light assembly be of simple and reliable construction. Moreover, it is desired that the light assembly not be of increased cost as compared to known light assemblies in the prior art while providing a reliable seal.
BRIEF SUMMARY OF THE INVENTION
[0010] In accordance with the present invention, a hermetically sealed light assembly is provided which overcomes the disadvantages of the prior art. According to the present invention, a thermoplastic elastomer boot of flexible or rigid design, is welded to a polypropylene housing to obtain a hermetic seal.
[0011] The invention provides a hermetically sealed light assembly that does not require additional parts or materials compared to light assemblies of the prior art. Furthermore, the light assembly is simple to manufacture and provides a robust seal. Moreover, the cost of materials for the light assembly is not increased compared to prior art light assemblies.
BRIEF DESCRIPTION OF THE DRAWINGS
[0012] [0012]FIG. 1 is a schematic side plan view of a vehicle lighting assembly housing in accordance with an exemplary embodiment of the present invention.
[0013] [0013]FIG. 2 is an enlarged partial schematic side plan view of a lighting assembly housing showing an alternative embodiment of a boot according to the present invention in an extended state.
[0014] [0014]FIG. 3 is an enlarged partial schematic side plan view of the lighting assembly housing of FIG. 2 showing the boot in a compressed state.
DETAILED DESCRIPTION OF THE INVENTION
[0015] An exemplary embodiment of the present invention is described in reference to FIG. 1. FIG. 1 generally illustrates vehicle lighting assembly 100 . Housing 102 is formed with groove 104 which accepts lip 106 of lens 108 . A seal is achieved between lip 106 and groove 104 by methods known in the art, such as by hot melting or the like. Reflector 114 is located within housing 102 and comprises opening 112 at the rearward portion of reflector 114 . Bulb 110 is located within opening 112 of reflector 114 . Opening 112 of reflector 114 is substantially aligned with opening 116 of housing 102 , which is located at the rearward end of housing 102 . Boot 118 is sealingly engaged at one end to housing 102 at opening 116 . Boot 118 is sealingly engaged at the other end to reflector 114 .
[0016] In the embodiment of FIG. 1, reflector 114 is adjustable. Accordingly, reflector 114 is movable relative to housing 102 . Therefore, boot 118 must be of a type which allows for relative motion between housing 102 and reflector 114 while maintaining a hermetic seal at opening 116 and opening 112 . In the embodiment of FIG. 1, this is achieved by constructing boot 118 from a thermoplastic elastomer (TPE), such as SANTOPRENE (SANTOPRENE is a registered trademark of, and commercially available from, Advanced Elastomer Systems, L. P. of Akron Ohio.). TPEs such as SANTOPRENE are synthetic products which may be produced so as to exhibit flexibility and durability similar to that of rubber material. These TPEs exhibit high tear strength and resistance to fatigue. TPEs can be produced in varying degrees of hardness and flexibility, from a membranous like product with a significant amount of flexibility to a rigid product. Even a rigid product, however, may be produced with a significant degree of elasticity.
[0017] When using a flexible TPE material, the boot may be in the shape of a simple cone or cylinder as shown in FIG. 1. The physical characteristics of the TPE will allow for the required relative motion between the housing and the reflector in the axial direction (forward-rearward axis) as well as any off-axial motion. Alternatively, a more rigid TPE may be desired. In these applications, the elastic nature of the TPE may be relied upon to allow for the required relative motion between the housing and the reflector. An alternative embodiment of the invention which relies upon the elastic nature of the TPE is discussed with reference to FIG. 2 and FIG. 3.
[0018] [0018]FIG. 2 is an enlarged partial schematic side plan view of a lighting assembly housing showing an alternative embodiment of a boot according to the present invention in an extended state. Lighting assembly housing 200 comprises housing 202 . Reflector 204 is located within housing 102 . Access to base 206 of reflector 204 is provided by opening 208 in housing 202 . Base 206 may be used to provide a means for mounting a light bulb (not shown) within reflector 204 . Boot 210 comprises a plurality of ribs 214 . Boot 210 , which is made from a TPE, is sealingly engaged at one end to base 206 of reflector 114 . A hermetic seal may be achieved according to any means known to those of skill in the relevant art. By way of example, but not of limitation, boot 210 may be sealed to base 206 by using an o-ring and a washer. In such an embodiment, screws 212 may be used to force the washer and o-ring against base 206 to achieve the hermetic seal.
[0019] Boot 210 is sealingly engaged at the other end to housing 202 at opening 208 . In the embodiment of FIG. 2, housing 202 comprises a thermoplastic polymer (TPP) such as polypropylene. Thermoplastic materials soften when subjected to heat, but do not cure or set when subsequently cooled. Accordingly, thermoplastic materials may be heated and injected molded into various forms. Upon cooling, the thermoplastic will harden into the shape of the mold, such as a light assembly housing. However, because the thermoplastic does not cure, the thermoplastic housing may be re-melted. This is beneficial since the thermoplastic housing may be joined to other items through various forms of welding such as, but not limited to, hot gas welding, spin welding, fusion welding, butt welding, ultra-sonic welding, vibration welding, IR welding or LASER welding.
[0020] As discussed above, boot 210 is made from a TPE. TPE's can be thought of as comprising two phases. One phase is a soft phase, which imparts the rubber like characteristics of the TPE. The other phase is a hard phase, which is essentially a thermoplastic phase. Accordingly, the TPE may also be welded. Thus, boot 210 may be welded to housing 202 . Welding has many advantages over chemical or mechanical sealing. For example, the time for joining is reduced compared to adhesive bonding. Moreover, the weld typically exhibits a high strength, and does not require additional chemicals or parts.
[0021] The ability to weld the TPE is influenced by the rubber content (soft phase) of the material. Thus, as the amount of soft phase material increases, the weldability of the TPE decreases. In practice, it has been discovered that using a TPE with a hardness of about 95 Shore A or 55 Shore D produces a boot which can be effectively welded while retaining sufficient flexibility to allow for relative motion between the housing and the boot of a light assembly.
[0022] Referring now to FIG. 3, the lighting assembly housing of FIG. 2 is shown with boot 210 in a compressed state. Because boot 210 is elastic and made in a bellows shape, reflector 204 may be moved in an axial direction without compromising the seal between boot 210 and reflector 204 or housing 202 . As compared to FIG. 2, FIG. 3 shows reflector 204 moved axially toward housing 202 , compressing boot 210 . Those of skill in the art will understand that a variety of alternative shapes may be used in practicing the present invention such as, but not limited to, bulbous or hour-glass shapes. Moreover, the bellows may comprise fewer or additional ribs as compared to the embodiment of FIG. 2 and FIG. 3. These and other variations being within the scope of the present invention.
[0023] Those of skill in the art will realize that as described herein, the present invention provides significant advantages over the prior art. The invention provides a hermetically sealed light assembly that does not require additional parts or materials compared to light assemblies of the prior art. Furthermore, the light assembly is simple to manufacture and provides a robust seal. Moreover, the cost of materials for the light assembly is not increased compared to prior art light assemblies.
[0024] While the present invention has been described in detail with reference to a certain exemplary embodiment thereof, such is offered by way of non-limiting example of the invention, as other versions are possible. It is anticipated that a variety of other modifications and changes will be apparent to those having ordinary skill in the art and that such modifications and changes are intended to be encompassed within the spirit and scope of the invention as defined by the following claims.
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The present invention comprises a lamp assembly with a boot hermetically cohered to the housing. The housing comprises a thermoplastic polymer and the boot comprises a thermoplastic elastomer. The boot is cohered to the housing by welding. According to one embodiment, the boot is sonic or vibration welded to the housing. The present invention may be used in the production of a wide range of lamp assemblies, including vehicle headlamp assemblies.
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BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a combustion heater system for use in a motor vehicle, and more particularly to a combustion heater system having a control unit for controlling the ignition and extinction of a combustion heater which utilizes the heat of combustion of a fuel in a motor vehicle with a clean power plant, such as an electric vehicle.
2. Description of the Prior Art
FIG. 4 of the accompanying drawings shows a conventional combustion heater system for use in a motor vehicle with a clean power plant, such as an electric vehicle. The illustrated combustion heater system has a combustion pad 102 disposed in a combustion chamber 101, a fuel supply passage 104 for supplying a fuel from a fuel tank 103 to the combustion pad 102, a solenoid-operated valve 105 for selectively opening and closing the fuel supply passage 104, a glow plug 106 for heating the combustion pad 102, a fan 107 for supplying air into the combustion chamber 101, and a control unit 108 for controlling the solenoid-operated valve 105, the glow plug 106, and the fan 107.
When the starter switch of the conventional combustion heater system is turned on, the control unit 108 rotates the fan 107 at a half output rate to supply air into the combustion chamber 101 as shown in FIG. 5A of the accompanying drawings, and the control unit 108 energizes the glow plug 106 to pre-glow the combustion pad 102 for 30 seconds, for example, as shown in FIG. 5B of the accompanying drawings. Thereafter, the control unit 108 actuates the solenoid-operated valve 105 to open the fuel supply passage 104 for thereby supplying the fuel to the combustion pad 102 as shown in FIG. 5C of the accompanying drawings. The control unit 108 continues to energize the glow plug 106 for 60 seconds, for example, to heat the combustion pad 102 up to a temperature at which the fuel can be ignited. When the fuel supplied to the combustion pad 102 is ignited by spontaneous combustion, the control unit 108 de-energizes the glow plug 106. After having waited for 20 seconds, for example, until the combustion of the fuel is stabilized, the control unit 108 rotates the fan 107 at a full output rate.
When the starter switch of the conventional combustion heater system is turned off, the control unit 108 inactivates the solenoid-operated valve 105 to close the fuel supply passage 104 for thereby stopping the supply of the fuel to the combustion pad 102 to extinguish the same as shown in FIG. 6B of the accompanying drawings. As shown in FIG. 6A of the accompanying drawings, the control unit 108 rotates the fan 107 at a full output rate to discharge any unburned gas from the combustion chamber 101. After elapse of a predetermined period of time, the control unit 108 turns off the fan 107. In some combustion heater systems, the fuel is extinguished by inactivating the fan to stop supplying the air into the combustion chamber, or the fuel is extinguished by stop supplying both the fuel and the air.
With the above conventional combustion heater system, however, when the fuel is to be ignited, the air is continuously supplied to the combustion chamber 101 by the fan 107 until the fuel supplied to the combustion pad 102 is ignited, i.e., from the time at which the fuel is supplied to the time at which the fuel is ignited by spontaneous combustion. Therefore, before the fuel is ignited, the fuel supplied to the combustion pad 102 is vaporized and discharged, resulting an undesirable unburned fuel emission. In addition, since the air required for the fuel to be combusted is supplied while the glow plug 106 is being energized, the glow plug 106 is deprived of heat by the air flow. As a consequence, a certain amount of electric energy is wasted by the glow plug 106, and a relatively long period of time is consumed before the fuel is ignited.
When the fuel is to be extinguished, the supply of the fuel to the combustion pad 102 is stopped. However, because the fan 107 is continuously actuated, the amount of heat and the amount of supplied air are brought out of balance. Though the flame is put out, the fuel attached to the combustion pad 102 is vaporized by the supplied air and discharged out of the combustion chamber 101. If the supplied air is stopped to extinguish the fuel, then the flame is put out, and the fuel remains unburned in the combustion pad 102. The remaining fuel is vaporized by the heat of the combustion pad 102 and discharged out of the combustion chamber 101.
Therefore, the conventional combustion heater system tends to produce a large amount of unburned fuel emission when the fuel is ignited and extinguished.
Japanese patent publication No. 57-40418, published Aug. 27, 1982, discloses an apparatus for controlling a heated water source in a combustion heater system for use in an automobile.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a combustion heater system for motor vehicles which is capable of igniting a fuel quickly and reliably and minimizing an undesirable unburned fuel emission before the fuel starts being combusted.
Another object of the present invention is to provide a combustion heater system for motor vehicles which is capable of extinguishing a fuel reliably and minimizing an undesirable unburned fuel emission before the fuel starts being combusted.
According to the present invention, there is provided a combustion heater system for use in a motor vehicle, comprising a combustion chamber, a combustion pad disposed in the combustion chamber, a fuel supply passage connected to the combustion pad for supplying a fuel to the combustion pad, valve means for selectively opening and closing the fuel supply passage, air supply means for supplying air to the combustion chamber, heating means for heating the combustion pad, spark means for producing sparks in the combustion chamber to ignite a fuel vapor emitted from the combustion pad, and control means for energizing the heating means to heat the combustion pad, actuating the valve means to open the fuel supply passage, actuating the air supply means to supply air to the combustion chamber, and subsequently energizing the spark means to produce sparks in the combustion chamber upon elapse of a preset period of time which begins with the energization of the heating means and is determined depending on conditions for vaporization of the fuel.
According to the present invention, there is also provided a combustion heater system comprising a combustion chamber housing a combustion pad for vaporizing a fuel with heat, heating means for heating the combustion pad, fuel supply means for supplying the fuel to the combustion pad, air supply means for supplying air to the combustion chamber, spark means for producing sparks in the combustion chamber to ignite a fuel vapor emitted from the combustion pad, and control means for energizing the heating means to heat the combustion pad, actuating the fuel supply means to supply the fuel to the combustion pad, actuating the air supply means supply air to the combustion chamber, and subsequently energizing the spark means to produce sparks upon elapse of a preset period of time thereby to ignite the fuel vapor emitted from the combustion pad, and for inactivating the fuel supply means to stop supplying the fuel to the combustion pad and subsequently inactivating the air supply means to stop supplying air to the combustion chamber.
According to the present invention, there is also provided a combustion heater system according to claim 8, further comprising flame condition detecting means for detecting a flame condition in the combustion chamber, the control means comprising means for continuously energizing the spark means to produce sparks upon elapse of a predetermined period of time depending on the flame condition detected by the flame condition detecting means, after elapse of the preset period of time.
According to the present invention, there is also provided a combustion heater system for use in a motor vehicle, comprising a combustion chamber, a combustion pad disposed in the combustion chamber, a fuel supply passage connected to the combustion pad for supplying a fuel to the combustion pad, valve means for selectively opening and closing the fuel supply passage, air supply means for supplying air to the combustion chamber, heating means for heating the combustion pad, spark means for producing sparks in the combustion chamber to ignite a fuel vapor emitted from the combustion pad, flame condition detecting means for detecting a flame condition in the combustion chamber, and control means for energizing the heating means to heat the combustion pad for a predetermined period of time which begins with the energization of the heating means, and subsequently energizing the spark means to produce sparks in the combustion chamber and continuously energizing the spark means until a flame condition is detected by the flame condition detecting means.
According to the present invention, there is also provided a combustion heater system for use in a motor vehicle, comprising a combustion chamber, a combustion pad disposed in the combustion chamber, a fuel supply passage connected to the combustion pad for supplying a fuel to the combustion pad, valve means for selectively opening and closing the fuel supply passage, air supply means for supplying air to the combustion chamber, heating means for heating the combustion pad, flame condition detecting means for detecting a flame condition in the combustion chamber, and control means for controlling the air supply means to vary the amount of air supplied therefrom to the combustion chamber depending on the flame condition detected by the flame condition detecting means.
According to the present invention, there is further provided a combustion heater system for use in a motor vehicle, comprising a combustion chamber, a combustion pad disposed in the combustion chamber, a fuel supply passage connected to the combustion pad for supplying a fuel to the combustion pad, valve means for selectively opening and closing the fuel supply passage, air supply means for supplying air to the combustion chamber, heating means for heating the combustion pad, flame condition detecting means for detecting a flame condition in the combustion chamber, and control means for controlling the air supply means to vary the amount of air supplied therefrom to the combustion chamber depending on the flame condition detected by the flame condition detecting means when the fuel supplied to the combustion pad is to be extinguished.
The above and further objects, details and advantages of the present invention will become apparent from the following detailed description of a preferred embodiment thereof, when read in conjunction with the accompanying drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic view of a combustion heater system according to the present invention;
FIGS. 2A through 2D are timing charts of various signals applied by a control unit of the combustion heater system to start activating a combustion heater;
FIGS. 3A and 3B are timing charts of various signals applied by the control unit to stop activating the combustion heater;
FIG. 4 is a schematic view of a conventional combustion heater system;
FIGS. 5A through 5C are timing charts of various signals applied by a control unit of the conventional combustion heater system shown in FIG. 4; and
FIGS. 6A and 6B are timing charts of various signals applied by the control unit to stop activating the conventional combustion heater system shown in FIG. 4.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENT
The principles of the present invention are particularly useful when embodied in a combustion heater system incorporated in an air-conditioning system on a motor vehicle.
The combustion heater system according to the present invention includes a combustion heater having a combustion chamber 1 which houses a combustion pad 2 therein.
The combustion pad 2 is connected to a fuel tank 3 for storing a liquid fuel such as gasoline, gas oil, or kerosene, through a fuel supply passage 4 which extends through a rear wall la of the combustion chamber 1. The fuel supply passage 4 can selectively be opened and closed by a solenoid-operated fuel valve 5 disposed therein which can be actuated by a solenoid 5a. A temperature sensor 2a for detecting the temperature around the combustion pad 2 is positioned near the combustion pad 2. Another temperature sensor 3a for detecting the temperature of the fuel stored in the fuel tank 3 is positioned in the fuel tank 3.
The combustion chamber 1 also houses a glow plug 6 mounted on a side wall lb thereof and positioned near the combustion pad 2, for heating the combustion pad 2. The combustion chamber 1 is connected to a fan 7 through an outlet duct 7b mounted on the rear wall la of the combustion chamber 1. The fan 7 is supplied with air through an inlet duct 7c in which there is disposed an air temperature sensor 7a for detecting the temperature of air flowing through the inlet duct 7c.
The combustion chamber 1 further houses a spark plug 8 positioned downstream of the glow plug 6 with respect to the direction in which air flows from the fan 7 through the outlet duct 7a into the combustion chamber 1. The spark plug 8 is supported on a side arm 2b connected to and extending from one side of the combustion pad 2 along the side wall lb of the combustion chamber 1.
Three flame sensors 9a, 9b, 9c also housed in the combustion chamber 1 are mounted on another side arm 2c connected to and extending from an opposite side of the combustion pad 2 along a side wall 1c of the combustion chamber 1 which is opposite to and spaced from the side wall lb. When the combustion heater is in operation, the fuel supplied from the fuel tank 3 to the combustion pad 2 is combusted producing a flame F in a space between the side arms 2b, 2c. The sensors 9a, 9b, 9c are successively arranged along the direction in which the flame F flows from the combustion pad 2, i.e., are spaced at successively different distances from the combustion pad 2. The sensors 9a, 9b, 9c serve to detect a flame condition in the combustion chamber 1, and output respective detected signals depending on the magnitude or position of the flame F. For example, the sensors 9a, 9b, 9c comprise temperature sensors, respectively, for detecting relatively high temperatures, and the condition of the flame F can be predicted from the temperature detected by these sensors 9a, 9b, 9c.
The combustion heater system includes a control unit 10 for controlling overall operation of the combustion heater. As described in detail below, the control unit 10 serves as means for controlling sparking in the combustion chamber 1, continued sparking in the combustion chamber 1, and the supply of air to the combustion chamber 1. In order to serve as these means, the control unit 10 controls the opening and closing of the solenoid-operated valve 5, the energization and de-energization of the glow plug 6, the operation of the fan 7, and the energization of the spark plug 8, and is supplied with detected signals from the flame sensors 9a, 9b, 9c. The temperature sensors 2a, 3a, 7a, 9a, 9b, 9c are electrically connected to the control unit 10. Input keys 10a are also connected to the control unit 10. The control unit 10 may comprise a microcomputer including a central processing unit, a random-access memory, a read-only memory, input and output interfaces, and a bus interconnecting these elements. The microcomputer is programmed to carry out the operation of the combustion heater as described below.
First, the control unit 10 operates to start activating the combustion heater as follows: When the main switch of the air-conditioning system combined with the combustion heater system is turned on, the control unit 10 applies a signal S1 (see FIG. 2D) to the solenoid 5a to open the solenoid-operated valve 5. The fuel supply passage 4 is opened to supply the fuel from the fuel tank 3 to the combustion pad 2.
At the same time, as shown in FIG. 2B, the control unit 10 applies a signal S2 to the glow plug 6 to energize the glow plug 6 for thereby causing the combustion pad 2 to pre-glow, i.e., heating the combustion pad 2 before the fuel supplied to the combustion pad 2 is vaporized. The control 10 also supplies a signal S3 to the fan 7 to rotate the fan 7 at a quarter output rate for thereby supplying air through the outlet duct 7b into the combustion chamber 1.
The combustion pad 2 is caused by the glow plug 6 to pre-glow for a period of time, i.e., a pre-glow time, which is required for the fuel to be vaporized from the combustion pad 2. Specifically, the control unit 10 has a look-up table or a map which stores data representing different pre-glow times in relation to different conditions which affect vaporization of the fuel, including temperatures around the combustion pad 2, temperatures of air supplied to the fan 7, temperatures of the fuel stored in the fuel tank 3, and fuel volatility values. When the control unit 10 starts to operate the combustion heater, the control unit 10 determines the period of time for which the combustion pad 2 is to pre-glow from the look-up table or the map in the control unit 10 based on the temperature around the combustion pad 2 as detected by the temperature sensor 2a, the temperature of the air supplied to the fan 7 as detected by the temperature sensor 7a, the temperature of the fuel in the fuel tank 3 as detected by the temperature sensor 3a, and the fuel volatility as inputted by the input keys 10a. Since the combustion pad 2 is controlled to pre-glow for exactly the period of time required for the fuel to be vaporized from the combustion pad 2, it is not heated for an excessively long period of time, thus preventing the vaporized fuel from being discharged, unburned, from the combustion heater.
After elapse of the pre-glow time, which may be 2 seconds, for example, the control unit 10 applies a pulsed signal S4 (see FIG. 2C) to the spark plug 8, which is energized to produce sparks for igniting the fuel vapor emitted from the combustion pad 2. Simultaneously, the control unit 10 increases the level of the signal S3 to rotate the fan 7 at a half output rate for supplying an increased volume of air into the combustion chamber 1.
When a predetermined period of time, such as 2 seconds, for example, has elapsed from the first spark produced by the spark plug 8, the control unit 10 checks the detected signals from the flame sensors 9a, 9b, 9c. If the fuel vapor is ignited, then the control unit 10 turns off the glow plug 6 as indicated by the solid-line curve in FIG. 2B. Thereafter, while checking the detected signals from the flame sensors 9a, 9b, 9c, the control unit 10 increases the level of the signal S3 to rotate the fan 7 at a three-quarter output rate and then a full output rate for successively increasing the volume of air supplied into the combustion chamber 1.
If the fuel vapor is not ignited upon elapse of the predetermined period of time after the first spark, then the control unit 10 keeps the glow plug 6 energized as indicated by the broken-line curve in FIG. 2B, and continuously controls the spark plug 8 to produce successive sparks in order to ignite the fuel vapor as indicated by the broken-line curve in FIG. 2C. At the same time, the control unit 10 maintains the level of the signal S3 to rotate the fan 7 at a half output rate as indicated by the broken-line curve in FIG. 2A.
As described above, the fuel supplied to the combustion pad 2 is heated and vaporized by the glow plug 6 which can be heated with a quick response, and the fuel vapor emitted from the combustion pad 2 is forcibly ignited by sparks produced by the spark plug 8 before the fuel vapor is ignited by spontaneous combustion which occurs at about 300° C. with gasoline, 260° C. with gas oil, and 230° C. with kerosene. Consequently, the time required for the fuel to be ignited is relatively short, and any unburned fuel vapor that is discharged from the combustion heater before it is ignited is minimized. Since any undesirable unburned fuel emission from the combustion heater is reduced, the fuel can economically be utilized.
Even if the fuel vapor is not ignited immediately, since sparks are successively produced by the spark plug 8 depending on the temperature in the combustion chamber 1, the fuel vapor can reliably be ignited. Accordingly, any undesirable unburned fuel emission from the combustion heater is also minimized.
The amount of air supplied to the combustion chamber 1 is increased stepwise as the fuel ignition process progresses. Specifically, before the fuel vapor is ignited, the amount of air supplied to the combustion chamber 1 is relatively small, and hence does not deprive the combustion pad 2 of heat while the combustion pad 2 is pre-glowing. Accordingly, the fuel supplied to the combustion pad 2 can reliably be vaporized by the heated combustion pad 2. During an initial stage of fuel ignition, the amount of air supplied to the combustion chamber 1 is increased, but not up to the full rate. Therefore, the fuel vapor starts being stably combusted as the flames produced by the initial ignition of the fuel vapor are not disturbed by the air flow introduced into the combustion chamber 1. Such a controlled air flow is also effective to suppress undesirable unburned fuel emission from the combustion heater.
The control unit 10 operates to stop activating the combustion heater as follows: When the main switch of the air-conditioning system is turned off, the control unit 10 de-energizes the solenoid 5a to close the solenoid-operated valve 5 as shown in FIG. 3B. The fuel supply passage 4 is closed to cut off the supply of the fuel from the fuel tank 3 to the combustion pad 2.
At the same time, while checking the detected signals from the flame sensors 9a, 9b, 9c, the control unit 10 successively reduces the level of the signal S3 to rotate the fan 7 at successively lower output rates for thereby reducing the volume of air supplied through the outlet duct 7a into the combustion chamber 1, as shown in FIG. 3A. Depending on the flame condition as detected by the flame sensors 9a, 9b, 9c, the control unit 10 may control the amount of air supplied to the combustion chamber 1 as indicated by the broken-line curves in FIG. 3A.
Since the amount of air supplied to the combustion chamber 1 is successively reduced depending on the flame condition in the combustion chamber 1, any fuel that remains in the combustion pad 2 after the fuel supply is cut off can fully be burned before the supply of air is completely stopped. Therefore, undesirable unburned fuel emission from the combustion heater is minimized when the combustion heater is inactivated.
The flame condition, i.e., the temperature, in the combustion chamber 1 can accurately be detected by the flame sensors 9a, 9b, 9c because the flame sensors 9a, 9b, 9c are spaced at different distances from the combustion pad 2. The accurately detected flame condition permits the control unit 10 to stop or continue sparking highly accurately and also to regulate the amount of air highly accurately while the combustion heater is in operation.
Although there has been described what is at present considered to be the preferred embodiment of the invention, it will be understood that the invention may be embodied in other specific forms without departing from the essential characteristics thereof. The present embodiment is therefore to be considered in all respects as illustrative, and not restrictive. The scope of the invention is indicated by the appended claims rather than by the foregoing description.
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A combustion heater system for use in a moter vehicle has a combustion chamber housing a combustion pad which is heated by a pre-glow plug for vaporizing a fuel that is supplied from a fuel tank through a solenoid-operated valve to the combustion pad. The combustion chamber is supplied with air from a fan, and houses a spark plug for producing sparks in the combustion chamber to ignite a fuel vapor emitted from the combustion pad. The combustion heater system has a control unit which energizes the pre-glow plug to heat the combustion pad, actuates the solenoid-operated valve to supply the fuel to the combustion pad, and actuates the fan to supply air to the combustion chamber. The control unit subsequently energizes the spark plug to produce sparks upon elapse of a preset period of time hereby to ignite the fuel vapor emitted from the combustion pad for producing flames in the combustion chamber. To extinguish the flames, the control unit inactivates the solenoid-operated valve to stop supplying the fuel to the combustion pad and subsequently inactivates the fan to stop supplying air to the combustion chamber.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation-in-part of and claims priority in U.S. patent application Ser. No. 14/532,957, filed Nov. 4, 2014, which is a continuation of and claims priority in U.S. patent application Ser. No. 13/412,359, filed Mar. 5, 2012, now U.S. Pat. No. 8,880,718, issued Nov. 4, 2014, which claims priority in U.S. Provisional Patent Application Ser. No. 61/448,997, filed Mar. 3, 2011, and is related to U.S. patent application Ser. No. 13/412,512, filed Mar. 5, 2012, which claims priority in U.S. Provisional Patent Application Ser. No. 61/448,972, filed Mar. 3, 2011, and is also related to U.S. patent application Ser. No. 13/095,601, filed Apr. 27, 2011, which claims priority in U.S. Provisional Patent Application Ser. No. 61/328,305, filed Apr. 27, 2010, all of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The present disclosed technology relates generally to a system and method for recording, uploading, and utilizing video recorded in real-time, and specifically to a front-end and back-end video archival system and method using video recorded in real-time to aid in emergency or weather response.
[0004] 2. Description of the Related Art
[0005] Digitally watermarking or embedding data into recorded video is well known in the art. Modern mobile phones, digital cameras, and other mobile devices are capable of recording video anywhere a user is located, and uploading that video to common video archive websites, such as youtube.com. These mobile devices may also include GPS functionality, allowing the video to be tagged with location data and other relevant data so that anyone who ultimately views the video can determine where and when a video was taken.
[0006] Presently, such mobile user-submitted videos may be uploaded to video archival or video sharing networks, but the value of the embedded video data is typically underused. For instance, a video may be uploaded to a publicly available video archive database where numerous end users are able to view the video, but the video may not be used immediately and the relevance of the time and location of the video that has been uploaded loses value.
[0007] Typical video archive databases either include embedded video data as an afterthought, or limit the access of that data to selected users. One such example of selective use of video data is U.S. Pat. No. 7,633,914 to Shaffer et al. (the “914 patent). Although video data may be uploaded and used for assessing critical security or other means in the geographic area of the video data, the '914 patent relies on users who have already accessed “virtual talk groups” to upload relevant video data. That video data is then only immediately accessible to members of the same virtual talk groups, which limits the effectiveness of the video data to a small number of users.
[0008] Embedded video or photograph data is also used by police departments for accurate evidence collection. U.S. Pat. No. 7,487,112 to Barnes, Jr. (the “112 patent”) describes this ability, but limits the use of the uploaded video or photographic data to the police department. Video or photographic data uploaded to the collection server is stored and not immediately used in any capacity. Such a technique merely simplifies the tasks of a police officer during evidence collection and does not fully embrace the value of embedded video data.
[0009] What is needed is a system which provides mobile users the ability to record video with embedded data, upload that video to a commonly accessible database where the video may be immediately reviewed, and any particular value that can be gathered from the uploaded video be submitted to emergency crews or other relevant parties for immediate review of the recently uploaded video. Heretofore there has not been a video archival system or method with the capabilities of the invention presented herein.
SUMMARY OF THE INVENTION
[0010] Disclosed herein in an exemplary embodiment is a system and method for uploading and archiving video recordings, including a front-end and a back-end application.
[0011] The preferred embodiment of the present invention includes a front-end application wherein video is recorded using a mobile device. The recorded video is embedded with date, time and GPS location data.
[0012] The video is stored on an online back-end database which catalogues the video according to the embedded data elements. The video may be selectively reviewed by relevant experts or emergency personnel for immediate response to the uploaded video and/or distribution to the proper parties. The video may also be archived for later review and use by any number of end-users.
[0013] An alternative embodiment includes the ability to reconstruct or recreate a virtual three-dimensional space from recorded video and audio of a scene or event, taken from multiple angles. At least three angles would be needed for a three-dimensional recreation, but additional angles improve the accuracy of the virtual space. This space can then be reviewed and analyzed, sounds can be replayed from multiple locations through the virtual space, and incidents can be recreated.
BRIEF DESCRIPTION OF THE DRAWINGS
[0014] The drawings constitute a part of this specification and include exemplary embodiments of the disclosed subject matter illustrating various objects and features thereof, wherein like references are generally numbered alike in the several views.
[0015] FIG. 1 is a block diagram showing the relationship between the various elements of the preferred embodiment of the present invention.
[0016] FIG. 2 is a flowchart showing the practice of a method of the preferred embodiment of the present invention.
[0017] FIG. 3 is a diagram illustrative of a user interface for viewing videos on a computer utilizing the preferred embodiment of the present invention.
[0018] FIG. 4 is a diagram illustrative of a user interface for viewing archived video associated with the preferred embodiment of the present invention.
[0019] FIG. 5 is a block diagram showing the relationship between various elements of an alternative embodiment of the present invention.
[0020] FIG. 6 is a flowchart showing the practice of a method of an alternative embodiment of the present invention.
[0021] FIG. 7 is a diagrammatic representation of an alternative embodiment of the present invention.
[0022] FIG. 8 is another diagrammatic representation thereof.
[0023] FIG. 9 is a flowchart diagramming the steps taken to practice the alternative embodiment of FIG. 7 .
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
I. Introduction and Environment
[0024] As required, detailed aspects of the disclosed subject matter are disclosed herein; however, it is to be understood that the disclosed aspects are merely exemplary of the invention, which may be embodied in various forms. Therefore, specific structural and functional details disclosed herein are not to be interpreted as limiting, but merely as a basis for the claims and as a representative basis for teaching one skilled in the art how to variously employ the present invention in virtually any appropriately detailed structure.
[0025] Certain terminology will be used in the following description for convenience in reference only and will not be limiting. For example, a personal computer including a display device for viewing a typical web browser or user interface will be commonly referred to throughout the following description. The type of computer, display, or user interface may vary when practicing an embodiment of the present invention.
[0026] A preferred embodiment of the present invention relies on a front-end mobile application 3 associated with a mobile personal computing device 7 , such as a mobile phone, personal digital assistant, or other hand-held computing-capable device. The mobile personal computing device 7 must access a wireless network 16 . A back-end mobile application 17 may be accessed via any personal computing device with capable access to a network, such as the World Wide Web.
II. Geo-Location Video Archive System and Method
[0027] Referring to the drawings in more detail, reference numeral 2 generally refers to a geo-location video archive system, comprising a front-end mobile application 3 , a back-end mobile application 17 , and an end user 30 .
[0028] FIG. 1 demonstrates the relationship between the front-end application 3 , the back-end application 17 , a wireless network 16 , and an end user 30 . The front-end application 3 is comprised of a mobile device 7 . This mobile device 7 may be any hand held mobile device capable of recording and uploading video data via the wireless network 16 to a database server 18 utilized by the back-end application 17 .
[0029] The mobile device 7 includes a camera 4 or other video capture ability capable of recording either still or video images, an antenna 6 , a processor 8 , a wireless network connection 10 , a memory 12 storing an application 14 , and a position reference 13 .
[0030] The antenna 6 is capable of receiving and transmitting data over a wireless network 16 , such as image data recorded by the camera 4 . The processor 8 is adapted for processing all data required by the mobile device. The wireless network connection 10 allows the mobile device 7 to access the wireless network 16 for transmission and reception of data. The memory 12 stores all data necessary for the function of the mobile device 7 , including image data recorded by the camera 4 . An application 14 for accessing the back-end mobile application 17 via the wireless network 16 is stored on the memory. The position reference 13 includes optional two-dimensional or three-dimensional positional information about the mobile device 7 . This positional reference 13 may optionally be attached to image data recorded with the camera 4 .
[0031] The primary purpose of the mobile application 7 is to capture high resolution video by use of the mobile device's 7 camera 4 . The application 14 will collect video in one to ten second slices and transmit it with related data. This data may include Global Positioning System (GPS) location in the form of Longitude and Latitude, Date and Time stamp, description of up to 140 characters, as well as declination based upon magnetic or true north that will be packaged in an XML-formatted file with the phone's ID and a user name. Combined with the video slice, the mobile application will send a “packet” 19 to the database server 18 .
[0032] The back-end mobile application 17 is comprised of a database server 18 which serves to receive all data submitted by mobile devices 7 included in the front-end application 3 , and an optional subject matter expert (expert) 29 capable of reviewing submitted data for real-time use and organized archiving.
[0033] The database server 18 further includes an archive database 20 , a memory 22 , a processor 24 , a video review station application 26 and a user web application 28 . Image data and other data submitted to the database server 18 via the front-end mobile application 3 are stored in the archive database 20 . The video review station application 26 is an optional feature that may be included for use by the expert 29 for reviewing submitted image data and other submitted data. The user web application 28 is an optional feature allowing end users 30 to access data uploaded to the database 18 for personal use.
[0034] Multiple mobile devices 7 may be incorporated with the front-end mobile application 7 . Each front-end application may upload recorded data simultaneously to the database server 18 . The database server 18 will receive a transmission packet 19 from various mobile devices 7 . If this is a new transmission, the video slice and the metadata will be split from the transmission packet and saved into a storage folder located in the archive database 20 . If the packet is a continuation of a current transmission, the video slice will be unpackaged from the packet, and merged with the previously received video slice. In addition the metadata transmitted with the packet will be merged with the current metadata XML. If this is the terminating packet, the video slice will be unpackaged from the packet, and merged with the previously received video slice. In addition, the metadata transmitted with the packet will be merged with the current metadata XML. Once complete, the video file and metadata will be saved into the archive database 20 . Finally, a confirmation 27 of the received video can be sent to the mobile device 7 , confirming that the video transmission was complete. In turn, this information may be made available to another application, web site, or other end user 30 for whatever needs it may have.
III. Database Video Upload, Review, and Use
[0035] In an embodiment of the present invention, an expert 29 will review video files uploaded to the database server 18 through the video review station application 26 . The video review station application 26 will collect video from the front-end application 3 . The application will gather the videos corresponding XML metadata and display the information for the expert 29 . This will include items such as date, time, location, and video length. The expert 29 will then tag the event as a category that best describes the video (i.e. tornado, flood, thunder storm), apply search keywords, and modify the description as needed. The expert 29 will then, using a set of defined standards, grade the video, such as on a rating of one to five “stars.” As examples, five stars may indicate: the highest quality video; video of devastating weather; or video meeting predefined quality definitions. At this time the video can be rejected if it does not meet video submission related requirements. Once this process has been completed, the expert 29 will save the video and corresponding XML to the proper database tables, making it available for searching.
[0036] FIG. 2 demonstrates the practice of the above method in more detail. This will start at 31 when a phenomenon or event occurs at 32 . A mobile user will use their mobile device to capture video of the event at 34 and will upload that video to the database server at 36 . As explained above, the video will be uploaded in slices and will be saved to the archive database at 38 for further review.
[0037] The database will check for raw video submissions at 40 and will determine if a new video has been uploaded or submitted to the server at 42 . If no new video data has been uploaded or submitted, the process continues checking the database for new submissions.
[0038] Upon detecting a new video submission, the video will be transferred to the expert for review at 44 . The expert checks to determine if the video meets the back-end application requirements at 46 . These requirements may include video relevance, video quality, and whether similar videos have already been uploaded for a single event. If the video does not meet all requirements, the video is marked as “rejected” at 48 , saved into a non-searchable database table at 50 , and stored in the video archive database at 38 .
[0039] If the expert determines that the video meets all requirements, the expert will then grade the video based on standard operating procedures at 52 . The video will be categorized at 54 to allow for easy searching of the video through the user web application. Categories may include video location, event description, or other defining terms that will allow end users to easily search for and find the relevant video. Searchable keywords are also added to the video at 56 , which will simplify the video search that will return the particular video being reviewed. The video description will be modified at 58 , if needed. This may be performed if, for example, the mobile user who uploaded the video incorrectly described the video in question. Finally, the video will be saved to searchable database tables at 60 and stored in the video archive database at 38 .
IV. Video Archive Service User Software
[0040] FIGS. 3 and 4 show the typical interface an end user 30 may see when accessing the user web application 28 . The user web application 28 allows all end users 30 to have access to all reviewed and archived videos available.
[0041] In the preferred embodiment, the interface is accessed through a personal computer via the World Wide Web or some other accessible network. FIG. 3 shows a window 61 will be accessed by the end user 30 . The window 61 includes a video playback 62 including a video title 64 , a play/pause button 66 , a play-back progress bar 68 and a progress slider 70 .
[0042] Additional data uploaded along with the video data may be included in the window 61 . This data may include location information about the video, such as longitude 72 , latitude 74 , city 76 , state 78 , and country 80 . Additionally, date 82 , time 84 , and device ID data 86 may be uploaded and stored, embedded within the video data at the time the video was captured. Each of these terms will allow users to find applicable videos relating to what they are searching.
[0043] A description 88 of the video, which may be written by the original mobile user or by the expert 29 , is included in the window, along with a series of search keywords 90 assigned by the expert 29 . The end user 30 has the option of saving the video which results from the user's search at 92 . The video may be stored locally on the end user's machine, or could be stored to the end user's profile so that the user may later return to the searched video. The end user 30 may also perform a new search 94 , including pervious search terms with new terms added, or the user may clear the search 96 and start a completely new search.
[0044] FIG. 4 shows an alternative search window 61 . Here, the end user 30 is capable of viewing the entire archived database list 100 . In the example shown by FIG. 4 , the video archive list 100 organizes the video by date and category, allowing the end user 30 to browse through all videos uploaded and saved to the database.
[0045] Along with the video playback 62 , video title 62 , play/pause button 66 , play-back progress bar 68 and progress slider 70 , the window 61 includes a user video rating 98 . This rating may be assigned by the expert 29 or by end users 30 who visit the site, view the video, and rate the video. The rating will allow future users to determine if there may be a better video to watch, depending on what they may be looking for.
V. Weather Video Archive Application
[0046] In one embodiment of the present invention, the video uploaded to the database 20 relates to current weather occurring somewhere in the world. The mobile user records video of real-time weather activity with a mobile device 7 , uploads this weather video to the database server 18 where it is reviewed by an expert 29 , and the weather video is placed into the archive database 20 where it may be reviewed by end users 30 through the user web application 28 . This allows end users to view an up-to-date weather video of any location where mobile users are uploading video from, including in the end user's immediate vicinity.
[0047] The primary section of interest of the user web application 28 will likely be an interactive map display showing various locations of un-archived video and current weather radar overlays. The user will have the ability to select the grade of video that is displayed on the map. Notifications of videos relating to specific locations will appear on the map as an overlay to indicate the location the video was captured. Hovering over the notifications will allow a brief time lapsed preview of the accompanying video. Activating the notifications will display the full video in a window 61 . At this point the user will have the ability to download the full video, copy link information to embed in a web site, or other video functionality.
VI. 911-V Alternative Embodiment
[0048] An alternative embodiment video upload and archive system 102 encompasses the use of a back-end application 117 that will take video collected from a front-end mobile application 103 , determine its location via longitude and latitude, and upload that information to a 911V system server 118 . If the location where the video has been recorded is within a current 911V application 128 site software installation, the video is automatically routed to the appropriate emergency authority 123 . If the location corresponds to a 911V application 128 site participant, the video is automatically submitted to that 911V emergency authority 123 with the location where the video was recorded. This will allow the site to immediately dispatch emergency services as needed based upon what is shown on the video.
[0049] If the location is not a participant in 911V, a call center specialist 129 contacts the appropriate public safety answer point (PSAP) 130 jurisdiction, based upon the actual location determined by the longitude and latitude embedded in the submitted video. The call center specialist 129 will have the ability to email the video submitted to the 911V system 118 to the PSAP 130 for review. All 911 or 911V contact information will be saved to the videos corresponding XML metadata, for future audits and investigations if needed.
[0050] FIG. 5 is a block diagram showing the interaction between the elements of the front-end mobile application 103 and the back-end mobile application 117 . The front-end application 103 is comprised of a mobile device 107 including a camera 104 or other image recording device, an antenna 106 , a processor 108 , a wireless network connection 110 , memory 112 including a stored application 114 , and a position reference 113 . As in the preferred embodiment, the mobile device 107 records an event with the camera 104 and transmits video data via packets 119 through a wireless network 116 to the back-end mobile application 117 . Position reference 113 is necessarily included with the uploaded video packet 119 to determine where the recorded emergency is occurring and to contact the correct authorities.
[0051] The back-end mobile application 117 is comprised of a 911V system server 118 and call center specialist 129 . The server 118 further includes an archive database 120 , memory 122 , a processor 124 , a video review station application 126 , a notification method 127 , and the 911V application 128 . The call center specialist 129 may review incoming video data and direct the video to the nearest PSAP 130 , or the 911V application 128 will determine the location of the uploaded video data, determine the proper notification method 127 , and automatically forward it to the nearest 911V emergency authority 123 .
[0052] FIG. 6 demonstrates the practice of a method of the alternative embodiment. The method starts at 131 with an emergency phenomenon or event occurring at 132 . A mobile user possessing a mobile device capable of recording and uploading video data captures the video data of the emergency at 134 and uploads it to the 911V web service at 136 . Video slices are stored in the video archive database at 138 as they are uploaded, and the system database checks for newly submitted raw video data at 140 . If no new video is submitted between checks at 142 , the process repeats until new video is detected.
[0053] Once new video is detected at 142 , the system determines the location of the video by longitude and latitude at 144 . The system determines whether the location of the uploaded video is a 911V site at 146 .
[0054] If the site where the video was recorded is located in a 911V site, the video is transferred to the PSAP at 148 and archived as “received and transferred” at 150 and stored in the video archived database at 138 .
[0055] If, however, the location where the video was recorded is not a 911V site, the call center specialist or the system itself will determine the appropriate PSAP jurisdiction to handle the reported emergency at 152 . The proper PSAP is contacted at 154 and the emergency is reported at 156 , including recording the call at 158 and adding contact documentation to the existing XML data at 160 . All of this data is saved to the database at 162 and stored in the video archive database at 138 .
[0056] It will be appreciated that the geo-location video archive system can be used for various other applications. Moreover, the geo-location video archive system can be compiled of additional elements or alternative elements to those mentioned herein, while returning similar results.
VII. Virtual Space Via Super Position (VSSP) System 202 Alternative Embodiment
[0057] An alternative embodiment system includes a virtual space via superposition (VSSP) system 202 which is capable of employing the techniques and elements of the preferred embodiment disclosed above. In the VSSP system 202 , multiple recording devices 206 are deployed throughout an area surrounding an incident or scene 204 . Each recording device 206 may be capable of recording video and/or audio from a scene and communicating that data wirelessly to a remote database server, either directly or by sending signals to a mobile smart device 207 paired with the recording device 206 .
[0058] FIG. 7 shows three recording devices 206 . 1 , 206 . 2 , 206 . 3 paired with respective mobile smart devices 207 . 1 , 207 . 2 , 207 . 3 . Each recording device has a unique view or perspective 208 . 1 , 208 . 2 , 208 . 3 of the scene or incident 204 from which it records video and/or audio data of the scene. Each piece of video and audio information is uploaded to the remote database similar to the geo-location archive system disclosed previously.
[0059] These different video and audio perspectives can be layered and combined into a single data output, allowing users to later view a three-dimensional virtual representation of the scene. The users can virtually explore the entire three dimensional scene using a computing device, allowing the user to see and hear what was going on at the scene in virtual time.
[0060] FIG. 8 shows this representation in a more simplified way. A three-dimensional virtual space 210 is created from data from at least three viewpoints 212 . 1 , 212 . 2 , 212 . 3 . Each viewpoint may contain video and audio data, and the final three-dimensional virtual space 210 will contain video and audio data from all viewpoints.
[0061] FIG. 9 lists the steps taken when practicing this embodiment of the present invention. The process starts at 252 and a phenomenon or event occurs or is directed to be recorded at 254 . This recording may include video and audio data records from multiple recording devices 206 and/or mobile smart devices 207 . Multiple mobile users capture the video and audio data at 256 using these devices, and the data is relayed through the mobile devices 207 at 258 . The recorded data is uploaded to a central database via a web-based service application 260 or other software program.
[0062] Data gathered and sent in this way is stored in a data archive database at 262 . All data is time and geographically stamped as accurately as possible. Having time and three dimensional geographic location data allows multiple data references to be layered together to generate a three-dimensional virtual representation of the event or scene.
[0063] A user may determine to generate a VSSP at 264 using the reference data collected at the scene. If the user does not determine to generate a VSSP, the system may request or be instructed that additional scene data is needed at 266 . This may occur if certain viewpoints are corrupted, blurry, or otherwise unusable. Additional video capture from a third or more reference points may then be collected to add to the VSSP. If this is required the steps loop back to step 256 where video and audio are capture. It should be noted that the time factor of the newly recorded data will not be in synch with previously recorded data, and so much be spliced with this in mind with the preexisting data. If additional data is not required at 266 , the data remains stored in the archive database until needed at 264 .
[0064] If a VSSP is generated at 264 , the system will pull together the first set of reference data at 268 , the second set of reference data at 270 , the third set of reference data at 272 , and additional reference data at 274 . At least three sets of reference data are needed to create a true, three-dimensional virtual space and to triangulate video and audio.
[0065] The at-least-three reference data sets are compiled at 276 to generate the VSSP. This creates a completely explorable virtual space which may be explored in real time or rewound or sped up as needed. The virtual space will be explored at 278 , and users may tag locations in the virtual space as well as times where video are audio cues are deemed important at 280 , and a final report may be generated at 282 indicating the user's findings. The process ends at 284 .
[0066] The virtual space provides investigators, journalists, film directors, or any person interested in reviewing a scene, event, or incident with enhanced means of exploring a space which previously has been unavailable. The user will be able to review the entire three dimensional space as if the event was occurring again, and may speed up, slow down, or even reverse time as needed to explore multiple viewpoints of the scene.
[0067] One likely use of this VSSP system would be for First Responders and Military (FRAM-X) use. The recording devices 206 would likely be sturdy, high-quality stand-alone devices which may either store data for upload to the database later or, as mentioned above, be tethered to a smart device 207 which can wirelessly transmit the recorded data as it is being recorded.
[0068] As an example, if multiple police officers are wearing the recording devices 206 during an incident, the incident can be highly scrutinized from multiple angles at a later date, even if one officer's recording equipment malfunctions.
[0069] It is to be understood that while certain aspects of the disclosed subject matter have been shown and described, the disclosed subject matter is not limited thereto and encompasses various other embodiments and aspects.
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A system and method for recording, uploading, and archiving video recordings, including a front-end and a back-end application. The preferred embodiment of the present invention includes a front-end application wherein video is recorded using a mobile device. The recorded video is embedded with date, time and GPS location data. The video is stored on an online back-end database which catalogues the video according to the embedded data elements. The video may be selectively reviewed by relevant experts or emergency personnel for immediate response to the uploaded video and/or distribution to the proper parties. The video may also be archived for later review and use by any number of end-users.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims priority under 35 U.S.C. 119(e) to U.S. Provisional Application Ser. No. 60/861,329 filed Nov. 28, 2006, the entire contents of which is hereby incorporated by reference.
FIELD OF INVENTION
The present invention relates to plant root balls and more specifically to an agricultural polymer protected root ball.
BACKGROUND
When a plant, such as a tree, a bush or a shrub, is harvested for transplanting or transplanted from one place to another, it is advisable to leave a certain amount of soil around a root system of the plant. This network of roots and the soil clinging to the roots is known as a root ball, no matter the size or shape, or whether on a plant grown in a field or in a container. This root ball is necessary to provide protection, moisture and nutrients to the roots.
The root ball should be protected when transporting a plant to a local distributor or end user. Many growers protect the root ball by either having the root ball in a plant container or wrapping the root ball with burlap and wire.
A plant may be transplanted into a container for transporting or it may be grown in the container. Plant containers come in various sizes to accommodate the root balls of various size plants. The root ball plus the amount of soil necessary to fill these containers around the root ball often makes the containers heavy. For example, a semi-mature Queen Palm tree, approximately 60 inches high, in a fifteen gallon container, may weigh around 80 pounds. This excessive weight makes the plant difficult to move and transport, raising the risk of injury for those transporting and handling the plant, particularly if a container must be removed prior to planting.
Further still, soil in a plant container can be messy. The soil may spill from the container during shipping and handling, often due to vibration that occurs during loading and transit of the plant. This may cause damage to the roots of the plant and/or spillage of soil from the top of the container. Also, if enough soil spills from the container, the plant itself may shift in the container, causing damage to the roots. Spilled soil may also cause a mess in the shipping vehicle, leading to safety concerns and cleanup costs. If the plant is being transplanted indoors, for example, into a hotel or mall, any spilled soil may damage floors or carpets. Also, damage often occurs to the roots of the plant when removing the root ball from the container, as well as when moving the root ball to its final location after removal from the container.
For plants not transported in a container, burlap wrapping and wire maintain the soil around the root ball. However, these provide minimal protection for the root system. For example, the burlap wrapping provides no protection if the plant is dropped. Also, like with plants in containers, damage often occurs to the roots of the plant when removing the burlap and wire from around the root ball before planting, as well as when moving the root ball to its final location.
SUMMARY
The present invention provides an agricultural polymer protected root ball and methods of applying an agricultural polymer to a root ball, to provide a light, stable coating around the root ball which nurtures and protects the roots of a plant.
In general, in one aspect, the invention features a root ball, and methods for making the root ball, having soil disposed about a root system and a coating of agricultural polymer disposed at least partially around the soil and root system.
In embodiments, the coating of agricultural polymer is disposed about the soil and root system by placing the root system into a vat filled with a mixture of agricultural polymer and water. The root system is then removed from the vat and the agricultural polymer is dried.
In various embodiments, the vat is a hole in the ground lined with plastic. In other embodiments, the vat is a container. The container may be recessed into the ground. In certain embodiments, the vat is configured to enable the entire root ball to be wet by the agricultural polymer.
In embodiments, the agricultural polymer may be thermal polyasparate, polyelectrolytes, polysaccharides or a combination thereof. The agricultural polymer may also be a mixture of agricultural polymer and water.
In general, in another aspect, the invention features a method of producing an agricultural polymer protected root ball including spraying a root ball with an agricultural polymer to form a coating about the root ball and then drying the agricultural polymer coating.
The invention can be implemented to realize one or more of the following advantages. An agricultural polymer produces a root ball that includes a semi-permeable, solid protective layer, leading to a more stable and robust root ball for transporting, handling and shipment.
The agricultural polymer enables transport of the plant without a container. For example, the grower may remove the root ball from the container and coat the root ball with an agricultural polymer to provide protection for the root system. The agricultural polymer enables water and nutrients to pass and enter the root ball, while maintaining the integrity of the root ball, and will biodegrade over time.
Damage to the root system caused by normal handling and vibrations of transporting a plant are minimized or eliminated. The lack of a container also makes the plant easier to handle and move, particularly for an end user, such as a typical homeowner, who is attempting to handle and transplant the plant.
Coating the root ball with an agricultural polymer enables the grower to reuse the containers, thereby resulting in cost savings as well as less waste in the form of discarded containers. This also enables easier installation by the end-user because the end-user simply places the plant in its final location. Further, because of the solid nature of the agricultural polymer, the root ball may be rolled on the ground without damaging the plant roots.
The agricultural polymer enables the transport of the plant laid on its side, such as in a vehicle, without soil coming out of a container and making a mess of the vehicle. Further, an end-user does not have to remove the plant from a container, which could be difficult and cause damage to the root system, and the agricultural polymer coating protects the roots while the plant is being handled and transplanted.
Other features and advantages of the invention are apparent from the following description, and from the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a front view of an exemplary tree and its root system encapsulated in a root ball.
FIG. 2 is a front view of the tree of FIG. 1 with an agricultural polymer coating encapsulating the root ball according to one embodiment of the invention.
FIG. 3 is a cut-away view of an exemplary vat used to apply the agricultural polymer.
FIG. 4 is a front view of an exemplary sprayer to apply the agricultural polymer.
Like reference numbers and designations in the various drawings indicate like elements.
DETAILED DESCRIPTION
As shown in FIG. 1 , a tree 5 includes a root system 10 having larger roots 15 and finer roots 20 . The finer roots 20 are important to help establish the tree when replanted because these finer roots 20 grow faster and gather more water and nutrients than the larger roots 15 . The larger roots' 15 primary purpose is to provide support and anchorage for the tree 5 , although they also gather water and nutrients for the tree 5 . As can be seen, the root system 10 is a complex mass of larger roots 15 and finer roots 20 .
When a tree 5 is removed from the ground or a container in which the tree 5 has been grown to be transplanted or sold, the roots 15 , 20 are generally left in a root ball 25 composed of soil from where the tree 5 was taken. Even if a root ball 25 is not maintained, soil will be trapped throughout the root system 10 , unless the root system 10 is washed.
Referring to FIG. 2 , after the root ball 25 of the tree 5 is removed from the ground or container, a solution containing agricultural polymer and water is applied to the root ball 25 . The agricultural polymer, such as thermal polyasparate or a combination of polyelectrolytes and polysaccharides, creates a semi-permeable agricultural polymer protective shell 40 that, once dry, hardens into a biodegradable plastic-like layer. Thereafter, the tree 5 may be transplanted with the agricultural polymer protective shell 40 retained on the root ball 25 . The agricultural polymer protective shell 40 biodegrades over a period of time, while enabling water and nutrients to reach the root system.
The agricultural polymer may be applied by any suitable method. For example, referring to FIG. 3 , one (1) to one and three-quarters (1¾) cup of agricultural polymer, such as E-Tack Soil Control Agent (available from Finn Corporation of Fairfield, Ohio), may be mixed with 5-gallons of water to be applied to the root ball 25 . The agricultural polymer and water solution 50 may be placed in a vat 55 into which the root ball 25 may be dipped. As shown in this example, the vat 55 is a hole dug in the ground 60 and lined with plastic 65 . Recessing the vat 55 into the ground enables easier handling of the tree 5 and reduces the likelihood that the root ball 25 will be damaged. The vat 55 is sized to enable the entire root ball 25 to be dipped into the vat 55 such that the agricultural polymer and water solution 50 wet the entire root ball 25 . The root ball 25 is left in the agricultural polymer and water solution 50 for approximately one (1) minute. The root ball 25 is removed from the agricultural polymer and water solution 50 and dried. The root ball 25 may then again be dipped into the agricultural polymer and water solution 50 to increase the thickness of the agricultural polymer protective shell 40 . However, the thickness of the agricultural polymer protective shell 40 need not be uniform.
Referring to FIG. 4 , in another exemplary embodiment, the agricultural polymer and water solution 50 is sprayed onto the root ball 25 . The tree 5 may be suspended with the root ball 25 off the ground 60 . A sprayer 70 is used to apply the agricultural polymer and water solution 50 onto the entire root ball 25 and permitted to dry. Multiple coats of the agricultural polymer and water solution 50 may be applied to achieve the desired thickness of the agricultural polymer protective shell 40 . Again, the thickness of the agricultural polymer protective shell 40 need not be uniform.
The root ball 25 with the agricultural polymer protective shell 40 may be further wrapped with an ultraviolet (UV) protective plastic wrap before sale and/or transport of the plant. The end user would only need to remove the UV protective plastic wrap before transplanting the plant with the root ball 25 and agricultural polymer protective shell 40 directly into the ground.
It is to be understood that the foregoing description is intended to illustrate and not to limit the scope of the invention, which is defined by the scope of the appended claims. Other embodiments are within the scope of the following claims. For example, while a tree has been described, the methods described can be used equally well on bushes and other plants. Also, while specific brand name products have been described, these specific products are not necessary to practice the methods described.
Further, while certain steps have been described, more or less steps may be used. For example, the root system may be cleaned of all soil to produce a plant with a clean root system (e.g., no contaminates or spores, such as foreign insects, microbes, bacteria and fungi) for shipment to areas of the United States or the world that prohibit foreign soil (i.e., soil from outside that area), and then repacked with clean soil before applying the agricultural polymer. The clean soil may include peat moss, sawdust or a combination thereof.
Also, while a certain mixture of agricultural polymer and water has been described, other mixture ratios may be necessary with other root balls having different soil conditions. Further, while the vat 55 has been shown as a hole dug into the ground and lined with plastic, the vat 55 may be a tub, a barrel or any other container into which the root ball 25 may be dipped.
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A root ball including soil disposed in and around root system and a layer of agricultural polymer around the soil and root system. The agricultural polymer creates a root ball having a semi-permeable, solid outer layer, which provides protection for the root system and eliminates the need for a container.
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FIELD OF THE INVENTION
[0001] The present invention relates generally to systems for injecting substances into underground formations, and in particular relates to novel systems and methods of combining fluids and proppant under high-pressure, and for injection of the resultant fluid stream into formations such as coal beds.
BACKGROUND OF THE INVENTION
[0002] The Horseshoe canyon coal formations in Alberta have been difficult to stimulate for coal bed methane production. These formations have been through a plethora of conventional stimulation treatments, ranging from foams to crosslink polymers. Due to the nature of the low reservoir pressures of these coal formations, or seams, and their sensitivity to damage by conventional stimulation fluids (defined herein as a liquid and/or gas), stimulation fluid recovery becomes almost impossible. The only other economically viable choices appear to be straight CO 2 or N 2 gas injection. High rate N 2 gas injection technique is a common practice in North American coal bed methane exploited plays, and CO 2 is used as a flood medium.
[0003] Although using CO 2 gas to stimulate a formation works fine, it has certain drawbacks, including:
1. Costly treatments; and, 2. CO 2 does not clean up quickly, and since water is commonly produced during stimulation, it will turn into carbonic acid which is extremely hard on surface production manifolding.
[0006] Using N 2 gas works the same way all fluids do to stimulate a formation, although extremely high rates are required to create enough stress to overcome the natural formation mechanics and actually fracture, or “frac”, the formation. Enhanced conductivity of a formation relies on the effect of hysteresis, namely when the frac faces come back together under stress, that these faces will not heal back to their original orientation. It would be desirable to use proppant (e.g. a sand or other suitable materials) to hold the fractured, or “fraced”, faces apart as used in conventional frac theory. However, the problem with this is that N 2 is pumped as a gas and will not suspend or carry proppant as do conventional fracturing fluid systems.
[0007] What is desired therefore is a novel method of fracturing, or “fracing”, a target formation (such as a coal or shale formation) using gases and proppants, and a novel system for mixing such gasses and proppants in a manner that would result in an “impregnated” fluid stream suitable for such fracing. Preferably, the method and system should be capable of combining N 2 gas and a proppant material, such as sand, to produce a suitable fluid stream for fracing a coal formation. The method and system should further provide for introduction of surfactants to the fluid stream to further enhance the performance of the proppant in the target formation.
SUMMARY OF THE PRESENT INVENTION
[0008] According to the present invention, there is provided in one aspect a high-pressure injection proppant system (also referred to as “HIPS”) in which proppant, such as sand, is preloaded into one or more high-pressure cylindrical or spherical vessels, and such proppant is delivered into a fluid stream, such a N 2 gas stream, via an arrangement, such as a screw auger, which meters the proppant volumes and rates into the fluid stream.
[0009] In another aspect the invention provides two vessels operationally mounted in parallel which can function separately or concurrently depending on the demand for proppant in a particular formation. When operated seperately, one vessel can be in use for fracing a formation while the other vessel is isolated, de-pressurized and reloaded with proppant via a pneumatic bulk proppant system. The other vessel is then ready for operation when the first vessel is depleted of proppant.
[0010] In yet another aspect the invention provides for the injection of surfactants (i.e. chemicals or like substances) into the fluid stream to enhance the performance of the proppant, to aid in the placement of the proppant into the fracture network, and to demote proppant flowback during production and embedment.
[0011] In another aspect the invention provides a high-pressure injection proppant apparatus comprising:
[0012] at least one pressure vessel;
[0013] means for filling the vessel with proppant;
[0014] means for delivering a fluid containing nitrogen gas to the vessel and pressuzing the vessel therewith; and,
[0015] a metering arrangement operatively coupled to the vessel and in fluid communication therewith for metering the proppant from the pressurized vessel into a fluid stream containing nitrogen gas for delivery to a target formation.
[0016] In yet another aspect the invention provides a method of injecting proppant into a target formation comprising:
[0017] providing at least one pressure vessel and a metering arrangement operatively coupled to the vessel and in fluid communication therewith;
[0018] charging the vessel with proppant;
[0019] pressurizing the vessel with a fluid containing nitrogen gas; and,
[0020] operating the metering arrangement to meter the proppant from the pressurized vessel into a fluid stream containing nitrogen for delivery to the target formation.
[0021] Further, the system of the present invention can be operated manually or by computer automation to aid in the accuracy of mixing of the components of the fluid stream.
BRIEF DESCRIPTION OF THE DRAWING FIGURES
[0022] Embodiments of the invention will now be described, by way of example only, with reference to the accompanying drawings, wherein:
[0023] FIG. 1 is an elevational side view of a mobile carrier carrying a high-pressure injection proppant system (“HIPS”) according to a first embodiment of the present invention, showing the cylindrical pressure vessels of the system in a reclined transportation mode;
[0024] FIG. 2 is a view of the system of FIG. 1 with the pressure vessels in an elevated operating mode;
[0025] FIG. 3 is a plan view of the rig and system of FIG. 2 ;
[0026] FIG. 4 is an elevational end view of the rig and system of FIG. 2 ;
[0027] FIG. 5 shows the system of FIG. 4 in isolation, with the rig omitted;
[0028] FIG. 6 is a view similar to FIG. 4 , but shows a second embodiment of the system of the present invention, in operating mode;
[0029] FIG. 7 is an elevational side view of the system of FIG. 6 ;
[0030] FIG. 8 is a plan view of FIG. 6 with the front portion of the rig omitted;
[0031] FIG. 9 is a perspective view, from the rear, of a third preferred embodiment of the system of the present invention showing a pair of spherical pressure vessels mounted on a mobile trailer;
[0032] FIG. 10 is an elevational side view of the system of FIG. 9 ;
[0033] FIG. 11 is a perspective view, from the front, of a fourth embodiment similar to the third embodiment, but having a single spherical pressure vessel;
[0034] FIG. 12 is an elevational side view showing the vessel and piping of FIG. 11 in isolation;
[0035] FIG. 13 is an elevational side view from the right side of FIG. 12 ;
[0036] FIG. 14 is an elevational side view from the opposed back side of FIG. 12 ;
[0037] FIG. 15 is an elevational side view from the left side of FIG. 12 ; and, FIG. 16 is a plan view from the top of FIG. 12 .
LIST OF REFERENCE NUMBERS IN DRAWINGS
[0000]
10 high-pressure injection proppant system
12 trailer
14 truck
15 hydraulic wet kit
16 axles of 12
18 wheels on 12
20 proppant bulk storage tank
22 low-pressure blower pump
24 first low-pressure air line
26 second low-pressure bulk load line
28 surfactant storage and pumping assembly
30 delivery tubing for 28
32 hydraulic lift cylinders
34 pivots
36 , 36 a , 36 b pressure gauges
38 densometer
40 pressure vessel(s)
42 outer wall of 40
43 reinforced portion of 42
44 inner chamber of 40
46 first vessel inlet for proppant
48 first/top end of 40
50 second vessel inlet/outlet
52 first vessel outlet
53 flange of 52
54 screw(s)
56 radial inlet of 54
57 radial outlet of 54
58 motor of 54
60 piping arrangement
61 high-pressure fluid stream
62 first inlet of 60
64 first (Y) diverter
66 first fluid stream
68 second fluid stream
70 venturi-type orifice
72 first outlet of 60
74 second (four way) diverter
76 first fluid sub-streams
78 second fluid sub-stream
80 piping
82 first valves of 60
84 third (T-shaped) diverter
86 third fluid sub-streams
87 fourth fluid sub-streams
88 second valves
90 third valves
92 piping
94 Y-joint
96 pressure vessel isolation valve
98 upstream injection port
99 downstream injection port
130 delivery line of second embodiment
140 pressure vessel(s) of second embodiment
142 outerwall of 140
144 a first inner chamber of 140
144 b second inner chamber of 140
144 c third inner chamber of 140
145 first bottomopening of 144 a
146 first vessel inlet
147 second top opening of 144 a
150 second vessel inlet
152 bottom vessel outlet of 144 c
154 screw(s) of second embodiment
158 motor of 154
160 piping arrangement of second embodiment
162 inlet
166 first fluid stream
167 Y-shaped diveter
168 second fluid stream
170 orifice
183 first valves
190 pressure relief valve
192 piping
196 isolation valve(s)
220 proppant storage tank
228 storage and pumping assembly
231 lower legs
240 spherical pressure vessel(s)
254 sand screw
280 valves
311 retractable arms
326 proppant supply line
327 proppant supply valve
340 pressure vessel
341 cap
346 proppant supply valve
350 top fluid inlet port
354 screw/auger
357 auger outlet
358 drive motor and seal assembly
360 piping arrangement
361 high pressure fluid stream/line
364 first fluid diverter
372 outlet
374 second fluid diverter
376 fluid auger by-pass line
380 piping for fluid by-pass
382 fluid by-pass line valve
388 top fluid supply valve
390 vent valve
391 cap for vent line
393 purge valve
394 y-joint (auger outlet by-pass)
395 choke
396 auger outlet valve
399 surfactant inlet
DESCRIPTION OF EMBODIMENTS
[0145] Reference is first made to FIGS. 1 to 3 which show a high-pressure injection proppant system, or “HIPS”, (generally designated by reference numeral 10 ) according to a first embodiment of the present invention. The system is mounted on a carrier, which is preferably a wheeled trailer 12 adapted to be pulled by a motorized vehicle, or truck 14 . It will be understood that the carrier may take various alternate forms, namely the trailer may itself be self-propelled, the truck and trailer may form one non-detachable unit, the system may be mounted on a skid for transport between sites, or the like. However, since the system is extremely heavy, not all carriers will be suitable for road transport as prescribed load limits for roads may be exceeded. Hence, in the present embodiment, the 24 wheeled trailer 12 is specifically designed to remain within such load limits (i.e. is “road legal”) by having three axles 16 with eight tires 18 per axle. Different axle and wheel combinations and quantities may be equally suitable, depending on the load to be transported. Likewise, the truck is suitably designed to haul the trailer 12 , and should include a hydraulic “wet kit” 15 to power the system 10 on the trailer.
[0146] The preferred system 10 includes a proppant storage means in the form of a cone-shaped tank 20 located on the trailer 12 . A relatively low-pressure blower pump 22 , conveniently mounted on the truck 14 close to a power source (i.e. the hydraulic wet kit 15 ), communicates with the tank 20 via a first low-pressure line 24 . The pump 22 permits the bulk transfer of proppant from the tank 20 at the front of the trailer to the two high-pressure vessels 40 at the back of the trailer via at least one second loading line 26 ( FIG. 2 ). Although one line 26 may be configured for suitable delivery of proppant, each vessel has a designated line 26 in the present embodiment.
[0147] The system further includes a surfactant storage and high pressure pumping assembly 28 located on the trailer. This assembly stores one or more surfactants for injection or “misting” (via a delivery tubing generally indicated by 30 ) into the high-pressure fluid stream associated with the pressure vessels 40 , as will be discussed later. The pumping assembly may employ as many high-pressure surfactant pumps as required. It is noted that in alternate embodiments, the assembly may be located elsewhere than on the trailer 12 , such as on another trailer, but must be capable of communicating with the fluid stream during operation for the desired misting. Likewise, the proppant storage tank 20 may be remotely located, but in communication with the vessels 40 during operation.
[0148] The surfactant referred to herein should be a chemical or like substance for enhancing the performance of the fluid stream proppant, for aiding in the placement of the proppant into a formation's fracture network, and/or for reducing proppant flowback during production and embedment. The proppant should be any material suitable for achieving the desired fracturing, or “fracing” of a target formation. The preferred system of the present invention is specifically geared toward fracing a coal formation for enhancing gas production therefrom, and the desired proppant is a form of sand. The use of the terms “proppant”, “surfactant”, “front”, “back” and the like is not intended to limit the present system's use or operation, nor the scope of the invention. Further, when describing the invention, all terms not defined herein have their common art-recognized meaning.
[0149] Referring now as well to FIG. 4 (showing the trailer 12 ) and FIG. 5 (omitting the trailer), a particular aspect of the system is the arrangement at the back of the trailer which has a means for directing/diverting a high pressure fluid stream 61 into the pair of pressure vessels 40 operationally arranged in parallel, and a means for metering/feeding proppant into the fluid stream. Specifically, a piping arrangement 60 below the vessels 40 has a first inlet 62 for receiving a desired fluid. In a preferred embodiment that fluid is nitrogen gas pumped under high pressure from a nitrogen source, such as a pumper truck. A first Y-shaped diverter 64 downstream of the inlet splits the incoming nitrogen 61 into first and second fluid streams 66 , 68 respectively. An adjustable venturi-type orifice 70 downstream of the diverter 64 is adapted to create a pressure drop, say in the range of 300 psi (or other desired amount), in the second fluid stream 68 passing therethrough. The orifice 70 should have the effect of diverting more volume of fluid into the first stream than the second stream, and for maintaining a positive fluid pressure in the screw(s) 58 , as will become apparent later. The second fluid stream 68 then proceeds under relatively lower pressure toward a first outlet 72 for discharge to a coiled tubing rig or like apparatus in communication with the target formation.
[0150] A second four-way diverter 74 downstream of the diverter 64 allows the first fluid stream to split again into first and second fluid sub-streams 76 and 78 respectively. Elongate piping 80 carries the second sub-stream 78 toward the top of the vessels, while the first sub-streams 76 are directed to the bottom of the vessels through respective first valves 82 . If only the left vessel is operating, then only the left valve 82 (as viewed in FIG. 5 ) is open for fluid entry, and the right valve 82 is closed, and visa versa. If both vessels are operating, then both valves 82 should be open. A third T-shaped diverter 84 further splits the second fluid sub-stream 78 into third fluid sub-streams 86 directed to the top of the vessels through respective second valves 88 . The diverter 84 and valves 88 also act as a pressure equalization manifold between the vessels 40 . Further, the piping 80 and associated valves 82 , 88 and 90 (discussed below) are used to equalize the fluid pressures at the top and bottom of the vessels 40 , and to de-pressurize the system to atmosphere when required.
[0151] Each pressure vessel 40 is formed by an elongate cylindrical tank having relatively thick outer walls 42 (e.g. 5 inches solid steel) to accommodate the high operating pressures (up to 9000 psi/63 MPa or more). The walls form an elongate interior cavity or chamber 44 for holding the desired proppant. The proppant is introduced into the chamber through a first vessel inlet 46 (shown in FIG. 2 ) at a first top end 48 of the vessel. A second vessel inlet 50 is provided at the top end of each tank for entry of the respective third fluid sub-streams 86 , and to communicate with a respective third pressure relief valve 90 for bleeding pressure from the respective vessel to atmosphere prior to receiving proppant through the proppant inlet 46 . A first vessel outlet 52 at the bottom of the vessel allows proppant and fluid to exit the vessel's chamber 44 and to encounter the first fluid sub-stream 76 , and to then proceed to the proppant metering means. It is noted that the identifiers such a “top” and “bottom” as used herein refer to the vessel in its generally vertically oriented operating position, as shown in FIGS. 2-5 , rather than when it is reclined about the pivot 34 by the hydraulic lift cylinders 32 into its generally horizontal transport position (as in FIG. 1 ). The vessels should be reinforced at 43 where they engage the hydraulic cylinders 32 and pivots 34 .
[0152] The proppant metering means is defined by a high pressure sand screw 54 disposed generally perpendicularly to each vessel's longitudinal centerline and it's outlet 52 . Other orientations of the screws should also be suitable. The screw has a flanged radial inlet 56 for attachment to a respective flange 53 of the vessel outlet 52 , and for receiving the proppant and fluid therefrom. A variable rate electric or other suitable motor 58 operates the screw to discharge, or meter, a desired amount of proppant through a radial screw outlet 57 into piping 92 . A Y-shaped joint 94 allows the proppant and fluids exiting the screw 54 to enter the second fluid stream 68 prior to exiting the first outlet 72 . A pressure vessel isolation valve 96 on each piping 92 upstream of the Y joint 94 operates to isolate a respective vessel from the second fluid stream 68 as desired (e.g. when that vessel is inoperative and depressurized for proppant recharging), to prevent fluid backflow into the vessel through the screw. Each screw may be readily removed from the system for servicing, repair, or switching to a different screw size by uncoupling the flanges 53 , 56 at one end, and at the other end by uncoupling from the isolation valve 96 .
[0153] The piping arrangement 60 further incorporates an “upstream” surfactant injection port 98 at the first inlet 62 for introducing surfactants from the delivery tubing 30 into the fluid stream 61 prior to its split into the first and second fluid streams 66 , 68 . Such introduction may also be accomplished further downstream after the fluid and proppant have been mixed, such as at a “downstream” surfactant injection port 99 located immediately prior to the first outlet 72 . Both ports 98 , 99 may also be used concurrently, and other ports may be added in the system if required.
[0154] An alternate second embodiment of the present invention is shown in FIGS. 6 to 8 where the screws 154 are located longitudinally within the pressure vessels 140 . The reference numerals used in these figures are similar to those used to describe the components of the system 10 , with the addition of a prefix “1”. Each vessel has in essence three longitudinally aligned chambers. A first elongate chamber 144 a is defined by the vessel's outer wall 142 for holding the proppent received through the first vessel inlet 146 via the delivery line 130 . A pressure relief valve 190 bleeds excess pressure before filling the chamber 144 a . A second elongate chamber 144 b is longitudinally disposed within the first chamber 144 a in a parallel relationship, and houses the screw 154 operated by the motor 158 . The bottom end of the second chamber 144 b has a first bottom opening 145 into the first chamber 144 a to allow entry of the proppant. The screw raises the proppant to the opposed top end where it is discharges out of a second top opening 147 into the open end of a hollow third chamber 144 c . The third chamber 144 c is also located within the first chamber 144 a and extends downwardly alongside the second chamber 144 b and opens at a bottom vessel outlet 152 where the proppant and high-pressure fluid exit the vessel into the piping arrangement 160 .
[0155] The piping arrangement 160 is similar to the piping arrangement 60 in that high pressure fluid, such as nitrogen gas, enters at the inlet 162 and is divided into first and second fluid streams 166 and 168 with the aid of orifice 170 . The first fluid stream is then directed to one or both vessels at the Y-shaped diverter 167 by controlling the first valves 183 . The first fluid stream enters the bottom of the first chamber 144 a via the second vessel inlet 150 . The pressurized fluid is urged through the proppant and up the screw where it proceeds through the top opening 147 and then down the third chamber 144 c to exit the bottom outlet 152 . When the screw is activated to discharge proppent through the top opening 147 , the proppant is entrained in the high-pressure fluid flow and is carried down the third chamber 144 c to the outlet 152 . The fluid and proppent exiting the outlet 152 proceed through piping 192 and the respective pressure vessel isolation valve 196 to rejoin the second fluid stream 168 moving to the first piping outlet 172 .
[0156] This system is not preferred over the first embodiment for several reasons. First, for a given size of pressure vessel, the vessel 140 holds less proppent than the vessel 40 since internal volume is lost to the second and third chambers 144 b , 144 c . Second, a longer and more costly screw must be employed in the vessel 140 , and such screw is more difficult to access or remove than in the first embodiment. The screw 154 must lift proppent against gravity, whereas the negative effects of gravity are reduced in the arrangement of the first embodiment.
[0157] The operation and advantages of the present invention may now be better understood, with reference to the first embodiment. For illustrative purposes it will be assumed that nitrogen and a form of sand are to be pumped into a coal formation. In the first embodiment, the rig is brought to the work site in an advantageous reclined transportation mode (as in FIG. 1 ) to avoid road clearance limitations. The trailer's wheel configuration is also designed to make the rig “road legal”, despite the extremely heavy weight of the system 10 .
[0158] The vessels 40 and associated components are then elevated into the operating mode ( FIG. 2 ) for use. If the vessel chambers 44 require charging with sand, then it is pumped from the tank 20 into at least one of the chambers via the line 26 and through respective first vessel inlet 46 . An advantage of this two vessel arrangement is that fracing may commence once one vessel is charged with sand. There is no need to wait for the second vessel to be filled to begin operations. Likewise, there is no need to disrupt ongoing operations once the first vessel is emptied of sand since pumping may readily switch to the second filled vessel. In the meantime, the first vessel can be refilled with sand and be ready for when the second vessel is emptied. In unusual circumstances where the rate and volume of sand injection requires both vessels to operate simultaneously, then operations may be disrupted periodically while the vessels are refilled.
[0159] Assuming that the left vessel 40 in FIG. 5 is charged and ready for operation, and the right vessel is not, then the operator should isolate the right vessel by closing the first and second valves 82 , 88 leading to the right vessel, as well as the respective (right side) isolation valve 96 . Conversely, the first and second valves 82 , 88 and the isolation valve 96 for the left vessel should be opened or activated. Once a high-pressure nitrogen stream 61 is established from a nearby nitrogen truck into the first inlet 62 , the orifice 70 should provide the necessary pressure drop and split into first and second nitrogen streams 66 , 68 . The first stream is then further split into the first nitrogen sub-stream 76 at the lower end of the vessel and into the third nitrogen sub-stream 86 which enters the vessel at the top. The first and second valves 82 , 88 control the relative pressures of the nitrogen gas to ensure that the nitrogen moves downwardly through the sand in the chamber 44 and does not reverse to force the sand upwardly, particularly as the sand is being depleted in the vessel. Both gravity and the nitrogen flowing out of the vessel should urge the sand from the chamber 44 toward the screw 54 . If the screw is not activated, the nitrogen should seep through the porous sand and around the stationary screw blades to escape out of the screw outlet 57 . However, once the screw is activated to carry sand to the screw outlet 57 , the sand should be carried in the fourth nitrogen sub-stream 87 to the (unsanded) second nitrogen stream at the Y-joint 94 , where both streams commingle and exit the first outlet 72 to a coiled tubing rig and ultimately to the coal formation.
[0160] If desired or required, surfactants may be introduced at either one or both of the upstream and downstream injection ports 98 , 99 . Injection at the downstream port 99 avoids circulation of the surfactant through the vessels and most of the system 10 . In contrast, injection into the relatively “dry” nitrogen stream at the upstream port 98 will “wet” the sand in the vessels.
[0161] This nitrogen and sand combination, mixed potentially with one or more surfactants, should enhance the stimulation of coal deposits for improved gas production over prior art methods, as discussed earlier.
[0162] It is noted that pressure gauges 36 and one or more densometers 38 are installed at selected locations in the system to monitor pressures and proppant concentrations in the fluid stream exiting the system, to ensure that the desired volume and rate of proppant is being delivered to a particular formation. In particular, the gauge 36 a measures the manifold inlet pressure to the screw 58 , and the gauge 36 b measures the manifold outlet pressure near the outlet 72 . If the exiting fluid stream is not satisfactory, then the orifice 70 and/or the various described valves and/or the speed of the screw(s) 58 for proppant delivery may be adjusted, either manually or preferably remotely by PLC (programmable logic controller) systems, to obtain the desired mix/values.
[0163] Further advantages of the present invention include:
the system provides great flexibility for various pumping operations; the system allows for a wide range of proppant density in the fluid stream; the system can use various types of proppant; the system's ability to mix proppant in the fluid stream, and in particular to mix sand with a N 2 gas stream, provides an important means of enhancing production of coal bed methane sales gas; the system is cost effective to build and operate; and, the trailer 12 carrying the system 10 is “street” (i.e. weight) legal.
[0170] An even more advantageous third preferred embodiment of the present system is shown in FIGS. 9 and 10 . In general, the system of this embodiment in essence functions the same way as the first embodiment, except that the vessels 240 have a spherical configuration rather cylindrical. The reference numerals used for this embodiment are similar to those used to describe the components of the system 10 , with the addition of a prefix “2”. There are several advantages to employing such spheres, including:
[0171] The sphere is a more efficient shape for confining contents under high-pressure;
[0172] A greater volume of proppant may be held than in a given cylindrical configuration; and,
[0173] The spherical configuration omits the need for separate operating and transporation modes. For holding a given volume of proppant, the sphere 240 need not be as tall as the cylinder 40 (when elevated in an operating position), and so the sphere provides a more advantageous road height clearance when mounted on the trailer. Hence, the spheres 240 are mounted in a single orientation on the trailer for both transport and operation, and need not be reclined for transportation nor inclined for operation as the cylindrical vessels 40 .
[0174] Each spherical pressure vessel 240 has a sand screw 254 located therebeneath in a manner similar to the first embodiment, and the piping system for proppant and nitrogen gas delivery is also similar. However, the location of certain features on the trailer 212 have changed, such as placement the proppant storage tank 220 and the surfactant storage and high pressure pumping assembly 228 at the rear of the trailer. Each sphere 240 also has a plurality of legs 231 spaced about a bottom portion thereof for supporting the sphere on the trailer, and three valves 280 at a top portion thereof for connection to respective piping for delivery of proppant, for delivery of nitrogen gas, and for venting.
[0175] A fourth embodiment of the invention in FIG. 11 shows a trailer carrying a single spherical pressure vessel 340 which is of a similar design to the third embodiment. Some of the reference numerals used for this embodiment are those used to describe like components of the system 10 , with the addition of a prefix “3”. The vessel's mounting assembly differs from the previous lower legs 231 in that retractable arms 311 are employed to engage a top portion of the sphere to hold it on the trailer. Also, the vessel has a single cap 341 which accesses the sphere's interior and operatively connects to the proppant and nitrogen gas supplies, and has a vent. Valves in either the cap, or in piping leading to the cap, control the flow of products into the sphere, and for venting of the vessel. Further, the auger 354 in this embodiment is inclined for better ground clearance. A drive motor and seal assembly 354 (shown in outline) is coupled to the upwardly inclined end of the auger to operate the auger.
[0176] It is noted that a configuration of a single vessel per trailer is not preferred as it will present certain disadvantages. If the capacity of the one vessel is insufficient to treat a particular formation, then fracing operations will have to be disrupted as the vessel is refilled with proppant.
[0177] A sample operating sequence of the fourth embodiment will now be set out, with reference to FIGS. 12-16 which show the vessel 340 and associated piping 360 in isolation from the trailer. The sequence is described for one pressure vessel, but is equally applicable to each vessel of a multi-vessel configuration:
[0178] Lower valves (such as the auger outlet valve 396 ) under the spherical pressure vessel are closed. The sand screw, or auger 354 , is off (inoperative). The pressure vessel 340 is empty and unpressurized.
[0179] The top proppant supply and vent valves 346 , 390 are opened and proppant is blown or pumped into the vessel until nearly full.
[0180] The top supply and vent valves 346 , 390 (capped at 391 ) are closed.
[0181] The top fluid (nitrogen) valve 388 is opened and the pressure vessel is pressurized up to the line pressure of the main horizontal fluid line 361 running along the bottom of the trailer. In this embodiment the vessel has a pressure rating up to about 9000 psi, and a proppant capacity of about 5 tonnes.
[0182] The outlet valve 396 at the end of the auger 354 is opened and the fluid (nitrogen) bypass line valve 382 at the auger outlet is opened. This flow of fluid (nitrogen) clears the auger outlet 357 .
[0183] The auger is started to bring proppant from the pressure vessel to the outlet 357 of the auger.
[0184] Since the top and bypass fluid (nitrogen) valves 388 , 382 are open, the high-pressure flow of fluid (nitrogen) assists the flow of, namely helps push, the proppant through the auger.
[0185] Once the pressure vessel is empty, the top fluid (nitrogen) valve 388 is closed, then the auger 354 is stopped, then the bypass fluid (nitrogen) line 382 is closed and then the auger outlet valve 396 at the discharge 357 of the auger is closed.
[0186] At this point the pressure vessel is vented down to atmospheric pressure via the vent valve 390 and/or purge valve 393 (& associated choke 395 ) and then refilled with proppant, and the above sequence is repeated.
[0187] The fluid stream, namely all or mostly nitrogen, in the main fluid line 361 across the bottom of the trailer is pumped at very high pressure. With the use of in-line restrictors, a portion of the fluid stream is diverted (via the first diverter 364 ) to the pressure vessel's top fluid inlet port 350 and to the auger fluid by-pass line 376 (via the second diverter 374 ), and another portion to the auger outlet bypass 394 , in a like manner to that shown in FIG. 5 for the first embodiment. After the first diverter 364 there is an inlet 399 for the surfactant where it is injected at high pressure into the fluid (nitrogen) stream in the main line 361 . After this injection point there is an auger outlet by-pass 394 for discharging the proppant and combining it with the fluid stream in line 361 . The resulting fluid stream at the outlet 372 of this line (analogous to the the first outlet 72 in FIG. 5 ) contains a mixture of nitrogen, suspended surfactant and proppant for use in a target formation.
[0188] The above description is intended in an illustrative rather than a restrictive sense, and variations to the specific configurations described may be apparent to skilled persons in adapting the present invention to other specific applications. Such variations are intended to form part of the present invention insofar as they are within the spirit and scope of the claims below. For instance, it may be possible to employ only one cylindrical vessel 42 per trailer, as in the FIG. 11 embodiment, but the single vessel configurations present certain disadvantages. If the capacity of the one vessel is insufficient to treat a particular formation, then fracing operations will have to be disrupted as the vessel is refilled with proppant. Likewise, three or more pressure vessels might be employed per trailer, but it is believed that the third vessel would be redundant, be cost inefficient, and would lead to weight restriction issues for the trailer. Any number of trailers with pressure vessels mounted thereon may be employed in series or parallel at a given site, but capacity and cost efficiency are among the factors that will dictate the optimal configuration. It should also be appreciated by those skilled in the art that, based on the above information, other vessel shapes may also provide suitable proppant storage and pressure capacities.
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A high-pressure injection proppant system for stimulating coal bed methane production preloads proppant, such as sand, into one or more high-pressure vessels, for delivery into a fluid stream, such a N 2 gas stream. A screw auger arrangement meters the proppant volumes and rates into the fluid stream. Two such vessels operationally mounted in parallel can function separately or concurrently depending on the demand for proppant in a particular formation. The system provides for the injection of surfactants into the fluid stream to enhance the performance of the proppant, to aid in the placement of the proppant into a fracture network, and to demote proppant flowback during production and embedment. The system can be operated manually or by computer automation to aid in the accuracy of the mixing of the fluid stream components.
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CROSS-REFERENCE TO RELATED APPLICATIONS
This application is the National Stage of International Application No. PCT/US2006/039441, filed Oct. 10, 2006, which claims benefit of U.S. Provisional Application No. 60/724,453, filed Oct. 7, 2005.
BACKGROUND OF THE INVENTION
The invention relates to the fields of cell enrichment, blood sampling, and microfluidic devices.
Lab-on-a-chip technologies for cell-based, basic scientific or clinical applications promise to integrate all procedures from primary sample collection to data analysis in small, inexpensive, and versatile devices (Andersson and Van Den Berg, Sensors and Actuators B-Chemical, 2003, 92, 315-325; Sia and Whitesides, Electrophoresis, 2003, 24, 3563-3576; Toner and Irimia, Annual Review of Biomedical Engineering, 2005, 7, 77-103). One step in this complex process is sample preparation, when cells from primary samples are typically separated, washed, and re-suspended in new buffer solutions, with or without specific stimulation steps, before they are made available for subsequent processing and analysis. However, most of the time this step is accomplished not on the chip but on the bench, by procedures like pipetting and centrifugation, because no common, easy-to-implement approaches exist today for on chip sample preparation.
Handling of mammalian cells in microfluidic devices poses some nontrivial challenges. Eukaryotic cells in general and human cells in particular are mechanically more fragile and more deformable than other cells. They are also biologically more sensitive and quicker to respond to changes in their environment. While various methods for handling cells in suspensions have been proposed, each technique has drawbacks that limit its potential. Methods using electric fields for trapping and exposing mammalian cells to new reagents (Rosenthal and Voldman, Biophysical Journal, 2005, 88, 2193-2205; Gascoyne and Vykoukal, Proceedings of the Ieee, 2004, 92, 22-42; Seger et al., Lab on a Chip, 2004, 4, 148-151) are dependent on the solution for cell suspension and on the cell type. Optical manipulation of relatively large mammalian cells (Arai et al., Electrophoresis, 2001, 22, 283-288) can be laborious and expensive and cannot be easily scaled up, while the use of mechanical structures (Panaro et al., Biomolecular Engineering, 2005, 21, 157-162; Wheeler et al., Analytical Chemistry, 2003, 75, 3581-3586; Glasgow et al. Wheeler, Ieee Transactions on Biomedical Engineering, 2001, 48, 570-578) is usually irreversible, since once cells are mechanically trapped they cannot be easily released.
Precise metering of whole blood samples is essential for many clinical diagnostic applications, e.g., the biochemical analysis of blood (Tudos et al., Lab on a Chip, 2001, 1, 83-95) and blood cell counting and analysis (Toner and Irimia, Annual Review of Biomedical Engineering, 2005, 7, 77-103). Volumes of blood as small as a few microliters can be precisely sampled using syringes and micropipettes. However, smaller volumes, like those used in microfabricated devices require different approaches not always suited to complex cell-rich fluids like blood. Vented capillaries with a hydrophobic barrier (Pugia et al., Clinical Chemistry, 2005, 51, 1923-1932; Ahn et al., Proceedings of the Ieee, 2004, 92, 154-173; Columbus and Palmer, Clinical Chemistry, 1991, 37, 1548-1556) could trap air bubbles between fluid segments that need to be mixed. Microdroplets on electrowetting platforms (Srinivasan et al., Lab on a Chip, 2004, 4, 310-315) have to be formed outside the device by pipetting; their minimum size is limited to the microliter range, and stickiness of blood proteins and cells on the hydrophobic surfaces may be problematic. Finally, valves have been designed to sample sub-microliter volumes of fluid and perform biochemical assays (Hansen et al., Proceedings of the National Academy of Sciences of the United States of America, 2002, 99, 16531-16536), although the geometry of the valves is not friendly for cells. Precise metering volumes are possible using valves in channels with vertical walls (Li et al., Electrophoresis, 2005, 26, 3758-3764).
Thus, there is a need for new devices and methods for manipulating samples in microfluidic devices.
SUMMARY OF THE INVENTION
The invention features a microfluidic device including a channel and a valve. The valve has an open state allowing fluid flow through the channel, a first closed state resulting in the formation of a first chamber in the channel, and a second closed state resulting in the formation of a second chamber in the channel. The invention also includes a method of using the above device.
The invention also features a method of trapping a fluid or a biological particle (e.g., a mammalian cell), introducing a fluid or a fluid containing a biological particle into a microfluidic device including a channel and a valve. In this embodiment the valve has an open state allowing the fluid to flow through the channel, a first closed state resulting in the formation of a first chamber in the channel, and a second closed state resulting in the formation of a second chamber in the channel.
In any of the devices of the invention, the valve can include a mobile diaphragm, microstructures, and a base member. In these devices, actuation of the mobile diaphragm results in movement of at least a portion of the microstructures relative to the base member or the mobile diaphragm relative to at least a portion of the microstructures, resulting in the formation of the first chamber or the second chamber. Combinations of these methods of actuation are also possible.
At least a portion of the microstructures can be disposed on the mobile diaphragm in any of the devices of the invention. In these devices, the actuation of the mobile diaphragm results in movement of at least a portion of the microstructures relative to the base member. Also, at least a portion of the microstructures can be disposed on the base member. In these devices, the actuation of the mobile diaphragm results in movement of the mobile diaphragm relative to at least a portion of the microstructures. The microstructures can be of a height less than the height of the channel in any of the above devices.
The actuation of the mobile diaphragm of the above devices may, or may not, result in a seal being formed between at least a portion of the microstructures and either the mobile diaphragm or the base member. The first chamber or the second chamber of the device can separate one fluid from a second fluid.
The first or second closed state can trap particles but allows fluid to flow through the channel.
By “biological particle” is meant any species of biological origin that is insoluble in aqueous media on the time scale of sample acquisition, preparation, storage, and analysis. Examples include cells (e.g., animal cells, plant cells, bacteria, and yeast), particulate cell components, viruses, and complexes including proteins, lipids, nucleic acids, and carbohydrates.
By “chamber” is meant a volume of a microfluidic device separated from another volume of a microfluidic device so that passage of material between the two volumes is constrained. The term chamber is meant to include a partial separation (e.g., where cells or other particles cannot pass between the two volumes, but fluid can pass between the two volumes).
By “channel” is meant a gap through which fluid may flow. A channel may be a capillary, a conduit, or a strip of hydrophilic pattern on an otherwise hydrophobic surface wherein aqueous fluids are confined.
By “microfluidic” is meant having at least one dimension of less than 1 mm.
By “microstructure” is meant an impediment to flow in a channel, e.g., a protrusion from one surface.
By “trapping a biological particle” is meant the restricting a biological particle to a desired chamber.
By “valve” is meant a structure that controls the flow of a fluid. The term valve includes partial control of a fluid, whereby certain elements in the fluid are prevented from flowing, while other elements are permitted to flow (for example based upon size).
Other features and advantages will be apparent from the following description and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a set of schematics showing a valve where the height of microstructure disposed onto the mobile diaphragm is greater than the height of the channel.
FIGS. 2A and 2B are schematics of a functioning cell lysis chamber using a microstructured diaphragm.
FIG. 2C is a set of photomicrographs of the functioning lysis chamber.
FIG. 2D is a set of schematics of a functioning device with microstructures on both the mobile diaphragm and base member.
FIG. 2E is a photomicrograph of a functioning device with microstructures on both the mobile diaphragm and base member.
FIG. 3A is a schematic showing fabrication of the device.
FIGS. 3B and 3C are schematics showing side and top view of the assembled device.
FIGS. 3D and 3E are photomicrographs from a scanning electron microscope of a microstructured diaphragm functioning as a valve with multiple inlets and one outlet. FIG. 3D shows the valve in the closed position. FIG. 3E shows the valve in the open position.
FIG. 4A is a schematic showing pairs of barriers used to sequester cells.
FIGS. 4B-4D are photomicrographs of the device. FIGS. 4C and 4D demonstrate the handling of 30 nL of whole blood.
FIG. 5A is a schematic of a diaphragm combining two different microstructures: a barrier with small leak channels and a fall barrier.
FIGS. 5B and 5C are photomicrographs showing cell trapping.
FIG. 5D is a graph showing cell enrichment.
FIG. 5E is a three dimensional schematic of the microstructured diaphragm for cell pre-concentration in lab-on-a-chip devices.
FIG. 5F is a set of schematics showing a functioning cell concentrator.
FIGS. 6A-6D are schematics showing circular ridges of different heights used to sequentially trap a cell in medium S 1 in the central compartment and solution S 2 in the middle compartment.
FIG. 6E is a photomicrograph of the microstructured diaphragm with circular ridges.
FIG. 6F is a graph showing the changes of relative concentrations in the center compartment as a function of time.
DETAILED DESCRIPTION OF THE INVENTION
In general, the invention features a microfluidic device containing a channel and a valve. The valve of the invention contains a mobile diaphragm and a base member. Actuation of the mobile diaphragm results in the relative movement of microstructures in the channel leading to the creation or destruction of chambers. In one example, the microstructures are disposed on the mobile diaphragm such that actuation of the diaphragm results in the microstructures forming chambers against a planar base member. Alternatively, the microstructures can be disposed on the base member, where actuation of a planar mobile diaphragm results in the microstructures forming chambers against the mobile diaphragm. Also, microstructures may also be disposed on both the mobile diaphragm and the base member.
No particular geometric arrangement of the mobile diaphragm and the base member is required, except that actuation of the diaphragm cause the creation or destruction of chambers. Typically, the diaphragm and base member will be disposed opposite and parallel to one another. However, other arrangements are possible, e.g., the angle between the mobile diaphragm and base member can be between 0 (inclusive) and 180 degrees (inclusive). In one embodiment, the invention also includes a nonplanar, e.g., curved, mobile diaphragm or base member.
When forming a chamber, the microstructures act with the base member and the channel as a whole to create a volume where passage of at least a portion of a fluid sample is constrained. The height of the microstructures used to create a chamber can be less than, equal to, or greater than ( FIG. 1 ) the height of the channel to which they are connected. An important feature of the invention is that when the valve is closed, microstructure may, or may not, form a seal with the base member. For example, a chamber may be formed that excludes passage of fluid between the inside and outside of the chamber, or a chamber may be formed that allows fluid to pass but prevents particulate matter, e.g., above a desired size (e.g., from 0.1 μm to 1 mm (10 −7 to 10 −3 m)), from entering or exiting a chamber. This embodiment of the invention can be used, for example, to trap a cell while permitting fluid to flow between two chambers.
The microstructures of the invention can form chambers of any shape (e.g., cylindrical, toroidal, spherical, rectangular, trapezoidal, or pyramidal). The thickness of the walls of the chamber will be determined, at least in part, by the thickness of the microstructures. The chambers formed by the actuation of the valves of the invention can be concentric or contiguous with each other.
Actuation of the mobile diaphragm is desirably accomplished pneumatically. Typically, a control channel is located adjacent to the mobile diaphragm. Increasing or decreasing the pressure in the control channel, relative to that in the channel in which the chambers form, causes the diaphragm to move. The diaphragm and microstructures may be designed so that formation of multiple chambers can be accomplished step-wise, i.e., different pressure differentials in the control chamber result in formation of different chambers, or simultaneously. The actuation of the mobile diaphragm of the invention can be used to create 1, 2, 3, 4, 10 or any number of chambers in a channel. Other methods for actuating a diaphragm are known in the art. For example, the diaphragm may be coupled to a manual or computer controlled piston capable of inducing the diaphragm to move relative to the base member. In other embodiments, the diaphragm may be actuated by electrical field, magnetic field, heat, light, or pH.
When reversible actuation of the mobile diaphragm is desired, an elastomeric or otherwise malleable material is employed. Examples include silicones and other polymeric elastomers. In certain embodiments, malleable metals or shape memory alloys may also be employed. When irreversible actuation is desired, materials that do not or do not easily return to a previous shape may be employed. The microstructures and the base member may be fabricated in any suitable material, as are commonly known in the microfluidics field. Examples include silicon, glass, metals, and other polymers. Combinations of materials may also be employed, e.g., a rigid material with an elastomeric coating to ensure a fluid tight seal. Materials employed may, or may not, be porous or selectively permeable. For example, microstructures or other components of the device may allow for fluid, e.g., gas or liquid exchange, or for chemical agent exchange, e.g., ions, drugs, etc. Reagents or other materials may also be dissolved, suspended, coated, or otherwise associated with the microstructures, base member, diaphgram, or other parts of the device. Such reagents may secrete into a chamber, e.g., during an assay, or react with components in the fluid in the chamber, e.g., to buffer pH, absorb waste by-products, or provide anchor sites for attachment. Microstructures may also be fabricated out of materials that disintegrate over time, e.g., to release the contents of a chamber after a desired amount of time, or disintegrate only after user intervention, e.g., raising temperature above the glass transition or decomposition temperature, dissolving in a solvent, or electrical breakdown or electrochemical degradation.
Methods for manufacturing microfluidic devices are known in the art. The exact methods employed will depend in part on the material used to manufacture the device. Typical techniques include photolithography, wet or dry chemical etching, electroforming, and molding. Exemplary manufacturing techniques are described herein.
As one example, the invention features a normally closed pneumatic valve ( FIGS. 2A and 2C ). This valve is constructed by the controlling the sealing of PDMS and glass using a thin film metal layer. Other mechanisms for avoiding the sealing of the membrane to the bottom layer can be used. These include holding the microstructures at some distance from the bottom by applying suction to the control chamber and deforming the membrane, using a pattern of soluble material that could be removed after bonding, deactivation of the surfaces that will come into contact with each other, or any other non-removable material preventing sticking of the microstructures to the opposing member (e.g. photoresist, photo-epoxy, and gel). The bottom of the membrane structure may be separated from glass by a thin (50 Å) layer of metal (e.g., chromium or gold) in the corresponding contact regions ( FIGS. 2B and 2C ). The remaining PDMS binds to the glass and forms conventional channels and chambers. In an additional embodiment of the invention, microstructures disposed on the mobile diaphragm can be used in combination with microstructures disposed onto the base member ( FIGS. 2D and 2E ).
Devices of the invention may be used for the manipulation and analysis of cells, fluids, and other analytes. The valves of the invention may reversibly decouple the flow of fluids and the displacement of particles, e.g., cells in suspensions for lab-on-a-chip applications. By using the microstructures on mobile diaphragms, the invention features precise control over the location of particles of interest, and new capabilities for controlling fluid and cell suspension flow. Exemplary devices of the invention include devices for blood sampling, cell enrichment, and sequential cell stimulation applications. In addition, the devices of the invention may be employed whenever controlled contacting of two or more fluids is desired.
The invention will now be described with reference to specific, non-limiting examples of its design, manufacture, and use.
EXAMPLE 1
Basic Device
One embodiment of the invention features a two-layer PDMS device on glass, that incorporates a microfluidic network and a control layer, e.g., for handling small populations of suspended cells for sample preparation type applications ( FIG. 3A ). The two layers of PDMS were fabricated by casting the elastomer on separate photopatterned epoxy molds. The top, control layer contained a number of channels and the actuation chambers for the pneumatic valves. The bottom network layer contained the circuitry of channels of different widths and heights for the manipulation of cells and fluids. The control and network layers were bonded together and a membrane was formed between the actuation chambers in the top control layer and the bottom network layer ( FIG. 3B ). The two-layer construct was then selectively bonded on the top of a glass slide. The microstructures on the diaphragm were aligned to thin film metal patterns preventing the adhesion of the microstructure to the glass substrate ( FIG. 3C ). At the same time, the rest of the device was irreversibly bonded to unprotected glass. In the simplest configuration, the fluid flow in a system of channels in the network layer was controlled by the transversal microstructure on a membrane. In inactive position, the transversal structure rested on the metal pattern and separated the single or multiple inlet channels from the outlet channel ( FIG. 3D ). Upon actuation, the transversal structure was lifted by the upward deformation of the membrane into the control channel, allowing the simultaneous opening of the inlet channels into the outlet channel ( FIG. 3E ). The excursion of the membrane was large enough to allow passage of any object up to 50 μm in size, either particles or cells, and larger displacements are possible by increasing the thickness of the control channel.
Photoresist Molds
Two separate molds were prepared on silicon wafers using standard photolithography techniques. The mold for the control channels used one 50 μm thickness layer of SU8 epoxy (Microlithography Corp., Newton, Mass.), photopatterned through a mylar mask (Fineline Imaging, Colorado Springs, Colo.) and processed according to the manufacturer's specifications. The mold for the fluidic network layer used either one layer (30 μm) or two layers (3 and 30 μm) of SU-8 epoxy. The single layer was photopatterned on a silicon wafer, using the same protocol as the control layer. When two layers were employed, the thin layer was processed first and then the thicker layer was aligned and exposed under similar conditions on top of the first one. Small errors in mask alignment for the two layers could be tolerated by designing the masks such that smaller and larger structures were extended and partially overlapped.
Glass slides (45×50×0.1 mm; Fisher Scientific, Pittsburgh, Pa.) were sputtered with chrome (50 Å; Lance Goddard Associates, Foster City, Calif.). Subsequently, the thin metal film was patterned using standard microfabrication techniques. At the end, the glass slides were diced into smaller slides using a glass scriber.
Device Assembly
Poly(dimethyl siloxane) (PDMS, Sylgard 184; Dow Corning, Midland, Mich.) was prepared according to the manufacturer's instructions. To create complementary microchannels in PDMS, a 4 mm thick layer, and separately a 100 μm layer were cast over the control and network molds, respectively. The thickness of the network layer was controlled by spinning PDMS on the network mold at 500 rpm for 40 seconds. Holes were punched through the control layer using a sharpened 25-gauge needle (NE251PL, Small Parts Inc, Miami Lakes, Fla.). The two PDMS layers were exposed to oxygen plasma (50 W, 2% O 2 , 25 seconds) in a parallel plate plasma asher (March Inc., Concord, Calif.) and bonded after contact and heating (75° C., 5 min). Through holes, defining the inlets and outlets for the network layer were subsequently punched using the same needle size. The bonding surfaces of the PDMS and the glass slides were treated with oxygen plasma. Precise alignment between the PDMS and the thin film metal patterns on the slides was achieved under a stereomicroscope (Leica MZ8, Leica, Heerbrugg, Switzerland). After the assembly of the device, the metal patch could be optionally removed using metal etchant solutions, to allow unobstructed view of the whole channel through the transparency of the glass or polymer. Extensive washing with distilled water from a syringe was employed to remove traces of the etching solution and avoid toxic effects on cells.
Tygon tubing (TGY-010, Small Parts) was inserted in the inlet and outlet holes and connected through blunt syringe needles (NE301PL, Small Parts) to fluid reservoirs (network channels) or 1 mL syringes (control channels). Pressure changes in the control channels were accomplished by manual displacement of the syringe plunger.
Cell Preparation
Human monocytic leukemia cells (THP-1, American Type Culture Collection, Manassas, Va.) were cultured in RPMI media (Invitrogen, Carlsbad, Calif.) supplemented with 10% fetal bovine serum (Invitrogen), 1 mM sodium pyruvate (Sigma Aldrich, St. Louis, Mo.) and 50 nM mercaptoethanol (Sigma Aldrich). Cells from the culture were centrifuged and resuspended in phosphate buffered solution (PBS, Invitrogen) to a concentration of 10×10 6 cells/mL. Several dilutions were prepared in the range 10 3 to 10 7 cells/mL by the addition of PBS to aliquots of the original suspension. Capillary blood was collected after pricking the skin of the middle finger of a healthy volunteer, and a volume up to 10 μL placed at the inlet of the device.
EXAMPLE 2
Sampling Precise Volumes from Cell Suspensions
Four barriers on separate membranes were combined to realize a T-junction type structure for sampling precise volumes from cell suspensions (e.g. whole blood). Two valves, their control chambers coupled, control the flow of the cell suspension along the vertical axis ( FIG. 4A ). A second pair of valves allowed the displacement of the precisely metered sample by flow of buffer along the horizontal axis into the outlet sampling channel ( FIG. 4B ). The microstructures on the valves, in the form of curved barriers defined the walls of a cylindrical chamber with a 30 nL volume ( FIG. 4C ). Repeated metering of whole blood was accomplished on the device by alternately operating the valves. The precision of the metering was verified by the absence of resident cells in the sampling chamber after the buffer wash ( FIG. 4D ).
The use of microstructured diaphragm for the implementation of four valves, in a chromatography T-junction-like design allowed the precise metering of 30 nL of blood. Chambers with volumes from a few nanoliters to several microliters were designed by changing the position of the microstructures or by altering the height of the chamber. Because of the efficient removal of all blood cells from the chamber after a sample, volumes of blood equal to multiples of the chamber volume could also be precisely metered. To accomplish this, repetitive, alternative opening and closing of the valves controlling the blood and the buffer can be used to load and unload the chamber.
Microstructured sieves can be quickly regenerated by the actuation of the supporting membrane and were implemented for controlled cell trapping and release. The new cell enrichment procedure was extremely effective for very low original cell concentrations when enrichment of three orders of magnitude was easily achieved. In addition, the device could efficiently handle very small samples, a situation when centrifugation would be ineffectual due to major cells losses while removing the supernatant. Such capabilities would be useful in microfluidic devices that are very likely to dilute the cell suspension by the addition of reagents and when the reconstitution of the initial cell concentration is important for later analysis. For example, selective destruction of cells in a blood sample during the preparation of the buffy-coat equivalent usually results in large-volume, low-cell concentration samples (Sethu et al., Analytical Chemistry, 2004, 76, 6247-6253). Subsequent cell analysis protocols would benefit from reducing the sample volume and increasing the cell concentration. In addition, on-chip processing is gentler and less likely to affect the cells of interest by exposure to mechanical stresses during centrifugation (Stibenz and Buhrer, Scandinavian Journal of Immunology, 1994, 39, 59-63; Alvarez et al., Human Reproduction, 1993, 8, 1087-1092; Katkov and Mazur, Cell Biochemistry and Biophysics, 1999, 31, 231-245). The new cell enrichment procedure may also be useful for the isolation of cells from dissociated tissues and removal of debris (Singh, Cytometry, 1998, 31, 229-232), or for separating particles cells based on size, in an approach comparable to mechanical filtering of blood cells (Toner and Irimia, Annual Review of Biomedical Engineering, 2005, 7, 77-103).
EXAMPLE 3
Cell Isolation
Several microstructures were combined on the same membrane for partial decoupling of cell movement and fluid flow. Two structures of different heights on the same membrane were used for concentrating a cell suspension, by splitting the liquid and the cells into distinct chambers ( FIGS. 5A , 5 E, and 5 F). A first, leaky barrier, in resting position, allowed only the passage of fluid through 3×10 μm channels while mechanically blocking the cells. A second, fall barrier directed the leaked fluid into a drain channel. An additional microstructured diaphragm valve was used to control the flow in the drain channel independently ( FIG. 5B ). A cell suspension was introduced through the inlet channel, and cells were trapped at the leaky barrier. With the accumulation of cells at the first barrier, the flow was obstructed, because of the blocking of the small leaky channels. The accumulated cells were then transported into the outlet channel by briefly lifting and then quickly releasing the microstructured diaphragm. Clusters of enriched cells were directed into the outlet channel ( FIG. 5C ) and the sieve was regenerated and ready to capture more cells. To avoid the waste of captured cells into the drain channel, the drain valve was closed during this step. Through this procedure, the density of a sparse cell suspension could be increased in the output channel by several orders of magnitude. Cell suspensions with concentrations ranging from 1×10 3 to 1×10 7 cells/mL were enriched to 1×10 7 cells/mL. The concentration increase was more dramatic, up to three orders of magnitude, in the case of sparse cell suspensions ( FIG. 5D ). With increasing concentration of the cell suspension, an increasing number of cells are trapped in the 30 μm space between the first and second microstructured barriers and wasted into the drain channel, limiting the yield of enrichment for cell suspensions above 1×10 7 cells/mL. For low concentration suspensions, the limiting factor for enrichment was the time required for draining the suspension liquid and trapping the maximum number of cells at the first barrier.
EXAMPLE 4
Chemical Stimulation of Cells
One cell was exposed to a fast temporal sequence of chemicals. A microstructured membrane with two concentric structures was employed to trap the cells and the reagents in a configuration that allowed the rapid exchange of solutions around the cell ( FIGS. 6A-D ). While the inner microstructure was the same height as the inlet channel, the outer one was shorter and could only touch the bottom glass when moderate pressure was applied through the control channel, and the membrane deformed downwards ( FIG. 6C ). The two concentric structures divided the chamber under the membrane into three distinct compartments. The inner compartment (S 1 ) was the compartment where cells were trapped at the beginning of the experiment in their original suspension fluid. The middle compartment (S 2 ) formed a ring around the inner compartment and was filled with the first solution of the sequence. The outer compartment (S 3 ) was filled with the second solution of the temporal sequence. To load the device, the membrane was lifted by decreasing the pressure in the control channel, and a cell suspension was introduced ( FIG. 6A ). One cell was trapped in the inner compartment (S 1 ) by venting the control chamber and relaxing the membrane ( FIG. 6B ). Subsequently, the first reagent was introduced, filling the middle and outer compartments. The middle compartment was then isolated by pushing down the membrane and was sealed between the two concentric structures ( FIG. 6C ). The device was completely loaded after the filling of the outer compartment with the second reagent ( FIG. 6E ). Perfect sealing was conveniently available for as long as needed, before sequential mixing was accomplished at the time of choice by lifting the membrane ( FIG. 6D ). The change of concentrations of solutions in the compartments over time, estimated from the quantified total fluorescence, is presented in FIG. 6F . We observed an initial exponential decay for the concentration in the inner compartment (S 1 ), that reached an equilibrium level consistent with the dilution in the larger, limited space under the structured membrane. We also measured an initial fast increase, over approximately 30 sec, followed by slower decrease of the first reagent (S 2 ) at the level of the cell in the inner compartment. The fast concentration increase was consistent with a cumulative effect of diffusion and convection from the middle compartment, while the slow decay was representative for diffusion-driven mixing. We recorded a 15 seconds delay in the increase of concentration at the cell level of the reagent from the outer compartment (S 3 ). The concentration increase was slower than for S 2 , but still faster than expected by diffusion alone, suggesting at least a brief convective process immediately following the actuation. The axisymmetric configuration of the system assured that a cell in the middle of the inner compartment was exposed only to a temporal gradient, in the absence of a spatial gradient around the cell. We estimated less than 1% deviations from uniform conditions occurred on the circumference of a 20 μm diameter cell during exposure after loading the intermediate compartment with fluorescein solution and lifting the microstructured membrane.
The study of cellular responses to chemical stimulation is of fundamental importance for many biology studies. While macroscopic techniques using pipettes and Petri dishes are still widely used in biology labs, there is increasing interest for the more precise methods available through microfluidics. Most often, when studying cells in suspensions, cells are trapped using flow and mechanical obstacles (Wheeler et al., Analytical Chemistry, 2003, 75, 3581-3586; Li and Li, Analytical Chemistry, 2005, 77, 4315-4322; Yang et al., Analytical Chemistry, 2002, 74, 3991-4001), centrifugation (Li et al., Lab on a Chip, 2004, 4, 174-180), dielectrophoresis (Seger et al., Lab on a Chip, 2004, 4, 148-151; Voldman et al., Biophysical Journal, 2001, 80, 531-541), or laser beams (Arai et al., Electrophoresis, 2001, 22, 283-288), and the soluble stimulus brought to the cells by convective flow. Alternatively, suspended cells are contained in a no-flow environment (Irimia et al., Analytical Chemistry, 2004, 76, 6137-6143), and solutions brought to cells by diffusion from short distances. The use of co-axial compartments in the microstructured approach accomplished two performances unmatched by any other current techniques. Uniform stimulation of cells along their circumference was for the first time possible and may become a useful tool for studying the response of cells to temporal stimuli in the absence of spatial gradients. Additionally, precise temporal control of sequential stimuli was possible through a single actuation. The temporal profile and sequence of stimulation can be adjusted by changing the size of the ring compartment and the size of the barriers, which once incorporated into the physical device, could assure reproducibility of experiments in the absence of sophisticated equipment.
In the above examples we demonstrated a new concept of microstructured membrane for the control of eukaryotic cells and fluid displacement in networks of microfluidic channels. Cell position and displacement in channels of high aspect ratios can be precisely controlled by reversible decoupling of cell and fluid movement using the microstructured membranes. Throughout the handling processes, cells were maintained in the same focal plane, allowing for easy observation using microscopy. Moreover, one unique feature of the microstructured membrane was the integration of multiple features on the same membrane with the possibility for simultaneous or sequential displacement, enabling complex actuation schemes with limited number of controls.
The microstructured membrane allowed the control of channels of any cross-section. High aspect ratios of 2:1 (height to width) or larger could easily be achieved, limited only by the SU8 photopatterning process or application requirements. For comparison, other PDMS valves are dependent on a rounded cross section of the channel (Unger et al., Science, 2000, 288, 113-116; Grover et al., Sensors and Actuators B-Chemical, 2003, 89, 315-323; Studer et al., Journal of Applied Physics, 2004, 95, 393-398; Weibel et al., Analytical Chemistry, 2005, 77, 4726-4733), and they can control channels with aspect ratios from 1:10, when fabricated using positive resist reflow (Unger et al., Science, 2000, 288, 113-116), to 1:1 when etched in a glass substrate (Grover et al., Sensors and Actuators B-Chemical, 2003, 89, 315-323). A valve with lateral actuation on a rectangular cross-section channels has been demonstrated, although only partial closure of the channels was possible (Sundararajan et al., Lab on a Chip, 2005, 5, 350-354). The direct consequence of the controlled channel geometric features was the easy control of suspensions of mammalian cells. While the rounded cross section works well for manipulating fluids and even small size (few microns) particles (like bacteria), it is not appropriate for handling eukaryotic cells having average sizes between 10 and 20 μm. Such large cells would not use the entire cross section of the channel or worse, are trapped at the acute angles at the edge of the rounded channels.
The microstructured membrane could seal a channel in the absence of the actuation pressure, only by elasticity of the membrane pressing against the valve seat, a feature shared with the three-layers PDMS valves (Grover et al., Sensors and Actuators B-Chemical, 2003, 89, 315-323; Li et al., Electrophoresis, 2005, 26, 3758-3764; Hosokawa and Maeda, Journal of Micromechanics and Microengineering, 2000, 10, 415-420). In contrast, most of the other elastomeric mechanical valves would seal upon the application of pressure through a thin membrane, and may introduce the challenge of maintaining the homeostasis of a cell suspension in the controlled channel. Gasses can diffuse easily through the membrane under the actuation pressure (Leclerc et al., Biotechnology Progress, 2004, 20, 750-755) and either diffuse in the cell suspension or form gas bubbles that can damage the cells. While a common solution for this problem is the filling of the control channels with liquid, recent results reported that the PDMS is permeable even to some commonly used liquids (Randall and Doyle, Proceedings of the National Academy of Sciences of the United States of America, 2005, 102, 10813-10818), and raise the concern of maintaining the homeostasis of the medium around cells during pressure actuation. Such potential shortcomings are avoided by the vacuum actuation of the microstructured membranes. Due to the elasticity of the PDMS, the microstructured membrane presses the microstructure against the valve seat and keeps the valve normally closed in the absence of actuation. The pressure that a valve could withstand without supplementary pressure in the control chamber was relatively low, in the range of few Pascals, but comparable to the pressures likely to drive very slow movement of cell suspensions.
Of practical importance is the unitary fabrication procedure, which allows the microstructured valve to be fabricated using soft lithography techniques based only on epoxy photoresists (e.g. SU8). However, the fabrication of a normally closed valve posed one significant challenge, namely how to selectively seal two distinct PDMS structures and simultaneously avoid having the valve become sealed during the bonding of the network layer. Previous technical solutions used mechanically clamping a PDMS membrane between the two glasses (Grover et al., Sensors and Actuators B-Chemical, 2003, 89, 315-323), partial bonding in combination with mechanical sticking (Li et al., Electrophoresis, 2005, 26, 3758-3764), or a water-soluble retardant (Baek et al., Journal of Micromechanics and Microengineering, 2005, 15, 1015-1020) for patterned PDMS bonding. In our approach, the patterned control of bonding was achieved by the patterning of a metal layer at the site of the valve seat. The thin layer of metal on the glass was then aligned to the valve seat and prevents the bonding of the PDMS to glass after exposure to oxygen plasma. The metal layer could eventually be etched at the end of the fabrication process resulting in fully transparent devices.
The unitary fabrication procedure is also important in reducing the costs associated with the fabrication of these devices. While for certain experiments the devices can be cleaned with various solutions and reused, in applications involving human blood or human cells, safety issues require these devices to be single use. Nonetheless, when translating the design into different materials, the implementation of unitary fabrication procedures becomes less challenging, ultimately resulting in cheaper, disposable devices.
OTHER EMBODIMENTS
All publications, patents, and patent applications mentioned in the above specification are hereby incorporated by reference. Various modifications and variations of the described method and system of the invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the invention as claimed should not be unduly limited to such specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to be within the scope of the invention.
Other embodiments are in the claims.
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Devices for fluid control and biological particle manipulation (e.g., cell enrichment and blood sampling) are disclosed. The devices a based on the ability to control the flow of fluids through the use of microfluidic valves. The valves are characterized, for example, by microstructures disposed on a mobile diaphragm.
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FIELD OF THE INVENTION
[0001] The present invention relates to a new process for producing 1,3,2-dioxaborinane compounds.
BACKGROUND OF THE INVENTION
[0002] The direct borylation of aromatic halides with pinacolborane is a growing business for pharmaceutical applications. The use of low cost diols such as 2-methyl-2,4-pentanediol and 2,2-dimethyl-1,3-propanediol will enable expansion of the direct borylation applications to agrochemical processes. There is a need for lower cost borane derivatives of diols for the preparation of active agents in the pharma and agrochemicals sectors.
[0003] The synthesis of 4,4,6-trimethyl-1,3,2-dioxaborinane (HexB) was first reported by Woods et al. (Woods, W. G.; Strong, P. L., J. Am. Chem. Soc. 1966, 88, 4667; U.S. Pat. No. 3,383,401 and U.S. Pat. No. 3,064,032) and involves a process for the formation of HexB with sodiumborohydride and the corresponding 2-chloro-4,4,6-trimethyl-1,3,2-dioxaborinane. Furthermore, a low yielding synthesis of HexB from diborane in diethyl ether was reported.
[0004] Murata et al. (Murata, M.; Takeshi, O.; Watanabe, S.; Masuda, Y. Synthesis, 2007, 3, 351) recently reported the synthesis of 4,4,6-trimethyl-1,3,2-dioxaborinane from di-methylsulfide borane (DMSB) and hexylene glycol. The synthesis results in HexB that contains traces of dimethylsulfide (DMS) and has a strong malodour.
[0005] Alternatively Chavant et al. (Praveen Ganesh, N.: d'Hondt, S.; Yves Chavant P.) report a procedure for the formation of diborane from iodine/NaBH 4 , in diglyme, followed by subsequently reacting it with a solution of hexylene glycol in toluene or dicloromethane, see J. Org. Chem. 2007, 72, 4510-4514.
[0006] RU-A-2 265 023 relates to a method of obtaining pinacolborane. 4,4,5,5-tetramethyl-1,3,2-dioxaborolane (pinacolborane) is obtained by reacting pinacol with diborane typically in the presence of diethylether as a solvent at a temperature in the range of from 5 to 36° C. Pinacol and diborane are used in a molar ratio in the range of 1:0.45 to 0.55.
[0007] HexB is a commercially available reagent that has the following advantages over other reagents:
high stability compared to other borane reagents due to stabilizing compounds formed during the process no pressure built up during DOT testing at 55° C. for six weeks in the presence of the stabilizing compounds. shipping is possible without decomposition no refrigerated shipping is required if sufficiently stabilized No additional stabilizer or additives are required beyond the process byproducts which act as stabilizers depending on the optimization of the preparation process, no distillation is required
SUMMARY OF THE INVENTION
[0014] The object of the present invention is to provide a new process for producing a 1,3,2-dioxaborinane compound which does not contain traces of dimethylsulfide (DMS) and is stench free and stable upon storage without requiring additional stabilizers or additives. Furthermore, the HexB obtained from the process should preferably be of a purity level that does not need any laborious workup or purification.
[0015] The object is achieved by a process for producing a 1,3,2-dioxaborinane compound of the general formula (I)
[0000]
[0000] in which each R individually is selected from the group consisting of H and C 1-6 -alkyl, by reacting a diol of the general formula (II)
[0000] HO—CRR—CRR—CRR—OH (II)
[0000] with diborane without using a solvent.
[0016] The residues R can be the same of different from each other.
[0017] According to one embodiment of the invention, dimethylether can be employed as a solvent.
[0018] According to the present invention it has been found that diols of the general formula (II) can be reacted with diborane without using a solvent, especially when the diborane is added to the diol or both are simultaneously and/or continuously fed to a reactor. The inventors found that in the above process without using a solvent HexB can be obtained which contains only stabilizing amounts of B(OR) 3 and consequently does not require a distillation. Typically, a product with a B(OR) 3 content as low as 0 or 0.01 to 10% by weight can be obtained. The process according to the present invention leads to HexB that is free from DMS, solvent and excessive amounts of borate. The product is stable upon storage at 55° C. for six weeks depending on the degree of stabilization. Therefore, no additives like DMS is necessary to stabilize the product.
[0019] The invention allows for the preparation and use of DMS-free borylation reagents. DMSB-based dioxaborinanes always require borane-complexes for synthesis and often contain DMS. The product is essentially or totally solvent free so that no solvent or DMS-by-product removal is necessary.
[0020] According to the present invention it has been found that compounds of the general formula B(OR′) 3 stabilize 1,3,2-dioxaborinane compounds, especially the compounds listed below.
[0021] Thus, the invention also relates to a method of stabilizing 1,3,2-dioxaborinane compounds involving the step of contacting the 1,3,2-dioxaborinane compound with a compound of the general formula (III) or oligomers thereof
[0000] B(OR′) 3 (III) with R′ independently OH, C 1-12 -alkyl, C 2-12 -hydroxyalkyl or where two R′ together form an C 3-24 -alkylene group, to link together the oxygen bonded to the boron.
[0025] The compounds of the general formula (III) can be added to the final 1,3,2-dioxaborinane compounds after their preparation. Preferably, the compounds of the general formula (III) are formed in the process for producing the 1,3,2-dioxaborinane compounds.
DETAILED DESCRIPTION OF THE INVENTION
[0026] The process of the present invention preferably leads to 1,32-dioxaborinane compounds of the formula (I) wherein from 2 to 4 residues, R groups, on the carbon atoms adjacent to the oxygen independently are C 1-3 -alkyl, especially C 1-2 -alkyl, specifically methyl and the other R groups are hydrogen.
[0027] More preferably, the compound of the general formula (I) is 4,4,6-trimethyl-1,3,2-dioxaborinane.
[0028] The process according to the present invention can be carried out at a wide range of temperatures. Preferably, the process is carried out at a temperature in the range of from −30 to 120° C., especially −10 to 50° C., preferably −5 to 30° C.
[0029] The reaction can be carried out in a wide range of pressures. Preferably, the pressure is in the range of 0.01 to 12 bar, more preferably 0.5 to 10 bar, especially 0.7 to 7 bar, preferably 1.4 to 3.6 bar.
[0030] Diborane and the diol of the general formula (II) can be employed in a wide range of proportions. Typically, the amount of diborane should be at least equimolar to the amount of diol. According to a preferred embodiment of the invention, an excess of 1 to 50 mol %, especially 5 to 30 mol % of diborane is employed with regard to the diol, and the reaction mixture is warmed to at least room temperature after the initial reaction. This leads to an equilibration from diboronated B 2 Hex 3 to HexB and results in a product with a low B(OR) 3 content. Since diborane is an expensive compound, the excess of diborane should be as low as possible to give HexB with the desired amount of stabilizing B(OR) 3 content. An optimized process may be performed with an excess of 5 mol % of diborane or less.
[0031] The product obtained by the process of the present invention can be directly used as a borylation reagent, thus requiring no further purification like distillation. Optionally, a distillation can be carried out. When the process using an excess of diborane is performed, the product obtained is preferably freed from excess diborane by sparging with an inert gas, especially by sparging with nitrogen or argon.
[0032] The process according to the present invention can be carried out continuously or as a batch process. Preferably, the process is carried out as a batch process wherein the diborane is added to the diol.
[0033] In the process according to the present invention, preferably a stabilizing amount of compounds of the general formula (III) or oligomers thereof
[0000] B(OR′) 3 (III) with R′ independently OH, C 1-12 -alkyl, C 2-12 -hydroxyalklyl
or where two R′ together form an C 3-24 -alkylene group,
[0036] R′ is preferably C 1-6 -alkyl, C 2-6 -hydroxyalkyl, or two R′ together form a C 5-18 -alkyl group, is formed in the process.
[0037] Preferably, in the compound of the general formula (III), the residues R′ are derived from the diol of the general formula (II). In this case, the compound of the general formula (III) can be B(Hex) 3 or B 2 (Hex) 3 as well as longer oligomers thereof, corresponding to B n (Hex) m . n and m can individually be 1,2,3 etc.
[0038] According to the present invention it has been found that the compounds of the general formula (III) help to stabilize the 1,3,2-dioxaborinane compounds of the general formula (I). The compounds of the general formula (III) may be added in the course or at the end of the process, or they are formed during the process from the reactants present in the reaction system. After completion of the reaction the stabilizing amounts of the compounds of the formula (III) need not be separated from the product so that they can stabilize the product. Preferably, the stabilizing amount is at a level that the 1,3,2-dioxaborinane compound, preferably 4,4,6-trimethyl-1,3,2-dioxaborinane (HexB) fulfills the department of transportation test (DOT test). By including the compounds of the general formula (III), the 1,3,2-dioxaborinane compounds fulfill this requirement. They preferably have a purity in the range of from 90 to 99.9%, more preferably 97 to 99%. To show the stabilizing effect of the compounds of the general formula (III), B 2 (Hex) 3 was synthesized and added to a HexB composition. It was found that the compound shows a stabilizing effect.
[0039] Furthermore, according to the invention it was found that amines show a stabilizing effect. Therefore, according to one embodiment of the invention, after the completion of the reaction at least one amine can be added to stabilize the compound of the general formula (I). Preferably, the amine is a trialkylamine, most preferably triethylamine. Especially triethylamine has a dramatic stabilizing effect and levels as low as 0.1 to 1% by weight, more preferably 0.3 to 0.7% by weight, are sufficient for passing the DOT test.
[0040] The amine is preferably added at the end of the preparation process, whereas the compounds of the general formula (III) can be added or formed during the process.
[0041] The process according to the present invention is preferably carried out in a semi-batch feed mode. In this process the diol of the general formula (II) is simultaneously fed together with diborane to a reactor. By adding diborane simultaneously to hexylene glycol or the diol of the general formula (II), a product decomposition can be avoided in case of interruption of diborane-feed or a production shutdown. Diborane should be present in the reactor as long as the diol is present. Therefore, a simultaneous feed of the two reactants is a much more robust process compared to an ordinary batch process. Therefore, the process is preferably carried out in the semi-batch feed-mode.
[0042] In a further preferred embodiment, an amount of the compound of the general formula (I) is present as a heel material in the reactor at the beginning of the process to act as a heat sink and to allow an agitation of the reaction mixture. Thus, first an amount of heel material is produced or introduced into the reactor. Subsequently, the co-feed of diborane and diol into the reactor is started. After completion of the reaction, the reactor can be emptied and the product may be used or introduced into a work-up process.
[0043] The semi-batch feed-mode delivers compounds of general formula (I) in the desired purity without decomposition of the final product, and only low amounts of compounds of the general formula (III) are formed. Their amount is sufficient for stabilizing the reaction product. The co-feed mode has the advantage that by feeding for example 20% of diborane ahead of diol, it is possible to stop feeding the process at any time without purity decrease. The most preferred process is a semi-batch feed process to prepare a heel material (minimum amount), followed by a co-feed mode.
[0044] The compound of the general formula (I) may be purified after the completion of the production by distillation. Preferably, a wiped film evaporator is used for the distillation since the residence time at high temperature is very low.
[0045] It is also possible to carry out the process according to the present invention in the presence of dimethylether as solvent. However, the solvent has to be removed after the process, so this process variant is less preferred.
[0046] Optionally, an amine can be added to the product in order to stabilize it. Preferably, the amount of added amine is in the range from 0.0001 to 5% by weight, based on the compound of the general formula (I).
[0047] The product obtained according to the present invention is stable upon storage without adding DMS. The storage stability is measured at 55° C. for six weeks.
[0048] The product obtained according to the present invention contains preferably as low amounts of B(OR) 3 as possible. The content of B(OR) 3 can be in the range of from 0 to 15 mol %, often 0.5 to 4 mol %, especially 0.5 to 3 mol %. The product does not contain any solvent impurities like ether solvents, aliphatic and aromatic hydrocarbons, chlorinated solvents, esters or impurities such as dimethylsulfide, amines, nitrites and carboxylic acids. Amines may, however, be added as stabilizers.
[0049] Those skilled in the art will appreciate that the invention described herein is subject to variations and modifications other than those specifically described herein. It is to be understood that the invention includes all such variations and modifications. The invention also includes all of the steps, features, compounds and compositions referred to or indicated in this specification, individually or collectively, and any and all combinations of any two or more of said steps or features.
[0050] While the present invention is described herein with the reference to illustrated embodiments, it should be understood that the invention is not limited to these examples. Therefore, the present invention is limited by the claims attached herein.
[0051] The invention is further illustrated by the following examples:
EXAMPLES
Example 1
[0052] The process is a two step procedure where A.) a minimal amount of hexylene glycol borane as heel material is produced and B.) a large volume of product is produced in co-feed mode.
[0053] Step A: Hexylene glycol borane is prepared as heel material by an uninterrupted semi-batch diborane feed into hexylene glycol using 20-50 psi (1.39-3.45 bar) backpressure and temperatures between 0 and 20° C. Once the diborane feed is completed, a minimum amount of heel material is present which serves as heat sink for a subsequent co-feed mode and as minimum liquid level to ensure that agitation is possible in the reactor. The heel forming step can be avoided by charging hexyleneglycol borane of past production lots to the reactor in order to immediately continue with step B (preferred operation).
[0054] Step B: The process is continued by continued feed mode (co-feed) by simultaneously adding gaseous diborane and hexylene glycol. Diborane excess is added in such way to ensure high levels of purity of the final product. Depending on the efficiency of the process setup 0-20% diborane excess might be required. No excess of diborane is preferred.
[0055] After completion of the feed, a digestion time of 1 hour in the cold and 1 hour at 15-30° C. is recommended to ensure high purity of the product. Any excess of diborane is removed by sparging with inert gas and venting it to a scrubber system. The product can be discharged into drums or holding tanks.
Example 2
[0056] 2-Methyl-2,4-pentanediol (118.2 g, 1.00 mole) was charged into a reactor (1 L) equipped with a dip-tube, thermocouple and attached to the diborane feed system (back pressure 30 psig). The diol was cooled to 0 20 C. and diborane (33.19 g, 1.20 mole, 1.2 eq.) was added in such a way that the temperature was maintained at 0-5° C. and a diborane flow rate of 10 g/h. When the diborane feed was completed after 3.5 hours, the temperature was kept at 0° C. for another 2 hours, then the mixture was allowed to warm to room temperature and continued stirring at r.t. for 2 hours. The backpressure was released and excess diborane was removed by sparging the reactor with nitrogen (0.75 hours). The reactor was emptied into a dry, nitrogen-flushed cylinder. The product was analyzed accordingly. The product was found to be 97.7% pure by 11 B NMR.
Example 3
[0000]
a.) Distillation at 35° C./12 torr of 73.53 g (95% pure HexB from reaction) gave 57 g (99.8%) of pure product along with 16.46 g (22.1%) of waste material (material containing borates and some).
b.) A second distillation was done on a larger ˜500 g scale. The maximum pot temperature was 85-90° C. resulting in 79% product recovery (100% pure by B NMR) and 21% product loss.
Example 4
[0059] The semi-batch protocol from Exp. 2 was repeated on a 0.5 mol scale at 25-30° C. using 20% excess diborane to result in 97.4% pure hexyleneglycol borane.
Example 5
[0060] The semi-batch protocol from Exp. 2 was repeated on a 2 mol scale at 0° C. using a 4 h feed time and using only 5% diborane in excess resulting in 97.5% pure hexyleneglycol borane.
Example 6
[0061] The semi-batch protocol from above was repeated on 3.5 mole scale using 20% excess diborane at 10° C. and a total feed time of 14 hour to result in material with 96.5% pure hexyleneglycol borane.
Example 7
[0062] HexB was prepared in semi-batch mode by feeding diborane to hexylene glycol resulting in 256.2 g (2.00 mole) of HexB (97.5% pure) which served as heel material. Meanwhile, hexylene glycol 236.2 g (2.00 mole) was charged into a Fisher Porter bottle, which was calibrated in such a way that the amount hexylene glycol added to the reactor can be monitored. The Fisher Porter bottle was connected to a dip-leg into the reactor. The reactor was pressurized to 40 psig N 2 . Then diborane was fed into the system. As soon as the theoretical amount of diborane (1 equ. “BH 3 ”) was added for completion of the continuous diborane feed, the hexylene glycol feed was started and diborane feed was continued until additional 2 moles of hexylene glycol (256.2 g) were added (4 moles of hexylene glycol in total in the reactor) and a total amount of diborane (68 g, 4.92 mol, 1.22 equ.) was added. Temperature was maintained at less than 15° C. Once 2 moles of hexylene glycol and diborane were added (thus 4 modes in total), the diborane feed was continued until an excess of 22% was reached. Stirring was continued for 2 hours while warming to room temperature, followed by another 2 hours at room temperature. The backpressure was released and excess diborane was sparged with nitrogen (0.75 hours). The reactor was emptied into a dry, nitrogen-flushed cylinder.
[0063] The material so obtained was 97.5% pure (2.5% borates) according to 11 B NMR.
Example 8
[0064] after completion of a batch of hexylene glycol borane, triethylamine (TEA) was added to the batch to stabilize HexB. To obtain 1 w % triethylamine in HexB, hexylene glycol borane (512.4 g, 2 mole) was stirred in a reactor with 5.12 g of triethylamine at ambient temperature for 30 minutes. The final product was discharged into a cylinder.
Example 9
Semibatch Diborane Feed Into Dimethylether
[0065] Hexylene glycol (238.8 g, 2.02 mole) was charged to a glass pressure reactor and cooled to 0° C. 239 g of dimethylether (DME) was charged to the reaction and the pressure rose to 40 psig. The mixture was stirred to result in a homogeneous mixture and the temperature was stable at 0° C. Diborane (32 g, 2.31 mole, 1.14 eq.) was fed to the reactor over a period of 3.25 hours while allowing the temperature to warm up to 12.1° C. After completion of the feed, cooling was turned off and the reactor content was allowed to warm to room temperature within 3.25 hours. The reactor was vented to release all volatile dimethylether. The reaction mixture was purged with nitrogen for 3 hours. The final product resulted in hexylene glycol borane with a purity of 95.9% by 11 B NMR.
Example 10
[0066] Mixtures of HexB with stabilizers were tested for decomposition on-set temperature and energy using DSC analysis (differential scanning calorimetry). A distinct correlation between borate content in the sample and on-set temperature was observed. Addition of B(OR′) 3 type compounds increased the decomposition on-set temperature to higher values demonstrating proof that the mixtures showed increased thermal stability.
[0000]
HexB Sample
Entry
(Additive or % Purity)
On-set. [° C.]
Energy [J/g]
1
1 w % TEA
179.0
−288.5
2
0.5 w % TEA
185.0
−364.2
3
0.1 w % TEA
225.0
−358.2
4
1.5 w % DME + 1 w %
257.0
−254.7
TEA
5
distilled, 100%
159.0
−310.5
6
98.7% pure (11B NMR)
248.0
−451.9
7
97.5% pure (11B NMR)
210
−438.7
8
92% pure (11B NMR)
(>350)
N.A.
9
1 w % DMS
169.0
−412.2
10
1 w % (B 2 Hex 3 )
203.0
−414.5
11
5 w % (B 2 Hex 3 )
298
−480.3
12
5 w % Et 2 O
172
−411.5
[0067] There is a correlation in on-set temperature of the mixture and the content of B(OR′) 3 type compounds. The higher the amount of B(OR′) 3 type compounds, the higher the on-set temperature. Upper temperature detection limit is 350° C. No decomposition onset peak detectable in example 8.
[0068] DOT tests with 2.3 wt % B 2 Hex 3 resulted in a pressure of 50 psi after 15 days. Samples containing 1 wt %, 2.3 wt % and 5 wt %, respectively, of B 2 Hex 3 , passed the DOT test, whereas samples containing 1 wt % DMS or 0.1 wt % TEA failed.
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A process for producing a 1,3,2-dioxaborinane compound of the general formula (I)
in which each R individually is selected from the group consisting of H and C 1-8 -alkyl, by reacting a diol of the general formula (II)
HO—CRR—CRR—CRR—OH (II) with diborane is performed without using a solvent.
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This is a continuation of application Ser. No. 689,858, filed Jan. 9, 1985, now abandoned.
BACKGROUND OF THE INVENTION
This invention relates to holding tanks for waste fluids and in particular to a novel holding tank to collect waste fluids from recreational vehicles for use in camping areas and parks where central sewer facilities are not feasible for individual campsites.
The disposal of waste fluids, such as sewer water and other fluids used in washing, cooking, and the like (collectively termed "grey water") presents a particular problem for the owners of camping areas and parks. Typically, health department or convervation rules and regulations require the operators of camping areas and parks to make provisions for the disposal of waste fluids. While central sewer facilities are on solution, the use of such facilities is often infeasible due to the excessive expense of such systems, the difficulty of moving a recreational vehicle to a dumping station when semi-permanently stationed, or because topological concerns make the installation of central systems or large central holding tanks impossible.
Most recreational vehicles are equipped with a small holding tank for sewage but not for greywater, and at best the onboard tank capacity is very limited. Since these waste fluids cannot be discharged into the soil because of health regulations, a campsite operator, in a facility where no central sewage is available, is often asked to clean the recreational vehicle tanks. Complying with individual requests is a time-consuming chore and also creates health and sanitary concerns when the campground operator cannot provide immediate service.
The present invention solves the above-identified problems. By providing an in-ground holding tank at the recreational vehicle site (hereafter the "campsite"), the recreational vehicle's owner can discharge his own on-board holding tank into the in-ground holding tank that is the subject of this invention. The camp operator is then free to schedule service of the in-ground tanks at his convenience. Thus, the problems of complying with individual requests and the difficulties associated with the campground owner's inability to provide service on demand to individual recreational vehicle owners are eliminated. In addition, since the in-ground tank is fitted with a coupling compatable with most standardized recreational vehicle discharge portals, the danger of spillage or contamination in the discharge process is greatly reduced and the entire process is much cleaner and safer. Further, the tank is made of a durable inexpensive material, such as a non-corrosive plastic or fiberglass, and thus provides an economical method for a campground operator to comply with necessary health and conservation requirements and at the same time ease his own burden and make his campsite safer and cleaner.
The use of a holding tank to hold liquids is known in the art. It is also known to locate a holding tank for liquids, including sewage, underground, as shown in U.S. Pat. No. 3,433,258 to Steele (1969). In addition septic tank and sewage disposal systems, including systems made of materials such as fiberglass, likewise are known in the art, representative examples of which known to the applicant are: U.S. Pat. Nos. 3,426,903 to Olecko (1969); 3,260,371 to Wall (1966); 3,221,881 to Weiler, et al., (1965); and 3,097,166 to Monsen (1963). However, none of these prior art references teaches or suggests a holding tank particularly adopted for use in recreational vehicle campsites nor do they teach or suggest a process of disposing of waste fluids from recreational vehicles utilizing the novel holding tank.
SUMMARY OF THE INVENTION
The disclosed invention is a holding tank for use in disposing of waste water from recreational vehicles. The holding tank is made of non-corrosive plastic or fiberglass, and is equipped with connections to allow integral connection with the disposal portal on recreational vehicles and to allow easy cleaning of the holding tank. Also disclosed is a process for disposing of waste fluids from recreational vehicles utilizing the holding tank.
One object of this invention is to provide a holding tank for waste water from recreational vehicles and a process for disposing of waste water from recreational vehicles.
A further object of this invention is to provide a holding tank that complies with the necessary health and conservation codes regulating the disposal of waste water.
Still another object of this invention is to provide a holding tank that is made of a light, seal-tight, and inexpensive material such as non-corrosive plastic or fiberglass.
A still further object of this invention is to provide a process for the removal of waste fluids from recreational vehicles using the disclosed holding tank.
These and additional objects of the invention will become apparent as the invention is described in detail hereafter.
DESCRIPTION OF DRAWINGS
The invention will now be described in greater detail with reference to the accompanying drawings, wherein:
FIG. 1 is a partial cut-away side view of the holding tank.
FIG. 2 depicts the holding tank in the ground as used in operation.
FIG. 3 depicts the vent valve located on the threaded cap.
DETAILED DESCRIPTION OF THE INVENTION
With reference to the drawings, FIG. 1 shows the holding tank with a generally cylindrical body (1) and end walls (2) all made from 1/4 inch non-corrosive plastic, fiberglass composite materials, or similar lightweight materials substantially impervious to chemical breakdown. The volume of the cylinder may vary between 30-175 gallons with the preferred volume between 60-100 gallons in a cylinder of approximately three (3) feet in length by two (2) feet in diameter. The body and walls are formed by well known methods to be impervious to leakage.
At the top of the cylindrical body (1) there are two circular apertures (3) and (4). Aperture (3) has a preferred diameter of 3 inches. An inlet pipe (5) is located in the aperture (3). A manual control valve (6) of standard construction is removably secured to the top of pipe (5) through a threaded connection or other suitable means. The control valve (6), when in the open position, allows waste fluid into the holding tank and when in the closed position seals the tank when the tank is not in use or when it is being cleaned. Affixed to the top of the control valve (6) is an adapter (7) that allows various fittings (described immediately hereafter) to be utilized. A number of well-known fittings are interchangeably utilizable to allow waste filud to be discharged from the recreational vehicle into the holding tank. One fitting (8) shown in FIG. 1 is a flexible hose connection (standard for use with most recreational vehicles) and a standard sealing adapter old in the art. The fitting (8) allows the tank to be placed in secure communication with the discharge portal of the recreational vehicle so that waste fluid may be discharged into the tank without leakage or spillage. Another fitting (not shown) allows grey water from the recreational vehicle to be disposed of into the holding tank though a smaller (approximately 1" diameter) flexible tube.
Aperture (4) has a preferred diameter of 4 inches. An outlet pipe (9) is located in aperture (4), said outlet pipe (9) having a threaded connection (10) at the top thereof. A threaded cap (11) removably secured to the outlet pipe (9) seals the holding tank and is removed to allow the tank to be pumped out.
A pressure relief valve (12) is provided at the top (13) of the tank (1). The pressure relief valve (12) is a one-way spring loaded check valve that can release gas pressure in the tank and then reseal the tank. In an alternate and equally preferred embodiment, the pressure relief valve (12) may be located at the top of cap (11). Also provided is a gauge (14) located at the top (13) of the holding tank. The volume gauge (14), which is old in the art, allows the campground operator to check the available volume in the tank by examining the analog display caliberated on the face of the gauge.
In operation the holding tank is placed in the ground next to the recreational vehicle so that the topsoil covers by approximately 1" the top (13) of the holding tank. The vent (12), and gauge (14) extend above the ground as do the input and output assemblies. When a recreational vehicle user wishes to discharge waste fluid into the holding tank, he simply attaches the appropriate fitting, such as (8), onto the recreational vehicle and opens the control valve (6). The holding tank is then in sealed communication with the storage tank in the recreational vehicle and waste fluids may be discharged into the holding tank. After the discharge is complete, the operator closes the control valve (6) resealing the holding tank. The fitting (8) may remain attached to the recreational vehicle or be decoupled from the venicle as the operator desires.
To empty the holding tank, the campground operator first places the control valve (6) in the closed position. He then removes the threaded cap (11) and places a pumping device into the holding tank through output pipe (9) and pumps the tank clean. After pumping is complete the pumping device is removed and the threaded cap (11) is replaced on the output pipe (9).
It should be understood that numerous changes in the details of construction may be made without departing from the spirit of the invention, especially as defined in the following claims.
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An in-ground holding tank to collect sewage and grey water from recreational vehicles in areas where central sewer facilities are not feasible. The holding tank has a typical volume of 60-100 gallons and is made of non-corrosive material. The tank contains input and removal assemblies, a pressure release valve, and may contain a volume gauge.
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BACKGROUND OF THE INVENTION
This invention relates to processing product components.
Product components can be intermixed to produce a wide variety of products having different physical characteristics. For example, a colloidal system may be a stable system comprising two immiscible substance phases with one phase dispersed as small droplets or particles in the other phase. Colloids may be classified according to the original phases of their constituents. For example, a solid dispersed in a liquid may be a dispersion. A semisolid colloidal system may be a gel. An emulsion may include one liquid dispersed in another.
For simplicity, we will call the dispersed phase “oil” and the continuous phase “water”, although the actual product components may vary widely. Additional components may be included in a product such as emulsifying agents, known as emulsifiers or surfactants, that can stabilize emulsions and facilitate their formation by surrounding the oil phase droplets and separating them from the water phase.
As is described in U.S. Pat. No. 5,720,551, incorporated in its entirety, high pressure homogenizers are often used to intermix product components using shear, impact, and cavitation forces in a small zone. To prevent rapid wear to a high pressure homogenizer caused by different materials (e.g., relatively large solids), product components may be preprocessed by equipment such as ball mills and roll mills to reduce the size of such materials.
SUMMARY OF THE INVENTION
In general, in one aspect, a method of processing product components includes directing a first jet of fluid along a first path and directing a second jet of fluid along a second path. The paths are oriented to cause interaction between the jets that form a stream oriented essentially opposite to one of the jet paths.
Embodiments may include one or more of the following features. The first and second paths may oriented in essentially opposite directions. May be adjacent to one of the jets (e.g., a cylindrical stream surrounding one of the jets). The jets of fluid may be from a common fluid source. The jets may have identical or different jet characteristics. For example, the jets may have different velocities, for example, by ejecting the two jets at jet orifices of two different diameters.
In general, in another aspect, a method of processing product components includes directing a first jet of fluid from a common fluid source along a first path, directing a second jet of fluid from the common fluid source along a second path. The paths are oriented essentially opposite one another to cause interaction between the jets that forms a cylindrical stream surrounding one of the jets.
In general, in another aspect, a method of processing product components includes directing a first jet of fluid along a first path, directing a second jet of fluid along a second path, and causing sheer and cavitation in a third fluid by positioning the third fluid between the jets.
Embodiments may include one or more of the following features. The third fluid may include solids (e.g., powders, granules, and slurries). A gas may be used to position the third liquid.
In general, in another aspect, a method of processing product components includes directing a first jet of fluid formed from a common fluid source along a first path and directing a second jet of fluid formed from the common fluid source along a second path essentially opposite to the first path. The jets have different velocities and cause sheer and cavitation in a third fluid positioned between the jets. The jets form a stream oriented opposite one of the paths.
In general, in another embodiment, an apparatus for processing product components includes two nozzles configured to deliver jets of fluid along two different paths, and an elongated chamber that contains an interaction region in which the two paths meet. The chamber is configured to form a stream of fluid from the two jets that follows a path that has essentially the opposite direction from one of the paths of one of the jets.
Embodiments may include one or more of the following features. The apparatus may also include an outlet port configured to emit the stream. The nozzles may be aligned essentially opposite one another. The apparatus may also include an inlet port configured for receiving a second fluid. The inlet port may be aligned to position the second fluid such that the jets cause sheer and cavitation in the second fluid. The apparatus may also include a port that may be configured to be either an inlet port or an outlet port.
The chamber may include one or more reactors which may have different characteristics (e.g., inner diameter, contour, and composition). Seals may be positioned between the reactors. The seals may have different seal characteristics (e.g., inner diameter).
In general, in another aspect, an apparatus for processing product components includes two nozzles, aligned essentially opposite one another, configured to deliver respective jets of fluid along two different paths. The apparatus also includes an elongated chamber containing an interaction region in which the two paths meets. The chamber includes reactors and seals and is configured to form a stream of fluid from the two jets essentially the opposite direction from one of the paths of one of the jets. The apparatus further includes an outlet port configured to emit the stream.
Advantages of the invention may include one or more of the following. Very small liquid droplets or solid particles may be produced in the course of combining product components (e.g., emulsifying, mixing, blending, suspending, dispersing, de-agglomerating, or reducing the size of solid and/or liquid materials). Nearly uniform sub-micron or nano-size droplets or particles are produced. A broad range of product components may be used while maximizing their effectiveness by introducing them separately into the double-jet cell. Fine emulsions may be produced using fast reacting components by adding each component separately and by controlling the locations of their interaction. Control of temperature before and during product formation allows multiple cavitation stages without damaging heat sensitive components, by enabling injection of components at different temperatures and by injecting compressed air or liquid nitrogen prior to the final formation step. The effects of cavitation on the liquid stream are maximized while minimizing the wear effects on the surrounding solid surfaces, by controlling orifice geometry, materials selection, surfaces, pressure and temperature. A sufficient turbulence is achieved to prevent agglomeration before the surfactants can fully react with the newly formed droplets. Agglomeration after treatment is minimized by rapid cooling, by injecting compressed air or nitrogen, and/or by rapid heat exchange, while the emulsion is subjected to sufficient turbulence to overcome the oil droplets' attractive forces and maintaining sufficient pressure to prevent the water from vaporizing.
Scale-up procedures from small laboratory scale devices to large production scale systems is made simpler because process parameters can be carefully controlled. The invention is applicable to colloids, emulsions, microemulsions, dispersions, liposomes, and cell rupture. A wide variety of immiscible liquids may be used in a wide range of ratios. Smaller amounts of (in some cases no) emulsifiers are required. The reproducibility of the process is improved. A wide variety of products may produced for diverse uses such as food, beverages, pharmaceuticals, paints, inks, toners, fuels, magnetic media, and cosmetics. The apparatus is easy to assemble, disassemble, clean, and maintain. The process may be used with fluids of high viscosity, high solid content, and fluids which are abrasive and corrosive.
The emulsification effect continues long enough for surfactants to react with newly formed oil droplets. Multiple stages of cavitation assure complete use of the surfactant with virtually no waste in the form of micelles. Multiple ports along the process stream may be used for cooling by injecting components at lower temperature. VOC (volatile organic compounds) may be replaced with hot water to produce the same end products. The water will be heated under high pressure to well above the melting point of the polymer or resin. The solid polymer or resins will be injected in its solid state, to be melted and pulverized by the hot water jet. The provision of multiple ports eliminates the problematic introduction of large solid particles into the high pressure pumps, and requires only standard industrial pumps. The invention also enables particle size reduction of extremely hard materials (e.g., ceramic and carbide powders).
Other advantages of the invention will become apparent in view of the following description, including the figures, and the claims.
BRIEF DESCRIPTION OF THE DRAWINGS
FIGS. 1 through 3 are block diagrams of emulsification systems.
FIG. 4 is a cross-sectional view of a double-jet cell assembly.
FIG. 5 is an enlarged cross-sectional view of an orifice of the double-jet cell assembly.
FIGS. 6 and 7 are schematic cross-sectional diagrams, not to scale, of fluid flow in an absorption cell.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In FIG. 1, product components are supplied from sources 110 , 112 , and 114 into a pre-mixing system 116 . For simplicity, only three types of components are shown by way of example: water, oil, and emulsifier; but a wide variety of other components, or more than three components, could be used depending on the product to be made. The pre-mixing system 116 is of a suitable kind (e.g. propeller mixer, colloid mill, homogenizer, etc.) for the type of product. After pre-mixing, the components are fed into a feed tank 118 . In some cases, the pre-mixing may be performed inside feed tank 118 . The pre-mixed product from tank 118 then flows through line 120 and valve 122 by means of transfer pump 124 to a high pressure process pump 128 . Transfer pump 124 may be any type of pump normally used for the product, provided it can generate the required feed pressure for proper operation of the high pressure process pump. Pressure indicator 126 is provided to monitor feed pressure to pump 128 . The high pressure process pump 128 is typically a positive displacement pump, e.g., a triplex or intensifier pump. From process pump 128 the product flows at high pressure through line 130 into coil 132 where pressure fluctuations generated by the action of pump 128 are regulated by expansion and contraction of coil tubing. It may be desirable or necessary to heat or cool the feed stock. Heating system 148 may circulate hot fluid in shell 154 via lines 150 and 152 , or cooling system 156 may be used. The heating medium may be hot oil or steam with the appropriate means to control the temperature and flow of the hot fluid such that the desired product temperature is attained upon exiting coil 132 . The product exits coil 132 through line 134 , where pressure indicator 136 and temperature indicator 138 monitor these parameters. Line 134 splits into lines 134 A and 134 B to lead the product into double-jet cell 140 from both ends, such that each of the two nozzles in cell 140 is supplied with product at high pressure, for example a pressure of 15,000 psi.
Processing of the product components, e.g., to form a colloid system, takes place in double-jet cell 140 where the feed stock is forced through two jet generating orifices and through an absorption cell wherein the jets are forced to flow in close proximity and in essentially opposite directions, thereby causing the jets' kinetic energy to be absorbed by the fluid streams. In each of the treatment stages (there may be one or more), intense forces of shear, impact, and/or cavitation break down the oil phase into extremely small and highly uniform droplets, and allow sufficient time for an emulsifier to interact with these small oil droplets to stabilize the emulsion. Before exiting the absorption cell, the processed product is forced to flow in close proximity to one of the jets which impels some of the processed product back into the absorption cell, thereby effecting repeated cycles of processing.
Immediately following the emulsification process the product flows through line 159 which may be a coil or other structure to effect rapid cooling. Cooling system 156 may circulate cold fluid in bath or shell 155 via lines 157 and 158 . The cooling fluid may be water or other fluids with the appropriate means to control the temperature and flow of the coolant such that the desired cooling rate and product temperature is attained. The product exits the cooler through line 142 where metering valve 144 and pressure indicator 145 are provided to control and monitor back-pressure during cooling and ensure that the hot emulsion remains in a liquid state while being cooled, thereby maintaining the emulsion integrity and stability. Finally, the finished product is collected in tank 146 .
In the system illustrated in FIG. 2, one or more product components are supplied from supply 110 into feed tank 118 , while other components are supplied from sources 112 and 114 directly into double-jet cell 140 . For simplicity and by way of example, water is fed into H.P. pump 128 while oil and emulsifier are fed directly into cell 140 ; but a wide variety of other components could be used depending on the product to be made. Water may be the continuous phase or the discontinuous phase depending on its ratio to oil. Typically, components that would be fed directly into cell 140 are materials that could not flow through the H.P. pump 128 and/or through the orifice inside cell 140 because they are too viscous and/or abrasive (e.g., resins, polymers, Alumina ceramic powder). Some components may be mixed together to reduce the number of separate feed lines, or there may be as many feed lines as product components.
Water from tank 118 flows through line 120 and valve 122 , by means of transfer pump 124 to the H.P. pump 128 . Elements 128 through 138 and 148 through 158 have similar functions to the same numbered elements of the system of FIG. 1 .
Oil and emulsifier, each representing a possibly unlimited number and variety of components which may be introduced separately, flow from sources 112 and 114 into double-jet cell 140 through lines 162 and 164 , each line having a pressure indicator 170 and 172 and a temperature indicator 174 and 176 , by means of metering pumps 166 and 168 . Metering pumps 166 and 168 are suitable for the type of product pumped (e.g. sanitary cream, injectable suspension, abrasive slurry) and the required flow and pressure ranges. For example, in small scale systems peristaltic pumps are used, while in production system and/or for high pressure injection, diaphragm or gear pumps are used.
Inside double-jet cell 140 the water is forced through two orifices creating two water jets. Other product components, as exemplified by the oil and emulsifier, are injected into double-jet cell 140 . The interaction between the extremely high velocity water jet at one end of double-jet cell 140 and the stagnant components from lines 162 and 164 subjects the product to a series of treatment stages. In each stage intense forces of shear, impact, and/or cavitation break down the oil and emulsifier to extremely small and highly uniform droplets, and allows sufficient time for the emulsifier to interact with the oil droplets. After the interaction between the water jet at one end of double-jet cell 140 and the components from lines 162 and 164 , the processed mixture meets the second water jet of the other end of double-jet cell 140 . The second water jet generates additional forces of shear, impact, and/or cavitation to further reduce the size of oil droplets and increase their uniformity. The second water jet also carries some of the processed product back into the absorption cell thereby effecting repeated cycles of processing. Immediately following the emulsification process, the emulsion is cooled and then exits the double-jet cell 140 and is collected, all in a manner similar to the one used in the system of FIG. 1 .
In the system illustrated in FIG. 3, a product's liquid phase is supplied from supply 210 into feed tank 118 , while a solid phase is supplied from source 212 into feed tank 200 . Compressed gas source 214 may be used to facilitate solids flow and/or to effect cooling inside double-jet cell 140 .
Liquid from tank 118 flows through line 120 and valve 122 by means of transfer pump 124 to the high pressure process pump 128 . Elements 128 through 138 and 148 through 158 have similar functions to the same numbered elements of the system in FIG. 1 .
Solids, representing a possibly unlimited number and variety of materials in various states (dry powders, granules, slurries, etc.), may be introduced separately through line 264 by means of transfer pump 268 into feed tank 200 . Transfer pump 268 may be selected for the type and state of the solids. For example, dry powders may be fed with a screw pump while granules or slurries may be fed with a diaphragm pump. The solids may be melted if necessary in feed tank 200 by means of heating system 148 and lines 150 and 152 . Such heating may be required for melting materials such as resins or polymers. Solids from tank 200 flow through line 201 and valve 202 by means of metering pump 203 into double-jet cell 140 . Metering pump 203 is suitable for the type of solids pumped and the required flow and pressure ranges. For solids that should be introduced in dry powder form, compressed gas 214 is supplied. Compressed gas (such as air or Nitrogen) from source 214 flows through line 262 and is regulated by regulator 270 . Gas flow into the feed tank discharge line 201 facilitates and regulates the flow of powder into double-jet cell 140 .
Inside double-jet cell 140 the liquid phase is forced through two dissimilar orifices, creating two dissimilar jets. The orifices are dissimilar in such a way to create a vacuum in one end of the cell and positive pressure in the other end. For example, one orifice is made larger then the other. The jet from the larger orifice creates a vacuum before entering the absorption cell and creates positive pressure at the other end of the absorption cell. The solid phase is injected into double-jet cell 140 at a point where the liquid jet has generated the vacuum.
The interaction between the extremely high velocity liquid jet at one end of double-jet cell 140 and the stagnant solids line 201 subjects the product to a series of treatment stages. In each stage intense forces of shear, impact, and/or cavitation break down the solids to extremely small and highly uniform particles (or droplets if in melted form), and allows sufficient time for the emulsifier to interact with the solids particles and/or droplets. After the interaction between the first liquid jet at one end of double-jet cell 140 and the solids from line 201 , the processed mixture meets the second liquid jet from the other end of double-jet cell 140 . The second liquid jet generates additional intense forces of shear, impact, and/or cavitation to further reduce the size of solid particles/droplets and increase their uniformity. The second liquid jet also carries some of the processed product back into the absorption cell, thereby effecting repeated cycles of processing. Immediately following this process, the processed product is cooled, exits the double-jet cell 140 , and is collected, all in a manner similar to the one used in the system of FIG. 1 . Alternatively, compressed gas through line 271 may be fed into double-jet cell 140 to effect rapid cooling. The decompression of the gas inside cell 140 is coupled with rapid cooling of the gas and thus of the product.
As seen in FIG. 4, the double-jet cell 140 is constructed using a series of pieces. In the example of a basic double-jet cell in FIG. 4 there are two (identical) inlet fittings 10 , two bodies 11 , retainer 12 , and coupling 16 . In one end of each inlet fitting 10 , a standard high pressure port 20 is provided, for example ⅜″ H/P (e.g. Autoclave Engineers #F375C). The other end of each inlet fitting 10 makes a pressure containing metal-to-metal seal with a nozzle 13 . Referring also to FIG. 5, sealing surface 40 of nozzle 13 fits into sealing surface 41 of inlet fitting 10 , while sealing surface 42 of nozzle 13 fits into sealing surface 43 in body 11 , making pressure containing metal-to-metal sealing between members 10 , 13 and 11 upon fastening inlet fitting 10 into body 11 . Nozzle 13 is press-fitted with a ceramic insert 2 which contains orifice 23 . An absorption cell 17 is constructed using a series of reactors 14 and seals 15 held within a lumen of retainer 12 and the ends of the bodies 11 . Reactors 14 are made of an abrasion resistant material such as ceramic or stainless steel depending on product abrasiveness and the reactor lumen inner diameter (e.g. 0.02 inch to 0.12 inch). Seals 15 are made of plastic unless the process requires elevated temperature, in which case other materials such as stainless steel may be used. Upon fastening simultaneously bodies 11 at the two ends of double-jet cell 140 , the series of reactors 14 and seals 15 form a pressure containing absorption cell. Ports 27 and 28 are standard ¼″ M/P (e.g. Autoclave Engineers #F250). The function of ports 27 and 28 varies depending on the system configuration (FIGS. 1 through 3 ).
In the type of system shown in FIG. 1, port 27 functions as the discharge port of double-jet cell 140 while port 28 is plugged. Pre-mixed components are fed into the double-jet cell through ports 20 at both ends of the double-jet cell, flow through round openings 21 (e.g. ⅛″ dia. hole), and flow through round openings 22 (e.g. {fraction (1/16)}″ dia. hole). The product liquid is then forced by high pressure through orifice 23 . The diameter of orifice 23 determines the maximum attainable pressure for any given flow rate. For example, a 0.015 in. dia. hole will enable 10,000 psi with a flow rate of 1 liter/min. of water. More viscous fluids require an orifice opening as large as 0.032 in. dia. to attain the same pressure and flow rate, while smaller systems with pump capacity under 1 liter/min. require an orifice as small as 0.005 in dia. to attain 10,000 psi. The high velocity jet is ejected from orifice 23 into opening 24 (e.g. {fraction (1/16)}″ dia. hole) in nozzle 13 and then into opening 25 (e.g. {fraction (3/32)}″ dia. hole) in body 11 . Opening 25 in body 11 communicates with round opening 26 (e.g. {fraction (3/32)}″ dia.) in body 11 . Processing of the product begins in orifices 23 at both ends of the double-jet cell, where the product is accelerated to a velocity exceeding 500 ft/sec. upon entering orifices 23 . This sudden acceleration which occurs simultaneously with a severe pressure drop causes cavitation in the orifice. Cavitation, as well as shear due to the extremely high differential velocity in the orifice, cause break down of the discontinuous phase droplets or particles.
Referring now to FIG. 6, coherent jet stream 50 formed in orifice 23 is maintained essentially unchanged as it flows through openings 24 , 25 and 35 in one end of double-jet cell 140 while coherent jet 51 is maintained essentially unchanged as it flows through openings 36 , 29 and 31 in the other end of cell 140 . Jet 50 enters the absorption cell through opening 27 , while jet 51 enters the other end of the absorption cell through opening 31 . The two jet streams 50 and 51 impact each other in cavity 32 and form a coherent flow stream 53 . The coherent flow pattern is formed and flows in the direction of exit cavity 32 . Stream 53 exits cavity 32 through opening 35 and ejects into opening 25 . Finally, the processed product 54 exits dual-jet cell 140 through opening 26 and opening 35 .
The absorption cell geometry may be easily varied to intensify or curtail the forces of shear, impact and/or cavitation that act on the product. Jet velocity is determined by the size and shape of orifices 23 and by the pressure setting of the H.P pump 128 . The velocity of coherent stream 53 is determined by the inner diameter of reactors 14 . Coherent stream 53 may flow in laminar or turbulent flow patterns, depending on the inner diameter of seals 15 . When seals 15 have the same inner diameters as reactors 14 (not shown), stream 53 will be laminar. When seals 15 have larger inner diameters than reactors 14 (shown), stream 53 will be turbulent. Large reactor inner diameters with laminar flow may be used to effect a more gentle process for products sensitive to shear or cavitation. Smaller reactor inner diameters with turbulent flow may be used to effect intense shear, repeated stages of cavitation, and impact through repeated interaction. The process may be made gradual or with several stages of increasing or decreasing process intensity by assembling various sizes of reactors 14 and seals 15 . Process duration may be easily determined by the number of reactors 15 . Retainer 12 is made with male and female threads of the same size. This enables connecting one, two, or three retainers (not shown) in a single dual-jet cell assembly which in turn enables use of different numbers of reactors (e.g., one to twenty).
In the type of system shown in FIG. 2, port 27 functions as inlet port for the oil phase, while port 28 functions as the discharge port of double-jet cell 140 . Water phase is fed into the double-jet cell 140 through ports 20 at both ends of cell 140 and is forced by high pressure through orifices 23 in a manner similar to the one used in the system of FIG. 4 .
Referring now to FIG. 7, in the system shown in FIG. 2, jet stream 50 is maintained essentially unchanged as it flows through openings 24 in one end of the double-jet cell while jet 51 is maintained essentially unchanged as it flows through openings 28 in the other end of the double-jet cell. Jet 50 is made more intense than jet 51 by using a larger orifice to generate jet 50 than to generate jet 51 . Since both ends of double-jet cell 140 are subjected to the same pressure, the flow rate through the larger orifice is higher then through the smaller orifice. The two jet streams 50 and 51 impact each other in cavity 32 and form a coherent flow stream 53 . Because jet 50 is more intense than jet 51 , coherent stream 53 exits the double-jet cell through opening 30 and port 28 . Because jet 50 flows uninterrupted and at a very high velocity through opening 25 , vacuum develops in opening 25 . The vacuum facilitates flow of oil through port 27 and opening 26 .
The process begins when the high velocity jet 50 meets the much lower velocity stream 56 of oil. The high differential velocity between jet 50 and stream 56 generates intense shear forces. Depending on local temperature, relative velocity and vapor pressure of the two phases, cavitation may be effected in opening 25 due to hydraulic separation. The process continues in cavity 32 where the impact between the two jets and the interaction between coherent stream 53 and jet 51 effect intense and controllable mixing in a manner similar to the one used in the system of FIG. 6 .
Stream 53 exits cavity 32 through opening 31 and ejects into opening 29 . Finally, the processed product 55 exits dual-jet cell 140 through opening 30 and port 28 .
In the type of system shown in FIG. 3, port 27 functions as an inlet port for the solids phase, while port 28 functions as the discharge port of double-jet cell 140 . The liquid phase is fed into the double-jet cell 140 through ports 20 at both ends of the double-jet cell 140 and is forced by high pressure through orifice 23 in a manner similar to the one used in the system of FIG. 4 . The liquid phase may be the continuous or discontinuous phase depending on the relative flow rates of solids and liquid. Processing in the double-jet cell 140 is in a manner similar to the one used in the system of FIG. 7 . The ability to introduce components directly into the double-jet cell, bypassing the H.P pump and orifices, enables processing of extremely viscous and/or abrasive materials. This feature is particularly useful for replacing a common use of VOC. The interaction between two high velocity jets 50 and 51 , and the repeated interaction between the coherent stream 53 and jet 51 , enable particle size reduction of extremely hard materials such as ceramic and carbide powders.
Other embodiments are within the scope of the following claims.
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Methods and apparatuses for processing product components. The methods include directing a first jet of fluid along a first path and directing a second jet of fluid along a second path to cause interaction between the jets that forms a stream oriented essentially opposite to one of the jet paths.
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CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of copending U.S. patent application Ser. No. 13/640,140, filed Jan. 31, 2013. U.S. patent application Ser. No. 13/640,140, filed Jan. 31, 2013 is the National Stage Entry of PCT/CA2011/050427, filed Jul. 12, 2011, which claims priority from Provisional Application 61/372,967, filed Aug. 12, 2010, and which claims priority from Provisional Application 61/363,568, filed Jul. 12, 2010. U.S. patent application Ser. No. 13/640,140, filed Jan. 31, 2013 is incorporated herein in its entirety by reference hereto.
BACKGROUND
[0002] The present disclosure is related to methods of laser processing of materials. More particularly, the present disclosure is related to methods of singulation and/or cleaving of wafers, substrates, and plates.
[0003] In current manufacturing, the singulation, dicing, scribing, cleaving, cutting, and facet treatment of wafers or glass panels is a critical processing step that typically relies on diamond cutting, with speeds of 30 cm/sec for flat panel display as an example. After diamond cutting, a mechanical roller applies stress to propagate cracks that cleave the sample. This process creates poor quality edges, microcracks, wide kerf width, and substantial debris that are major disadvantages in the lifetime, quality, and reliability of the product, while also incurring additional cleaning and polishing steps. The cost of de-ionized water to run the diamond scribers are more than the cost of ownership of the scriber and the technique is not environmentally friendly since water gets contaminated and needs refining that itself adds the costs. By advance techniques dyes on the wafers are getting smaller and closer to each other that limit the diamond scribing. 30 μm is a good scribing width and 15 μm is challenging. Since diamond scribing uses mechanical force to scribe the substrate, thin samples are very difficult to scribe. The FPD industry is seeking to reduce glass thicknesses to 150-300 μm from conventional 400-700 μm that is used currently and scribing the plates is the major issue. Indeed the FPD industry is looking to use thin tempered glass instead of ordinary glass for durability.
[0004] Laser ablative machining is an active development area for singulation, dicing, scribing, cleaving, cutting, and facet treatment, but has disadvantages, particularly in transparent materials, such as slow processing speed, generation of cracks, contamination by ablation debris, and moderated sized kerf width. Further, thermal transport during the laser interaction can lead to large regions of collateral thermal damage (i.e. heat affected zone). Laser ablation processes can be dramatically improved by selecting lasers with wavelengths that are strongly absorbed by the medium (for example, deep UV excimer lasers or far-infrared CO2 laser). However, the above disadvantages cannot be eliminated due to the aggressive interactions inherent in this physical ablation process.
[0005] Alternatively, laser ablation can also be improved at the surface of transparent media by reducing the duration of the laser pulse. This is especially advantageous for lasers that are transparent inside the processing medium. When focused onto or inside transparent materials, the high laser intensity induces nonlinear absorption effects to provide a dynamic opacity that can be controlled to accurately deposit appropriate laser energy into a small volume of the material as defined by the focal volume. The short duration of the pulse offers several further advantages over longer duration laser pulses such as eliminating plasma reflections and reducing collateral damage through the small component of thermal diffusion and other heat transport effects during the much shorter time scale of such laser pulses. Femtosecond and picosecond laser ablation therefore offer significant benefits in machining of both opaque and transparent materials. However, machining of transparent materials with pulses even as short as tens to hundreds of femtosecond is also associated with the formation of rough surfaces and microcracks in the vicinity of laser-formed hole or trench that is especially problematic for brittle materials like glasses and optical crystals. Further, ablation debris will contaminate the nearby sample and surrounding surfaces.
[0006] A kerf-free method of cutting or scribing glass and related materials relies on a combination of laser heating and cooling, for example, with a CO2 laser and a water jet. [U.S. Pat. No. 5,609,284 (Kondratenko); U.S. Pat. No. 6,787,732 UV laser (Xuan)] Under appropriate conditions of heating and cooling in close proximity, high tensile stresses are generated that induces cracks deep into the material, that can be propagated in flexible curvilinear paths by simply scanning the laser-cooling sources across the surface. In this way, thermal-stress induced scribing provides a clean splitting of the material without the disadvantages of a mechanical scribe or diamond saw, and with no component of laser ablation to generate debris. However, the method relies on stress-induced crack formation to direct the scribe and requires [WO/2001/032571 LASER DRIVEN GLASS CUT-INITIATION] a mechanical or laser means to initiate the crack formation. Short duration laser pulses generally offer the benefit of being able to propagate efficiently inside transparent materials, and locally induce modification inside the bulk by nonlinear absorption processes at the focal position of a lens. However, the propagation of ultrafast laser pulses (>˜5 MW peak power) in transparent optical media is complicated by the strong reshaping of the spatial and temporal profile of the laser pulse through a combined action of linear and nonlinear effects such as group-velocity dispersion (GVD), linear diffraction, self-phase modulation (SPM), self-focusing, multiphoton/tunnel ionization (MPI/TI) of electrons from the valence band to the conduction band, plasma defocusing, and self-steepening [S L Chin et al. Canadian Journal of Physics, 83, 863-905 (2005)]. These effects play out to varying degrees that depend on the laser parameters, material nonlinear properties, and the focusing condition into the material.
[0007] Kamata et al. [SPIE Proceedings 6881-46, High-speed scribing of flat-panel display glasses by use of a 100-kHz, 10-W femtosecond laser, M. Kamata, T. Imahoko, N. Inoue, T. Sumiyoshi, H. Sekita, Cyber Laser Inc. (Japan); M. Obara, Keio Univ. (Japan)] describe a high speed scribing technique for flat panel display (FPD) glasses. A 100-kHz Ti:sapphire chirped-pulse-amplified laser of frequency-doubled 780 nm, 300 fs, 100 μJ output was focused into the vicinity of the rear surface of a glass substrate to exceed the glass damage threshold, and generate voids by optical breakdown of the material. The voids reach the back surface due to the high repetition rate of the laser. The connected voids produce internal stresses and damage as well as surface ablation that facilitate dicing by mechanical stress or thermal shock in a direction along the laser scribe line. While this method potentially offers fast scribe speeds of 300 mm/s, there exists a finite kerf width, surface damage, facet roughness, and ablation debris as the internally formed voids reach the surface.
SUMMARY
[0008] In a first embodiment, there is provided a method of preparing a substrate for cleavage, the method comprising the steps of: irradiating the substrate with one or more pulses of a focused laser beam, wherein the substrate is transparent to the laser beam, and wherein the one or more of pulses have an energy and pulse duration selected to produce a filament within the substrate; translating the substrate relative to the focused laser beam to irradiate the substrate and produce an additional filament at one or more additional locations; wherein the filaments comprise an array defining an internally scribed path for cleaving the substrate. The method preferably includes the step of cleaving the substrate.
[0009] The substrate is preferably translated relative to the focused laser beam with a rate selected to produce a filament spacing on a micron scale. Properties of the one or more laser pulses are preferably selected to provide a sufficient beam intensity within the substrate to cause self-focusing of the laser beam.
[0010] The one or more pulses may be provided two or more times with a prescribed frequency, and the substrate may be translated relative to the focused laser beam with a substantially constant rate, thus providing a constant spacing of filaments in the array.
[0011] The one or more pulses include a single pulse or a train of two or more pulses. Preferably, a time delay between successive pulses in the pulse train is less than a time duration over which relaxation of one or more material modification dynamics occurs. A pulse duration of each of the one or more pulses is preferably less than about 100 ps, and more preferably less than about 10 ps.
[0012] A location of a beam focus of the focused laser beam may be selected to generate the filaments within the substrate, wherein at least one surface of the substrate is substantially free from ablation. A location of a beam focus of the focused laser beam may be selected to generate a V groove within at least one surface of the substrate.
[0013] The substrate may be a glass or a semiconductor and may be selected from the group consisting of transparent ceramics, polymers, transparent conductors, wide bandgap glasses, crystals, crystal quartz, diamond, and sapphire.
[0014] The substrate may comprise two or more layers, and wherein a location of a beam focus of the focused laser beam is selected to generate filaments within at least one of the two or more layers. The multilayer substrate may comprise multi-layer flat panel display glass, such as a liquid crystal display (LCD), flat panel display (FPD), and organic light emitting display (OLED). The substrate may also be selected from the group consisting of autoglass, tubing, windows, biochips, optical sensors, planar lightwave circuits, optical fibers, drinking glass ware, art glass, silicon, III-V semiconductors, microelectronic chips, memory chips, sensor chips, light emitting diodes (LED), laser diodes (LD), and vertical cavity surface emitting laser (VCSEL).
[0015] A location of a beam focus of the focused laser beam may be selected to generate filaments within two or more of the two or more layers, wherein the focused laser beam generates a filament in one layer, propagates into at least one additional layer, and generates a filament is the at least one additional layer.
[0016] Alternatively, the location of a beam focus of the focused laser beam may be first selected to generate filaments within a first layer of the two or more layers, and the method may further comprise the steps of: positioning a second beam focus within a second layer of the two or more layers; irradiating the second layer and translating the substrate to produce a second array defining a second internally scribed path for cleaving the substrate. The substrate may be irradiated from an opposite side relative to when irradiating the first layer. Furthermore, prior to irradiating the second layer, a position of the second beam focus may be laterally translated relative a position of the beam focus when irradiating the first layer. A second focused laser beam may be used to irradiate the second layer.
[0017] A further understanding of the functional and advantageous aspects of the disclosure can be realized by reference to the following detailed description and drawings.
BRIEF DESCRIPTION OF THE DRAWINGS
[0018] Embodiments of the disclosure will now be described, by way of example only, with reference to the drawings, in which:
[0019] FIG. 1( a ) presents a front view of the laser filamentation scribing arrangement for scribing transparent materials. FIG. 1( b ) presents a side view of the laser filamentation scribing arrangement for scribing transparent materials.
[0020] FIG. 2( a ) presents a front view of laser filamentation with V groove scribing of a transparent substrate. FIG. 2( b ) presents V groove scribing with suppressed filament formation.
[0021] FIG. 3 illustrates laser scribing of transparent material with internal filament formation with V groove formation on the top and bottom surface applying reflective element with focusing arrangement.
[0022] FIG. 4 shows laser scribing using two focusing apparatus applied from top and bottom surface.
[0023] FIG. 5 presents a side view of a scribed substrate, where the top, bottom or both edges can be chamfered.
[0024] FIG. 6 presents a focusing arrangement of delivering multiple converging laser beams for creating multiple filaments simultaneously in a transparent substrate at different physical positions, directions, angles, and depths, such that the filaments are overlapping to enable the single-step cleaving of beveled facets or other facet shapes.
[0025] FIG. 7( a ) presents a focusing arrangement for laser filamentation scribing a top transparent substrate without damaging top surface of a bottom substrate. FIG. 7( b ) presents a focusing arrangement for laser filamentation scribing the bottom substrate from a top location. FIG. 7( c ) presents a focusing arrangement for laser filamentation scribing a double plate assembly which can be scribed, separated, or laser scribed simultaneously, forming filaments in both substrates without optical breakdown in the medium between the plates so that the double plate assembly can be separated along similar curvilinear or straight lines.
[0026] FIG. 8 illustrates laser scribing of a double layer apparatus including two transparent substrates using two focusing beams. Each focus can be adjusted to form a filament, V groove or a combination thereof.
[0027] FIG. 9( a ) provides top and side views of a double layer glass after scribing where only internal filaments are formed. FIG. 9( b ) provides a view of internal filaments and top surface V grooves formed in double layer glass. FIG. 9( c ) provides a view of a V groove formed on the top surfaces of both plates.
[0028] FIG. 10 illustrates scribing laminated glass from top and bottom side with and without offset.
[0029] FIG. 11 illustrates a method of laser bursts filament scribing of stacks of very thin substrates.
[0030] FIG. 12 is an optical microscope image of a glass plate viewed through a polished facet prior to mechanical cleaving, showing laser filamentation tracks formed under identical laser exposure with laser focusing by the lens positioned near the lower (a), middle (b) and top (c) regions of the glass plate.
[0031] FIG. 13( a ) shows a microscope image of glass imaged at the top surface prior to mechanical cleaving, with a track of laser filaments written inside the bulk glass. FIG. 13( b ) shows a microscope image of glass imaged at the bottom surface prior to mechanical cleaving, with a track of laser filaments written inside the bulk glass.
[0032] FIG. 14( a ) shows facet edge views of glass plates after mechanical cleaving in which a track of laser filaments was formed at moderate (a) scanning speed. FIG. 14( b ) shows facet edge views of glass plates after mechanical cleaving in which a track of laser filaments was formed at fast (b) scanning speed during the laser exposure.
[0033] FIG. 15( a ) shows facet edge microscope views comparing the laser modification in 1 mm thick glass formed with an identical number of equal-energy laser pulses applied at low repetition rate. FIG. 15( b ) shows facet edge microscope views comparing the laser modification in 1 mm thick glass formed with an identical number of equal-energy laser pulses applied in single pulse high energy low repetition rate pulse trains. The single pulse has energy of all pulses in one burst train.
[0034] FIG. 16( a ) provides microscope images of scribed glass applying a V groove and filament with a high repetition rate laser showing a side view. FIG. 16( b ) provides microscope images of scribed glass applying a V groove and filament with a high repetition rate laser showing a top view. FIG. 16( c ) provides microscope images of scribed glass applying a V groove and filament with a high repetition rate laser showing a front view.
[0035] FIG. 17 is a front view of three different V groove formation using high repetition rate laser.
[0036] FIG. 18( a ) provides an image of a side view showing the scribing of flat panel display glass wherein two laminated glass layers with 400 um thickness are scribed simultaneously. FIG. 18( b ) provides an image of a front view showing the scribing of flat panel display glass wherein two laminated glass layers with 400 um thickness are scribed simultaneously.
DETAILED DESCRIPTION
[0037] Various embodiments and aspects of the disclosure will be described with reference to details discussed below. The following description and drawings are illustrative of the disclosure and are not to be construed as limiting the disclosure. Numerous specific details are described to provide a thorough understanding of various embodiments of the present disclosure. However, in certain instances, well-known or conventional details are not described in order to provide a concise discussion of embodiments of the present disclosure.
[0038] As used herein, the terms, “comprises” and “comprising” are to be construed as being inclusive and open ended, and not exclusive. Specifically, when used in the specification and claims, the terms, “comprises” and “comprising” and variations thereof mean the specified features, steps or components are included. These terms are not to be interpreted to exclude the presence of other features, steps or components.
[0039] As used herein, the term “exemplary” means “serving as an example, instance, or illustration,” and should not be construed as preferred or advantageous over other configurations disclosed herein.
[0040] As used herein, the terms “about” and “approximately”, when used in conjunction with ranges of dimensions of particles, compositions of mixtures or other physical properties or characteristics, are meant to cover slight variations that may exist in the upper and lower limits of the ranges of dimensions so as to not exclude embodiments where on average most of the dimensions are satisfied but where statistically dimensions may exist outside this region. It is not the intention to exclude embodiments such as these from the present disclosure.
[0041] As used herein, the term “transparent” means a material that is at least partially transparent to an incident optical beam. More preferably, a transparent substrate is characterized by absorption depth that is sufficiently large to support the generation of an internal filament by an incident beam according to embodiments described below.
[0042] FIG. 1( a ) presents a front view of the laser filamentation scribing arrangement for scribing transparent materials. FIG. 1( b ) presents a side view of the laser filamentation scribing arrangement for scribing transparent materials.
[0043] Short duration laser pulses 10 are focused with objective lens 12 inside transparent substrate 14 . At appropriate laser pulse energy, the laser pulse, or sequence of pulses, or burst-train of pulses, a laser filament 18 is generated within the substrate, producing internal microstructural modification with a shape defined by the laser filament volume. By moving the sample relative to the laser beam during pulsed laser exposure, a continuous trace of filament tracks 20 are permanently inscribed into the glass volume as defined by the curvilinear or straight path followed by the laser in the sample.
[0044] Without intending to be limited by theory, it is believed that the filaments are produced by weak focusing, high intensity short duration laser light, which can self-focus by the nonlinear Kerr effect, thus forming a so-called filament. This high spatio-temporal localization of the light field can deposit laser energy in a long narrow channel, while also being associated with other complex nonlinear propagation effects such as white light generation and formation of dynamic ring radiation structures surrounding this localized radiation.
[0045] On the simplest level, the filamentation process is believed to depend mainly on two competing processes. First, the spatial intensity profile of the laser pulse acts like a focusing lens due to the nonlinear optical Kerr effect. This causes the beam to self-focus, resulting in an increase of the peak intensity. This effect is limited and balanced by increasing diffraction as the diameter decreases until a stable beam waist diameter is reached that can propagate distances many times longer than that expected from a simple calculation of the confocal beam parameter (or depth of focus) from this spot size.
[0046] At high peak intensity, multiphoton ionization, field ionization, and electron impact ionization of the medium sets in to create low-density plasma in the high intensity portion of the laser beam. This plasma temporarily lowers the refractive index in the centre of the beam path causing the beam to defocus and break up the filament. The dynamic balance between Kerr effect self-focusing and plasma defocusing can lead to multiple re-focused laser interaction filaments through to formation of a stable filament, sometimes called a plasma channel. As show in the examples below, using picosecond pulses, the present inventors have found that when the pulse focuses, it stays confined for about 500 to 1000 μm (depending on the focusing lens which is used), and then spatially diverges when there is no more material for refocusing and forming the next filament, or when the pulses do not have enough energy to refocus to form another plasma channel.
[0047] Optical breakdown, on the other hand, is the result of a tightly focused laser beam inside a transparent medium that forms a localized dense plasma around the geometrical focus. The plasma generation mechanism is based on initial multi-photon excitation of electrons, followed by inverse Bremsstrahlung, impact ionization, and electron avalanche processes. Such processes underscore the refractive index and void formation processes described above [U.S. Pat. No. 6,154,593; SPIE Proceedings 6881-46], and form the basis of most short-pulse laser applications for material processing. In this optical breakdown domain, the singulation, dicing, scribing, cleaving, cutting, and facet treatment of transparent materials has disadvantages such as slow processing speed, generation of cracks, contamination by ablation debris, and large kerf width.
[0048] In contrast, laser filamentation offers a new direction for internal laser processing of transparent materials that can avoid ablation or surface damage, dramatically reduce kerf width, avoid crack generation, and speed processing times for such scribing applications. Further, high repetition rate lasers defines a new direction to enhance the formation of laser beam filaments with heat accumulation and other transient responses of the material on time scales faster than thermal diffusion out of the focal volume (typically <10 microseconds).
[0049] Accordingly, embodiments disclosed herein harnesses short duration laser pulses (preferably with a pulse duration less than about 100 ps) to generate a filament inside a transparent medium. The method avoids dense plasma generation such as through optical break down that can be easily produced in tight optical focusing conditions as typically applied and used in femtosecond laser machining. In weak focusing, which is preferential, the nonlinear Kerr effect is believed to create an extended laser interaction focal volume that greatly exceeds the conventional depth of focus, overcoming the optical diffraction that normally diverges the beam from the small self-focused beam waist.
[0050] Once a filamentation array is formed in the transparent substrate, only small mechanical pressure is required to cleave the substrate into two parts on a surface shape that is precisely defined by the internal laser-filamentation curtain. The laser-scribed facets typically show no or little cracking and microvoids or channels are not evident along the scribed zone. There is substantially no debris generated on the top or bottom surfaces since laser ablation at the surfaces can be avoided by confining the laser filament solely within the bulk glass. On the other hand, simple changes to the laser exposure or sample focusing conditions can move the filament to the surface and thus induce laser ablation machining if desired, as described further below. This assists in creating very sharp V groves on the surface of the substrate. To scribe very thin substrates (less than 400 um thick) creating a sharp V groove is desired. Other common ablation techniques generally create U grooves or rounded V grooves. V grooves also can form on both top and bottom surface of the sample making scribed edges chamfered.
[0051] Laser energy deposited along such filaments leads to internal material modification that can be in the form of defects, color centers, stress, microchannels, microvoids, and/or microcracks. The present method entails lateral translation of the focused laser beam to form an array of closely positioned filament-induced modification tracks. This filament array defines a pseudo-continuous curtain of modification inside the transparent medium without generating laser ablation damage at either of the top or bottom surfaces. This curtain renders the glass plate highly susceptible to cleaving when only very slight pressure (force) is applied, or may spontaneously cleave under internal stress. The cleaved facets are devoid of ablation debris, show minimal or no microcracks and microvents, and accurately follow the flexible curvilinear or straight path marked internally by the laser with only very small kerf width as defined by the self-focused beam waist.
[0052] The application of high repetition rate bursts of short-pulse lasers offers the advantage of heat accumulation and other transient effects such that thermal transport and other related mechanisms are not fully relaxed prior to the arrival of subsequent laser pulses [U.S. Pat. No. 6,552,301 B2 Burst-UF laser Machining]. In this way, heat accumulation, for example, can present a thin heated sheath of ductile glass to subsequent laser pulses that prevents the seeding of microcracks while also retaining the advantages (i.e. nonlinear absorption, reduced collateral damage) of short pulse ablative machining in an otherwise brittle material. In all the above laser ablation methods, the cutting, scribing, or dicing of transparent materials will generate ablation debris contamination and consume a kerf width to accommodate the removed material, while also generating collateral laser damage. Therefore, a non-ablative method of laser processing would be desirable.
[0053] The application of high repetition rate short-pulse lasers thus offers a means for dramatically increasing the processing (scan) speed for such filamentation cleaving. However, at sufficiently high repetition rate (transition around 100 MHz to 1 MHz), the modification dynamics of the filament is dramatically enhanced through a combination of transient effects involving one or more of heat accumulation, plasma dynamics, temporary and permanent defects, color centers, stresses, and material defects that accumulate and do not relax fully during the train of pulses to modify the sequential pulse-to-pulse interactions. Laser filaments formed by such burst trains offer significant advantage in lowering the energy threshold for filament formation, increasing the filament length to hundreds of microns or several millimeters, thermally annealing of the filament modification zone to minimize collateral damage, improving process reproducibility, and increasing the processing speed compared with the use of low repetition rate lasers. In one non-limiting manifestation at such high repetition rate, there is insufficient time (i.e. 10 nsec to 1 μs) between laser pulses for thermal diffusion to remove the absorbed laser energy, and heat thereby accumulates locally with each laser pulse. In this way, the temperature in the interaction volume rises during subsequent laser pulses, leading to laser interactions with more efficient heating and less thermal cycling. In this domain, brittle materials become more ductile to mitigate crack formation. Other transient effects include temporary defects and plasma that survive from previous laser pulse interactions. These transient effects then serve to extend the filamentation process to long interaction lengths, and/or improve absorption of laser energy in subsequent pulses.
[0054] As shown below, the laser filamentation method can be tuned by various methods to generate multi-filament tracks broken with non-filamenting zones through repeated cycles of Kerr-lens focusing and plasma defocusing. Such multi-level tracks can be formed in a thick transparent sample, across several layers of glasses separated by transparent gas or other transparent materials, or in multiple layers of different transparent materials. By controlling the laser exposure to only form filaments in the solid transparent layers, one can avoid ablation and debris generation on each of the surfaces in the single or multi-layer plates. This offers significant advantages in manufacturing, for example, where thick glasses or delicate multilayer transparent plates must be cleaved with smooth and crack free facets.
[0055] The filamentation method applies to a wide range of materials that are transparent to the incident laser beam, including glasses, crystals, selected ceramics, polymers, liquid-encapsulated devices, multi-layer materials or devices, and assemblies of composite materials. In the present disclosure, it is further to be understood that the spectral range of the incident laser beam is not limited to the visible spectrum, but represents any material that is transparent to a laser wavelength also in the vacuum ultraviolet, ultraviolet, visible, near-infrared, or infrared spectra. For example, silicon is transparent to 1500 nm light but opaque to visible light. Thus, laser filaments may be formed in silicon with short pulse laser light generated at this 1500 nm wavelength either directly (i.e. Erbium-doped glass lasers) or by nonlinear mixing (i.e. optical parametric amplification) in crystals or other nonlinear medium.
[0056] In substrates that are transparent within the visible spectrum, the laser filament may result in the generation of white light, which without being limited by theory, is believed to be generated by self phase modulation in the substrate and observed to emerge for the laser filamentation zone in a wide cone angle 16 after the filament ends due to factors such reduced laser pulse energy or plasma defocusing.
[0057] The length and position of the filament is readily controlled by the lens focusing position, the numerical aperture of objective lens, the laser pulse energy, wavelength, duration and repetition rate, the number of laser pulses applied to form each filament track, and the optical and thermo-physical properties of the transparent medium. Collectively, these exposure conditions can be manipulated to create sufficiently long and strong filaments to nearly extend over the full thickness of the sample and end without breaking into the top or bottom surfaces. In this way, surface ablation and debris can be avoided at both surfaces and only the interior of the transparent substrate is thus modified. With appropriate beam focusing, the laser filament can terminate and cause the laser beam to exit the glass bottom surface at high divergence angle 16 such that laser machining or damage is avoided at the bottom surface of the transparent plate.
[0058] FIG. 2( a ) presents a front view of laser filamentation with V groove scribing of a transparent substrate. FIG. 2( b ) presents V groove scribing with suppressed filament formation.
[0059] FIG. 2( a ) presents a schematic arrangement for forming laser filaments 20 with surface V groove formation 22 . FIG. 2( b ) presents V groove formation with suppressed filament formation. For higher quality scribing with edge chamfered property, laser processing can be arranged such that filaments forms inside the transparent material and very sharp V groove that is the result of ablation from on top of the surface. For some applications where clean facet is required or higher scribing speed is considered, filaments can be suppressed or completely removed.
[0060] In one embodiment, the method is employed for the scribing and cleaving of optical display glass substrates such as flat panel displays. A flat panel display is the sandwich of two glasses substrates. The bottom glass substrate may be printed with circuits, pixels, connectors, and/or transistors, among other electrical elements. A gap between the substrates is filled with liquid crystal materials. The top and left edge of the LCD can be scribed without any offset but the right and bottom edge typically has an offset of about 5 mm which is call the pad area, and all electronics connected through this region to the LCD elements.
[0061] This area is the source of a major bottleneck that limits using high power lasers for flat panel display laser scribing, because during top layer scribing, all the circuitry on the bottom layer may be damaged. To simulate a flat panel device, the inventors placed a top glass substrate on the surface of a coated mirror. During laser filament scribing of the top glass of a double glass plate, it is preferably to adjust the location of filaments formed within the top glass plate so as to avoid damage on the bottom layer that generally contains a metal coating (as described above). The results from this experiment highlighted two important points. Firstly, laser scribing can be achieved without damaging the coating of the bottom substrate pad area, and secondly, when filaments located in a special position closer to the bottom surface, reflection from the bottom metal surface may machine or process the bottom surface of the top layer, creating a V groove on the bottom.
[0062] Further investigation results in the method illustrated in FIG. 3 , where the diffracted beam 16 is converged back by means of proper concave mirror 24 or combination of mirror and lens to machine the bottom surface of the target to produce second V groove 26 . The apparatus has the benefit of making V groove in the bottom edge without using second laser machining from bottom side.
[0063] For some applications where a clean or shiny facet is required, the arrangement of FIG. 4 may be employed to create sharp V grooves on the top and bottom layer of the glass. In this mode of operation both edges are chamfered through laser scribing via the addition of a second beam 28 and objective 30 , and no need for further chamfering or grinding that would otherwise necessitate washing and drying. The side and front view of the cleaved sample is shown in FIG. 5 , where the surface of V groove 32 is shown after cleaving.
[0064] FIG. 6 presents an example of a focusing arrangement for delivering multiple converging laser beams into a transparent plate for creating multiple filaments simultaneously. The beams 10 and 34 maybe separated from a single laser source using well know beam splitter devices and focused with separate lenses 12 and 36 as shown. Alternatively, diffractive optics, multi-lens systems and hybrid beam splitting and focusing systems may be employed in arrangements well known to an optical practitioner to create the multiple converging beams that enter the plate at different physical positions, directions, angles, and depths. In this way, filamentation modification tracks 18 are created in parallel in straight or curvilinear paths such that multiple parts of the plate can be laser written at the same time and subsequently scribed along the multiple modification tracks for higher overall processing speed.
[0065] FIG. 7( a ) presents a focusing arrangement for laser filamentation scribing a top transparent substrate without damaging top surface of a bottom substrate. FIG. 7( b ) presents a focusing arrangement for laser filamentation scribing the bottom substrate from a top location. FIG. 7( c ) presents a focusing arrangement for laser filamentation scribing a double plate assembly which can be scribed, separated, or laser scribed simultaneously, forming filaments in both substrates without optical breakdown in the medium between the plates so that the double plate assembly can be separated along similar curvilinear or straight lines.
[0066] A schematic arrangement for two different focusing conditions for laser filamentation writing is shown that confines the array 38 of modification tracks 40 solely in a top transparent substrate 42 ( FIG. 7( a ) ) as a first laser exposure step, and followed sequentially by filamentation writing that solely confines the array 44 of modification tracks 46 inside a lower transparent plate 48 ( FIG. 7( b ) ) in a second laser pass. The laser exposure is tuned to avoid ablation or other laser damage and generation of ablation debris on any of the four surfaces during each laser pass. During scribing of the top plate, no damage occurs in the bottom layer, and visa versa.
[0067] One advantage of this one-sided processing is that the assembly of transparent plates does not need to be flipped over to access the second plate 48 due to the transparency of the first plate to the converging laser beam 50 . For example, by position the 12 lens closer to the top glass plate 42 in the second pass ( FIG. 7 b ), the filamentation is not initiated in the first plate and near full laser energy enters the second plate where filamentation is then initiated. A second advantage of this approach is that the two plates can be separated along similar lines during the same scribing step which is attractive particularly for assembled transparent plates in flat panel display. This method is extensible to multiple transparent plates.
[0068] FIG. 7( c ) shows an arrangement for inducing laser filamentation simultaneously in two or more transparent plates 42 and 48 . This method enables a single pass exposure of both transparent plates to form near-identical shapes or paths of the filamentation modification tracks 38 and 44 . In this case, laser parameters are adjusted to create a first filament 38 or array of filament tracks 40 within the top plate 42 , such that the filamentation terminates prior to reaching the bottom surface of the top plate, for example, by plasma de-focusing. The diverging laser beam is sufficiently expanded after forming the first filament track to prevent ablation, optical breakdown, or other damage to bottom surface of the top plate, the medium between the two plates, and the top surface of the bottom plate 48 .
[0069] However, during propagation in this region, self focusing persists and results in the creation of a second filament 44 that is confined solely in the bottom layer transparent plate 48 . As such, a single laser beam simultaneously forms two or more separated filaments 38 and 44 that create parallel modification tracks 40 and 46 in two or more stacked plates at the same time. In this way, an assembly of two or more transparent plates can by scribed or separated along the near-parallel filamentation tracks and through all transparent plates in one cleaving step. The medium between the transparent plates must have good transparency and may consist of air, gas vacuum, liquid, solid or combination thereof. Alternatively, the transparent plates may be in physical or near-physical contact without any spacing. This method is extensible to filament processing in multiply stacked transparent plates.
[0070] FIG. 8 provides another embodiment of the multibeam filamentation scribing method (shown initially in FIG. 4 ) for processing double or multiple stacked or layer transparent plates and assemblies. Two converging laser beams are presented to the plate assembly 42 and 48 for creating independent and isolated filaments 38 and 44 in physically separated or contacted transparent plates. Laser exposure conditions are adjusted for each laser beam 10 and 28 (i.e. by vertical displacement of lenses 12 and 30 ) to localize the filament in each plate. The filament tracks are then formed in similar or off-set positions with similar or different angles and depths. The filamentation tracks may be cleaved simultaneously such that the stack or assembly of optical plates is separated as one unit in a batch process. The upper and lower beams may be provided from a common optical source using conventional beam splitter or may original from two different laser sources. The upper and lower beams may be aligned along a common axis, or spatially offset. Preferably, the relative spatial positioning of the two beams is configurable.
[0071] FIG. 9( a ) illustrates a method of processing double layer glass (formed from plates 42 and 48 ) in which each layer is processed in two locations, but where one pair of filaments 52 and 54 is aligned and another pair of filaments 56 and 58 are offset laterally from each other. Such an arrangement can be obtained by using the method illustrated in FIG. 8 , where each plate is processed by a separate laser beam. Alternatively, the filaments may be processed using one of the methods illustrated in FIGS. 7( a ), 7( b ) and 7( c ) .
[0072] FIG. 9( b ) shows a similar arrangement in which a filament is formed in both the upper 42 and 48 plates with groove formation ( 60 , 62 , 64 and 66 ) on the top of each glass, where the method illustrated in FIG. 7 is preferably employed. Similarly, FIG. 9( c ) illustrates a case where only V grooves 68 , 70 , 72 and 74 are developed on the surface of each plate 42 and 48 . Note that V groove or filament for the bottom glass can be formed in bottom surface using similar apparatus as shown in FIG. 4 and FIG. 8 .
[0073] In the context of flat panel displays, it is to be noted that providing a V groove on the top surface of the bottom layer requires the machining of extra connections in the pad area. Furthermore, due to shadow effect of connections, filaments don't form in all places. Nonetheless, the substrate may be cleaved with relative easy without perfect facet view. In some cases, edges may be improved by grinding.
[0074] FIG. 10 shows the resulting formation of filaments and V-grooves in double layer glass after scribing using the method as shown in FIG. 8 . As described above, the upper plate is scribed from the top and the lower plate is scribed from bottom, where V-grooves 76 and 78 are formed. A V groove, a filament, or a combination thereof (as shown in the Figure) may be formed. As shown, upper and lower filaments may be offset, where the filament 56 and V grove 64 in the upper plate is spatially offset relative to the filament 58 and V groove 78 in the lower plate. Alternatively, upper and lower filaments may be aligned, where the filament 52 and V grove 60 in the upper plate is spatially aligned with filament 54 and V groove 76 in the lower plate. In such a configuration, forming a filament and V groove readily achievable in this configuration, and the scribed regions are efficiently separated during cleaving. Generally speaking, cleaving of top layer is occurs with relative ease, but the inventors have determined that in some cases, the bottom layer warrants careful attention and it may be necessary to properly adjust a cleaving roller prior to the cleaving step. Those skilled in the art will readily appreciate that adjustment may be made by selecting a roller configuration that yields the desired cleave quality.
[0075] New approaches in photonics industry involve assemblies of multiple layers of transparent plates that form a stack. For example, touch screen LCDs and 3D LCDs employ three layers of glass. The parallel processing of such a multi-layer stack 80 is shown in FIG. 11 , where the scribe line 82 is shown as being provided to each plate in the stack. As shown in FIGS. 7( a ) and 7( b ) , multiple plates in such a stack may be processed by varying the working distance of the objective 12 , which enables multiple plates within the stack to be individually scribed. Scribing can be done from both surfaces (similar to the method shown in FIG. 7 ). Only a top focusing apparatus is shown in the specific case provided here.
[0076] The following examples are presented to enable those skilled in the art to understand and to practice the present disclosure. They should not be considered as a limitation on the scope of the embodiments provided herein, but merely as being illustrative and representative thereof.
Examples
[0077] To demonstrate selected embodiments, a glass plate was laser processed using a pulsed laser system with an effective wavelength of about 800 nm, producing 100 fs pulses at a repetition rate of 38 MHz. The laser wavelength was selected to be within the infrared spectral region, where the glass plate is transparent. Focusing optics were selected to provide a beam focus of approximately 10 μm. Initially, the laser system was configured to apply a pulse train of 8 pulses, where the burst of pulses forming the pulse train occurred at a repetition rate of 500 Hz. Various configurations of aforementioned embodiments were employed, as described further below.
[0078] FIG. 12( a ) , FIG. 12( b ) and FIG. 12( c ) show microscope images in a side view of 1 mm thick glass plates viewed through a polished edge facet immediately after laser exposure. The plate was not separated along the filament track for this case in order to view the internal filament structure. As noted above, a single burst of 8 pulses at 38 MHz repetition rate was applied to form each filament track. Furthermore, the burst train was presented at 500 Hz repetition rate while scanning the sample at a moderate speed of 5 mm/s, such that filament tracks were separated into individual tracks with a 10 μm period. The filamentation modification tracks were observed to have a diameter of less than about 3 μm, which is less than the theoretical focal spot size of 10 μm for this focusing arrangement, evidencing the nonlinear self focusing process giving rise to the observed filamentation.
[0079] The geometric focus of the laser beam in the sample was varied by the lens-to-sample displacement to illustrate the control over the formation of the filaments within the sample. In FIG. 12( a ) , the beam focus was positioned near the bottom of the plate, while in FIGS. 12( b ) and 12( c ) , the beam focus was located near the middle and top of the plate, respectively. FIGS. 12( a ) and 12( b ) show multiple layers of filament tracks ( 84 , 86 , 88 and 90 ) formed through the inside of the glass plate. Notably, the filaments are produced at multiple depths due to defocusing and re-focusing effects as described above.
[0080] FIG. 12( a ) , FIG. 12( b ) and FIG. 12( c ) thus demonstrate the controlled positioning of the filamentation tracks relative to the surfaces of the plate. In FIG. 12( a ) , where the beam focus was located near the bottom of the plate, the filaments were formed in the top half of the plate and do not extend across the full thickness of the plate. In FIG. 12( c ) , where the beam focus was positioned near the top of the plate, relative short filaments 92 of approximately 200 μm are formed in the center of the plate, and top surface ablation and ablation debris are evident. A preferably form for scribing is depicted in FIG. 12( b ) where approximately 750 μm long bands of filaments extend through most of the transparent plate thickness without reaching the surfaces. In this domain, ablative machining or other damage was not generated at both of these surfaces.
[0081] While the spacing of the filament tracks in FIG. 12( a ) , FIG. 12( b ) and FIG. 12( c ) is sufficient to cleave the thick 1 mm glass plate, it was found that moderately high mechanical force was required to cleave the plate along the desired path defined by the filament array. In several tests, it was observed that the glass occasionally cleaved to outside the laser modification track. Therefore, a closer spacing of the filament tracks (i.e. a smaller array pitch) is preferable for cleaving such thick (1 mm) plates.
[0082] Those skilled in the art will readily appreciate that suitable values for the array spacing and filament depth will depend on the material type and size of a given plate. For example, two plates of equal thickness but different material composition may have different suitable values for the array spacing and filament depth. Selection of suitable values for a given plate material and thickness may be achieved by varying the array spacing and filament depth to obtain a desired cleave quality and required cleave force.
[0083] Referring again to FIG. 12 , since the array pitch is 10 μm and the observed filament diameter is approximately 3 microns, only a narrow region is heat affected compared with theoretical laser spot size of 10 μm. In other laser material processing methods, obtaining a small heat affected zone is a challenge. One specific advantage of the present method, as evidenced by the results shown in FIG. 12 , is that the width of the heat affected zone on the top and bottom surfaces look the approximately the same. This is an important characteristic of the present method, since the filamentation properties remain substantially confined during formation, which is desirable for accurately cleaving a plate.
[0084] FIGS. 13( a ) and 13( b ) presents optical microscope images focused respectively on the top and bottom surface of the glass sample, as recorded for the sample shown in FIG. 12( b ) . In between these surfaces, the internal filamentation modification appears unfocused as expected when the modification zone is physically more than 100 μm from either surface due to the limited focal depth of the microscope. The images reveal the complete absence of laser ablation, physical damage or other modification at each of the surfaces while only supporting the internal formation of along laser modification track.
[0085] The width of the filamentation modification zone was observed to be about 10 μm when the microscope was focused internally within the glass. This width exceeds the 3-μm modification diameter seen in FIG. 12 for isolated laser filaments and is ascribed to differing zones of narrow high contrast filament tracks (visible in FIG. 12 ) that have been shrouded in a lower contrast modification zone (not visible in FIG. 12 ). Without intending to be limited by theory, this low contrast zone that is ascribed to an accumulative modification process (i.e. heat affected zone) is induced by the multiple pulses in the burst.
[0086] The filamentation modification zone maintains a near constant 10 μm width through its full depth range of hundred's of microns in the present glass sample that clearly demonstrates the self-focusing phenomenon. Thus, the filamentation modification presents a 10 μm ‘internal’ kerf width or heat affected zone for such processing. However, the absence of damage or physical changes at the surface indicate that a much smaller or near-zero kerf width is practically available at the surface where one typically only finds other components mounted (paint, electronics, electrodes, packaging, electro-optics, MEMS, sensors, actuators, microfluidics, etc.). Hence, a near-zero kerf width at the surface of transparent substrates or wafers is a significant processing advantage to avoid damage or modification to such components during laser processing. This is one of the important properties of the present disclosure for laser filamentation scribing as the physical modification may be confined inside the bulk transparent medium and away from sensitive components or coatings.
[0087] To facility cleaving, laser exposure conditions as presented for FIG. 12( b ) were applied to a similar 1 mm thick glass sample while using a slower scanning speed to more closely or densely space the filament tracks. Individual filament tracks were no longer resolvable by optical microscopy. FIG. 14( a ) shows the end facet view after the sample was mechanically cleaved along the near continuous laser-formed filamentation plane. Under these conditions, only very slight force or pressure is required to induce a mechanical cleave. The cleave accurately follows the filament track and readily propagates the full length of the track to separate the sample. The resulting facet is very flat and with sharply defined edges that are free of debris, chips, and vents.
[0088] The optical morphology shows smooth cleavage surfaces interdispersed with rippled structures having feature sizes of tens of microns that are generally smooth and absent of cracks. The smooth facet regions correspond to regions where little or no filamentation tracks were observable in views such as shown in FIG. 12 . Sharply defined top and bottom surface edges may be obtained by controlling the laser exposure to confine the filament formation entirely within the glass plate and prevent ablation at the surfaces. The laser filamentation interaction here generates high stress gradients that form along an internal plane or surface shape defined by the laser exposure path. This stress field enables a new means for accurately scribing transparent media in paths controlled by the laser exposure.
[0089] FIG. 14( b ) presents a side view optical image of the 1 mm thick glass sample shown in FIG. 12( b ) after cleaving. Due to the faster scan speed applied during this laser exposure, less over stress was generated due to the coarse filament spacing (10 μm). As a result, more mechanical force was necessary to separate the plate. The cleaved facet now includes microcracks, vents, and more jagged or coarse morphology than as seen for the case in FIG. 14( a ) with slower scanning speed. Such microcracks are less desirable in many applications as the microcracks may seed much large cracks under packaging or subsequent processing steps, or by thermal cycling in the application field that can prematurely damage the operation or lifetime of the device.
[0090] The laser filamentation and scribing examples presented in FIGS. 12-14 for glass clearly demonstrate the aforementioned embodiments in a high-repetition rate method of forming filaments with short pulses lasers is employed. Each filament was formed with a single burst of 8 pulses, with pulses separated by 26 ns and with each pulse having 40-μJ energy. Under such burst conditions, heat accumulation and other transient effects do not dissipate in the short time between pulses, thus enhancing the interaction of subsequent laser pulses with in the filamentation column (plasma channel) of the prior pulse. As such, filaments were formed much more easily, over much longer lengths, and with lower pulse energy, higher reproducibility and improved control than for the case when laser pulses were applied at low repetition rate.
[0091] FIG. 15( a ) shows a microscope image of a cleaved glass plate of 1 mm thickness in which filaments were formed at a low 500 Hz repetition rate (2 ms between laser pulses). The scanning rate was adjusted to deliver 8 pulses per interaction site with each pulse having the same 40 μj pulse energy as used in the above burst-train examples. The total exposure per single filament was therefore 320 μj in both cases of burst ( FIGS. 12-14 ) and non-burst ( FIG. 15 ) beam delivery. The long time separation between pulses in the non-burst case ( FIG. 15( a ) ) ensures relaxation of all the material modification dynamics prior to the arrival of the next laser pulse. This precludes any filamentation enhancement effect as heat accumulation and other transient effects are fully relaxed in the long interval between pulses.
[0092] Without intending to be limited by theory, the relaxation of material modification dynamics are believed to lead to much weaker overall laser-material interaction in creating filaments and inducing internal modification within the present glass substrate. As a consequence, non-burst laser interactions take place in a very small volume that is near the top glass surface as shown in FIG. 15( a ) . Further, laser interactions produced small volume cavities inside the glass that can seen in FIG. 15( a ) as the rough surface in the top 100 μm of the facet. In order to enable reliable scribing along such laser tracks, it is necessary to pass the laser much more slowly (than the case in FIG. 15( a ) ) through the sample and/or to apply several repeated passes of the laser over the same track to build up sufficiently strong internal modification.
[0093] For direct comparison with burst-train filament writing, FIG. 15( b ) shows an edge facet image of a similar glass plate in which filaments were each formed in the low-repetition rate of 500 Hz at 320 μJ energy per pulse (i.e. 320 μJ for burst train: single pulse in the train). Much longer filaments (˜180 μm) than in the low-repetition rate 8-pulse exposure of FIG. 15( a ) is observed. The filaments are deeply buried within the bulk glass so too avoid surface ablation or other laser damage. Nonetheless, the observed filament length is smaller than that observed for burst filamentation at a similar mean fluence. In both cases of FIGS. 15( a ) and 15( b ) , a common rapid scan speed was applied to provide a broad spacing of the filament array for observational purposes.
[0094] Accordingly, these results illustrate that the nature of the filament can be readily manipulated by varying the pulsed nature of the laser exposure. In other words, in addition to the parameters of energy, wavelength, and beam focusing conditions (i.e. numerical aperture, focal position in sample), pulse parameters can be tailored to obtain a desired filament profile. In particular, number of pulses in a pulse burst and the delay time between successive pulses can be varied to control the form of the filaments produced. As noted above, in one embodiment, filaments are produced by providing a burst of pulses for generating each filament, where each burst comprises a series of pulses provided with a relative delay that is less than the timescale for the relaxation of all the material modification dynamics.
[0095] In the industrial application of single sheet glass scribing, flat panel glass scribing, silicon and/or sapphire wafer scribing, there is a demand for higher scribing speeds using laser systems with proven reliability. To demonstrate such an embodiment, experiments were performed using a high repetition rate commercial ultrafast laser system having a pulse duration in the picosecond range.
[0096] As shown in FIG. 16( a ) , a V groove with a filament descending from the V groove was produced in a glass substrate having a thickness of 700 microns. The depth and width of the V is about 20 μm and the filament extended to a length of about 600 μm. FIG. 16( b ) provides a top view of the glass substrate. The observed kerf width is about 20 μm, covered with about 5 μm recast in the sides. As shown in the Figure, no visible debris is accumulated on the surface. FIG. 16( c ) shows a front view of the glass after it is cleaved, highlighting the deep penetration of the filaments into the glass substrate that assist in cleaving the sample.
[0097] In a subsequent experiment, the focusing condition was changed to minimize the filament length. For some applications, filament formation is not desired, and/or a clean facet is desirable. A side view showing three different V grooves is provided in FIG. 17 . Note that the chamfer angle is different for each V. The chamfer angle and depth can be adjusted by changing the focus and beam divergence. The width, depth and sharpness of the V grooves are of high quality comparing to other laser scribing techniques where they generally create wider kerf width or shorter depth structures with grooves having a U-shaped and causing a large amount of debris to accumulate on the surface.
[0098] FIG. 18 presents the simultaneous laser filamentation scribing of an assembly of two 400 um thick double layer glasses by the method and arrangement described by FIG. 7( c ) . A single laser beam was focused into the top glass plate to form a long filament. The laser beam passed through the air gap without creating damage to the two middle glass surfaces. However, self-focusing effects created a second filament to form with the same beam in the second (lower) plate such that two filament tracks were formed separately in each thin glass plate.
[0099] FIG. 18( a ) shows a side view of the scribed laminated glass before cleaving and FIG. 18( b ) shows optical microscope images of the front surfaces of top and bottom layer glasses after cleaving. The modification tracks are largely confined with in the bulk of the glass, and thus, no ablation debris or microcracks are present in any of the surfaces. The kerf width of the filamentation modification is less than 10 μm in both plates which represents the heat affect zone of the laser. Individual filament tracks are resolvable around which internal stress fields were generated that enabled the mechanical scribing. The facet has clean flat surfaces with only a small degree of contouring around the filament tracks observable. The edges are relatively sharp and absent of microcracks. The facet has the general appearance of a grinded surface, and may be referred to as having been produced by “laser grinding”. Such clean and “laser grinded” surfaces may be obtained by creating filaments that are tightly spaced, and preferably, adjacent to each other.
[0100] It is to be noted that for each of the optical microscope images in FIGS. 12 to 18 , the glass samples are presented as processed by laser exposure without any cleaning steps following the laser exposure or after the cleaving steps.
[0101] The present method of low and high (burst) repetition rate filamentation was found to be effective in glass for pulse durations tested in the range of about 30 fs to 10 ps. However, those skilled in the art will appreciate that the preferably pulse duration range for other materials may be different. Those skilled in the art may determine a suitable pulse duration for other materials by varying the pulse duration and examining the characteristics of the filaments produced.
[0102] Without intending to be limited by theory, it is believe that embodiments as disclosed herein utilize self-focusing to generate filaments (plasma channels) in transparent materials. Therefore, laser pulse durations in the range of 1 femtosecond to 100 ps are considered the practical operating domain of the present disclosure for generating appropriately high intensity to drive Kerr-lens self focusing in most transparent media.
[0103] The present disclosure also anticipates the formation of thermal gradients in the transparent substrate through non-uniform heating by the focused short duration laser light. Such effects may be enhanced by heat accumulation effects when burst-trains of pulses are applied. In this domain, thermal lensing serves as an alternate means for generating a filament or long-focusing channel to produce filament modification tracks in transparent materials for scribing application.
[0104] The filamentation modification of transparent media enables rapid and low-damage singulation, dicing, scribing, cleaving, cutting, and facet treatment of transparent materials that are typically in the form of a flat or curved plate, and thus serve in numerous manufacturing applications. The method generally applies to any transparent medium in which a filament may form. For glass materials, this includes dicing or cleaving of liquid crystal display (LCD), flat panel display (FPD), organic display (OLED), glass plates, multilayer thin glass plates, autoglass, tubing, windows, biochips, optical sensors, planar lightwave circuits, optical fibers, drinking glass ware, and art work. For crystals such as silicon, III-V, and other semiconductor materials, particularly, those in thin wafer form, applications include singulation of microelectronic chips, memory chips, sensor chips, light emitting diodes (LED), laser diodes (LD), vertical cavity surface emitting laser (VCSEL) and other optoelectronic devices. This filament process will also apply to dicing, cutting, drilling or scribing of transparent ceramics, polymers, transparent conductors (i.e. ITO), wide bandgap glasses and crystals (such as crystal quartz, diamond, sapphire). The applications also extend to all composite materials and assemblies were at least one material component is transparent to the laser wavelength to facilitate such filamentation processing. Examples include silica on silicon, silicon on glass, metal-coated glass panel display, printed circuit boards, microelectronic chips, optical circuits, multi-layer FPD or LCD, biochips, sensors, actuators, MEMs, micro Total Analysis Systems (μTAS), and multi-layered polymer packaging.
[0105] The specific embodiments described above have been shown by way of example, and it should be understood that these embodiments may be susceptible to various modifications and alternative forms. It should be further understood that the claims are not intended to be limited to the particular forms disclosed, but rather to cover all modifications, equivalents, and alternatives falling within the spirit and scope of this disclosure.
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A method is provided for the internal processing of a transparent substrate in preparation for a cleaving step. The substrate is irradiated with a focused laser beam that is comprised of pulses having an energy and pulse duration selected to produce a filament within the substrate. The substrate is translated relative to the laser beam to irradiate the substrate and produce an additional filament at one or more additional locations. The resulting filaments form an array defining an internally scribed path for cleaving said substrate. Laser beam parameters may be varied to adjust the filament length and position, and to optionally introduce V-channels or grooves, rendering bevels to the laser-cleaved edges. Preferably, the laser pulses are delivered in a burst train for lowering the energy threshold for filament formation and increasing the filament length.
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CROSS REFERENCE TO RELATED APPLICATIONS
This application is a continuation-in-part of U.S. application Ser. No. 14/265.765 filed on 30 Apr. 2014, which claims benefit of 35 U.S.C. §119(a) of German Application Nos. 10 2013 104 409.3 filed 30 Apr. 2013 and 10 2014 100 750.6 filed 23 Jan. 2014, the entire contents of each of which are incorporated herein by reference.
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method for the production of glass components, a redrawing apparatus for conducting such a method as well as a glass component.
2 Description of Related Art
In principle, the redrawing of glasses is known, in particular a comprehensive state of the art about the redrawing of blanks and/or blanks with circular cross-section, for the drawing of glass fibers exists.
During a redrawing method a glass piece is partially heated and drawn in the longitudinal direction with the help of suitable mechanical equipment When the glass piece—the blank—is fed into a heating mm at a constant speed and when the heated glass is drawn with a constant speed, then this results in a reduction of the cross-section shape of the blank which depends on the ratio of the speeds. So, when for example tubular blanks are used, then again tubular products are prepared, but with smaller diameter. The cross-section shape of the products is similar to that of the blank, wherein for the most part it is even desirable to achieve a reproduction of the blank in a reduced scale of 1:1 by suitable measures (see EP 0 819 655 B1).
In a step of redrawing glasses normally an oblong blank is fixed on one end in a holder and heated at the other end in tor example a muffle kiln. Once the glass has become deformable, it is drawn by the exertion of drawing force at the end of the blank being fixed in the holder. When during that the blank is moved forward into the muffle, then with a suitable selection of the temperatures this results in a product with a smaller cross-section, but a similar geometry. For example, a blank with circular cross-section is drawn into a glass fiber. The selection of the speeds of drawing the product of for example a component and optionally moving forward the blank determines the reduction factor of the cross-section. Normally, the ratio of thickness to width of the cross-section of the blank remains constant. In the case of drawing glass fibers this is desired, because starting from a blank with circular cross-section a glass fiber having also a circular cross-section can be drawn.
It has been proved that it is difficult to redraw flat components, i.e. components having a ratio of width to thickness of the cross-section of for example 80:1. Only with blanks having a very high width it is possible to draw components with also a high width. So e.g. from a blank having a cross-section of 70 mm width and 10 mm thickness (B/D=7) a component having a cross-section of 7 mm width and 1 mm thickness (b/d=7) can be produced.
A component having a cross-section with a higher width and the same thickness is only possible, when a blank having a cross-section with a higher width or lower thickness is used. The use of a blank having a higher width often fails due to the impossible producibility, and the use of a blank having a lower thickness is increasingly inefficient, since the blank during redrawing has to be exchanged more often.
In U.S. Pat. No. 7,231,786 B2 is described, how plane glass panes can be produced by redrawing. For achieving a product with higher width, in this case grippers are used which draw the soft glass into the width direction, prior to expanding the glass into the longitudinal direction with the help of edge rollers.
In U.S. Pat. No. 3,635,687 A a redrawing method is described, in which by cooling of the edge region of the flat blank a change of the ratio of width to thickness (B/D) is achieved. But with this method a maximum increase of the ratio of width to thickness by a factor of 10.7 can be achieved.
In EP 0 819 655 81 a method for forming glass is described. In this case in the forming step also redrawing can be used. But it is not described, how the ratio of width to thickness (B/D) is adjusted. Here after heating the glass is locally heated or cooled for manipulating the geometry.
However, the manipulations described in these references only result in a smaller change of the geometry of the blank in comparison to the final shape and/or to the shape of the drawn component Furthermore, these methods are associated with relatively high effort. In particular in the case, when grippers or rolls should be used, a sophisticated redrawing apparatus is required which is susceptible to defects.
SUMMARY
Thus, the object of the present invention is the provision of an efficient method for the production of glass components. Furthermore, a method should be provided which makes it possible to increase the ratio of width to thickness of the blank (B/D) m comparison to the ratio of width to thickness of the glass component (b/d). In particular, a method for the production of flat glass components should he provided, through which from a blank having a width B and a thickness D a flat glass component having a width b and a thickness d can be prepared, wherein the ratio b/d is much higher than the ratio B/D.
The object according to the present invention is solved by the embodiments which are described in the patent claims.
The method for redrawing glass according to the present invention serves for example for the production of flat glass components. It comprises the following steps:
providing of a blank of glass having an average thickness D and an average width B, heating of a deformation zone of the blank, drawing the blank, till an average thickness d and an average width b is achieved, wherein the deformation zone is the part of the blank in which the blank has a thickness of between 0.95*D and 1.05*d and wherein the deformation zone has a height of at most 15*D.
The method is characterized in that the deformation zone is very small in comparison to the state of the art. The deformation zone (=meniscus) has a height of at most 15*D, preferably at most 12*D. Other preferred embodiments include a deformation zone having a height of at most 6*D, preferably at most 5*D and particularly preferably at most 4*D. In preferred embodiments of this invention the deformation zone has a height of at mast 250 mm, more preferred at most 100 mm, more preferred at most 40 mm and most preferred at most 30 mm.
Preferably, the deformation, zone extends over the whole width of the blank. “Height” of the deformation zone means the extent thereof in the direction into which the blank is drawn. The deformation zone (=meniscus) is the region in which the blank has a thickness of between 0.95*D and 1.05*d. Thus, it is a region in which the glass can be deformed. The thickness is smaller than the original thickness D, but the final thickness d is still not achieved. In the deformation zone for example a temperature T 2 may prevail, at which the glass of the blank has a viscosity η 2 of between 10 4 dPas and 10 8 dPas.
The width b of the drawn glass component increasingly decreases with increasing viscosity in the deformation zone. When in the case of softening for example the drawing speed is increased for achieving a target value of 100 μm for the thickness d of the glass component, the width b of the glass component in comparison to width B of the blank would considerably be decreased. Therefore, for obtaining a flat glass component with a high ratio b/d it is advantageous, when the glass of the blank in the deformation zone has a viscosity η 2 which is lower than the viscosity of the respective glass at the softening point (EW). Therefore, the glass of the blank in the deformation stone has preferably a viscosity η 2 of at most <10 7.6 dPas, further preferably at most 10 7.5 dPas, even further preferably at most 10 7.6 dPas, exceptionally preferably at most 10 6.5 dPas. Furthermore, a viscosity η 2 which is lower than the viscosity of the respective glass at the softening point is also advantageous, because the drawing force being required for drawing the glass increasingly increases with increasing viscosity. Thus, a lower viscosity is also associated with a lower required drawing force.
However, the viscosity η 2 of the glass of the blank in the deformation zone should also not be too low, since otherwise a uniform drawing of the glass becomes more difficult. Preferably, the glass of the blank in the deformation zone has a viscosity η 2 of at least 10 4.0 dPas, further preferably at least 10 4.5 dPas, even further preferably at least 10 5.0 dPas, exceptionally preferably at least 10 5.8 dPas.
The invention described here may be combined with a cooling of the edge region of the blank in analogy with U.S. Pat. No. 3,635,687 A, to achieve an even higher width and/or a better thickness distribution. Also a higher edge temperature is possible for achieving a better thickness distribution.
The deformation zone is the part of the blank with a thickness of 0.95*D up to 1.05*d. Preferably, this is the part of the blank which during said method at a certain time point has temperature T 2 . At this temperature the viscosity of the glass of the blank is in a range which allows deformation of the glass.
The blank has an upper end and a lower end. The deformation zone is located between the upper and the lower ends. Beyond the deformation zone the temperature of the blank is preferably lower than T 2 . Because of that the deformation of the blank substantially only occurs in the region of the deformation zone. Above and below this region preferably the thickness and also the width remain substantially constant. For the sake of convenience throughout this description the term “blank” is used, when the glass is processed in this method, only after the end of the final process step according to the present invention the product Is called “glass component”.
Preferably, the increase of the ratio of width to thickness of the blank is substantially achieved by the measure that the thickness d of the glass component produced is substantially lower than the thickness D of the blank. Preferably, the thickness d is at most D/10, further preferably at most D/30 and particularly preferably at most D/75. In other preferred, embodiments the thickness d is at most D/100 or even at most D/200. Then, the glass component has preferably a thickness d of lower than 10 mm, further preferably lower than 1 mm, more preferably lower than 100 μm, further preferably lower than 50 μm and particularly preferably lower than 30 μm or even lower than 15 μm or lower than 5 μm. With the present invention it is possible, to produce such thin glass components in high quality und with relatively large surface areas.
Preferably, width b of the glass component produced in relation to width B of the blank is hardly decreased. This means that the ratio B/b is preferably at most 2, further preferably at most 1.6 and particularly preferably at most 1.25.
The method can be conducted in a redrawing apparatus which is also part, of the present invention. For the purpose of heating the blank, can be inserted into the redrawing apparatus. Preferably, the redrawing facility comprises a holder in which one end of the blank can be fixed. The holder is preferably located in an upper section of the redrawing apparatus. Then, the blank is fixed with its upper end in the holder.
The redrawing apparatus comprises at least one heating facility. The heating facility is preferably arranged in a central region of the redrawing apparatus. The heating facility may preferably be an electric resistance heater, a burner arrangement, a radiation heater, a laser with or without laser scanner or a combination thereof. The heating facility is preferably designed such that it can heat the blank being disposed in a deformation region in such a manner that the deformation mm of the blank is heated to temperature T 2 . The deformation region is a region which is preferably located inside the redrawing apparatus. The heating facility increases the temperature of the deformation region and/or a part of the blank to a temperature which is so high that a blank which is disposed in the deformation region is heated within its deformation zone to temperature T 2 . When a heating facility is used which is suitable for targeted heating of only a part of the blank, such as a laser, then the temperature in the deformation region is hardly increased.
The deformation region has preferably a height which results in a deformation zone in the blank having a height of at most 15*D, more preferably at most 12*D. Other preferred embodiments include deformation zones having a height of at most 6*D (in particular at most 100 mm), preferably at most 5*D (in particular at most 40 mm) and particularly preferably at most 4*D (in particular at most 30 mm). Therefore, according to the heating manner and the blank dimensions the deformation region can be designed in different lengths.
The heating facility increases the temperature in the deformation region and/or a part of the blank which preferably has only such an extent that in the blank the deformation zone being designed according to the present invention is heated: to temperature T 2 . The parts of the blank which are above and below the deformation zone have preferably a temperature which is lower than T 2 . According to the present invention, this is preferably achieved by a heating facility comprising one or more baffles which shadow those parts of the blank which are beyond the deformation region. Alternatively or additionally a heating facility allowing a focused heating of the blank in the deformation region, such as for example a laser or a laser scanner, can be used. A further alternative embodiment relates to a heating facility with only low height which is disposed near to the deformation zone so that substantially the heat does not spread into regions beyond the deformation region.
The heating facility may be a radiation beater, wherein the heating effect of which is focused and/or limited to the deformation region by suitable radiation guiding and/or restricting means. For example, a KIR (short-wave IR) heater may be used, wherein by shadowing a deformation region is created which is very small according to the present invention. Also cooled (with gas, water or air) baffles may be used. A further heating facility which may be used is a laser. In this case for the radiation guidance of the laser a laser scanner may be used.
The apparatus may comprise a cooling facility being preferably arranged in a lower region of the redrawing facility, in particular directly below the heating facility. With this facility, directly after the deforming step, the viscosity of the glass is preferably changed to values of >10 9 dPas so that no appreciable deformation takes place any longer. This cooling is preferably conducted such that it results in a viscosity change rate of at least 10 6 dPas/s. Depending on the glass of the blank this corresponds for example to temperatures T 3 in a range of 400 to 1000° C.
The method according to the present invention preferably comprises the further step of:
cooling the blank after leaving the deformation region.
The further cooling of the blank to viscosities >10 9 dPas may be achieved by cooling at ambient temperature (e.g. 10 to 25° C). But the blank may also be cooled in an active manner in a fluid, such as for example in a gas stream. It is particularly preferable, when the product is cooled so slowly in a cooling region which follows the deformation region that the residual tensions at least allow subsequent cross-cutting as well as the removal of sheet edges without any introversive cracks.
Preferably, the deformation region is arranged such and/or the heating facility is designed such that the deformation zone is created within the blank. The deformation zone is that part, of the blank which during the process has a thickness of 0.95*D to 1.05*d. By heating of the deformation zone of the blank the viscosity of the glass at the respective site decreases so much that the blank can be drawn. This means that the blank becomes longer. By the drawing step the thickness D of the blank becomes lower. Since the blank is preferably fixed with the upper end in a holder which preferable is located in an upper region of the redrawing facility, the drawing of the blank may be effected by exposure of gravitation. But in preferable embodiments the redrawing facility comprises a drawing facility which preferably exerts drawing forces at a part of the blank below the deformation region, in particular at the lower end of the blank.
The drawing facility is preferably arranged in a lower region of the redrawing facility. In this case the drawing facility may be designed such that is comprises rolls acting on opposing sides of the blank. The blank may detachably be mounted with a lower end at a second holder. In particular, the second holder is a component of the drawing facility. At the second holder for example a weight may be mounted which then draws the blank into the longitudinal direction. Alternative means for drawing the blank are also within the scope of this invention. Preferably, the drawing force used is lower than 350 N/400 mm blank width (B), further preferably lower than 300 N/400 mm blank width, even further preferably lower than 100 N/400 mm blank width, exceptionally preferably lower than 50 N/400 mm blank width. Preferably, the drawing force is higher than 1 N/400 mm blank width, further preferably higher than 5 N/400 mm blank width, even further preferably higher than 10 N/400 mm blank width, exceptionally preferably higher than 20 N/400 mm blank width.
In a preferable embodiment the blank is fed into the direction of the deformation zone so that the method can be conducted in a continuous manner. For this purpose the redrawing apparatus preferably comprises a feeding facility which is suitable for moving the blank, into the deformation region. So the redrawing apparatus can be used in continuous operation. The feeding facility preferably moves the blank into the deformation region with a speed v N which, is lower than the speed v Z with which the blank is drawn. So the blank is drawn into the longitudinal direction. The ratio of v N to v Z is in particular <1, preferably at most 0.8, further preferably at most 0.4 and particularly preferably at most 0.1. The difference of these two speeds determines the extent of the reduction of the width and the thickness of the blank.
Prior to heating the blank is preferably preheated. For this purpose the redrawing apparatus preferably comprises a preheating zone in which the blank may be heated to a temperature T 1 . The preheating zone is preferably arranged in an upper region of the redrawing apparatus. Temperature T 1 corresponds for example to a viscosity η 1 of 10 10 to 10 14 dPas. Thus, the blank is preferably preheated, before it enters the deformation region. So a faster movement through the deformation region becomes possible, since the time which is necessary for achieving temperature T 2 is shorter. With the preheating zone it cart also be avoided that glasses with high temperature expansion coefficients break due to temperature gradients which are too high.
In preferable embodiments the deformation zone is heated to a temperature T 2 which corresponds to a viscosity of the glass of the blank of 10 5.8 to 10 7.6 dPas, in particular 10 5.8 to <10 7.6 dPas. The viscosity of a glass depends on the temperature. At each temperature the glass has a. certain viscosity. The temperature T 2 which is necessary for achieving the desired viscosity η 2 in the deformation zone depends on the glass. The viscosity of a glass will be determined according to DIN ISO 7884˜2, ˜3, ˜4, ˜5.
The blank preferably consists of a glass which is selected from fluorophosphate glasses, phosphate glasses, soda-lime glasses, lead glasses, silicate glasses, aluminosilicate glasses and borosilicate glasses. The glass used may be a technical glass, in particular technical flat glass, or an optical glass.
Preferred technical, glasses are soda-lime glasses and borosilicate glasses. In preferable embodiments the glasses are display glasses or thin glasses for barrier layers in plastic laminates.
Preferred optical glasses are phosphate glasses and fluorophosphate glasses. Phosphate glasses are optical glasses containing P 2 O 5 as glass former. Then, P 2 O 5 is the main component of the glass. When a part of the phosphate in a phosphate glass is replaced by fluorine, then fluorophosphate glasses are obtained. For the synthesis of fluorophosphate glasses instead of oxidic compounds such as for example Na 2 O the respective fluorides such as NaF are added to the glass mixture.
According to the present invention preferably a flat blank is used, wherein according to the present invention a “flat blank” means that the width B of the blank is higher than the thickness D thereof. Preferably, the ratio of width to thickness of the blank (B/D) is at least 5, more preferably at least 7.
Preferably, the blank has a thickness D of at least 0.05 mm, more preferably at least 1 mm. The thickness is preferably at most 40 mm, more preferably at most 30 mm. The width B of the blank is preferably at least 50 mm, more preferably at least 100 mm, most preferably at least 300 mm.
The length of the blank L is preferably at least 500 mm, more preferably at least 1000 mm. Generally it is true that the method can be conducted in a more efficient manner, when the blank is longer. So also still longer blanks may be considered and may be advantageous. Also an execution of a method may be considered in which the blank is fed in a continuous manner or the blank is uncoiled from a roll. Furthermore, preferably the following is true: L>B.
The method, according to the present invention may also be conducted with a blank which is coiled on a first roll. In this case the blank is also fixed in an upper region of the redrawing apparatus, but in such a manner that the blank can be uncoiled from the roll. The free end of the blank is then drawn by means of the drawing facility. The drawing facility then draws the blank through the deformation region in a preferably continuous and constant manner so that within the blank a deformation zone according to the present invention is formed. The glass component so prepared after passing the redrawing apparatus is preferably coiled onto a second roll.
The blank may comprise or may not comprise a sheet edge (a thickened boundary region). By the provision of the blank on a roll and/or the coiling of the flat glass component onto a roll the method in total can be conducted more efficiently, since the blanks have not to be inserted singly into the apparatus in a laborious manner.
Finally, for example by cutting, the obtained glass component may be separated into single pieces. Furthermore, also the optionally somewhat thickened boundary regions (sheet edges) of the glass component may be cut off. If necessary, the glass component may also be polished and/or coated.
With the method according to the present invention glass components with a very large useable surface area of glass can be obtained. This means that the part of the glass component with the required quality is very large. In the method of this invention the part of the surface area of sheet edges which optionally have to be removed before the use is small. Preferably, the glass components have a ratio of thickness to width of 1:2 to 1:250,000. In more preferred embodiments, this ratio is from 1:200 to 1:200,000; further preferred this ratio is from 1:2,500 to 1:150,000; other preferred ranges of this ratio include 1:3,000 to 1:100,000 and 1:5,000 to 1:20,000. Of course, the useable surface area of the glass is higher when this ratio is small, i.e. when the obtained glass component is wider. In the prior art such small ratios are often not achieved because the processes used do not provide for an increase of b/d in relation to B/D (see above). In other words, in order to achieve such a preferred ratio of thickness to width the thickness must be decreased to a much greater extent than the width.
Preferably, the blank can be classified in a striae class of at most C. The striae class is a result of the optical path difference. For striae class C or better the optical path difference through a flat plate has to be 21 30 nm.
According to the present invention is also a glass component which is obtainable by the method according to the present invention. The glass component comprises at least one, in particular two fire-polished surfaces. Fire-polished surfaces are very smooth, i.e. their roughness is very low. In the case of fire-polishing in contrast to mechanical, polishing a surface will not be abraded, but the material to be polished is heated to such a high temperature that it flows and thus becomes smooth. Therefore the costs for the production of a smooth surface by fire-polishing are substantially lower than for the production of a highly smooth mechanically polished surface.
With the method according to the present invention glass components with at least one fire-polished surface are obtained. Referred to the glass component according to the present invention, the term “surfaces” means the upper and/or lower sides, thus both faces which in comparison to the residual faces are the largest.
The fire-polished surface(s) of the glass components of this invention preferably have a root mean square roughness (R q or also RMS) of at most 5 nm, preferably at most 3 nm and particularly preferably at most 1 nm. The depth of roughness R t of the thin glasses is preferably at most 6 nm, further preferably at most 4 nm and particularly preferably at most 2 nm. The depth of roughness will be determined according to DIN EN ISO 4287.
In the case of mechanically polished surfaces the roughness values are worse. Furthermore, in the case of mechanically polished surfaces with the help of an atomic force microscope (AFM) polishing traces can be observed. In addition, also with the help of an AFM residues of the mechanic polishing agent, such as diamond powder, iron oxide and/or CeO 2 , can be observed.
Since mechanically polished surfaces have to be cleaned after a polishing step, leaching of certain ions at the surface of the glass occurs. This depletion of certain ions can be detected with the help of secondary ion mass spectrometry (ToF-SIMS). Such ions are for example Ca, Zn, Ba and alkali metals.
In the following the invention should be explained by means of the following figures and embodiment examples.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows in a schematic manner a side view of an exemplary embodiment of a redrawing apparatus according to the present invention.
FIG. 2 shows the schematic operating sequence of a method, according to prior art.
FIG. 3 shows in a schematic manner a blank.
FIG. 4 shows in a schematic manner a mode of action of an optional radiation heater.
FIG. 5 shows the dependency of the widths of a glass product on the height of the deformation zone in a redrawing process.
FIG. 6 shows the distribution of thickness d of a flat glass product across width b of an example (example 3).
FIG. 7 shows in an exemplary manner average width b (gross width) of the drawn glass component and the drawing three.
FIG. 8 shows in an exemplary manner the ratio of average width b (gross width) to average thickness d (net thickness) of the drawn glass component and the drawing force which is necessary for drawing.
DETAILED DESCRIPTION
FIG. 1 shows in a side view the schematic structure of an exemplary embodiment of a redrawing apparatus according to the present invention. In the redrawing apparatus a blank 1 is moved top down through the apparatus. The redrawing apparatus comprises two heating facilities 2 being arranged in a center region of the apparatus. In this embodiment the heating facilities are shielded by baffles 3 in such a manner that a deformation region 4 is formed. A part of blank 1 which is disposed in deformation region 4 is heated, such that it reaches temperature T 2 . This part of the blank is the deformation zone 5 having height H. Blank 1 is drawn down with the help of a drawing facility 6 which here is realized in the form of two driven rolls. As a result that the feeding facility 7 , here also designed in the form of rolls, feeds blank 1 in a speed which is lower than the speed of the drawing facility 6 , blank 1 is deformed in deforming region 4 . Because of that blank 1 becomes thinner; the thickness after the deforming step d is smaller than that prior the deforming step D. Prior to feeding blank 1 into deformation region 4 it is preheated to temperature T 1 with the help of preheating facility 8 , here symbolized by a burner flame. After passing the deformation region 4 blank 1 is fed into a cooling facility 9 , here symbolized by an ice crystal.
FIG. 2 shows the schematic operating sequence of a method according to prior art. A difference to FIG. 1 is that in this case the change of width 8 of the blank is shown. Blank 1 is moved into a deformation region 4 . Deformation region 4 is heated with a heating facility 2 —here a resistance heater. Blank 1 is heated such that in the glass a deformation zone is formed, where the glass has low viscosity. But this deformation zone is much larger than the deformation zone according to the present invention due to the lack of any limitation and the height of heating facility 2 . So a particularly distinct reduction of the width of blank 1 results. Also a drawing facility 6 is shown which draws blank 1 into the longitudinal direction.
FIG. 3 shows in a schematic manner a blank with length L, thickness D and width B.
FIG. 4 shows in a schematic manner the mode of action of an optional radiation heater 2 which may be used as a heating facility. Dependent on its distance to blank 1 the height of deformation zone 5 is different. In this figure it is also shown, how by means of shadowing facility/baffle 3 the deformation zone can be limited to obtain a deformation zone 5 with a height which is as low as possible. Thus both, the distance and also the design of the heating facility 2 may serve for the adjustment of the height of deformation zone 5 .
FIG. 5 shows the dependency of the widths of a glass product on the height of the deformation zone in a redrawing process. It can be seen that a deformation zone with a lower height results in a reduction of the decrease of the width of the blank.
FIG. 6 shows the distribution of thickness d of a flat glass product across width b of the product of example 3. Here can be seen that the sheet edges at the rims of the glass product are relatively small. The part with a homogenous low thickness can be used for the application of the glass product, but the sheet edges have to be removed. The use of the method according to the present invention results in a particularly high rate of yield.
FIG. 7 shows in an exemplary manner average width b (gross width) of the drawn glass component and the drawing force which is required for drawing, each in dependency on the viscosity of the glass of the blank in the deformation zone, in the case of a blank having a thickness of 4 mm and a width of 400 mm which is fed into a muffle with a height of 40 mm with a speed of 5 mm/min. The glass is drawn with 200 mm/min. It can be clearly seen that the required drawing force increasingly increases with increasing viscosity. Furthermore it can be seen that average width b of the product obtained increasingly decreases with increasing viscosity.
FIG. 8 shows in an exemplary manner the ratio of average width b (gross width) to average thickness d (net thickness) of the drawn glass component and the drawing force which is necessary for drawing, each in dependency or the viscosity of the glass of the blank in the deformation zone, in the case of a blank having a thickness of 4 mm and a width of 400 mm which is fed into the muffle with a height of 40 mm with a speed of 5 mm/min. The glass is drawn with 200 mm/min. It can be seen that the ratio b/d of the product obtained increasingly decreases with increasing viscosity. In comparison to the decrease of average width b with increasing viscosity shown in FIG. 7 the ratio b/d decreases in a relatively higher extent, with increasing viscosity.
EXAMPLES
Example 1
Drawing of Optical Glass
Here the optical glass (fluorophosphate glass) is east into a bar form having dimensions of e.g. B =120 mm and D=14 mm. Then this bar is inserted into the redrawing apparatus and heated in a preheating zone to a temperature which corresponds to the glass-transition point (ca. 10 13 dPas). By moving the blank downwards into a deformation region with a height of 40 mm and a temperature which at least corresponds to a viscosity of <10 7.6 dPas and in the maximum a viscosity of ca. 10 4 dPas. The leaving glass is guided through a cooling zone and fixed in a drawing facility and drawn faster than the blank is fed. So this results in a ribbon of glass having a width of 100 mm and an average thickness of 0.3 mm.
Example 2
Drawing of Flat Glass
As a blank a flat glass (Borofloat®) having a width of 300 and a thickness of 10 mm is provided. After passing a preheating zone (ca. Tg) this blank is moved into the deformation zone. This zone is heated over the whole width and a height of 20 mm to a minimum temperature which corresponds to a viscosity of 10 4 dPas to <10 7.6 dPas. After passing a cooling zone the leaving glass is fixed in a drawing facility. By a suitable selection of the speed of the blank and the speed of the product an average thickness of at most 100 μm is adjusted and the product is coiled onto a cylinder. So this results in a product having a width of at least 250 mm.
Example 3
Drawing of Flat Glass
A blank made of flat glass (Borofloat®) having a width of 50 mm and a thickness of 1.1 mm is provided. After passing a preheating zone (ca. Tg) this blank is moved into the deformation zone. In the deformation zone the glass is heated over the whole width and a height of 3 mm to a temperature which corresponds to a viscosity of ca. 10 7 dPas. After passing a cooling zone on the leaving glass a weight is attached (drawing facility). By a suitable selection of the speed of the blank and the size of the weight an average thickness of about 50 μm is adjusted. So this results in a product having a width of at least 40 mm.
TABLE 1
Examples and comparative examples
U.S. Pat. No.
U.S. Pat. No.
According
3,635,687
3,635,687
to the
without edge
with edge
present
cooler
cooler
invention
Length of deformation
508
508
30
region [mm]
Width of blank B [mm]
508.0
508.0
120.0
Thickness of blank D [mm]
6.4
6.4
14.0
Ratio B/D
80.0
80.0
8.6
Width of component
19.1
61.4
100.0
b [mm]
Average thickness of
0.1
0.1
0.3
component d [mm]
Ratio b/d
250.0
853.3
333.3
(Ratio b/d)/(ratio B/D)
3.1
10.7
38.9
LIST OF REFERENCE SIGNS
1 blank
2 heating facility
3 baffle
4 deformation region
5 deformation zone
6 drawing facility
7 feeding facility
8 preheating facility
9 cooling facility
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A method for the production of glass components, an apparatus for carrying out the method, and a glass component that is obtainable through the method are provided. The method is a drawing method wherein a forming zone of a preform is heated to a temperature that allows drawing of the glass. The method includes a forming zone of the preform that is very small. Thereby the width of the preform is decreased to a smaller extent than its thickness. The glass components that can be obtained by this method have very smooth surfaces.
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[0001] This invention relates generally to the field of immunotherapy and, more specifically, to methods for enhancing host immune responses.
BACKGROUND OF THE INVENTION
[0002] The immune system of mammals has evolved to protect the host against the growth and proliferation of potentially deleterious agents. These agents include infectious microorganisms such as bacteria, viruses, fungi, and parasites which exist in the environment and which, upon introduction to the body of the host, can induce varied pathological conditions. Other pathological conditions may derive from agents not acquired from the environment, but rather which arise spontaneously within the body of the host. The best examples are the numerous malignancies known to occur in mammals. Ideally, the presence of these deleterious agents in a host triggers the mobilization of the immune system to effect the destruction of the agent and, thus, restore the sanctity of the host environment.
[0003] The destruction of pathogenic agents by the immune system involves a variety of effector mechanisms which can be grouped generally into two categories: innate and specific immunity. The first line of defense is mediated by the mechanisms of innate immunity. Innate immunity does not discriminate among the myriad agents that might gain entry into the host's body. Rather, it responds in a generalized manner that employs the inflammatory response, phagocytes, and plasma-borne components such as complement and interferons. In contrast, specific immunity does discriminate among pathogenic agents. Specific immunity is mediated by B and T lymphocytes and it serves, in large part, to amplify and focus the effector mechanisms of innate immunity.
[0004] The elaboration of an effective immune response requires contributions from both innate and specific immune mechanisms. The function of each of these arms of the immune system individually, as well as their interaction with each other, is carefully coordinated, both in a temporal/spatial manner and in terms of the particular cell types that participate. This coordination results from the actions of a number of soluble immunostimulatory mediators or “immune system stimulators” (Reviewed in, Trinchieri, et al., J. Cell. Biochem. 53:301-308 (1993)). Certain of these immune system stimulators initiate and perpetuate the inflammatory response and the attendant systemic sequelae. Examples of these include, but are not limited to, the proinflammatory mediators tumor necrosis factors α and β, interleukin-1, interleukin-6, interleukin-8, interferon-γ, and the chemokines RANTES, macrophage inflammatory proteins 1-α and 1-β, and macrophage chemotactic and activating factor. Other immune system stimulators facilitate interactions between B and T lymphocytes of specific immunity. Examples of these include, but are not limited to, interleukin-2, interleukin-4, interleukin-5, interleukin-6, and interferon-γ. Still other immune system stimulators mediate bidirectional communication between specific immunity and innate immunity. Examples of these include, but are not limited to, interferon-γ, interleukin-1, tumor necrosis factors α and β, and interleukin-12. All of these immune system stimulators exert their effects by binding to specific receptors on the surface of host cells, resulting in the delivery of intracellular signals that alter the function of the target cell. Cooperatively, these mediators stimulate the activation and proliferation of immune cells, recruit them to particular anatomical sites, and permit their collaboration in the elimination of the offending agent. The immune response induced in any individual is determined by the particular complement of immune system stimulators produced, and by the relative abundance of each.
[0005] In contrast to the immune system stimulators described above, the immune system has evolved other soluble mediators that serve to inhibit immune responses (Reviewed in, Arend, W. P., Adv. Int. Med. 40:365-394 (1995)). These “immune system inhibitors” provide the immune system with the ability to dampen responses in order to prevent the establishment of a chronic inflammatory state with the potential to damage the host's tissues. Regulation of host immune function by immune system inhibitors is accomplished through a variety of mechanisms as described below.
[0006] First, certain immune system inhibitors bind directly to immune system stimulators and, thus, prevent them from binding to plasma membrane receptors on host cells. Examples of these types of immune system inhibitors include, but are not limited to, the soluble receptors for tumor necrosis factors α and β, interferon-γ, interleukin-1, interleukin-2, interleukin-4, interleukin-6, and interleukin-7.
[0007] Second, certain immune system inhibitors antagonize the binding of immune system stimulators to their receptors. By way of example, interleukin-1 receptor antagonist is known to bind to the interleukin-1 membrane receptor. It does not deliver activation signals to the target cell but, by virtue of occupying the interleukin-1 membrane receptor, blocks the effects of interleukin-1.
[0008] Third, particular immune system inhibitors exert their effects by binding to receptors on host cells and signalling a decrease in their production of immune system stimulators. Examples include, but are not limited to, interferon-β, which decreases the production of two key proinflammatory mediators, tumor necrosis factor-α and interleukin-1 (Coclet-Ninin et al., Eur. Cytokine Network 8:345-349 (1997)), and interleukin-10, which suppresses the development of cell-mediated immune responses by inhibiting the production of the immune system stimulator, interleukin-12 (D'Andrea, et al., J. Exp. Med. 178:1041-1048 (1993)). In addition to decreasing the production of immune system stimulators, certain immune system inhibitors also enhance the production of other immune system inhibitors. By way of example, interferon-α 2b inhibits interleukin-1 and tumor necrosis factor-α production and increases the production of the corresponding immune system inhibitors, interleukin-1 receptor antagonist and soluble receptors for tumor necrosis factors α and β (Dinarello, C. A., Sem. in Oncol. 24(3 Suppl. 9):81-93 (1997).
[0009] Fourth, certain immune system inhibitors act directly on immune cells, inhibiting their proliferation and function, thereby, decreasing the vigor of the immune response. By way of example, transforming growth factor-β inhibits a variety of immune cells, and significantly limits inflammation and cell-mediated immune responses (Reviewed in, Letterio and Roberts, Ann. Rev. Immunol. 16:137-161 (1998)). Collectively, these various immunosuppressive mechanisms are intended to regulate the immune response, both quantitatively and qualitatively, to minimize the potential for collateral damage to the host's own tissues.
[0010] In addition to the inhibitors produced by the host's immune system for self-regulation, other immune system inhibitors are produced by infectious microorganisms. For example, many viruses produce molecules which are viral homologues of host immune system inhibitors (Reviewed in, Spriggs, M. K., Ann. Rev. Immunol. 14:101-130 (1996)). These include homologues of host complement inhibitors, interleukin-10, and soluble receptors for interleukin-1, tumor necrosis factors α and β, and interferons α, β and γ. Similarly, helminthic parasites produce homologues of host immune system inhibitors (Reviewed in, Riffkin, et al., Immunol. Cell Biol. 74:564-574 (1996)), and several bacterial genera are known to produce immunosuppressive products (Reviewed in, Reimann, et al., Scand. J. Immunol. 31:543-546 (1990)). All of these immune system inhibitors serve to suppress the immune response during the initial stages of infection, to provide advantage to the microbe, and to enhance the virulence and chronicity of the infection.
[0011] A role for host-derived immune system inhibitors in chronic disease also has been established. In the majority of cases, this reflects a polarized T cell response during the initial infection, wherein the production of immunosuppressive mediators (i.e., interleukin-4, interleukin-10, and/or transforming growth factor-β dominates over the production of immunostimulatory mediators (i.e., interleukin-2, interferon-γ, and/or tumor necrosis factor-β) (Reviewed in, Lucey, et al., Clin. Micro. Rev. 9:532-562 (1996)). Over-production of immunosuppressive mediators of this type has been shown to produce chronic, non-healing pathologies in a number of medically important diseases. These include, but are not limited to, diseases resulting from infection with: 1) the parasites, Plasmodium falciparum (Sarthou, et al. Infect. Immun. 65:3271-3276 (1997)), Tzypanosoma cruzi (Reviewed in, Laucella, et al. Revista Argentina de Microbioloqia 28:99-109 (1996)), Leishmania major (Reviewed in, Etges and Muller, J. Mol. Med. 76:372-390 (1998)), and certain helminths (Riffkin, et al., supra); 2) the intracellular bacteria, Mycobacterium tuberculosis (Baliko, et al., FEMS Immunol. Med. Micro. 22:199-204 (1998)), Mycobacterium avium (Bermudez and Champsi, Infect. Immun. 61:3093-3097 (1993)), Mycobacterium leprae (Sieling, et al. J. Immunol. 150:5501-5510 (1993)), Mycobacterium bovis (Kaufmann, et al., Ciba Fdn. Symp. 195:123-132 (1995)), Brucella abortus (Fernandes and Baldwin, Infect. Immun. 63:1130-1133 (1995)), and Listeria monocytogenes (Blauer, et al., J. Interferon Cytokine Res. 15:105-114 (1995)); and, 3) the intracellular fungus, Candida albicans (Reviewed in, Romani, et al., Immunol. Res. 14:148-162 (1995)). The inability to spontaneously resolve infection is influenced by other host-derived immune system inhibitors as well. By way of example, interleukin-1 receptor antagonist and the soluble receptors for tumor necrosis factors α and β are produced in response to interleukin-1 and tumor necrosis factor α and/or β production driven by the presence of numerous infectious agents. Examples include, but are not limited to, infections by Plasmodium falciparum (Jakobsen, et al. Infect. Immun. 66:1654-1659 (1998), Sarthou, et al., supra), Mycobacterium tuberculosis (Balcewicz-Sablinska, et al., J. Immunol. 161:2636-2641 (1998)), and Mycobacterium avium (Eriks and Emerson, Infect. Immun. 65:2100-2106 (1997)). In cases where the production of any of the aforementioned immune system inhibitors, either individually or in combination, dampens or otherwise alters immune responsiveness before the elimination of the pathogenic agent, a chronic infection may result.
[0012] In addition this role in infectious disease, host-derived immune system inhibitors contribute also to chronic malignant disease. Compelling evidence is provided by studies of soluble tumor necrosis factor receptor type I (sTNFRI) in cancer patients. Nanomolar concentrations of sTNFRI are synthesized by a variety of activated immune cells in cancer patients and, in many cases, by the tumors themselves (Aderka et al., Cancer Res. 51: 5602-5607 (1991); Adolf and Apfler, J. Immunol. Meth. 143: 127-36 (1991)). In addition, circulating sTNFRI levels often are elevated significantly in cancer patients (Aderka, et al., supra; Kalmanti, et al., Int. J. Hematol. 57: 147-152 (1993); Elsasser-Beile, et al., Tumor Biol. 15: 17-24 (1994); Gadducci, et al., Anticancer Res. 16: 3125-3128 (1996); Digel, et al., J. Clin. Invest. 89: 1690-1693 (1992) ), decline during remission and increase during advanced stages of tumor development (Aderka, et al., supra; Kalmanti, et al., supra; Elsasser-Beile, et al., supra; Gadducci, et al., supra) and, when present at high levels, correlate with poorer treatment outcomes (Aderka, et al., supra). These observations suggest that sTNFRI aids tumor survival by inhibiting anti-tumor immune mechanisms which employ tumor necrosis factors a and/or β (TNF), and they argue favorably for the clinical manipulation of sTNFRI levels as a therapeutic strategy for cancer.
[0013] Direct evidence that the removal of immune system inhibitors provides clinical benefit derives from the evaluation of Ultrapheresis, a promising experimental cancer therapy (Lentz, M. R., J. Biol. Response Modif. 8: 511-27 (1989); Lentz, M. R., Ther. Apheresis 3: 40-49 (1999); Lentz, M. R., Jpn. J. Apheresis 16: 107-14 (1997)). Ultrapheresis involves extracorporeal fractionation of plasma components by ultrafiltration. Ultrapheresis selectively removes plasma components within a defined molecular size range, and it has been shown to provide significant clinical advantage to patients presenting with a variety of tumor types. Ultrapheresis induces pronounced inflammation at tumor sites, often in less than one hour post-initiation. This rapidity suggests a role for preformed chemical and/or cellular mediators in the elaboration of this inflammatory response, and it reflects the removal of naturally occurring plasma inhibitors of that response. Indeed, immune system inhibitors of TNF α and β, interleukin-1, and interleukin-6 are removed by Ultrapheresis (Lentz, M. R., Ther. Apheresis 3: 40-49 (1999)). Notably, the removal of sTNFRI has been correlated with the observed clinical responses (Lentz, M. R., Ther. Apheresis 3: 40-49 (1999); Lentz, M. R., Jpn. J. Apheresis 16: 107-14 (1997)).
[0014] Ultrapheresis is in direct contrast to more traditional approaches which have endeavored to boost immunity through the addition of immune system stimulators. Pre-eminent among these has been the infusion of supraphysiological levels of TNF (Sidhu and Bollon, Pharmacol. Ther. 57: 79-128 (1993)), and of interleukin-2 (Maas, et al., Cancer Immunol. Immunother. 36: 141-148 (1993)), which indirectly stimulates the production of TNF. These therapies have enjoyed limited success (Sidhu and Bollon, supra; Maas, et al., supra) due to the fact: 1) that at the levels employed they proved extremely toxic; and, 2) that each increases the plasma levels of the immune system inhibitor, sTNFRI (Lantz, et al., Cytokine 2: 402-406 (1990); Miles, et al., Brit. J. Cancer 66: 1195-1199 (1992)). Together, these observations support the utility of Ultrapheresis as a biotherapeutic approach to cancer-one which involves the removal of immune system inhibitors, rather than the addition of immune system stimulators.
[0015] Although Ultrapheresis provides advantages over traditional therapeutic approaches, there are certain drawbacks that limit its clinical usefulness. Not only are immune system inhibitors removed by Ultrapheresis, but other plasma components, including beneficial ones, are removed since the discrimination between removed and retained plasma components is based solely on molecular size. An additional drawback to Ultrapheresis is the significant loss of circulatory volume during treatment, which must be offset by the infusion of replacement fluid. The most effective replacement fluid is an ultrafiltrate produced, in an identical manner, from the plasma of non-tumor bearing donors. A typical treatment regimen (15 treatments, each with the removal of approximately 7 liters of ultrafiltrate) requires over 200 liters of donor plasma for the production of replacement fluid. The chronic shortage of donor plasma, combined with the risks of infection by human immunodeficiency virus, hepatitis A, B, and C or other etiologic agents, represents a severe impediment to the widespread implementation of Ultrapheresis.
[0016] Because of the beneficial effects associated with the removal of immune system inhibitors, there exists a need for methods which can be used to specifically deplete those inhibitors from circulation. Such methods ideally should be specific and not remove other circulatory components, and they should not result in any significant loss of circulatory volume. The present invention satisfies these needs and provides related advantages as well.
SUMMARY OF THE INVENTION
[0017] The present invention provides a method for stimulating immune responses in a mammal through the depletion of immune system inhibitors present in the circulation of said mammal. The depletion of immune system inhibitors can be effected by removing biological fluids from said mammal and contacting these biological fluids with a binding partner capable of selectively binding to the targeted immune system inhibitor.
[0018] Binding partners useful in these methods can be antibodies, both polyclonal or monoclonal antibodies, or fractions thereof, having specificity for a targeted immune system inhibitor. Additionally, binding partners to which the immune system inhibitor naturally binds may be used. Synthetic peptides created to attach specifically to targeted immune system inhibitors also are useful as binding partners in the present methods. Moreover, mixtures of binding partners having specificity for multiple immune system inhibitors may be used.
[0019] In a particularly useful embodiment, the binding partner is immobilized previously on a solid support to create an “absorbent matrix” (FIG. 1). The exposure of biological fluids to such an absorbent matrix will permit binding by the immune system inhibitor, thus, effecting a decrease in its abundance in the biological fluids. The treated biological fluid can be returned to the patient. The total volume of biological fluid to be treated and the treatment rate are parameters individualized for each patient, guided by the induction of vigorous immune responses while minimizing toxicity. The solid support (i.e., inert medium) can be composed of any material useful for such purpose, including, for example, hollow fibers, cellulose-based fibers, synthetic fibers, flat or pleated membranes, silica-based particles, or macroporous beads.
[0020] In another embodiment, the binding partner can be mixed with the biological fluid in a “stirred reactor” (FIG. 2). The binding partner-immune system inhibitor complex then can be removed by mechanical or by chemical or biological means, and the altered biological fluid can be returned to the patient.
[0021] The present invention also provides apparatus incorporating either the absorbent matrix or the stirred reactor.
BRIEF DESCRIPTION OF THE FIGURES
[0022] [0022]FIG. 1 schematically illustrates the “absorbent matrix” configuration described herein. In this example, blood is removed from the patient and separated into a cellular and an acellular component, or fractions thereof. The acellular component, or fractions thereof, is exposed to the absorbent matrix to effect the binding and, thus, depletion of the targeted immune system inhibitor. The altered acellular component, or fractions thereof, then is returned contemporaneously to the patient.
[0023] [0023]FIG. 2 schematically illustrates the “stirred reactor” configuration described herein. In this example, blood is removed from the patient and separated into a cellular and an acellular component, or fractions thereof. A binding partner is added to the acellular component, or fractions thereof. Subsequently, the binding partner/immune system inhibitor complex is removed by mechanical or by chemical or biological means from the acellular component, or fractions thereof, and the altered biological fluid is returned contemporaneously to the patient.
[0024] [0024]FIG. 3 shows the depletion of sTNFRI from human plasma by absorbent matrices constructed with monoclonal and polyclonal anti-sTNFRI antibody preparations, and with a monoclonal antibody of irrelevant specificity.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The present invention provides novel methods to reduce the levels of immune system inhibitors in the circulation of a host mammal, thereby, potentiating an immune response capable of resolving a pathological condition. By enhancing the magnitude of the host's immune response, the invention avoids the problems associated with the repeated administration of chemotherapeutic agents which often have undesirable side effects (e.g., chemotherapeutic agents used in treating cancer).
[0026] The methods of the present invention generally are accomplished by: (a) obtaining a biological fluid from a mammal having a pathological condition; (b) contacting the biological fluid with a binding partner capable of selectively binding to a targeted immune system inhibitor to produce an altered biological fluid having a reduced amount of the targeted immune system inhibitor; and, thereafter (c) administering the altered biological fluid to the mammal As used herein, the term “immune system stimulator” refers to soluble mediators that increase the magnitude of an immune response, or which encourage the development of particular immune mechanisms that are more effective in resolving a specific pathological condition.
[0027] As used herein, the term “immune system inhibitor” refers to a soluble mediator that decreases the magnitude of an immune response, or which discourages the development of particular immune mechanisms that are more effective in resolving a specific pathological condition, or which encourages the development of particular immune mechanisms that are less effective in resolving a specific pathological condition. Examples of host-derived immune system inhibitors include interleukin-1 receptor antagonist, transforming growth factor-β, interleukin-4, interleukin-10, or the soluble receptors for interleukin-1, interleukin-2, interleukin-4, interleukin-6, interleukin-7, interferon-7 and tumor necrosis factors α and β. Immune system inhibitors produced by microorganisms are also potential targets including, for example, complement inhibitors, and homologues of interleukin-10, soluble receptors for interleukin-1, interferons α, β, and γ, and tumor necrosis factors α and β. As used herein, the term “targeted” immune system inhibitor refers to that inhibitor, or collection of inhibitors, which is to be removed from the biological fluid by the present method.
[0028] As used herein, the term “mammal” can be a human or a non-human animal, such as dog, cat, horse, cattle, pig, or sheep for example. The term “patient” is used synonymously with the term “mammal” in describing the invention.
[0029] As used herein, the term “pathological condition” refers to any condition where the persistence, within a host, of an agent, immunologically distinct from the host, is a component of or contributes to a disease state. Examples of such pathological conditions include, but are not limited to those resulting from persistent viral, bacterial, parasitic, and fungal infections, and cancer. Among individuals exhibiting such chronic diseases, those in whom the levels of immune system inhibitors are elevated are particularly suitable for the treatment of the invention. Plasma levels of immune system inhibitors can be determined using methods well-known in the art (See, for example, Adolf and Apfler, supra). Those skilled in the art readily can determine pathological conditions that would benefit from the depletion of immune system inhibitors according to the present methods.
[0030] As it relates to the present invention, the term “biological fluid” refers to the acellular component of the circulatory system including plasma, serum, lymphatic fluid, or fractions thereof. The biological fluids can be removed from the mammal by any means known to those skilled in the art, including, for example, conventional apheresis methods (See, Apheresis: Principles and Practice, McLeod , B. C., Price, T. H., and Drew, M. J., eds., AABB Press, Bethesda, Md. (1997)). The amount of biological fluid to be extracted from a mammal at a given time will depend on a number of factors, including the age and weight of the host mammal and the volume required to achieve therapeutic benefit. As an initial guideline, one plasma volume (approximately 5-7 liters in an adult human) can be removed and, thereafter, depleted of the targeted immune system inhibitor according to the present methods.
[0031] As used herein, the term “selectively binds” means that a molecule binds to one type of target molecule, but not substantially to other types of molecules. The term “specifically binds” is used interchangeably herein with “selectively binds”.
[0032] As used herein, the term “binding partner” is intended to include any molecule chosen for its ability to selectively bind to the targeted immune system inhibitor. The binding partner can be one which naturally binds the targeted immune system inhibitor. For example, tumor necrosis factor α or β can be used as a binding partner for sTNFRI. Alternatively, other binding partners, chosen for their ability to selectively bind to the targeted immune system inhibitor, can be used. These include fragments of the natural binding partner, polyclonal or monoclonal antibody preparations or fragments thereof, or synthetic peptides.
[0033] The present invention further relates to the use of various mixtures of binding partners. One mixture can be composed of multiple binding partners that selectively bind to different binding sites on a single targeted immune system inhibitor. Another mixture can be composed of multiple binding partners, each of which selectively binds to a single site on different targeted immune system inhibitors. Alternatively, the mixture can be composed of multiple binding partners that selectively bind to different binding sites on different targeted immune system inhibitors. The mixtures referred to above may include mixtures of antibodies or fractions thereof, mixtures of natural binding partners, mixtures of synthetic peptides, or mixtures of any combinations thereof.
[0034] For certain embodiments in which it would be desirable to increase the molecular weight of the binding partner/immune system inhibitor complex, the binding partner can be conjugated to a carrier. Examples of such carriers include, but are not limited to, proteins, complex carbohydrates, and synthetic polymers such as polyethylene glycol.
[0035] Additionally, binding partners can be constructed as multifunctional antibodies according to methods known in the art.
[0036] For example, bifunctional antibodies having two functionally active binding sites per molecule or trifunctional antibodies having three functionally active binding sites per molecule can be made by known methods. As used herein, “functionally active binding sites” refer to sites that are capable of binding to one or more targeted immune system inhibitors. By way of illustration, a bifunctional antibody can be produced that has functionally active binding sites, each of which selectively binds to different targeted immune system inhibitors.
[0037] Methods for producing the various binding partners useful in the present invention are well known to those skilled in the art.
[0038] Such methods include, for example, serologic, hybridoma, recombinant DNA, and synthetic techniques, or a combination thereof.
[0039] In one embodiment of the present methods, the binding partner is attached to an inert medium to form an absorbent matrix (FIG. 1). As used herein, the term “inert medium” is intended to include solid supports to which the binding partner(s) can be attached. Particularly useful supports are materials that are used for such purposes including, for example, cellulose-based hollow fibers, synthetic hollow fibers, silica-based particles, flat or pleated membranes, and macroporous beads. Such inert media can be obtained commercially or can be readily made by those skilled in the art. The binding partner can be attached to the inert medium by any means known to those skilled in the art including, for example, covalent conjugation. Alternatively, the binding partner may be associated with the inert matrix through high-affinity, non-covalent interaction with an additional molecule which has been covalently attached to the inert medium. For example, a biotinylated binding partner may interact with avidin or streptavidin previously conjugated to the inert medium.
[0040] The absorbent matrix thus produced can be contacted with a biological fluid, or a fraction thereof, through the use of an extracorporeal circuit. The development and use of extracorporeal, absorbent matrices has been extensively reviewed. (See, Kessler, L., Blood Purification 11:150-157 (1993)).
[0041] In another embodiment, herein referred to as the “stirred reactor” (FIG. 2), the biological fluid is exposed to the binding partner in a mixing chamber and, thereafter, the binding partner/immune system inhibitor complex is removed by means known to those skilled in the art, including, for example, by mechanical or by chemical or biological separation methods. For example, a mechanical separation method can be used in cases where the binding partner, and therefore the binding partner/immune system inhibitor complex, represent the largest components of the treated biological fluid. In these cases, filtration can be used to retain the binding partner and immune system inhibitors associated therewith, while allowing all other components of the biological fluid to permeate through the filter and, thus, to be returned to the patient. In an example of a chemical or biological separation method, the binding partner and immune system inhibitors associated therewith, can be removed from the treated biological fluid through exposure to an absorbent matrix capable of specifically attaching to the binding partner. For example, a matrix constructed with antibodies reactive with mouse immunoglobulins (e.g., goat anti-mouse IgG) would serve this purpose in cases where the binding partner were a mouse monoclonal IgG. Similarly, were biotin conjugated to the binding partner prior to its addition to the biological fluid, a matrix constructed with avidin or streptavidin could be used to deplete the binding partner and immune system inhibitors associated therewith from the treated fluid.
[0042] In the final step of the present methods, the treated or altered biological fluid, having a reduced amount of targeted immune system inhibitor, is returned to the patient receiving treatment along with untreated fractions of the biological fluid, if any such fractions were produced during the treatment. The altered biological fluid can be administered to the mammal by any means known to those skilled in the art, including, for example, by infusion directly into the circulatory system. The altered biological fluid can be administered immediately after contact with the binding partner in a contemporaneous, extracorporeal circuit. In this circuit, the biological fluid is (a) collected, (b) separated into cellular and acellular components, if desired, (c) exposed to the binding partner, and if needed, separated from the binding partner bound to the targeted immune system inhibitor, (d) combined with the cellular component, if needed, and (e) readministered to the patient as altered biological fluid. Alternatively, the administration of the altered biological fluid can be delayed under appropriate storage conditions readily determined by those skilled in the art.
[0043] It may be desirable to repeat the entire process. Those skilled in the art can readily determine the benefits of repeated treatment by monitoring the clinical status of the patient, and correlating that status with the concentration(s) of the targeted immune system inhibitor(s) in circulation prior to, during, and after treatment.
[0044] The present invention further provides novel apparatus for reducing the amount of a targeted immune system inhibitor in a biological fluid. These apparatus are composed of: (a) a means for separating the biological fluid into a cellular component and an acellular component or fraction thereof; (b) an absorbent matrix or a stirred reactor as described above to produce an altered acellular component or fraction thereof; and (c) a means for combining the cellular fraction with the altered acellular component or fraction thereof. These apparatus are particularly useful for whole blood as the biological fluid in which the cellular component is separated either from whole plasma or a fraction thereof.
[0045] The means for initially fractionating the biological fluid into the cellular component and the acellular component, or a fraction thereof, and for recombining the cellular component with the acellular component, or fraction thereof, after treatment are known to those skilled in the art. (See, Apheresis: Principles and Practice , supra.)
[0046] In one specific embodiment, the immune system inhibitor to be targeted is sTNFRI (Seckinger, et al., J. Biol. Chem. 264: 11966-73 (1989); Gatanaga, et al., Proc. Natl. Acad. Sci. 87: 8781-84 (1990)), a naturally occurring inhibitor of the pluripotent immune system stimulator, TNF. sTNFRI is produced by proteolytic cleavage which liberates the extracellular domain of the membrane tumor necrosis factor receptor type I from its transmembrane and intracellular domains (Schall, et al., Cell 61: 361-70 (1990); Himmler, et al., DNA and Cell Biol. 9: 705-715 (1990)). sTNFRI retains the ability to bind to TNF with high affinity and, thus, to inhibit the binding of TNF to the membrane receptor on cell surfaces.
[0047] The levels of sTNFRI in biological fluids are increased in a variety of conditions which are characterized by an antecedent increase in TNF. These include bacterial, viral, and parasitic infections, and cancer as described above. In each of these disease states, the presence of the offending agent stimulates TNF production which stimulates a corresponding increase in sTNFRI production. sTNFRI production is intended to reduce localized, as well as systemic, toxicity associated with elevated TNF levels and to restore immunologic homeostasis.
[0048] In tumor bearing hosts, over-production of sTNFRI may profoundly affect the course of disease, considering the critical role of TNF in a variety of anti-tumor immune responses (Reviewed in, Beutler and Cerami, Ann. Rev. Immunol. 7:625-655 (1989)). TNF directly induces tumor cell death by binding to the type I membrane-associated TNF receptor. Moreover, the death of vascular endothelial cells is induced by TNF binding, destroying the circulatory network serving the tumor and further contributing to tumor cell death. Critical roles for TNF in natural killer cell- and cytotoxic T lymphocyte-mediated cytolysis also have been documented. Inhibition of any or all of these effector mechanisms by sTNFRI has the potential to dramatically enhance tumor survival.
[0049] That sTNFRI promotes tumor survival, and that its removal enhances anti-tumor immunity, has been demonstrated. In an experimental mouse tumor model, sTNFRI production was found to protect transformed cells in vitro from the cytotoxic effects of TNF, and from cytolysis mediated by natural killer cells and cytotoxic T lymphocytes (Selinsky, et al., Immunol. 94: 88-93 (1998)). In addition, the secretion of sTNFRI by transformed cells has been shown to markedly enhance their tumorigenicity and persistence in vivo (Selinsky and Howell, unpublished). Moreover, removal of circulating sTNFRI has been found to provide clinical benefit to cancer patients, as demonstrated by human trials of Ultrapheresis as discussed above (Lentz, M. R., supra). These observations affirm the importance of this molecule in tumor survival, and suggest the development of methods for more specific removal of sTNFRI as promising new avenues for cancer immunotherapy.
[0050] The following examples are intended to illustrate but not limit the invention.
EXAMPLE 1
Production, Purification, and Characterization of the Immune System Inhibitor, Human sTNFRI
[0051] The sTNFRI used in the present studies was produced recombinantly in cell culture. The construction of the eukaryotic expression plasmid, the methods for transforming cultured cells, and for assaying the production of sTNFRI by the transformed cells have been described (Selinsky, et al., supra). The sTNFRI expression plasmid was introduced into HeLa cells (American Type Culture Collection #CCL 2), and an sTNFRI-producing transfectant cell line was isolated by limiting dilution. This cloned cell line was cultured in a fluidized-bed reactor at 37° C. in RPMI-1640, supplemented with 2.5% (v/v) fetal bovine serum and penicillin/streptomycin, each at 100 micrograms per milliliter. sTNFRI secreted into the culture medium was purified by affinity chromatography on a TNF-Sepharose-4B affinity matrix essentially as described (Engelmann, et al., J. Biol. Chem. 265:1531-1536).
[0052] sTNFRI was detected and quantified in the present studies by capture ELISA (Selinsky, et al., supra). In addition, the biological activity of recombinant sTNFRI, i.e., its ability to bind TNF, was confirmed by ELISA. Assay plates were coated with human TNF-α (Chemicon), blocked with bovine serum albumin, and sTNFRI, purified from culture supernatants as described above, was added. Bound sTNFRI was detected through the sequential addition of biotinylated-goat anti-human sTNFRI, alkaline phosphatase-conjugated streptavidin, and ρ-nitrophenylphosphate.
EXAMPLE 2
Production of Absorbent Matrices
[0053] Binding partners used in the present studies include an IgG fraction of goat anti-human sTNFRI antisera (R&D Systems, Cat.#AF425-PB) and a monoclonal antibody reactive with sTNFRI (Biosource International, Cat.#AHR3912). An additional monoclonal antibody, OT145 (Cat.#TCR1657), reactive with a human T cell receptor protein, was purchased from T Cell Diagnostics (now, Endogen) and was used as a control binding partner. Each of these respective binding partners was covalently conjugated to cyanogen bromide-activated Sepharose-4B (Pharmacia Biotech), a macroporous bead which facilitates the covalent attachment of proteins. Antibodies were conjugated at 1.0 milligram of protein per milliliter of swollen gel, and the matrices were washed extensively according to the manufacturer's specifications. Matrices were equilibrated in phosphate buffered saline prior to use.
EXAMPLE 3
Depletion of the Immune System Inhibitor, sTNFRI, from Human Plasma Using Absorbent Matrices
[0054] Normal human plasma was spiked with purified sTNFRI to a final concentration of 10 nanograms per milliliter, a concentration comparable to those found in the circulation of cancer patients (Gadducci, et al., supra). One milliliter of the spiked plasma was mixed with 0.25 milliliter of the respective absorbent matrices at 0° C. and a plasma sample was removed at time=0. The samples were warmed rapidly to 37° C., and incubated with agitation for an additional 45 minutes. Plasma samples were removed for analysis at 15 minute intervals and, immediately after collection, were separated from the beads by centrifugation. Samples were analyzed by ELISA to quantify the levels of sTNFRI, and to permit the determination of the extent of depletion.
[0055] [0055]FIG. 3 shows the results of the sTNFRI depletion. The absorbent matrix produced with the goat anti-human sTNFRI polyclonal antibody rapidly removed the sTNFRI from the plasma sample; 90% of the sTNFRI was depleted within 15 minutes. The residual 1 nanogram per milliliter of sTNFRI in these samples is within the range of sTNFRI concentrations found in healthy individuals (Aderka, et al., supra; Chouaib, et al., Immunol. Today 12:141-145 (1991)). The matrix produced with the monoclonal anti-human sTNFRI antibody, in contrast, only removed approximately one-fifth of the plasma sTNFRI. The differences in the ability of these two matrices to deplete sTNFRI likely reflect the influence of avidity which is enabled by the heterogeneity of epitope specificities present in the polyclonal antibody preparation. The control matrix produced no reduction in sTNFRI levels, confirming the specificity of the depletion observed with the anti-sTNFRI antibody matrices.
[0056] Although the invention has been described with reference to the presently preferred embodiments, it should be understood that various modifications can be made without departing from the spirit of the invention. Accordingly, the invention is limited only by the following claims.
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The present invention provides a method for enhancing an immune response in a mammal to facilitate the elimination of a chronic pathology. The method involves the removal of immune system inhibitors from the circulation of the mammal, thus, enabling a more vigorous immune response to the pathogenic agent. The removal of immune system inhibitors is accomplished by contacting biological fluids of a mammal with one or more binding partner(s) capable of binding to and, thus, depleting the targeted immune system inhibitor(s) from the biological fluids. Particularly useful in the invention is an absorbent matrix composed of an inert, biocompatible substrate joined covalently to a binding partner, such as an antibody, capable of specifically binding to the targeted immune system inhibitor.
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BACKGROUND OF THE INVENTION
The present invention relates to novel 5-thiocarbamoyl-1,3,4-oxadiazoles which are active as insecticides.
The cyclization of thio- and dithiocarbazic acid ester derivatives which are acylated in position 3 by the radical of a carboxyic, sulfonic, carbamic, phosphoric, thiophosphoric or thiophosphonic acid with phosgene to give compounds of the formula: ##STR2## where y is O or S, Acyl is --COC 6 H 5 , --SO 2 C 6 H 5 , CO 2 C 2 H 5 , CON(CH 3 ) 2 or ##STR3## is disclosed by Rufenacht in Helvetica Chimica Acta 56, 162-175 (1973). The compounds where Acyl is phosphoryl or thiophosphoryl ##STR4## are disclosed as having an "insecticidal, acaricidal, and nematicidal effect"; however, the compounds where X and O are disclosed as unstable.
Rufenacht, supra, also discloses the preparation of compounds of the formulae: ##STR5## The compounds of formula (B) are disclosed as "having an insecticidal and acaricidal effect" but also as "not stable enough under the conditions of practical pesticide use".
U.S. Pat. No. 3,661,926 issued to Van den Bos et al. discloses 2-oxo-3-dialkoxyphosphoro-5-alkyl (or cycloalkyl of 5 to 7 carbons)-1,3,4-oxadiazolines as insecticidal.
U.S. Pat. No. 3,523,951 issued to Rufenacht teaches derivatives of 1,3,4-thiadiazole as possessing insecticidal activity.
My commonly assigned patent application, "Insecticidal 2-Oxo-3-Dialkoxyphosphoro-5-Cyclopropyl-1,3,4-Oxadiazoline, Ser. No. 343,088, filed Jan. 27, 1982, now U.S. Pat. No. 4,426,379 discloses compounds of the formula: ##STR6## wherein R is hydrogen, lower alkyl or lower alkoxy; R 1 and R 2 are independently lower alkyl; and Y is either oxygen or sulfur.
My commonly assigned U.S. patent application, "Insecticidal N-Carbamoyl-Oxadiazonin-5-Ones and Thiones" Ser. No. 514,073 filed July 15, 1983, discloses insecticidal compounds of the formula: ##STR7## wherein X is oxygen or sulfur; R 1 and R 2 are independently lower alkyl having from 1 to 4 carbon atoms; and R 3 is lower alkyl having from 1 to 6 carbon atoms, lower cycloalkyl having from 3 to 6 carbon atoms optionally substituted with methyl or ethyl, lower alkoxyalkyl having up to a total of 8 carbon atoms or lower alkylthioalkyl having up to a total of 8 carbon atoms.
SUMMARY OF THE INVENTION
The present invention relates to insecticidal 5-thiocarbamoyl-1,3,4-oxadiazoles of the formula: ##STR8## wherein R 1 and R 2 are independently lower alkyl having from 1 to 4 carbon atoms; and R 3 is lower alkyl having from 1 to 6 carbon atoms, lower cycloalkyl having from 3 to 6 carbon atoms optionally substituted with methyl or ethyl, lower alkoxyalkyl having up to a total of 8 carbon atoms or lower alkylthioalkyl having up to a total of 8 carbon atoms.
Among other factors, the present invention is based on my finding that these compounds are surprisingly active as insecticides, and are particularly effective against common insect pests such as aphids and cockroaches.
Preferred compounds include those which have R 3 groups in which the carbon atom attached to the oxadiazole ring is a tertiary carbon.
DEFINITIONS
As used herein, the following terms have the following meanings, unless expressly stated to the contrary.
The term "alkyl" refers to both straight- and branched-chain alkyl groups. The term "lower alkyl" refers to both straight- and branched-chain alkyl groups having a total of from 1 to 6 carbon atoms and includes primary, secondary and tertiary alkyl groups. Typical lower alkyls include, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, n-hexyl, and the like.
The term "alkylene" refers to the group --(CH 2 ) m -- wherein m is an integer greater than zero. Typical alkylene groups include methylene, ethylene, propylene, and the like.
The term "alkoxy" refers to the group --OR' wherein R' is an alkyl group. The term "lower alkoxy" refers to alkoxy groups having from 1 to 6 carbon atoms; examples include methoxy, ethoxy, n-hexoxy, n-propoxy, isopropoxy, isobutoxy, and the like.
The term "alkoxyalkyl" refers to an alkyl group substituted with an alkoxy group. The term "lower alkoxyalkyl" refers to groups having up to a total of 8 carbon atoms and includes, for example, ethoxymethyl, methoxymethyl, 2-methoxypropyl, and the like.
The term "alkylthio" refers to the group --SR' wherein R' is an alkyl group. The term "lower alkylthio" refers to alkylthio groups having from 1 to 6 carbon atoms; examples include methylthio, ethylthio, n-hexylthio, n-propylthio, isopropylthio, isobutylthio, and the like.
The term "alkylthioalkyl" refers to an alkyl group substituted with an alkylthio group. The term "lower alkylthioalkyl" refers to groups having up to a total of 8 carbon atoms and includes, for example, ethylthiomethyl, methylthiomethyl, 2-methylthiopropyl, and the like.
The term "cycloalkyl" refers to cyclic alkyl groups. The term "lower cycloalkyl" refers to groups having from 3 to 6 carbon atoms in the ring, and includes cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.
The term "tertiary carbon" refers to the group ##STR9## wherein R', R"' and R"' are independently lower alkyl, or R"' is an alkoxy or alkylthio group, or R"' and R"' taken together are an alkylene group, thus forming a cycloalkyl group.
The term "oxadiazole" refers to the group ##STR10## The conventional numbering system for this group is shown below: ##STR11##
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention may be prepared according to the following reaction scheme: ##STR12##
Reaction (1) is conducted by combining approximately equimolar amounts of II and III. It is preferred to add III slowly to cooled and stirred II. The reaction is conducted at a temperature from about 0° C. to about 50° C., preferably from about 0° C. to about 25° C., and is generally complete within about 3 to about 8 hours. The product, IV, is isolated by conventional procedures such as washing, extraction, drying, stripping, and the like, or alternatively, is used in Reaction (2) without further isolation and/or purification.
Reaction (2) is conducted by combining approximately equimolar amounts of IV and V in solvent. It is preferred to slowly add V to a cooled and stirred mixture of IV and water. Suitable solvents include protic solvents such as low molecular weight alcohols (methanol, ethanol, isopropyl alcohol, etc.), water and the like. Hydrazine, V, may be used either in its anhydrous form or as a hydrazine hydrate such as hydrazine monohydrate. If anhydrous hydrazine is used, it is preferred to add a small amount of water (about 5 to 10 ml) to the reaction mixture. The reaction is conducted at a temperature from about 0° C. to about 50° C., preferably from about 0° C. to about 25° C., and is generally complete within about 8 to about 12 hours. The product, VI, is isolated by conventional procedures such as washing, extraction, drying, stripping, or the like, or alternatively, may be used in Reaction (3) without further isolation and/or purification.
Reaction (3) is conducted by combining VI, VII and solvent. Although approximately equimolar amounts of VI and VII may be used, it may be preferred to use an excess of VII due to its volatility. Although the reactants may be combined in any order, it is preferred to add VII to a stirred solution of VI in solvent. The VI-solvent may be cooled for the addition of VII, since the addition is exothermic. Suitable solvents include polar organic solvents such as dimethylformamide, dimethylsulfoxide, and the like. The reaction is conducted at a temperature from about 0° C. to about 50° C., preferably about 0° C. to about 25° C., and is generally complete within about 8 to about 18 hours. The product, VIII, is isolated by conventional procedures such as washing, extraction, drying, stripping, chromatography, distillation, and the like.
Reaction (4) is conducted by first combining IX and VII in solvent; it is preferred to add IX to a cooled solution (about -10° C. to about 10° C.) of VII in solvent. The resulting mixture is allowed to stir about 1/2 to about 1 hour to allow the reagents to react. Then X is added to the reaction system. It is preferred to cool the reaction system again prior to adding X. The reaction system is then stirred about 1 to about 2 hours to allow for reaction. Then, XI is added to the reaction system, which has been preferably cooled before adding the XI. The reaction is conducted at a temperature from about 0° C. to about 50° C., and is generally complete within about 5 to about 12 hours. For convenience, the reaction mixture may be stirred about 8 to about 12 hours between the various additions. If desired, the reaction system is cooled to about -10° C. to about 20° C. before each addition, because of the exothermic nature of the additions. Suitable solvents include polar organic solvents such as dimethoxyethane, tetrahydrofuran, and the like. The product, I, is isolated by conventional procedures such as washing, extraction, drying, stripping, chromatography, distillation, and the like.
Alternatively, I may be prepared from VIII according to Reaction (4a) which uses XII in place of phosgene (X) and dialkylamine (XI). Thus, Reaction (4a) is conducted by first combining IX and VIII in solvent. It is preferred to add IX slowly to a stirred mixture of VIII in solvent which has been cooled to about -10° C. to about 10° C. The resulting mixture is then stirred about 2 to about 6 hours to allow for complete reaction of the reagents, cooled as previously, and then XII is added slowly. The reaction is conducted at a temperature of about 0° C. to about 50° C., and is generally complete within 2 to about 8 hours. Suitable solvents include polar organic solvents such as dimethoxyethane, tetrahydrofuran, and the like.
UTILITY
The compounds of this invention are useful for controlling insects, particularly such insects as aphids and cockroaches. However, some insecticidal compounds of this invention may be more insecticidially active than others against particular pests.
Like most insecticidals, they are not usually applied full strength, but are generally incorporated with conventional biologically inert extenders or carriers normally employed for facilitating dispersion of active ingredients for agricultural chemical application, recognizing the accepted fact that the formulation and mode of application may effect the activity of a material. The toxicants of this invention may be applied as sprays, dusts, or granules to the insects, their environment or hosts susceptible to insect attack. They may be formulated as granules of large particle size, powdery dusts, wettable powders, emulsifiable concentrates, solutions, or as any of several other known types of formulations, depending on the desired mode of application.
Wettable powders are in the form of finely divided particles which disperse readily in water or other dispersants. These compositions normally contain from 5-80% toxicant and the rest inert material which includes dispersing agents, emulsifying agents, and wetting agents. The powder may be applied to the soil as a dry dust or preferably as a suspension in water. Typical carriers include fuller's earth, kaolin clays, silicas, and other highly absorbent, readily wet, inorganic diluents. Typical wetting, dispersing or emulsifying agents used in insecticidal formulations include, for example, the alkyl and alkylaryl sulfonates and sulfonates and their sodium salts; alkylamide sulfonates, including fatty methyl taurides; alkylaryl polyether alcohols, sulfated higher alcohols, and polyvinyl alcohols; polyethylene oxides; sulfonated animal and vegetable oils; sulfonated petroleum oils; fatty acid esters of polyhydric alcohols and the ethylene oxide addition products of such esters; and the addition products of long-chain mercaptans and ethylene oxide. Many other types of useful surface-active agents are available in commerce. The surface-active agent, when used, normally comprises from 1-15% by weight of the pesticidal composition.
Dusts are freely flowing admixtures of the active ingredient with finely divided solids such as talc, natural clays, keiselguhr, pyrophyllite, chalk, diatomaceous earths, calcium phosphates, calcium and magnesium carbonates, sulfur, lime, flours, and other organic and inorganic solids which act as dispersants and carriers for the toxicant. These finely divided solids have an average particle size of less than about 50 microns. A typical dust formulation useful herein contains 75% silica and 25% of the toxicant.
Useful liquid concentrates include the emulsifiable concentrates, which are homogeneous liquid or paste compositions which are readily dispersed in water or other dispersants, and may consist entirely of the toxicant with a liquid or solid emulsifying agent, or may also contain a liquid carrier such as xylene, heavy aromatic naphthas, isophorone, and other nonvolatile organic solvents. For application, these concentrates are dispersed in water or other liquid carriers, and are normally applied as a spray to the area to be treated.
Other useful formulations for insecticidal applications include simple solutions of the active ingredient in a dispersant in which it is completely soluble at the desired concentration such as acetone, alkylated naphthalenes, xylene, or other organic solvents. Granular formulations, wherein the toxicant is carried on relatively coarse particles, are of particular utility for aerial distribution or for penetration of cover-crop canopy. Baits, prepared by mixing solid or liquid concentrates of the toxicant with a suitable food such as a mixture of cornmeal and sugar, are useful formulations for control of insect pests. Pressurized sprays, typically aerosols wherein the active ingredient is dispersed in finely divided form as a result of vaporization of a low-boiling dispersant solvent carrier such as the Freons, may also be used. All of these techniques for formulating and applying the active ingredient are well known in the art.
The percentages by weight of the toxicant may vary according to the manner in which the composition is to be applied and the particular type of formulation, but in general comprise 0.1-95% of the toxicant by weight of the insecticidal composition.
The insecticidal compositions may be formulated and applied with other active ingredients, including nematocides, insecticides, fungicides, bactericides, plant-growth regulators, fertilizers, etc. In applying the chemical, an effective amount and concentration of the toxicant of this invention is, of course, employed.
The terms "insecticide" and "insect" as used herein refer to their broad and commonly understood usage rather than to those creatures which, in the strict biological sense, are classified as insects. Thus, the term "insect" is used not only to include small invertebrate animals belonging to the class "Insecta", but also to other related classes of arthropods, whose members are segmented invertebrates having more or fewer than six legs, such as spiders, mites, ticks, centipedes, worms, and the like.
A further understanding of the invention can be had in the following non-limiting Examples. Wherein, unless expressly stated to the contrary, all temperatures and temperatures ranges refer to the Centigrade system and the term "ambient" or "room temperature" refers to about 20°-25° C. The term "percent" refers to weight percent and the term "mol" or "mols" refers to gram mols. The term "equivalent" refers to a quantity of reagent equal in mols, to the mols of the preceding or succeeding reatant recited in that example in terms of finite mols or finite weight or volume. Also, unless expressly stated to the contrary, geometric isomer and racemic mixtures are used as starting materials and correspondingly, isomer mixtures are obtained as products.
EXAMPLES
Example 1
Preparation of ##STR13##
Ethyl Trimethylacetylthioate
In a three-neck flask, 50.0 g (0.411 mole) trimethylacetyl chloride were placed, then stirred and cooled in an ice-water bath. Ethanethiol, 25.5 g (0.411 mole), was then slowly added dropwise. The reaction mixture was stirred overnight and then refluxed about 8 hours, to expel hydrogen chloride gas. The reaction was stirred at room temperature over the weekend. The reaction flask was evacuated to remove any additional hydrogen chloride gas. The yield was 57.0 g. The product was used in Example 2 without further isolation.
EXAMPLE 2
Preparation of ##STR14##
Trimethylacetyl Hydrazide
Ethyl trimethylacetylthioate (the product of Example 1), 57.0 g (0.39 mole), and ethanol were placed in a three-neck flask, then stirred and cooled with a dry ice/acetone bath. Hydrazine monohydrate, 19.5 g (0.39 mole) then was added slowly dropwise (in a very exothermic reaction). The reaction mixture was stirred overnight at room temperature, refluxed about 8 hours, and then stirred overnight at room temperature. The solvent was removed in vacuo. The above-identified product was used in Example 3 without further purification.
EXAMPLE 3
Preparation of ##STR15##
2-Mercapto-5-tert-butyl-1,3,4-Oxadiazole
A stirred mixture of 32.5 g (0.28 mole) trimethylacetyl hydrazide (the product of Example 2), in 250 ml dimethylformamide was cooled to about 0° C. in a dry ice/acetone bath. To that mixture, 21.3 g (0.28 mole) carbon disulfide was added slowly dropwise (in a moderately exothermic reaction). The reaction mixture was stirred overnight at room temperature and then refluxed about 4 hours. The reaction mixture was cooled in an ice-water bath to give an oil which was extracted with methylene chloride, dried over magnesium sulfate, stripped and chromatographed on silica gel, eluting with methylene chloride to give the above-identified product as a solid, melting point 79°-80° C.
Elemental analysis for C 6 H 10 N 2 OS showed: calculated %C 45.55%, %H 6.37, and %N 17.70; found %C 45.84, %H 6.47, and %N 17.84.
EXAMPLE 4
Preparation of ##STR16##
S-(N,N-Dimethylcarbamoyl)-2-Thio-5-tert-butyl-1,3,4-Oxadiazole
To a stirred mixture of 10.0 g (0.063 mole) 2-mercapto-5-tert-butyl-1,3,4-oxadiazole (the product of Example 3) in 200 ml dimethoxyethane cooled to about -10° C. in a dry ice/acetone bath, 3.0 g of 50% sodium hydride (0.063 mole) was added slowly (in a very exothermic reaction). The reaction mixture was stirred about 2 hours. The reaction mixture was cooled as before and 49.9 g of 12.5% phosgene (0.063 mole) were added (in a very exothermic reaction). The reaction mixture was stirred overnight at room temperature. The reaction mixture was cooled again as before and 5.7 g (0.126 mole) anhydrous dimethylamine was added (in an exothermic reaction). The resulting mixture was stirred overnight at room temperature. The mixture was washed with about 40 ml water, extracted with methylene chloride, dried over magnesium sulfate, and stripped to give an oil. Chromatography on silica gel, eluting with methylene chloride, gave the above-identified product as a yellow oil.
Elemental analysis for C 9 H 15 N 3 O 2 S showed: calculated %C 47.14%, %H 6.59, and %N 18.33; found %C 47.15, %H 6.66, and %N 18.39.
EXAMPLE 5
Preparation of ##STR17##
Ethyl Cyclopropane Carboxythioate
In a three-neck, 500-ml flask, 56.0 g (0.469 mole) cyclopropane carboxylic acid chloride were placed, stirred and cooled to about 10° C. with an ice-water bath. Ethanethiol, 29.1 g (0.469 mole) was then added rapidly dropwise. The reaction mixture was allowed to come to room temperature and was stirred over the weekend at room temperature. The reaction mixture was refluxed about 8 hours and stirred overnight at room temperature; the refluxing and stirring were repeated twice. About 57.3 g of the above-identified product was obtained which was used in Example 6 without further isolation.
EXAMPLE 6
Preparation of ##STR18##
Cyclopropane Carboxylic Acid Hydrazide
To a stirred mixture of 57.3 g (0.440 mole) ethyl cyclopropane carboxythioate (the product of Example 5) in about 25 ml water which was cooled to about -10° C. with a dry ice/acetone bath, 22.0 g (0.440 mole) hydrazine monohydrate was added slowly dropwise (with an exothermic reaction). The mixture first turned orange and then dark green. The reaction mixture was stirred overnight at room temperature, refluxed about 8 hours, and then stirred over the weekend at room temperature. The mixture was extracted with methylene chloride (about 200 ml) and chloroform (about 200 ml) mixed together. The organic phase was dried over magnesium sulfate and then stripped in the hood. The product was then used in Example 7 without further isolation.
EXAMPLE 7
Prepartion of ##STR19##
2-Mercapto-5-Cyclopropyl-1,3,4-Oxadiazole
To a stirred mixture of 17.9 g (0.179 mole) cyclopropane carboxylic acid hydrazide (the product of Example 6) in about 75 ml dimethylformamide, 68.0 g (0.894 mole) carbon disulfide was added (and all solids dissolved). The solution turned orange and then green. The reaction mixture was stirred about 1 hour at room temperature, refluxed about 3 hours, and stirred overnight at room temperature. The mixture was added to an ice-water bath to give an oil. The mixture was extracted with methylene chloride. The methylene chloride fraction was dried over magnesium sulfate and stripped. Chromatography on silica gel, eluting with methylene chloride, gave the above-identified product as a solid, melting point 76°-78° C.
Elemental analysis for C 5 H 6 N 2 OS showed: calculated %C 42.23%, %H 4.24, and %N 19.71; found %C 42.47, %H 4.39, and %N 20.05.
EXAMPLE 8
Preparation of ##STR20##
S-(N,N-Dimethylcarbamoyl)-2-Thio-5-Cyclopropyl-1,3,4-Oxadiazole
To a stirred solution of 8.0 g (0.056 mole) 2-mercapto-5-cyclopropyl-1,3,4-oxadiazole (the product of Example 7) is about 200 ml dimethoxyethane which was cooled to about -10° C. in a dry ice/acetone bath, 2.7 g of 50% sodium hydride (0.056 mole) was added slowly (in a very vigorous exothermic reaction). The reaction mixture was stirred about 3 hours at ambient temperature. The mixture was then cooled to about -30° C. with a dry ice/acetone bath, and 44.3 g of 12.5% phosgene (0.056 mole) were added. The resulting mixture was stirred about 12 hours at about 25° C. The reaction mixture was cooled to about 0° C. with a dry ice/acetone bath and 5.05 g (0.0112 mole) anhydrous dimethylamine were added. The resulting mixture was stirred overnight at about 25° C. The mixture was washed with water, extracted with methylene chloride, dried over magnesium chloride and stripped. Chromatography on silica gel, eluting with ether, gave the product as a yellow oil.
Elemental analysis for C 8 H 11 N 3 O 2 S showed: calculated %C 45.06%, %H 5.20, and %N 19.70; found %C 45.24, %H 5.26, and %N 18.34.
EXAMPLE 9
Preparation of ##STR21##
S-(N,N-Dimethylcarbamoyl)-2-Thio-5-Isopropyl-1,3,4-Oxadiazole
To a stirred solution of 13.0 g (0.090 mole) 2-mercapto-5-isopropyl-1,3,4-oxadiazole in about 250 ml dimethoxyethane which had been cooled to about -40° C. with a dry ice/acetone bath, 4.3 g of 50% sodium hydride (0.090 mole) was added slowly (in a vigorous exothermic reaction). The reaction mixture was stirred about 1 hour and cooled as before; then 9.6 g (0.09 mole) N,N-dimethylcarbamoyl chloride was added slowly dropwise. The reaction mixture was stirred overnight at room temperature, refluxed about 4 hours, and stirred overnight at room temperature. The mixture was washed with about 50 ml water and extracted with methylene chloride. The organic phase was dried over magnesium sulfate and stripped. Chromatography on silica gel, eluting with methylene chloride, gave the product as an amber oil.
Elemental analysis for C 8 H 13 N 3 O 2 S showed: calculated %C 44.63%, %H 6.09, and %N 19.52; found %C 46.52, %H 6.51, and %N 20.45.
Compounds made in accordance with Examples 1 to 9 are shown in Table I.
In addition, by following the procedures described in Examples 1 to 9 using the appropriate starting materials, the following compounds are made:
S-(N,N-dimethylcarbamoyl)-2-thio-5-methoxymethyl-1,3,4-oxadiazole; and
S-(N,N-dimethylcarbamoyl)-2-thio-5-(2-methylthio-isopropyl)-1,3,4-oxadiazole.
EXAMPLE A
Aphid Control
The compounds of the invention were tested for their insecticidal activity against Cotton Aphids (Aphis gossypii Glover). An acetone solution of the candidate toxicant containing a small amount of nonionic emulsifier was diluted with water to 40 ppm. Cucumber leaves infested with the Cotton Aphids were dipped in the toxicant solution. Mortality readings were taken after 24 hours. The results are tabulated in Table II in terms of percent control.
EXAMPLE B
Aphid Systemic Evaluation
This procedure is used to assess the ability of a candidate insecticide to be absorbed through the plant root system and translocate to the foliage.
Two cucumber plants planted in a 4-inch fiber pot with a soil surface area of 80 cm 2 are used. Forty ml of an 80-ppm solution of the candidate insecticide is poured around the plants in each pot. (This corresponds to 40 γ/cm 2 of actual toxicant.) The plants are maintained throughout in a greenhouse at 75°-85° F. Forty-eight hours after the drenching, the treated plants are infested with aphids by placing well-colonized leaves over the treated leaves so as to allow the aphids to migrate easily from the inoculated leaf to the treated leaf. Three days after infestation, mortality readings were taken. The results are tabulated in Table II in terms of percent control.
EXAMPLE C
Mite Adult
Two-spotted Mite (Tetranychus urticae): An acetone solution of the candidate toxicant containing a small amount of nonionic emulsifier was diluted with water to 40 ppm. Lima bean leaves which were infested with mites were dipped in the toxicant solution. Mortality readings were taken after 24 hours. The results are tabulated in Table II in terms of percent control.
EXAMPLE D
Mite Egg Control
Compounds of this invention were tested for their ovicidal activity against eggs of the two-spotted spider mite (Tetranychus urticae). An acetone solution of the test toxicant containing a small amount of nonionic emulsifier was diluted with water to give a concentration of 40 ppm. Two days before testing, 2-week-old lima bean plants were infested with spider mites. Two days after infestation, leaves from the infested plants were dipped in the toxicant solution, placed in a petri dish with filter paper and allowed to dry in the open dish at room temperature. The treated leaves were then held in covered dishes at about 31° C. to 33° C. for seven days. On the eighth day, egg mortality readings were taken. The results, expressed as percent control, are tabulated in Table II.
EXAMPLE E
Housefly
Housefly (Musca domestica L.): A 500-ppm acetone solution of the candidate toxicant was placed in a microsprayer (atomizer). A random mixture of anesthetized male and female flies were placed in a contaiiner and 55 mg of the above-described acetone solution was sprayed on them. A lid was placed on the container. A mortality reading was made after 24 hours. The results are tabulated in Table II in terms of percent control.
EXAMPLE F
American Cockroach
American Cockroach (Periplaneta americana L.): A 500-ppm acetone solution of the candidate toxicant was placed in a microsprayer (atomizer). A random mixture of anesthetized male and female roaches was placed in a container and 55 mg of the above-described acetone solution was sprayed on them. A lid was placed on the container. A mortality reading was made after 24 hours. The results are tabulated in Table II in terms of percent control.
EXAMPLE G
Alfalfa Weevil
Alfalfa Weevil (H. burnneipennis Boheman): A 500-ppm acetone solution of the candidate toxicant was placed in a microsprayer (atomizer). A random mixture of anesthetized male and female flies was placed in a container and 55 mg of the above-described acetone solution was sprayed on them. A lid was placed on the container. A mortality reading was made after 24 hours. The results are tabulated in Table II in terms of percent control.
EXAMPLE H
Cabbage Looper Control
The compounds of the invention were tested for their insecticidal activity against Cabbage Looper (Trichoplusia ni). An acetone solution of the candidate toxicant containing a small amount of nonionic emulsifier was diluted with water to 500 ppm. Excised cucumber leaves were dipped in the toxicant solution and allowed to dry. They were then infested with Cabbage Looper larvae. Mortality readings were taken after 24 hours. The results are tabulated in Table II in terms of percent control.
TABLE I__________________________________________________________________________Compounds of the Formula: ##STR22## ELEMENTAL ANALYSIS Physical % Carbon % Hydrogen % NitrogenCompound No. R.sup.1 R.sup.2 R.sup.3 State Calc. Found Calc. Found Calc. Found__________________________________________________________________________1 30287 CH.sub.3 CH.sub.3 ##STR23## Yellow Oil 45.06 45.24 5.20 5.26 19.70 18.34 2 30288 CH.sub.3 CH.sub.3 C(CH.sub.3).sub.3 Yellow Oil 47.16 47.15 6.59 6.66 18.33 18.393 30572 CH.sub.3 CH.sub.3 CH(CH.sub.3).sub.2 Amber Oil 44.63 46.52 6.09 6.51 19.52 20.45__________________________________________________________________________
TABLE II______________________________________CompoundNo. A AS MA ME HF AR AW CL______________________________________1 30287 100 100 0 -- 70 100 10 02 30288 100 100 0 0 100 100 100 1003 30572 99 100 0 0 0 99 0 50______________________________________ A = Aphid AS = Aphid Systemic MA = Mite Adult ME = Mite Egg HF = Housefly AR = American Cockroach AW = Alfalfa Weevil CL = Cabbage Looper
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Compounds of the formula: ##STR1## wherein R 1 and R 2 are independently lower alkyl having from 1 to 4 carbon atoms; and R 3 is lower alkyl having from 1 to 6 carbon atoms, lower cycloalkyl having from 3 to 6 carbon atoms optionally substituted with methyl or ethyl, lower alkoxyalkyl having up to a total of 8 carbon atoms or lower alkylthioalkyl having up to a total of 8 carbon atoms are insecticidal.
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BACKGROUND OF THE INVENTION
The present invention concerns a bucket-, claw-, scraper blade- or compacting-type attachment intended to be fitted to an arm of a machine to which a rock breaker is connected.
Hydraulic rock breakers comprising a tool are used during operations involving the destruction of surfacing or hard ground layers and for breaking blocks of rock or concrete during earthwork or demolition operations.
Use of such a machine causes extensive production of spoil, which hampers the destruction operation. This spoil must therefore be regularly removed or compacted. Soil overlying rock may also need to be removed before using the rock breaker.
DESCRIPTION OF THE PRIOR ART
For this reason, rock breaker usage implies regular implementation of one or more attachments, such as a spoil removal device or a compacting device. Generally, each attachment is mechanically fixed to the end of the articulated arm of a distinct earthwork machine, such as a mechanical or hydraulic excavator. However, only one earthwork machine can be used, on which a rock breaker fitted with a tool or a spoil removal device is fitted according to the operation in progress.
On currently known machines, when the articulated arm is fitted with a rock breaker and the spoil produced needs to be removed, the rock breaker has to be removed before installing the required spoil removal device. During removal, the rock breaker has to be disconnected from its supply circuit, which is generally hydraulic.
These fitting and dismantling operations involving the rock breaker or attachment required for usage are long and reduce significantly the availability of the carrier machine.
There are already a number of devices designed to curtail these dismantling and disconnection operations.
For example, document EP 0 717 154 describes a hydraulic rock breaker comprising a tool connected to one end of an articulated arm and on which is attached a spoil removal bucket, which can swivel and be retracted when the rock breaker is used. However, this bucket cannot be removed. A machine according to this document certainly allows fitting and dismantling of the bucket to be avoided, when the rock breaker is being used, but it nevertheless remains necessary to remove the tool, when the user wants to use the bucket. Furthermore, the presence of the bucket at the end of the articulated arm of the carrier machine during hydraulic rock breaker usage is detrimental to the unit handling capacity and reduces its use to limited areas because of the spatial requirement of the bucket.
SUMMARY OF THE INVENTION
The aim of the present invention is to overcome the previously stated drawbacks and, to this end, consists in a bucket-, claw-, scraper blade- or compacting-type attachment intended to be fitted to one end of a rock breaker equipped with a tool, characterized in that it comprises, on the one hand, means allowing it to be correctly positioned with respect to the rock breaker and its tool and, on the other hand, means allowing it to be temporarily fixed at the end of the rock breaker and to be removable without dismantling the tool.
When the operator of the machine wishes to use the attachment instead of the tool, he places the attachment at the end of the rock breaker, the means allowing the attachment to be positioned with respect to the tool providing a clearance, into which the tool can be inserted and located. Once positioning has been completed, fixing means allow the attachment to be locked in translation and in rotation. Tool disconnection is therefore unnecessary because of this and the attachment can be used even with the tool in place. This means that operations required for tool changing turn out to be greatly minimized and do not disrupt proper usage of the rock breaker.
Preferably, the attachment comprises a back wall with an external face fitted with a guide tube intended to be engaged on the tool. This tube is intended to receive the tool, which then plays the part of an upright providing reinforcement and support. Attachment stability is thereby increased.
Preferably again, the tube has an insertion end widened into the shape of a funnel. Tool insertion into the tube is much easier because of this.
Preferably, the insertion end is surmounted by a socket fitted with at least one positioning pin.
According to a first form of embodiment, the tube comprises two orifices facing each other, allowing a fixing key intended to be engaged in a recess in, or in a hole through, the tool.
According to another form of embodiment of this attachment, the means allowing it to be fixed include at least two fixing lugs mounted on the top wall of the attachment, each incorporating an eye, and through which a retaining bar can be inserted and fixed, passing over a collar or similar belonging to the rock breaker body.
According to yet another form of embodiment, this attachment comprises a top wall surmounted by a lock-bolt, which can pass alternately from a locked position, in which it is capable of locking a part of the rock breaker body, to an unlocked position, in which it is capable of releasing this body.
In this case, the attachment comprises advantageously elastic means tending to place automatically the lock-bolt in its locked position and a pressure cylinder or mechanism capable of acting on the lock-bolt to throw it into the open position. This allows the operator to connect and disconnect the attachment at distance without acting directly on it.
According to one form of embodiment, this attachment comprises elastic means tending to place automatically the lock-bolt in its locked position and a release mechanism comprising a plate, mounted to slide with respect to the top wall of the attachment and transversely to the axis of the tool, such that, in the locked position of the tool, one end of the plate bears on a cam-shaped surface of the lock-bolt and its other end bears on an inclined surface of a collar of the tool, and that during movement of the tool, its collar displaces the plate toward the lock-bolt, which causes the latter to pivot in an opening direction.
According to another characteristic of the invention, this attachment comprises means of rotational locking onto the rock breaker comprising a noncircular-shaped socket intended to co-operate by interlocking with a complementary surface of the bottom end of the rock breaker body.
The invention will be better understood through the following description referring to the appended schematic drawing representing several forms of embodiment of this attachment.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a perspective view of an attachment and a rock breaker seen in a removed position.
FIG. 2 is a perspective view of the attachment in FIG. 1 fixed to the rock breaker.
FIG. 3 is a partial view of a longitudinal cross section through the attachment and the earthmoving machine represented in FIG. 2 .
FIG. 4 is a cross-sectional view along transverse line IV-IV in FIG. 3 .
FIG. 5 is a cross-sectional view along line V-V in FIG. 3 .
FIG. 6 is a perspective view of an attachment and a rock breaker according to a second embodiment of the invention, in a removed position.
FIG. 7 is a perspective view of the attachment in FIG. 6 fixed to the rock breaker.
FIG. 8 is a schematic view of a longitudinal cross section through an attachment according to a third embodiment of the invention attached to a perforating tool.
FIG. 9 is a cross-sectional view of an attachment according to a fourth embodiment of the invention fixed to a rock breaker.
FIGS. 10 and 11 represent longitudinal cross sections through an alternative to the device in FIG. 9 .
DESCRIPTION OF THE PREFERRED EMBODIMENTS
An attachment 1 according to the invention, such as the one represented in FIGS. 1 to 5 , is a bucket-type device for removing spoil. As in all conventional buckets, the structure of this one comprises horizontal top and bottom walls 2 and 3 respectively, connected by two parallel side walls 4 and a back wall 5 .
The bucket 1 also comprises both a horizontal socket 6 extending in prolongation of the top wall 3 toward the back of the bucket 1 and an essentially vertical tube 7 extending along the external face of the back wall 5 . Moreover, the socket has an opening 8 of slightly larger cross-sectional area than the cross-sectional area of the tube 7 and this opening is located on the axis of the latter tube.
More precisely, the tube 7 has an insertion end widened into the shape of a funnel supporting the socket 6 .
Moreover, the top face of the socket 6 has an essentially annular peripheral edge 9 delimiting an essentially ovoid bearing surface 10 with a noncircular extension 11 partially overhanging the top wall 3 of the bucket 1 . Positioning pins 12 are positioned at regular intervals around the edge 9 and each has an inclined surface sloping toward the opening 8 .
Outside the edge 9 , the top wall 3 has two fixing lugs 13 directed upwards and positioned facing each other on each side of the bearing surface 10 at its extension 11 . Each fixing lug 13 incorporates an eye 14 , which emerges just above the edge 9 and which is located facing the eye 14 of the other fixing lug 13 .
This bucket 1 is intended to equip a hydraulic rock breaker, partially represented in FIGS. 1 to 5 , comprising a body 15 of essentially circular cross section and with an end 16 to which a tool 17 is connected. Moreover, the end 16 of the body 15 is provided with a collar 18 featuring, on the one hand, a cross section complementary to the bearing surface 10 of the bucket 1 and, on the other hand, a thickness essentially equal to the height of the edge 9 . A part 19 of the collar 18 therefore projects from the body 15 because of the ovoid cross section of the collar 18 .
A user wishing to connect the bucket 1 according to the invention to the end of the body 15 of the rock breaker proceeds in the following way.
The bucket 1 is positioned such that the tube 7 and the opening 8 are aligned with the tool 17 . The latter tool is inserted through the opening 8 , then into the tube 7 , which plays the part of a slide keeping the bucket 1 stationary with respect to the axis of the body 15 . The funnel formed by the insertion end of the tube 7 facilitates insertion of the tool 17 into the tube 7 .
The bucket 1 is displaced in this way until the collar 18 is introduced within the edge 9 and comes into contact with the bearing surface 10 , the projecting part 19 of the collar 18 then being in contact with the extension 11 of the bearing surface 10 .
Positioned in this way, the bucket 1 can be fixed to the body 15 . To perform this, a retaining bar 20 is inserted through the eyes 14 of the fixing lugs 13 then locked, for example using pins 20 a . FIGS. 2 to 5 show the bucket 1 attached to the body 15 of the rock breaker in this way.
Since the cross sections of the collar 18 and the bearing surface 10 are noncircular, the bucket 1 cannot rotate about the axis of the body 15 because the projecting part 19 of the collar 18 would come up against the edge 9 . Translation of the bucket 1 along the axis of the articulated arm 15 is also inhibited by the retaining bar 20 , up against which the projecting part 19 of the collar 18 would come. The retaining bar 20 also prevents deviation of the bucket 1 with respect to the axis of the tool 17 , when using this bucket 1 . The tube 7 also inhibits such a deviation and allows the forces exerted in this direction on the retaining bar 20 and on the projecting part 19 of the collar 18 to be reduced.
When proceeding to remove the bucket 1 , the pins are simply unfastened without tooling and the retaining bar 20 is then drawn out. Released in this way, the bucket can be slid along the axis of the tool 17 to extract it from the tube 7 and the socket 6 .
It emerges from the description that operations for installing and removing the bucket 1 do not require removal of the tool 17 .
As represented in FIGS. 6 and 7 , a collar with an oval cross section and two opposed projecting parts can be provided in order to better the forces distribute and to allow safer fixing of a bucket 22 on a rock breaker body 23 .
The bucket 22 differs from the bucket 1 by the fact that it comprises a horizontal socket 24 , which extends in prolongation of the top wall 3 toward the back of the bucket 22 and features an opening 25 . More precisely, the top face of the socket 24 has a peripheral edge 26 delimiting an essentially oval bearing surface 27 , complementary to the collar of the body 23 , with a front end 28 and a rear end 29 . Positioning teeth 30 are provided at regular intervals along the edge 26 .
Furthermore, outside the edge 26 , the socket 24 has a first pair of fixing lugs 31 and a second pair of fixing lugs 32 ; the lugs 31 , 32 of each pair being positioned facing each other on each side of the bearing surface 27 at its front end 28 and rear end 29 respectively. Each fixing lug 31 , 32 is provided with an eye, which emerges just above the edge 26 and is located facing the eye of the other fixing lug 31 , 32 of the corresponding pair. The tube 7 located along the bucket is then no longer required.
Attachment of the bucket 22 is performed in the same way as for the bucket 1 . The perforating tool 17 is inserted into the opening 25 until the collar is introduced within the edge 26 and is in contact with the bearing surface 27 , the projecting parts of the collar then being in contact with the front end 28 and the rear end 29 of the bearing surface 27 .
Positioned thus, the bucket 22 can be fixed to the body 23 . To perform this, a retaining bar 33 is inserted through the eyes of the fixing lugs 31 , then locked using pins. Similarly, a retaining bar 34 is inserted through the eyes of the fixing lugs 32 , then also locked in this position.
FIG. 8 shows a bucket 35 adapted to a tool 36 . This bucket 35 differs from the bucket 1 by the fact that it comprises neither a socket nor an insertion end and by the fact that the tube 7 comprises two orifices (not represented) facing each other. The tool 36 differs from the tool 17 only by the fact that it comprises a recess 37 intended for passing a fixing key 38 .
When proceeding to fix the bucket 35 onto the tool 36 , the tool 36 is simply inserted into the tube 7 until the recess 37 is aligned with the orifices in the tube 7 . The key 38 is then successively inserted through a first orifice in the tube 7 , the recess 37 and the second orifice in the tube 7 , then it is locked in this position.
The key 38 locks the bucket 35 in both rotation and translation. Furthermore, the tube 7 stabilizes the bucket 35 and prevents any deviation of it with respect to the axis of the perforating tool 36 .
Obviously, this fixing method can be combined with the other fixing methods described.
FIG. 9 shows a bucket 39 fitted onto a rock breaker 40 .
The bucket 39 comprises a horizontal socket 41 which extends in prolongation of the top wall 3 toward the back of the bucket 39 and features an opening 42 . This socket 41 differs from the socket 6 of the bucket 1 by the fact that it comprises a partial peripheral edge 43 , open in front, which defines a contact surface 48 intended for receiving the rock breaker 40 . Positioning teeth 44 are provided at regular intervals along the edge 43 .
The front of the socket 41 comprises, on the one hand, a lug 45 , on which a pivoting lock-bolt 46 with an orthogonal return 47 is mounted and, on the other hand, a heel 49 formed such that it provides a sufficient clearance to allow rotation of the lock-bolt 46 . A spring 52 connects the heel 49 to the socket 41 such that the latter is automatically thrown into its locked position.
The rock breaker 40 is of essentially circular cross section and has an end 54 , to which a tool 17 is connected. A bearing pad 55 is fixed to the outside of the rock breaker 40 at the end 54 such that it is directed toward the front of the bucket 39 , when the latter is connected. A pressure cylinder 56 , from which a stem 57 extends, is fixed above the bearing pad 55 . This pressure cylinder 56 is fixed high enough to ensure the stem 57 can press on the return 47 of the lock-bolt 46 , when the bucket is mounted.
The spring 52 pushes back the lock-bolt 46 into the locked position before the bucket 39 is installed on the rock breaker 40 . The stem 57 retracts into the pressure cylinder.
To connect the bucket 39 , the perforating tool 17 is inserted into the tube 7 until, on the one hand, the end 54 is in contact with the bearing surface 44 inside the edge 43 and, on the other hand, the bearing pad 55 is facing the lock-bolt 46 . During insertion, the end 54 of the rock-breaker 40 returns, through its bearing pad 55 , the lock-bolt 46 toward its unlocked position, acting against the spring 52 associated with it. This results in the end 54 of the rock-breaker 40 being gripped between the lock-bolt 46 , which bears on the bearing pad 55 , and the back part of the edge 43 .
To remove the bucket 39 , the pressure cylinder 56 should be actuated in a stem extension direction such that it is caused to press on the return 47 of the lock-bolt 46 . In doing this, the latter pivots in the trigonometrical direction toward its unlocked position, in which it no longer presses the rock-breaker 40 against the edge 43 . It is then possible to extract the rock-breaker 40 and the perforating tool 17 from the edge 43 and the tube 7 respectively to remove the bucket.
FIGS. 10 and 11 represent an alternative to the device in FIG. 9 , in which the same components are designated by the same references as before. This form of embodiment differs from the former by the attachment unlocking mechanism. This mechanism comprises a plate 58 mounted to slide with respect to the top wall 3 of the attachment, perpendicularly to the axis of the tool 17 . One end of this plate 58 bears on a cam-shaped surface 59 of the lock-bolt 46 and its opposite end bears against an inclined surface 60 of a collar 61 of the tool 17 . This plate is subjected to the action of a tension spring 62 , which acts on it in a displacement direction toward the collar. In the unlocked position, represented in FIG. 10 , the plate 58 bears on the underside of the collar 61 .
To unlock and disconnect the attachment, the rock breaker should be operated, even sporadically, to displace the tool 17 downwards, a movement during which the inclined surface 60 of the collar 61 pushes the plate 58 , which acts on the cam 59 to throw the lock-bolt 46 outwards, as shown in FIG. 11 , and to release the bottom wall 54 of the rock breaker. Unlocking is thereby performed using the inherent energy of the rock breaker and without the need for manual intervention by the operator, who can remain at his control station.
Whilst the invention has been described in conjunction with specific execution examples, it is obvious that it is in no way limited and includes all technical equivalents of the described means as well as their combinations, if these fall within the scope of the invention.
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The invention relates to a bucket-, claw-, scraper-blade- or compacting-type attachment ( 1 ) which is intended to be fitted at one end ( 18 ) of a rock breaker ( 15 ) comprising a tool ( 17 ). The inventive attachment comprises: (i) means ( 7, 8, 9, 12 ) enabling the correct positioning thereof in relation to the rock breaker and the tool; and (ii) means ( 13, 14, 20 ) for fixing same temporarily and removably to the end of the rock breaker, without dismantling the tool ( 17 ).
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[0001] Pursuant to 35 U.S.C. §119 (a), this application claims the benefit of earlier filing date and right of priority to Korean Patent Application No. 10-2010-0086741, filed on Sep. 3, 2010, the contents of which are hereby incorporated by reference in their entirety.
BACKGROUND OF THE DISCLOSURE
[0002] 1. Field
[0003] Exemplary embodiments of the present disclosure may relate to an energy metering system, an energy metering method and a watt hour meter of supporting dynamic time-varying energy pricing, wherein information on energy use history of a user can be recorded in detail and managed under various energy pricing systems where energy prices are changed in time.
[0004] 2. Background
[0005] Many attempts have been made recently to efficiently use limited natural resources. Concomitant with the attempts, methods have been waged to differentiate energy prices based on energy production and consumption circumstances, and a technology called smart grid or smart meter has been gaining attentions of various fields.
[0006] The smart grid is a next generation bi-directional technological framework to realize efficient power usage by constructing a new transmission network having a communication channel along with the transmission network and using this intelligent transmission network. The background idea of the smart grid is to realize efficient management of the amount of power use, swift handling of an incident, remote control of the amount of power use, distributed power generation using power generation facilities outside the control of a power company, or charging management of an electric vehicle. An essential element of the smart grid is the smart meter.
[0007] From a view point of a user toward the smart grid, the user can utilize energy at a most reasonable time zone suitable for the user by searching for the zone in response to change in energy prices.
[0008] The term “smart meter” is an electronic meter added by communication function to enable a bi-directional communication between energy suppliers and consumers, whereby energy usage can be remotely, accurately and on-time checked without a human meter reader, there is no need of human meter readers physically going to energy consumers at a regular interval, and metering cost and energy consumption can be advantageously saved.
[0009] Meantime, as energy price is changed in time along with advancement of new energy-related technologies including the smart meter and smart grid, users can positively adjust energy consumption in response to energy prices and situations.
[0010] Under these circumstances, a technique is inevitably needed for managing an energy usage history due to reasons including, but not limited to, provision of energy price information changing in time, provision of how each user uses the energy and obtainment of calculation base of energy consumption rate.
SUMMARY OF THE DISCLOSURE
[0011] The present disclosure is disclosed to meet the aforementioned need, and therefore, it is an object of the present disclosure to provide an energy metering system, an energy metering method and a watt hour meter of supporting dynamic time-varying energy pricing, wherein information on energy use history of a user, such as how much of energy and when a user has consumed, and what energy price the user has used the energy, can be recorded in detail and managed under various dynamic time-varying energy pricing systems.
[0012] Technical subjects to be solved by the present disclosure are not restricted to the above-mentioned description, and any other technical problems not mentioned so far will be clearly appreciated from the following description by the skilled in the art.
[0013] In one general aspect of the present disclosure, there is provided an energy metering system, the system supporting dynamic time-varying energy pricing, comprising: a remote server managing the dynamic time-varying energy pricing system where energy price changes in time; a communication network connecting the remote server and an energy meter; and the energy meter measuring energy consumption flowing via the energy metering system, and receiving time-based energy price information from the communication network, wherein the energy meter extracts current time-applied energy price information from the time-based energy price information, and time-sequentially records in storage means a record including time information of relevant unit time for each unit time, the extracted energy price information and energy consumption information at relevant unit time.
[0014] In another general aspect of the present disclosure, there is provided an energy metering method, the method supporting dynamic time-varying energy pricing system, the method comprising: receiving, by an energy meter, time-based energy price information from a remote server through a communication network; measuring, by the energy meter, energy consumption and monitoring whether a pre-set unit time has elapsed; and time-sequentially recording in storage means, by the energy meter, a record including time information of relevant unit time for each unit time, energy price information applied to relevant unit time and energy consumption information at the relevant unit time.
[0015] Optionally, the energy meter measures any one of electricity, gas and water consumption.
[0016] Optionally, the unit time is any one of one minute, two minutes, three minutes, four minutes, five minutes, six minutes, ten minutes, 12 minutes, 15 minutes, 20 minutes, 30 minutes, one hour and one day.
[0017] In still another general aspect of the present disclosure, there is provided a watt hour meter, the meter supporting dynamic time-varying energy pricing system, the meter comprising: communication means receiving time-based electric price information from a remote server or a user; metering means measuring power consumption flowing through the watt hour meter; storage means recording the measured power consumption and operation information of the watt hour meter; time check means measuring a current time; and processing means processing the watt hour meter in which electric price is dynamically changed in time, wherein the processing means extracts current time-applied electric price information from time-based electric price information received from the communication means, and time-sequentially records in storage means a record including time information of relevant unit time for each unit time, the extracted electric price information and power consumption information at relevant unit time.
[0018] Optionally, the watt hour meter further includes display means capable of displaying electric price information.
[0019] Optionally, the display means displays the current time-applied electric price information at all times or intermittently.
[0020] Optionally, the display means periodically displays the current time-applied electric price information.
[0021] Optionally, the processing means displays future time-scheduled electric price information through the display means.
[0022] Optionally, the current time measured by the time check means is adjustable.
[0023] Optionally, the current time is adjustable by communication with other devices, or personally adjustable by a user through a user interface disposed at the watt hour meter.
[0024] Optionally, the unit time is any one of one minute, two minutes, three minutes, four minutes, five minutes, six minutes, ten minutes, 12 minutes, 15 minutes, 20 minutes, 30 minutes, one hour and one day.
[0025] Optionally, the unit time-based power information includes forward direction power information supplied to a load during relevant unit time.
[0026] Optionally, the forward direction power information includes one or more of effective power, ineffective power, apparent power, current amount and voltage amount.
[0027] Optionally, the time-based electric price information includes one or more of effective power unit price (won/kwh), ineffective power unit price (won/kvarh), apparent power unit price (won/kVAh), current amount unit price (won/kl 2 h) and voltage unit price (won/KV 2 h), each relative to forward direction power energy, where won is Korean currency.
[0028] Optionally, the unit time-based power information includes reverse direction power information supplied from alternative energy source to power supply line during relevant unit time.
[0029] Optionally, the time-based electric price information includes power factor unit price.
[0030] Optionally, the time-based electric price information includes rate information based on TOU (Time Of Use), CPP (Critical Peak Pricing) or RTP (Real Time Pricing).
[0031] Optionally, the watt hour meter further includes function of transmitting the electric price information to other device.
[0032] Optionally, the other device includes IHD (In Home Display).
ADVANTAGEOUS EFFECTS
[0033] According to the present disclosure, records showing energy use history of a user for each unit time are sequentially recorded, each record including time information of relevant unit time for each unit time, energy price information applied to relevant unit time and energy consumption information at the relevant unit time, whereby information on how much, when and at what price the user has used the energy can be accurately and quite obviously managed. The energy use history can be displayed by energy meter by itself, or displayed through a home display device and can be checked at any time.
[0034] Therefore, his or her energy use history can be easily checked out without recourse to collecting energy pricing information tables or checking energy consumption for each time zone and energy pricing information tables one by one in order to find out his or her energy use history.
[0035] Once details on their energy use history are easily checked out by users, the users can adjust energy consumption more positively to save energy, thereby living up to current trend heading for reasonable energy consumption.
[0036] Furthermore, as the energy use history includes energy consumption information for each unit time and energy pricing information on relevant time, the energy use history may be advantageously utilized as a base for calculating energy use charge. In a non-limiting example, an energy supply company may use an energy use history managed by the energy meter to settle energy use charge, and use the energy use history as back-up information for charging.
[0037] In addition, the energy use history may be advantageously utilized as an important evidential data in case an energy use charge conflicts with users occur.
BRIEF DESCRIPTION OF THE DRAWINGS
[0038] Accompanying drawings are included to provide a further understanding of arrangements and embodiments of the present disclosure and are incorporated in and constitute a part of this application. Now, non-limiting and non-exhaustive exemplary embodiments of the disclosure are described with reference to the following drawings, in which:
[0039] FIG. 1 is a schematic view illustrating an energy metering system according to an exemplary embodiment of the present disclosure;
[0040] FIG. 2 illustrates various examples of energy pricing structures that change in time;
[0041] FIG. 3 illustrates an example of record structure recording energy use history;
[0042] FIGS. 4 and 5 illustrate examples of a structure recording and managing an energy use history in storage means
[0043] FIG. 6 is an energy metering method according to exemplary embodiments of the present disclosure;
[0044] FIG. 7 is a watt hour meter according to an exemplary embodiment of the present disclosure;
[0045] FIG. 8 is a watt hour meter according to another exemplary embodiment of the present disclosure;
[0046] FIG. 9 is an example in which a current electric price is displayed on a screen.
[0047] FIG. 10 is an example in which an energy use history is displayed on a screen; and
[0048] FIG. 11 is an example illustrating forward power and reverse power.
[0049] Additional advantages, objects, and features of the disclosure will be set forth in part in the description which follows and in part will become apparent to those having ordinary skill in the art upon examination of the following or may be learned from practice of the disclosure. The objectives and other advantages of the disclosure may be realized and attained by the method particularly pointed out in the written description and claims hereof as well as the appended drawings.
DETAILED DESCRIPTION
[0050] Hereinafter, exemplary embodiments of the present disclosure are described in detail with reference to the accompanying drawings. It will be appreciated that for simplicity and/or clarity of illustration, elements illustrated in the figure have not necessarily been drawn to scale. For example, the dimensions of some of the elements may be exaggerated relative to other elements for clarity. Further, if considered appropriate, reference numerals have been repeated among the figures to indicate corresponding and/or analogous elements.
[0051] Particular terms may be defined to describe the disclosure in the best mode as known by the inventors. Accordingly, the meaning of specific terms or words used in the specification and the claims should not be limited to the literal or commonly employed sense, but should be construed in accordance with the spirit and scope of the disclosure. The definitions of these terms therefore may be determined based on the contents throughout the specification.
[0052] In the following detailed description, numerous specific details are set forth to provide a thorough understanding of claimed subject matter. However, it will be understood by those skilled in the art that claimed subject matter may be practiced without these specific details. In other instances, well-known methods, procedures, components and/or circuits have not been described in detail.
[0053] In the following description and/or claims, the terms coupled and/or connected, along with their derivatives, may be used. In particular embodiments, connected may be used to indicate that two or more elements are in direct physical and/or electrical contact with each other. Coupled may mean that two or more elements are in direct physical and/or electrical contact. However, coupled may also mean that two or more elements may not be in direct contact with each other, but yet may still cooperate and/or interact with each other. For example, “coupled”, and “connected” may mean that two or more elements do not contact each other but are indirectly joined together via another element or intermediate elements.
[0054] Furthermore, the term “and/or” may mean “and”, it may mean “or”, it may mean “exclusive-or”, it may mean “one”, it may mean “some, but not all”, it may mean “neither”, and/or it may mean “both”, although the scope of claimed subject matter is not limited in this respect.
[0055] In the following description and/or claims, the terms “comprise” and “include,” along with their derivatives, may be used and are intended as synonyms for each other. Furthermore, the terms “including”, “includes”, “having”, “has”, “with”, or variants thereof are used in the detailed description and/or the claims to denote non-exhaustive inclusion in a manner similar to the term “comprising”.
[0056] Words such as “thereafter,” “then,” “next,” etc. are not intended to limit the order of the processes; these words are simply used to guide the reader through the description of the methods. The terms “first,” “second,” and the like, herein do not denote any order, quantity, or importance, but rather are used to distinguish one element from another, and the terms “a” and “an” herein do not denote a limitation of quantity, but rather denote the presence of at least one of the referenced item.
[0057] In describing the present disclosure, detailed descriptions of constructions or processes known in the art may be omitted to avoid obscuring appreciation of the invention by a person of ordinary skill in the art with unnecessary detail regarding such known constructions and functions.
[0058] Now, exemplary embodiments of the present disclosure will be described in detail with reference to the accompanying drawings.
[0059] Referring to FIG. 1 , energy supplied by an energy supply company ( 11 ) is transmitted to each consumer ( 10 ) through an energy supply line ( 13 ), where the consumer ( 10 ) uses the energy supplied through the energy supply line ( 13 ). The term of “energy” in the present disclosure includes any one of gas, electricity and water, unless specified otherwise.
[0060] An energy metering system according to the present disclosure includes a remote server and an energy meter ( 23 ) installed at each consumer, where the remote server and the energy meter communicate through various wireless/wired communication networks ( 22 ) and exchange information related to various energies.
[0061] The remote server ( 21 ), which is a server performing a function related to energy supply services provided by the energy supply company ( 11 ), transmits time-based energy pricing information to the energy meter ( 23 ) through the communication network ( 22 ). Energy pricing structure is subject to change based on TOU (Time Of Use) pricing, CPP (Critical Peak Pricing) and RTP (Real-Time Pricing) system.
[0062] FIG. 2 a illustrates a TOU system mainly used in factories, shopping districts and large buildings and shows that energy prices change in time. FIG. 2 b illustrates a CPP system, showing that energy prices change in time, with highest price at a peak section. FIG. 2 c illustrates a RTP system where energy prices change in real time. These energy pricing structures may be variably and unlimitedly configured in consideration of energy supply and consumption patterns.
[0063] The communication network ( 22 ) communicating with the remote server ( 21 ) and the energy meter ( 23 ) may include various communication networks. In a non-limiting example, the communication network ( 22 ) may include a power line communication network, an Internet network, a CDMA (Code Division Multiple Access) network, a PCS (Personal Communication Service) network, a PHS (Personal Handyphone System) network and a Wibro (Wireless Broadband Internet) network.
[0064] The energy consumer ( 10 ) is present with various loads ( 16 - 1 16 - k ) consuming the energy transmitted through the energy supply line ( 13 ). The energy meter ( 23 ) may a watt hour meter, a gas meter or a water meter. Basically, the energy meter ( 23 ) serves to measure energy consumption consumed by each load ( 16 - 1 16 - k ). The energy meter ( 23 ) may be variably configured based on types of energies and required functions. The energy meter ( 23 ) receives the energy pricing information based on time transmitted by the remote server ( 21 ) through the communication network ( 22 ), and operates using the information.
[0065] Particularly, the energy meter ( 23 ) records and manages an energy use (consumption) history of energy consumer ( 10 ), where the energy use history is information on how much, when and at what price a user (consumer) has used the energy, and is recorded and managed in the form of information by unit time, and where unit time may be arbitrarily set up. To be more specific, the unit time may be set up in any one of one minute, two minutes, three minutes, four minutes, five minutes, six minutes, ten minutes, 12 minutes, 15 minutes, 20 minutes, 30 minutes, one hour and one day.
[0066] The types of information manageable by the energy use history may be variable, and in the present disclosure, the energy use history includes at least time information of relevant unit time, energy pricing information applied to the relevant unit time and energy consumption information at the relevant unit time.
[0067] Referring to FIGS. 3 , 4 and 5 , an energy metering method in which the energy meter ( 23 ) records and manages the energy use history will be described in detail.
[0068] Referring to FIG. 3 , each record ( 30 ) of the energy use history includes, as mentioned above, a field ( 31 ) recording at least time information of relevant unit time, a field ( 32 ) recording energy pricing information applied to the relevant unit time and a field ( 33 ) recording energy consumption information at the relevant unit time.
[0069] The term of “time information of relevant unit time” means information capable of notifying the duration of the unit time, the term of “energy pricing information applied to the relevant unit time” means information capable of energy price at the relevant unit time, where the energy meter ( 23 ) extracts the energy pricing information of the relevant unit time from the energy pricing information based on time received from the remote server ( 21 ). The term of “energy consumption information at the relevant unit time” means energy consumption used by each load during the relevant unit time.
[0070] Referring to FIG. 4 , the energy meter ( 23 ) time-sequentially records a record corresponding to each unit time in the order of time in storage means, where the storage means is a non-volatile storage medium capable of reading and writing digital data for storing and maintaining various pieces of information necessary for operation of the energy meter ( 23 ).
[0071] A unit time is imagined to be five minute in FIG. 4 . The record # 1 is recorded with information that an energy as much as Q 1 has been used at a P 1 energy price at a relevant unit time, a record # 2 is recorded with information that an energy as much as Q 2 has been used at a P 2 energy price at a relevant unit time, and a record # 3 is recorded with information that an energy as much as Q 3 has been used at a P 3 energy price at a relevant unit time.
[0072] Although a time information field ( 31 ) of relevant unit time is recorded with a start time of each unit time as ‘year/month/day/time/minute’, it should be apparent that a start time and a finish time of each unit time can be all recorded.
[0073] The time information of relevant unit time recorded in the first field ( 31 ) may be arbitrary information capable of grasping the relevant record in relation to unit time (duration of the unit time). The energy consumption information of relevant unit time recorded in the third field ( 33 ) may be energy consumption per unit time, but may be accumulated energy consumption information. This is because the energy consumption per unit time can be known if a prior unit time value is deducted from a current unit time value, even if the accumulated energy consumption is recorded.
[0074] FIG. 5 illustrates an example of maintaining each record in ring structure.
[0075] If the ring structure is filled from record # 1 to record #n, a record relative to next unit time maintains the energy use history in a method of recording the energy consumption information in the oldest record. In a non-limiting example, the energy use history corresponding to each unit time is sequentially recorded in from record # 1 to record #n, and ‘n+1’th record is recorded in the record # 1 . The management of energy use history thus described is advantageous in that it is not restricted by storage capacity of the storage means, and the latest nth record can be maintained at all times.
[0076] The energy meter ( 23 ) may display the energy use history information maintained in storage means on an intrinsic screen or may provide a user interface capable of checking, by a user, the energy use history stored in the storage means. Furthermore, the energy meter ( 23 ) may transmit the energy use history recorded in the storage means to other devices ( 15 ) through various wired/wireless communication methods.
[0077] The other device ( 15 ) defines a display device capable of visually displaying the energy use history by receiving from the energy meter ( 23 ). In a non-limiting example, the other device may include an IHD (In Home Display) installed in the energy consumer ( 10 ) capable of displaying various energy-related information and a user mobile phone.
[0078] FIG. 6 is a schematic view illustrating an energy metering method according to an exemplary embodiment of the present disclosure, whereby an energy meter supporting dynamic time-varying energy pricing can manage an energy use history. The energy meter may include a watt hour meter, a gas meter and a water meter installed at each energy consumer, and is capable of communicating with a remote server through a communication network.
[0079] The energy meter basically measures energy consumption, e.g., an accumulated energy consumption consumed by each relevant energy consumer. In case the energy meter receives time-based energy pricing information from a remote server through a communication network (S 211 - 1 ), the energy meter stores the received time-based energy pricing information in storage means ( 23 - 1 ) (S 211 - 2 ).
[0080] Meanwhile, the energy meter keeps monitoring whether a preset unit time has elapsed while measuring energy consumption used by the energy consumer (S 213 - 1 ). The monitoring whether the preset unit time has elapsed at step S 213 - 1 is intended to manage the energy use history for each unit time. The unit time may be arbitrarily set up as necessary, and in a non-limiting example, the unit time may be set up at one minute, two minutes, three minutes, four minutes, five minutes, six minutes, ten minutes, 12 minutes, 15 minutes, 20 minutes, 30 minutes, one hour and one day.
[0081] As a result of the monitoring at step S 213 - 1 , if the unit time has elapsed (S 213 - 2 ), the energy meter records time information of relevant unit time, energy pricing information applied to the relevant unit time and energy consumption information at the relevant unit time in storage means ( 23 - 1 ) (S 213 - 3 ), where the time information on relevant unit time means information capable of notifying duration of the unit time, the energy pricing information applied to the relevant unit time means capable of notifying how much the energy price at the relevant unit time, which can be extracted from the time-based energy pricing information received from the remote server, and the energy consumption information at the relevant unit time means energy consumption used by each load during the relevant unit time.
[0082] The energy meter at step S 213 - 3 time-sequentially records a record corresponding to each unit time as described in FIGS. 3 , 4 and 5 . The process of the energy meter receiving the energy pricing information from the remote server through steps S 211 - 1 and S 211 - 2 , and the process of time-sequentially storing and managing the energy use history for each unit time through steps S 213 - 1 , S 213 - 2 and S 213 - 3 are processes that can be implemented in parallel. That is, the time-based energy pricing information may be updated by the remote server at any time when the need arises.
[0083] FIG. 7 is a schematic view illustrating a watt hour meter ( 70 ) according to a first exemplary embodiment of the present disclosure, where the watt hour meter ( 70 ) may include communication means ( 71 ), metering means ( 72 ), time check means ( 73 ), storage means ( 74 ) and processing means ( 79 ).
[0084] Each load ( 17 - 1 ˜ 17 - k ) at the power consumer consumes electric energy supplied through the power supply line ( 13 - 1 ), where the metering means ( 72 ) measures power consumption (e.g., accumulated power consumption) consumed by each load ( 17 - 1 ˜ 17 - k ) of the power consumer.
[0085] The communication means ( 71 ) functions to receive time-based electric power pricing information transmitted from the remote server or a user terminal ( 18 ). First communication means ( 71 - 1 ) receives time-based electric power pricing information from the remote server ( 21 ) through the communication network ( 22 ), and second communication means ( 71 - 2 ) receives time-based electric power pricing information from the user terminal ( 18 ). The second communication means ( 71 - 2 ) may communicate with the user terminal ( 18 ) using various wired/wireless communication methods.
[0086] The first and second communication means ( 71 - 1 , 71 - 2 ) may be integrally realized based on the communication network ( 22 ) communicating with the remote server ( 21 ) by the first communication means ( 71 - 1 ) and types of networks communicating with the user terminal ( 18 ) by the second communication means ( 71 - 2 ).
[0087] The types of user terminal ( 18 ) may be variably provided. In a non-limiting example, the user terminal may be an IHD (In Home Display) installed in the energy consumer ( 10 ) capable of displaying various energy-related information, or a user mobile phone.
[0088] Furthermore, the processing means ( 79 ) may transmit to the user terminal ( 18 ) through the second communication means ( 71 - 2 ) information such as current electric power pricing information and the energy use history, and in this case, the user terminal ( 18 ) may visually display the information received from the watt hour meter ( 70 ). That is, the user terminal ( 18 ) may transmit necessary information to the watt hour meter ( 70 ) through various wired/wireless communication methods, and may receive various pieces of energy-related information from the watt hour meter ( 70 ) and display the information.
[0089] The time-based electric power pricing information received through the communication means ( 71 ) may include, as shown in FIG. 2 , various tariff system-based tariff information such as TOU (Time Of Use) pricing, CPP (Critical Peak Pricing) and RTP (Real-Time Pricing).
[0090] The time check means ( 73 ) serving to measure a current time may be formed by using a RTC (Real Time Clock). The current time measured by the time check means ( 73 ) may be adjustable to correct a time measurement error. At this time, the current time may be adjusted by communication with other devices. In a non-limiting example, the remote server ( 21 ) or the user terminal ( 18 ) may transmit a time adjustment instruction, and the processing means ( 79 ) may adjust the current time of the time check means ( 73 ) in response to the received time adjustment instruction.
[0091] Furthermore, the watt hour meter ( 70 ) may include a key having a function of displaying the current time and capable of adjusting the current time. In this case, the current time on the watt hour meter ( 70 ) may be personally adjusted by the user.
[0092] The storage means ( 74 ) is non-volatile digital data storage medium recording electric power consumption information measured by the metering means ( 72 ) and operation information of the watt hour meter.
[0093] The processing means ( 79 ) may be formed by using a microprocessor or a CPU (Central Processing Unit), and processes dynamically varying electric prices that change in time.
[0094] Particularly, with reference to the present disclosure, the processing means ( 79 ) receives electric power pricing information through the communication means ( 71 ), stores in the storage means ( 74 ) the electric power consumption information measured by the metering means ( 72 ) and manages the information, and extracts electric power pricing information applied to current time, from the time-based electric power pricing information.
[0095] Furthermore, the processing means ( 79 ) uses the current time information measured by the time check means ( 73 ) to monitor whether the preset unit time has elapsed, and stores the energy use history for each unit time in the storage means ( 74 ).
[0096] Although the energy use history stored in the storage means ( 74 ) by the processing means ( 74 ) at every unit time may be variably configured as need arises, the energy use history includes at least time information of relevant unit time, electric power pricing information applied to the relevant unit time and electric power consumption information at the relevant unit time.
[0097] The unit time may be arbitrarily set up. To be more specific, the unit time may be set up in any one of one minute, two minutes, three minutes, four minutes, five minutes, six minutes, ten minutes, 12 minutes, 15 minutes, 20 minutes, 30 minutes, one hour and one day.
[0098] At this time, the time information of relevant unit time is information notifying duration of the unit time, the electric power pricing information applied to the relevant unit time is information notifying electric power prices at the relevant unit time, and the electric power consumption information at the relevant unit time means electric power consumption used during the relevant unit time.
[0099] As illustrated in FIG. 3 , the energy use history for each unit time may be stored by record unit, where each record may include time information field of relevant unit time, electric pricing information field applied to the relevant unit time and electric power consumption information field at the relevant unit time. The records at each unit time may be time-sequentially recorded as shown in FIGS. 4 and 5 .
[0100] FIG. 8 is a schematic view illustrating a watt hour meter ( 70 ) according to a second exemplary embodiment of the present disclosure, where the watt hour meter ( 70 ) may further include input means ( 75 ) and display means ( 77 ) in addition to the watt hour meter according to the first exemplary embodiment of the present disclosure, and where either one of the input means ( 75 ) or display means ( 77 ), or all the input means ( 75 ) or display means ( 77 ) may be included in the watt hour meter according to the second exemplary embodiment of the present disclosure.
[0101] The display means ( 77 ) serves to visually display information related to operation of the watt hour meter ( 70 ). Particularly, the processing means ( 79 ) may variably display on the display means ( 77 ) various pieces of information related to the electric power prices including electric power pricing information applied to the current time and the energy use history.
[0102] As one example, the electric power price information applied to the current time may be displayed at all times or intermittently. Furthermore, the electric power price information applied to the current time may be periodically displayed. In a non-limiting example, current electric power pricing information at each unit time may be displayed. The processing means ( 79 ) may extract electric pricing information scheduled at a future time from the time-based electric power pricing information, and display the information on the display means ( 77 ).
[0103] The input means ( 75 ) may input information or instruction related to operation of watt hour meter ( 70 ) using various input devices, by a user, including a key button and a touch screen.
[0104] In a non-limiting example, the time-based electric power pricing information may be publicized through an Internet network, where the user may personally input the time-based electric power pricing information through the input means ( 75 ). Furthermore, if there is an error in the current time measured by the time check means ( 73 ), the current time information may be adjusted through the input means ( 75 ).
[0105] FIG. 9 is a schematic view illustrating an example of a screen ( 91 ) displaying a current electric price displayed by the display means ( 77 ) or the user terminal ( 18 ), where the current electric price extracted from the time-based electric pricing information is displayed on a relevant item ( 91 - 1 ).
[0106] FIG. 10 is a schematic view illustrating an example of a screen ( 93 ) displaying an energy use history, where the screen displays time information at each unit time, electric pricing information applied to the relevant unit time and electric power consumption information for each unit time. The user may manipulate scroll buttons ( 93 - 1 , 93 - 2 ) to check each energy use history not shown on the current screen.
[0107] Meantime, the electric power consumption information at each unit time may be forward direction electric power consumption information supplied to the loads ( 17 - 1 ˜ 17 - k ) during relevant unit time, as shown in FIG. 11 . The forward direction electric power consumption means electric power quantity (i.e., electric power consumption to be paid as an electric power charge) used by an electric power consumer.
[0108] The forward direction power information includes effective power, ineffective power, apparent power, current amount and voltage amount. At this time, the time-based electric price information includes effective power unit price (won/kwh), ineffective power unit price (won/kvarh), apparent power unit price (won/kVAh), current amount unit price (won/kl 2 h) and voltage unit price (won/KV 2 h), where won is Korean currency, each relative to information on forward direction power energy, and the electric pricing information may include a power factor unit price.
[0109] That is, if power factor is bad, waste of electric energy becomes serious, such that the electric power price can be differentiated in response to power factor of electric power consumer.
[0110] The electric power information at each unit time may also include information on reverse direction electric power supplied to the power supply line ( 13 - 1 ) from an alternative energy source ( 19 ) during a relevant unit time as shown in FIG. 11 . The reverse direction electric power means electric power sold by electric power consumers to a power supply company.
[0111] Each electric power consumer may be equipped with various alternative energy sources such as wind power generating facilities, solar power generating facilities and batteries, and the electric energy generated by the alternative energy source ( 19 ) may be re-sold to the electric power company. The reverse direction electric power may include effective power, ineffective power, apparent power, current amount and voltage amount.
[0112] At this time, the electric price information includes effective power unit price (won/kwh), ineffective power unit price (won/kvarh), apparent power unit price (won/kVAh), current amount unit price (won/kl 2 h) and voltage unit price (won/KV 2 h), each relative to information on reverse direction power energy, where won is Korean currency.
[0113] The price of electricity sold by the power supply company to the electric power consumer, and the price of electricity sold by the electric power consumer to the power supply company may be differentiated, such that the electric price on forward direction electric consumption and the electric price on reverse direction electric consumption may be dissimilar.
[0114] The energy metering system and the energy metering method and the watt hour meter of supporting dynamic time-varying energy pricing according to the present disclosure may, however, be embodied in many different forms and should not be construed as limited to the embodiments set forth herein. Thus, it is intended that embodiments of the present disclosure may cover the modifications and variations of this disclosure provided they come within the scope of the appended claims and their equivalents.
[0115] While particular features or aspects may have been disclosed with respect to several embodiments, such features or aspects may be selectively combined with one or more other features and/or aspects of other embodiments as may be desired.
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The present disclosure is disclosed to record in detail and manage information on energy use history of a user under various energy pricing systems where energy prices are changed in time. To this end, an energy meter receives time-based energy price information from a remote server, and time-sequentially records a record including time information of relevant unit time for each unit time, energy price information applied to relevant unit time and energy consumption information at the relevant unit time, whereby the information on how much, when and at what price the user has used the energy can be accurately and quite obviously managed. The energy use history can be used in various fields as data for promoting reasonable energy use, and as a base for calculating energy use charge.
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BACKGROUND OF THE INVENTION
A desirable feature of certain hand-held lights, such as battery operated flashlights, is the capability of adjusting the beam width. In certain instances, it is useful to provide a concentrated beam of light of constant diameter, while in other instances, it is desirable for the beam to spread and thereby illuminate a large area. This has been achieved in the past by selecting the position of the bulb with respect to the parabolic reflector commonly used in flashlights. A bulb is located at the focus of a parabolic reflector and rays from the bulb are collimated by the reflector to provide a beam which is of substantially constant diameter. In the past, a beam that is conical in shape, that is, one that spreads, has been achieved by moving the bulb so as not to be located at the focus of the reflector. The distance between the bulb location and the focus will affect the amount of beam spread. Flashlights that have had this capability in the past have been too expensive to manufacture to be saleable in the mass market. Also, prior flashlights with adjustable beam width incorporate a head fixed with respect to the main body, which is undesirable in certain instances. U.S. Pat. Nos. 1,991,753 to Kurlander and 1,674,650 to Leser disclose such prior flashlights.
SUMMARY OF THE INVENTION
It is therefore an important object of the present invention to provide an improved hand-held light having capability of beam width adjustment.
Another object in connection with the foregoing is to provide such a hand-held light which is sufficiently economical to make to appeal to the mass market.
Another object is to provide a hand-held light which has capability of adjusting its beam width and also the orientation of the head.
In summary there is provided a hand-held light comprising a head having a wall, a carriage slidably mounted on the wall and slidable between first and second extremes, a socket on the carriage for holding a bulb, and means on the carriage accessible on the exterior of the head for being engaged by one's finger to move the carriage to a selected position between the first and second extremes.
The invention consists of certain novel features and a combination of parts hereinafter fully described, illustrated in the accompanying drawings, and particularly pointed out in the appended claims, it being understood that various changes in the details may be made without departing from the spirit, or sacrificing any of the advantages of the present invention.
BRIEF DESCRIPTION OF THE DRAWINGS
For the purpose of facilitating an understanding of the invention, there is illustrated in the accompanying drawings a preferred embodiment thereof, from an inspection of which, when considered in connection with the following description, the invention, its construction and operation, and many of its advantages should be readily understood and appreciated.
FIG. 1 is a side elevational view of a battery operated flashlight incorporating the features of the present invention;
FIG. 2 is a top plan view of the flashlight;
FIG. 3 is a front elevational view of the flashlight on an enlarged scale, with most of the cover assembly broken away to expose the interior of the head;
FIG. 4 is a view in vertical section on an enlarged scale taken along the line 4--4 of FIG. 3;
FIG. 5 is a view in vertical section taken along the line 5--5 of FIG. 3, but with the carriage shown separated from the head;
FIG. 6 is a fragmentary top plan view of a portion of the head taken along the line 6--6 of FIG. 5; and
FIG. 7 is a fragmentary front elevational view of the top portion of the head taken along the line 7--7 of FIG. 6.
DESCRIPTION OF THE PREFERRED EMBODIMENT
Turning now to the drawings and more particularly to FIGS. 1 and 2 thereof, there is depicted a flashlight constructed in accordance with the present invention, the flashlight being generally designated by the numeral 10. The flashlight 10 includes a housing 15 carrying an upstanding handle 16. The housing 15 contains a battery, which preferably is rechargeable, together with a power supply and other electronics for recharging of the battery and the like. Preferably the housing 15 and the handle 16 are molded of plastic in two parts and held together by screws or the like. The housing 15 is generally rectangular and is elongated front to back, the front being toward the left as viewed in FIG. 1 and the back being toward the right. The front of the handle 16 and the front of the housing 15 are part cylindrical to accommodate a head 20. An on-off switch 17 is located in the handle at its front. The switch is moved forwardly to turn on the flashlight and rearwardly to turn it off. One can operate the on-off switch 17 with one's thumb while his hand is grasping the handle 16.
The head 20 is preferably of one-piece plastic construction having a pair of laterally spaced-apart side walls 21, a top wall 22, a bottom wall 23 and a part cylindrical rear wall 24 that merges into and is a continuation of the top and bottom walls 22 and 23. The curvature of the rear wall 24 matches the curvature of the front of the handle 16 and the housing 15 to accommodate tilting movement of the head 20 with respect to the housing 15. Each of the side walls 21 has a keeper in the form of an opening 25 at the front thereof.
The flashlight 10 further comprises a cover assembly 30 including a generally rectangular bezel 31. Fingers 32 extend rearwardly from the side walls of the bezel 31 and engage in the openings 25.
Turning now to FIG. 3, the cover assembly 30 includes a lens 33 which serves to focus the light. A parabolic reflector 34 is also included in the cover assembly 30, a planar extension 35 of such reflector being located behind the lens 33. The lens 33 and the reflector 34 are preferably permanently attached to the bezel 31. Only a fragmentary portion of the reflector 34 is depicted but it is to be understood that centrally thereof is an opening to receive the socket and bulb carried thereby.
Mounting structure 40 is provided to swivelly attach the head 20 to the housing 15. Protruding forwardly from the front of the housing 15 are two laterally spaced-apart, forwardly extending legs 41 which respectively extend through two spaced-apart slits 42 in the rear wall 24 of the head 20. The thickness of the legs 41 is less than the width of the slits 42. The legs 41 have outwardly curved outer ends, that is, they are curved toward the side walls 21. The mounting structure 40 further includes a pair of legs 43 integral with the rear wall 24 and extending forwardly therefrom. The outer ends of the legs 41 are spring biased against the legs 43. The legs 43 respectively carry pins 44 which extend into holes respectively in the legs 41. Thus the pins 44 define an axis about which the head 20 swivels with respect to the housing 15. The capability of the head 20 being oriented as desired to direct the beam of light is not directly part of this invention. However, further details thereof may be had by referring to copending application Ser. No. 460,590, filed Jan. 24, 1983, entitled Hand-Held Light with Swivel Head.
A socket 50 (FIG. 5) carries a bulb 51 which protrudes through the central opening in the reflector 34. The socket 50 is basically formed of plastic although it has the usual metallic elements. A sleeve 52 is slipped onto the socket 50 and has a rim 53 which retains the bulb 51 in place. Wires 54 are attached to the socket, are taped to one of the legs 41 and extend through the associated slit 42 into the housing 15 for connection to the battery and circuitry therein. The plastic socket 50 is integral with a carriage 60. Details of the carriage 60 are best seen in FIG. 5. The carriage 60 includes an elongated plate-like member 61 which has a concave front edge 62. The socket 50 is located at the deepest point on such edge. The member 61 has a lower end 63, the rear portion of which is cut out at 64 for reasons to be explained. The other end of the member 61 carries a rectangular, transversely extending flange 66. Above the flange 66 and substantially aligned with the member 61 is a rectangular wall 67 having a length substantially less than that of the flange 66.
A rectangular transversely extending actuator or tab 70 is located on top of the wall 67. The upper surface 71 of the tab 70 is partly roughened or ridged to facilitate being gripped by one's thumb. The under surface 72 of the tab 70 has a smooth rear portion and a plurality of transversely extending ridges 73 on the front half. Each ridge and the space between ridges is substantially triangular in transverse cross section. The rear of the wall 67 defines a rear limit surface 74. Protruding laterally on each side of the wall 67 is a lug 75. The vertical front surface of each of the lugs 75 defines a front limit surface 76.
Referring to FIGS. 5, 6 and 7, there is formed in the top wall 22 of the head 20 a recess 80 having a floor 81 and side walls 82. The front of the top wall 22 is uninterrupted and defines an arm 83. The floor 81 has a pair of laterally spaced-apart upper ribs 84 extending front to back and being located respectively closely adjacent the side walls 82. Similarly, the undersurface of the floor 81 has a pair of ribs 85 which are vertically aligned with the ribs 84. The floor 81 is cut out at 86 in which cut out is located a pair of laterally spaced-apart forwardly directed fingers 87 that are bent and biased upwardly. The forward end of each finger 87 carries an upwardly directed detent 88. Referring to FIG. 6, the detent has surfaces 89 and 90 at the same inclination as the ridges 73 in the tab 70. In an operative embodiment the inclination was 45°. The front of each finger 87 is inclined to provide a camming surface 91 which is continuation of the surface 89. To shorten the finger slightly, the surface 91 has a different inclination, such as 60°.
The tab 70 rests on the ribs 84 which provide line contact to reduce friction that would occur between the tab 70 and the floor 81. Similarly, the flange 66 engages the ribs 85 which provides line contact to minimize friction. The detent engages in the space between a pair of ridges 73 to cause the carriage 60 to stay at a selected position until positive actuation. The tab 70 and the flange 66 effectively sandwich the floor 81 therebetween. Such construction minimizes deviation of the carriage 60 from the vertical orientation depicted. The tendency of the carriage 60 to rotate in any direction is therefore minimized.
Because the socket 50 is connected by wires 54 to the interior of the housing 15, the head can be oriented as desired and as is explained in greater detail in the above-mentioned copending application. This construction enables adjustment of the beam width without sacrificing its orientation capability.
Each finger 87 carries near the forward end thereof an inwardly directed lug 92, the lugs 92 being laterally aligned. The front of each of the lugs 92 is inclined to provide a camming surface 93. The rear of each lug 92 defines a substantially vertical front limit surface 94. The rear end of the cut out 86 is also substantially vertical and defines a rear limit surface 95. The bottom wall 23 of the head 20 carries a pair of spaced-apart rails 97 (FIG. 5), the distance between the rails 97 being slightly greater than the thickness of the member 61. The carriage 60 is positioned in the head 20 such that the end 63 is located between the rails 97 and the tab 70 is located in the recess 80.
In initial assembly, the tab 70 is inserted into the recess 80, the lugs 75 being respectively aligned with the lugs 92. As the tab 70 is urged rearwardly, the camming surfaces 93 respectively engage the lugs 75 causing the fingers 87 to deflect downwardly. The tab 70 can be moved further rearwardly until the lugs 92 clear the lugs 75 at which time the lugs 92 snap up against the surface 72, the detents 88 respectively entering into the space between the first pair of ridges 73. As the tab 70 is moved rearwardly, the ridges 73 deflect the fingers 87 downwardly so as to disengage the detents 88. In this manner, the tab 70 may be moved to any desired position. After assembly of the carriage 60 into the head 20, the carriage 60 is not readily removed without inserting an instrument to manually deflect the fingers 87.
The forwardmost position of the carriage 60 as shown in phantom in FIG. 4, is attained when the limit surface 76 engages the limit surface 94. The rearmost position of the carriage 60 is attained when the limit surface 74 strikes the limit surface 95, as shown by the solid line in FIG. 4. The cutout 64 in the lower end of the member 61 enables clearance of the lower end of the curved rear wall 24 of the head 20.
It will be noted in FIG. 2 that the tab 70 is located directly in front of the on-off switch 17. One holding the flashlight 10 by having his fingers encircling the handle 16 can use his thumb to operate the switch 17 for turning the flashlight on and off and to move the tab 70 forwardly and rearwardly using the same thumb. Moving the tab 70 rearwardly moves the bulb 51 (FIG. 5) rearwardly, its rearmost position being at the focus of the reflector 34. At that point the beam generated by the flashlight 10 is concentrated and its diameter is theoretically constant. Movement of the tab 70 forwardly moves the light bulb 51 forwardly and away from the reflector focus. The light beam is thereby caused to spread, increasing the illumination area. When the tab 70 is in its forwardmost position, the size of the illumination area is maximized.
What has been described therefore is an improved hand-held light which has means to vary the beam width. The light can also be designed to have a rotatable head in conjunction with the beam width feature. Even with these features, the light is economical to manufacture. While a flashlight has been specifically described, the present invention is applicable to other hand-held lights.
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A flashlight has a battery housing and a head. A carriage is slidably mounted on opposing walls of the head. The carriage carries a socket for holding a flashlight bulb. A tab on the carriage is accessible to one's finger to enable movement of the carriage and the bulb carried thereby in any one of a number of positions, thereby to control the beam width.
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CLAIM OF PRIORITY
[0001] This application claims the priority of U.S. Ser. No. 62/294,715 filed on Feb. 12, 2016, the contents of which are fully incorporated herein by reference.
FIELD OF THE EMBODIMENTS
[0002] The field of the embodiments of the present invention relate to electronic inhalation devices, namely electronic cigarettes and other vaping devices with superior performance and increased automated control over device variables.
BACKGROUND OF THE EMBODIMENTS
[0003] Vaping devices, such as electronic cigarettes or “e-cigs,” allow a user to breathe a vaporized or atomized glycerin or propylene glycol based solution containing nicotine and/or flavorings and/or other compounds. Electronic cigarettes have existed for some time, but it wasn't until the turn of the century that the modern e-cig was brought to the masses. These devices produce a smokeless vapor of the liquid solution using an “atomizer” or heating element contained in fluid connection with a liquid reservoir.
[0004] The proliferation of such devices has brought about many variations upon the basic model, including those that may be readily modified in some capacity by the user. For example, some e-cigs are capable of communicating with electronic devices and running programs via those devices to influence the activity of the e-cig. Yet other e-cigs allow for the creation of profiles for individual users depending on their personal preferences. Even further, some vaping devices are now built using a variety of parts by a user to create a completely custom vaping experience.
[0005] However, these abilities readily cause a number of unintended consequences by users. For example, as noted, many individuals prefer to mix and match components to create a custom vaping experience. The mixing and matching of parts requires intimate knowledge of how the parts interact with one another to create a functional e-cig. Many times individuals will choose parts that are not compatible and can cause the resulting e-cig to be non-functional or cause damage to the components or even harm to the user.
[0006] Further, there is no e-cig or other type of electronic vaping device that can wholly prevent burning or degradation of the liquid used in the vaping process. It is paramount that the resistance of the atomizer or electronic inhalation device is understood such that the voltage and wattage of the device may be calibrated to perfection. Failure to do so may cause dangerous aldehyde containing compounds to be formed and otherwise cause degradation of the liquid bringing about a sub-par vaping experience and potential harm to the user.
[0007] Thus, there is a need for an electronic inhalation device that takes into account these needs and prevents the formation of aldehydes and further prevents improper voltages and wattages from being used for a particular atomizer or liquid. This serves to create a constant and consistent flavor profile and preserve battery life of the device. The present invention and its embodiments meets and exceeds these objectives.
Review of Related Technology
[0008] U.S. Patent Application 2015/0075546 pertains to an add-on module for an electronic cigarette or vaporizer that provides an electronic means to communicate with remote computers and electronic devices and to provide a dynamic means to control temperature over time, manage and save device settings, dynamically control temperatures, monitor sensors, and transmit and read this data from remote computing devices for display, alteration and storage.
[0009] U.S. Patent Application 2014/0123990 pertains to a real time variable voltage programmable electronic cigarette device that has a main body, a controller, a memory, a visual indicator, a multidirectional joystick for operating and programming the electronic cigarette, a visual indicator for real-time status feedback, and a USB connector for computer connectivity. Programming the device includes the ability to create vaping profiles. The programmable function enables a user to set the voltage output and power output level applied to the atomizer when energized.
[0010] Various systems and methodologies are known in the art. However, their structure and means of operation are substantially different from the present disclosure. The other inventions fail to solve all the problems taught by the present disclosure. At least one embodiment of this invention is presented in the drawings below and will be described in more detail herein.
SUMMARY OF THE EMBODIMENTS
[0011] In general, the present invention and its embodiments provide an electronic inhalation device such as an electronic cigarette, atomizer, and/or other vaping device that provides a user with superior performance and automated control over device variables thereby removing the “guesswork” from operating the device.
[0012] In some embodiments, the present invention comprises a smart module that is operably coupled to an existing electronic inhalation device. In other embodiments, the present invention is a “pen” type electronic inhalation device with the smart module wholly integrated with the electronic inhalation device. Other embodiments not explicitly named herein may also exist under the purview of this invention.
[0013] In one embodiment, the smart module is configured to properly interpret the attached atomizer's electrical resistance and subsequently calibrate the proper electrical output. This prevents the electronic inhalation device from overheating the coil contained within the atomizer and producing temperatures that will degrade the liquid(s) used for vaping. Further, in other embodiments, the user may be able to input a code for the corresponding “flash points” of the intended liquid to determine the optimum output for both delivery of compounds formulated and also for the proper temperature range of the device.
[0014] In yet other embodiments, the device is configured to interface with an electronic device such as a smart phone. This may, for example, enable the electronic inhalation device to be paired with a dedicated app or program to monitor variables attributable to the electronic inhalation device, modifying variables attributable to the electronic inhalation device, or the like or some combination thereof.
[0015] In one embodiment of the present invention there is a smart module for an electronic inhalation device, the smart module comprising: an adapter configured to couple to the electronic inhalation device; a processor; a non-transitory computer-readable medium comprising machine readable instructions, which when executed by the processor, cause the processor to perform a method, the method comprising the steps of, monitoring at least one electrical property of the electronic inhalation device, and adjusting an electronic output of the smart module based on the at least one electrical property of the electronic inhalation device; and a power source.
[0016] In another embodiment of the present invention there is an electronic inhalation system comprising: a smart module for an electronic inhalation device, the smart module comprising, a threaded adapter configured to couple to the electronic inhalation device; a processor; a non-transitory computer-readable medium comprising computer readable instructions, which when executed by the processor, cause the processor to perform a method, the method comprising the steps of, monitoring an electrical resistance of metallic coil of the electronic inhalation device, and adjusting an electronic output of the electronic inhalation device based on the electrical resistance of the metallic coil; a power source; and wherein the electronic inhalation device is configured to couple to the smart module.
[0017] In yet another embodiment of the present invention there is an electronic inhalation system comprising: an atomizer having at least one metallic coil; a cartridge configured to house a liquid; a smart module comprising, a processor, a non-transitory computer-readable medium comprising computer readable instructions, which when executed by the processor, cause the processor to perform a method, the method comprising the steps of, monitoring an electrical resistance of the at least one metallic coil of the atomizer, and adjusting an electronic output of the electronic inhalation device based on the electrical resistance of the at least one metallic coil, wherein the electronic output is at least one of a wattage or a voltage; and a power source.
[0018] In general, the present invention succeeds in conferring the following, and others not mentioned, benefits and objectives.
[0019] It is an object of the present invention to provide an electronic inhalation device that automatically interprets the electrical resistance of a metallic coil of an atomizer.
[0020] It is an object of the present invention to provide an electronic inhalation device that prevents over heating of the coil, thereby preventing degradation of the e-liquid.
[0021] It is an object of the present invention to provide an electronic inhalation device that allows for user modification of the settings of the device.
[0022] It is an object of the present invention to provide an electronic inhalation device that is configured to interface with an electronic device.
[0023] It is an object of the present invention to provide an electronic inhalation device that tallies or counts the number of “puffs” a user takes of the device.
[0024] It is an object of the present invention to provide an electronic inhalation device that automatically determines the proper operating temperature and other parameters for the device.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] FIG. 1 is an exploded view of at least some of the components of an embodiment of the present invention.
[0026] FIG. 2 is a perspective view of an embodiment of the present invention.
[0027] FIG. 3 is a perspective view of a second embodiment of the present invention.
[0028] FIG. 4 is a perspective view of a third embodiment of the present invention.
[0029] FIG. 5 is a front view of a display of an embodiment of the present invention.
[0030] FIG. 6 is a front view of an alternate display of an embodiment of the present invention.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0031] The preferred embodiments of the present invention will now be described with reference to the drawings. Identical elements in the various figures are identified with the same reference numerals.
[0032] Reference will now be made in detail to each embodiment of the present invention. Such embodiments are provided by way of explanation of the present invention, which is not intended to be limited thereto. In fact, those of ordinary skill in the art may appreciate upon reading the present specification and viewing the present drawings that various modifications and variations can be made thereto.
[0033] Referring now to FIG. 1 , there is an embodiment of the present invention in an exploded view illustrating at least some of the components of the embodiment. The smart module 100 , as shown, contains at least a top cover 101 , threading 104 , insulators 111 , power source 106 , depressible buttons 107 , activation button 110 , display 108 , bottom cover 102 , power source holder 113 , power source housing 112 , printed circuit board (PCB) 105 , processor 117 , memory 118 , EVA 103 , display cover 109 or some combination thereof.
[0034] The smart module 100 may be capable of being threadably engaged via threads 104 (or otherwise coupled) to retrofit to an electronic inhalation device 120 (see FIG. 2 ), such as an electronic cigarette or atomizer or the like. In other embodiments, the smart module 100 is fully integrated into the electronic inhalation device thereby forming a single unit device (see FIG. 4 ).
[0035] When coupled to an electronic inhalation device 120 , an operable electronic connection is established between the smart module 100 and the electronic inhalation device 120 . Upon establishing this connection, the smart module 100 is configured to automatically detect the resistance of the wire coil contained within the atomizer, or similar structure, of the electronic inhalation device 120 . Further, the composition of the metallic coil(s) may be ascertained (e.g., nickel, Kanthal, etc.). Once the resistance and/or composition has been determined, the smart module 100 can determine which mode it would be preferential to operate: 1) resistance mode—where wattage or voltage is fixed or 2) temperature mode—where the temperature is automatically calculated and set. The resistance mode device is shown in FIG. 5 and the temperature mode device is shown in FIG. 6 , however, each smart module 100 may be capable of operating on only one or in both modes as described herein.
[0036] The resistance detection may be achieved in a number of fashions and may operate similar to an ohmmeter including but not limited to the sending of a first electric pulse or a first constant current or first constant voltage or a combination thereof.
[0037] Such a pulse or current will allow calculations to be performed via the processor 117 , to determine the resistance of the coil in the atomizer. A “test puff” may be required to allow the requisite data to be gathered and the necessary calculations to be completed. In addition, this realization of the resistance may further occur in real time as the connection is made between the smart module 100 and the electronic inhalation device 120 .
[0038] By enabling the calculations to be completed as described above, both (or either) of a wattage and a voltage may be calculated for which the electronic inhalation device 120 will operate as limited by the smart module 100 . These specific values, may be dependent on the resistance in the atomizer, and will allow for autonomous and automatic setting of the smart module variables.
[0039] In addition, the processor 117 and memory 118 may be programmed and have stored thereon information (machine readable instructions) that acts as safety measures for operation of the smart module 100 . For example, the smart module 100 may be able to prevent firing or activation if no liquid or an inadequate amount of liquid is present in the reservoir of the electronic inhalation device 120 . In other embodiments, to prevent overheating or inadvertent activation, the smart module 100 automatically deactivates after about ten (10) seconds of continuous use. In other embodiments the time for deactivation to occur may vary and may be configurable by the user.
[0040] Further, the functional wattage and voltage can be optimized for the specific atomizer or electronic inhalation device 120 being employed by the user. This, is turn, prevents overheating of the coil(s) of the atomizer or electronic inhalation device 120 . By preventing the coil(s) of the atomizer from overheating, the operational temperatures of the electronic inhalation device will be such that degradation of the vaping liquid will be eliminated or diminished. Overheating of the vaping liquid can create an acrid taste for the user as well as lead to the formation of aldehyde containing compounds which are highly dangerous for the user.
[0041] FIGS. 2-4 demonstrate varying embodiments of the present invention. The embodiments shown in FIGS. 2 and 3 are similar in respect to have a smart module 100 that is coupled to an electronic inhalation device 120 . The embodiment shown in FIG. 4 is integrated into a “pen” device thereby removing the need for the bulky smart module 100 .
[0042] Referring now to FIGS. 2 and 3 each of the smart modules 100 is shown with function buttons 107 , an activation button 110 , and a display 108 . When the smart module 100 is coupled to the electronic inhalation device 120 , the display 108 is configured to communicate to a user information specific to the setup of the device (see FIGS. 4-5 ). Such information may include the operating temperature, wattage, resistance, and the like. Each of the embodiments may be capable of automatically detecting, without user input, the parameters of the electronic inhalation device 120 for proper usage, optimal flavor, and prolonged battery life.
[0043] In FIG. 4 , the button functions as both a function button 107 and an activation button 109 . Further, the smart module 100 is in a “pen”-like structure allowing the combination of the smart module 100 and electronic inhalation device 120 to form a more traditionally shaped e-cigarette type device.
[0044] In some embodiments, this not only allows for resistance control, as noted herein, by the smart module 100 but further allows for temperature control via the function button 107 . In some embodiments, depressing the function button 107 three times causes the device to change between predetermined temperatures for usage. In other embodiments, holding and depressing the function button 107 causes it to serve as an activation button 109 which causes the device to activate and allows vapor to be drawn by the user. In some embodiments, a light source is used to alert the user to the particular settings of the device. In other embodiments, a display is included to communicate this information to the user.
[0045] Referring now to FIGS. 5 and 6 , there are displays associated with embodiments of the present invention. In FIG. 5 , the display 108 has a battery display 121 , voltage display 123 , resistance display 122 , wattage display 124 visible. In some embodiments, the display 108 may have more or fewer variables visible at one time. In other embodiments, the manner of display (i.e., variables which are displayed) may change and such a change may be initiated by the user to customize their experience. The display 108 , as shown, is flanked by function buttons 107 and activation button 109 . In FIG. 6 , the display 108 features a battery display 121 , resistance display 122 , temperature display 126 , and temperature readout 126 . Again, the display 108 is flanked by function buttons 107 and activation button 109 . Further, the display 108 , as shown, may have the same potential modifications as described above.
[0046] FIG. 5 illustrates a smart module 100 intended to allow a user to modify the voltage and/or the wattage output of the smart module 100 . A user preferably couples the electronic inhalation device to the smart module 100 and the resistance of the coil in the electronic inhalation device (atomizer) is read automatically. In some instances, a nickel wire may be employed by the electronic inhalation device, and in other instances a resistive-type wire may be employed. Once the resistance is read, the voltage and wattage can be automatically set to optimize the flavor profiles, minimize harmful byproducts, and preserve battery life, amongst other desirables.
[0047] In addition, a user may use the function buttons 107 to cause the voltage and or wattage to increase or decrease to further suit their particular needs. Further, a use may use a particular combination of buttons including the activation button 109 to switch between varying modifiers to be shown on the display. In some embodiments, this may include depressing multiple buttons at once or in other embodiments using a single button depressed in succession. For example, in FIG. 5 , to switch from the wattage output being modified to the voltage output, a user may depress the activation button 109 three times in succession. After which, the user may use the function buttons 107 to increase or decrease the voltage of the device.
[0048] In another embodiment, holding a function button 107 and the activation button 109 may cause the display 108 to change to a “puff counting display” which counts the number of puffs or hits taken by a user during usage of the device. This change in display may remain active on the display or may only show for a predetermined amount of time before reverting back to a display similar to that shown in FIG. 5 . Other functions and information not explicitly stated herein may also be shown by the display.
[0049] Referring now to FIG. 6 , the display 108 features at least a resistance display 122 , temperature display 126 , and temperature readout 126 . The resistance is automatically calculated by the device which then, in this embodiment, causes the temperature to be automatically configured to maximize flavor profiles, prevent formation of harmful byproducts, and preserve battery life, amongst other desirable features. The temperature readout 125 may adjust when the activation button 109 is held showing the temperature of the coil as it heats and then causing it to remain steady while the activation button is held. The user can further manipulate the temperature using the function buttons 107 .
[0050] The battery display 121 shows a relative level of “life” left in the battery or other power source of the smart module 100 . In some embodiments, this is shown graphically whereas in other it forms a percentage or other visual readout capable of being interpreted. The power source may be rechargeable via conventional recharging means such as a USB port or may require changing of the power source once depleted.
[0051] The smart module 100 described in FIGS. 1-6 has been generally described and other iterations may be employed combining some or all of the elements described herein. In some instances, other uses are envisioned for the smart module 100 .
[0052] In some embodiments, the smart module 100 further comprises a digital gyroscope contained therein. Not only does this allow for the device to “understand” it orientation, it can also be used to track the movements corresponding to the device being brought to a user's lips and if the device is indeed used to vape each time the device is brought to the lips indicating usage patterns for the user. Further, the gyroscope may prevent in inadvertent activation of the device when in an upright position, as shown in the FIGS., as opposed to the “tilted” position when the device would typically be brought to a user's lips for vaping.
[0053] In another embodiment, the device interfaces with an electronic device such as a laptop computer, desktop computer, gaming system, smart phone, smart watch, head mounted display, smart television, multimedia player, and the like or some combination thereof. Such a connection may require the smart module 100 to employ a wireless transceiver, such as a Bluetooth® transceiver, to facilitate communication between the remote devices.
[0054] Once communicatively paired to the electronic device, the user may be able to control and/or monitor the smart module 100 and any associated electronic inhalation device 120 from the electronic device. Further, the device may be monitored or manipulated by a third party such as a medical professional. In such an implementation, a doctor may monitor the usage and issue various alerts to the user as a part of a smoking cessation program. Other potential uses and embodiments are also envisioned.
[0055] Further, the device may be used to atomize or aerosolize other materials outside of the conventional nicotine based glycol formulations currently abundant in the marketplace. In some embodiments, various pharmaceuticals may be used in conjunction with the device providing an inhalable form of the pharmaceutical whereby absorption and bioavailability will be increased. In one embodiment the “active” ingredient in the liquid is cannabidiol (CBD). In other embodiments, the device may be used with liquids containing other medicants such as antidotes or countermeasures to harmful substances (chemical weapons, biological substances, radiation, etc.) which people may encounter.
[0056] In yet other embodiments, a user may use the various inputs, or depressible buttons, of the smart module to enter a code corresponding to a “flash point” of the liquid containing the cartridge of the electronic inhalation device. This enables the parameters of the smart module to be modified such that it corresponds to this flash point thereby preserving the flavor of the liquid as well as preserving battery life of the device.
[0057] Although this invention has been described with a certain degree of particularity, it is to be understood that the present disclosure has been made only by way of illustration and that numerous changes in the details of construction and arrangement of parts may be resorted to without departing from the spirit and the scope of the invention.
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The present disclosure relates to electronic inhalation devices, namely electronic cigarettes and other vaping devices with superior performance and user control over device variables. In some instances, the present device is configured to properly interpret the attached atomizer's electrical resistance and subsequently calibrate the proper electrical output. This prevents the device from overheating the coil and producing temperatures that will degrade the expected liquids. Further, the user may be able to input a code for the corresponding “flash points” of the intended liquid to determine the optimum output for both delivery of compounds formulated and also for the proper temperature range of the device. In other embodiments, the device is configured to interface with an electronic device such as a smart phone.
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RELATED APPLICATION
This is a continuation of U.S. application Ser. No. 13/425,820 filed on Mar. 21, 2012, which is a continuation of U.S. application Ser. No. 12/131,092 filed on Jun. 1, 2008, now U.S. Pat. No. 8,177,188 granted on May 15, 2012, which is a divisional of U.S. application Ser. No. 10/223,236 filed on Aug. 19, 2002, now U.S. Pat. No. 7,490,625 granted on Feb. 17, 2009, which is a continuation-in-part of U.S. application Ser. No. 09/840,688, filed on Apr. 23, 2001, now U.S. Pat. No. 6,435,010 granted on Aug. 20, 2002.
FIELD OF THE INVENTION
The present invention relates to valves for controlling fluid flow, and, in particular, a control valve assembly having valves integrated with a valve manifold for compactly controlling fluid coupled devices.
BACKGROUND OF THE INVENTION
Manufacturers of hydraulic, pneumatic, and containment equipment customarily test the fluid integrity of their components to ensure safe operation in the field. Standards are generally prescribed for leakage rates at test pressures and times correlated to the desired component specifications.
Currently, leak detection systems are an assembly of separate components housed in portable test units. Using a myriad of valves and pneumatic lines a component to be tested is attached to the test unit and independent valves are sequenced to route pressurized fluid, customarily air, to the component, which is then isolated. The leakage rate at the component is then measured and a part accepted or rejected based thereon. The multiple valves and lines may be integrated into a portable test stand for on-site testing. Nonetheless, the pneumatic system is expansive and cumbersome, with each element posing the potential for associated malfunction and leaks. Further, automation of a testing protocol is difficult because of the independent relationship of the components. Where varying test pressures are required for other components, the system must be retrofitted for each such use.
For example, the leak detection apparatus as disclosed in U.S. Pat. No. 5,898,105 to Owens references a manually operated systems wherein the testing procedures is controlled by plural manual valves and associated conduit occasioning the aforementioned problems and limitations.
Similarly, the hydrostatic testing apparatus as disclosed in U.S. Pat. No. 3,577,768 to Aprill provides a portable unit comprised of a plurality of independent valves and associated lines for conducting testing on equipment and fluid lines. The valves are manually sequenced for isolating test components from a single pressure source. U.S. Pat. No. 5,440,918 to Oster also discloses a testing apparatus wherein a plurality of conventional valving and measuring components are individually fluidly connected.
Remotely controlled leak detection systems, such as disclosed in U.S. Pat. No. 5,557,965 to Fiechtner, have been proposed for monitoring underground liquid supplies. Such systems, however, also rely on an assembly of separate lines and valves. A similar system is disclosed in U.S. Pat. No. 5,046,519 to Stenstrom et al. U.S. Pat. No. 5,072,621 to Hasselmann.
U.S. Pat. No. 5,540,083 to Sato et al. discloses remotely controlled electromagnetically operated valves for measuring leakage in vessels and parts. Separate valve and hydraulic lines are required.
In an effort to overcome the foregoing limitations, it would be desirable to provide a portable leakage detection system for testing the fluid integrity of fluid systems and components that include integrated valving and porting within a compact envelope for automatically controlling a variable testing protocol. The leak detector includes a valve block having internal porting selectively controlled by four identical and unique pneumatic poppet valves for pressurizing the test part, isolating the test part for determining leakage rates with pressure and flow sensors communicating with the porting, and exhausting the test line upon completion of the leakage test. The poppet valves engage valve seats incorporated within the porting. The poppet valves are actuated by pilot valve pressure acting on a pilot piston to effect closure of the valve. The sensors interface with a microprocessor for comparing measurements with the test protocol and indicate pass or fail performance. Upon removal of the pilot valve pressure, the resident pressure in the porting shifts the valve to the open position. The leak detector includes plural inlets for accommodating variable pressure protocols. The leak detector thus eliminates the need for external fluid connections and conduits between the various detector components, eliminates the need for two-way valving actuation, and provides for connection with external test units with a single, easy to install, pneumatic line.
In another aspect of the invention, the poppet valves may be disposed in sets in a valve manifold to simulate conventional valve functionalities with a plurality of fluidic devices. For three way valve functionality, a pair of the pitot valves operates in controlled phased opposition to apply and vent pressure to a one way actuator. For four way valve functionality, a second set of oppositely configured valve are used for conventional operation of dual controlled devices such as two way actuators.
BRIEF DESCRIPTION OF THE DRAWINGS
The above and other objects and advantages of the present invention will become apparent upon reading the following detailed description taken in conjunction with the accompanying drawings in which:
FIG. 1 is a perspective view of a leak detection valve assembly and control module in accordance with an embodiment of the invention;
FIG. 2 is a schematic drawing of a leak detection system incorporating the valve assembly of FIG. 1 ;
FIG. 3 is a top view of the valve assembly;
FIG. 4 is a front view of the valve assembly;
FIG. 5 is a vertical cross sectional view taken along line 5 - 5 in FIG. 3 ;
FIG. 6 is a vertical cross sectional view taken along line 6 - 6 in FIG. 4 ;
FIG. 7 is a horizontal cross sectional view taken along line 7 - 7 in FIG. 4 ;
FIG. 8 is a horizontal cross sectional view taken along line 8 - 8 in FIG. 4 ;
FIG. 9 is a fragmentary cross sectional view of a unique poppet valve assembly;
FIG. 10 is a schematic diagram of the leak detection system;
FIG. 11 is a truth table for the leak detection system;
FIG. 12 is a schematic diagram for the control system for the leak detection system;
FIG. 13 is a perspective view of another embodiment of a valve assembly for a leak detection system;
FIG. 14 is a perspective view of a valve manifold assembly in accordance with another embodiment of the invention;
FIG. 15 is a top view of the valve manifold assembly shown in FIG. 14 ;
FIG. 16 is a front view of the valve manifold assembly shown in FIG. 14 ;
FIG. 17 is a left end view of the valve manifold assembly shown in FIG. 14 ;
FIG. 18 is a cross sectional view of the valve manifold assembly shown in FIG. 14 , with the control module removed and including cross sectional view of valve sets taken along lines A-A and B-B in FIG. 16 and a schematic view of the control system for the valve sets for three way and four way valve functionality;
FIG. 19 is a fragmentary cross sectional view taken along line 19 - 19 in FIG. 18 ; and
FIG. 20 is a cross sectional view of a valve manifold according another embodiment of the invention illustrating a two way valve functionality.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Referring to the drawings for the purpose of describing the preferred embodiment and not for limiting same, FIGS. 1 and 2 illustrate a leak detection system 10 for determining the pressure integrity of components when subjected to pressure conditions during a test period. The leak detection system 10 comprises a valve assembly 12 and a control module 14 operatively coupled with a flow sensor 16 and pressure sensor 18 . As hereinafter described in detail, the leak detector 10 is operative for testing the fluid integrity of test parts to determine is leakage standards are being achieved.
Referring additionally to FIG. 10 , the valve assembly 12 is fluidly connected with a low pressure source 20 along line 22 , a high pressure source 24 along line 26 , a test unit 28 for testing such parts along line 30 , and an exhaust 32 along line 34 . Supplemental valves may be disposed in the lines for controlling flow therethrough.
The control module 14 comprises a pilot valve assembly 36 including pilot valves 40 , 42 , 44 , and 46 fluidly connected with a high pressure valve unit 50 , a low pressure valve unit 52 , an exhaust valve unit 54 and an isolation valve unit 56 along lines 60 , 62 , 64 and 66 , respectively. The pressure sensor 18 is coupled with the isolation valve unit 56 by line 68 . The flow sensor 16 is connected with the valve units at manifold line 70 and with test part line 30 along line 72 . The pilot valves are connected to pilot pressure 74 by manifold line 76 . The lines and attendant fittings will vary in accordance with the parts undergoing testing and the test conditions.
Referring to FIGS. 3 through 8 , the valve assembly 12 comprises a valve block 40 housing via ports to be described below a low pressure valve unit 80 , a high pressure valve unit 82 , an exhaust valve unit 84 and an isolation valve unit 86 .
As shown in FIGS. 5 and 8 , the low pressure valve unit 80 is fluidly connected with line 28 and low pressure source 20 by a low pressure inlet port 90 intersecting with a vertical cross port 92 . The high pressure valve unit 82 is fluidly connected with line 26 and high pressure source 24 by a high pressure inlet port 94 intersecting with a vertical cross port 96 . As shown in FIG. 6 , the isolation valve unit 86 is fluidly connected with the line 30 by the isolation port 98 and vertical port 99 . The exhaust valve unit 84 is fluidly connected with line 32 by exhaust port 100 . As shown in FIG. 4 , the ports 90 , 94 and 100 are disposed on the front face 102 of the valve block 12 . The isolation port 98 is disposed on the rear face 104 of the valve block 12 . The ports 100 and 98 are located laterally in a central vertical plane. The ports 90 and 94 are symmetrically disposed on opposite sides of the exhaust port 100 and therebelow. The ports 100 , 94 and 90 lie in a common horizontal plane. Each of the ports is provided with an outer threaded bore for connection to the associated lines with an appropriate fitting for the fluid application.
All of the valve units have a common architecture as representatively shown in FIG. 9 . Therein, a valve unit 110 including a poppet 112 having a valve stem 113 supported by sealing disk 114 for reciprocation between a raised vent position as illustrated and a lowered sealed position in counterbore 115 . The poppet 112 includes a cylindrical valve body 116 carrying 0-ring 117 that engages the annular valve seat 118 of counterbore 115 formed coaxially with a vertical port 120 . The outer rim of the sealing disk 114 is supported at the base of a secondary counterbore vertically above bore 115 . The secondary counterbore outwardly terminates at an internally threaded end. A vent cap 124 includes a cylindrical sleeve 125 threadedly received in the threaded bore and a circular base 126 having a threaded center hole 128 . An actuating piston 129 including 0-ring 130 is axially slidably carried at the interior surface of the sleeve of the vent cap 124 for movement between a raised position engaging the base 128 and a lowered position engaging the top of the valve stem 113 for moving the poppet 112 to the sealed condition. Angularly disposed vent holes 131 are formed in the sleeve 125 for venting the piston. An air line connected with the pilot pressure line is connected at the center hole 128 for connection with the pilot pressure control system.
In typical operation, when pilot pressure is applied in the chamber above the piston 129 , the piston 129 is forced downwardly thereby shifting the poppet 112 to the sealed position. When the pilot pressure is removed and the port 120 is pressurized, the poppet 112 and the piston 129 are driven to the raised, open position. Assist springs may be deployed, particularly in the isolation valve, for providing additional biasing to the open condition.
As shown in FIGS. 5 through 8 , with respect to the exhaust port 100 and valve unit 84 , a counterbore 138 is formed in the bottom surface of the valve block 40 coaxially therewith. A circular sealing blank 140 is retained at a step in the counterbore 138 by a split retaining ring 142 retained in a corresponding annular groove thus defining a pressure chamber 144 . A C-shaped distribution channel or port 150 extends from the chamber 144 upwardly and intersects the counterbores 115 of valve units 110 .
Accordingly, when either of the pressure valve units is pressurized from its source and the pilot control to the piston is interrupted, the air flow in the ports 92 , 96 , 99 shifts the poppets to raised, open positions, thereby pressurizing the distribution port 150 and chamber 144 resulting in pressure communication therebetween. Referring to FIGS. 3, 7 and 8 , a pair of vertical ports 160 communicate upstream of the isolation valve unit 84 for connecting one line of the flow sensor 16 and the pressure sensor 18 . A pair of vertical ports 162 communicates on the other side of the isolation valve units 84 with the distribution port 150 . Accordingly, the flow sensor 16 in a conventional manner measures pressure transients on the part under leakage test while the pressure sensor 18 measures pressure conditions on both sides of the isolation valve.
The valve unit is operationally connected to an independent test unit whereat parts to be leak tested may be deployed. The test protocol may specify a high pressure test for a defined test period or a low pressure test for a defined test period. Test parts are deemed successful if the leakage under pressure as determined by the flow sensor 16 is below a predetermined threshold. The control system 14 is effective for establishing the appropriate protocol.
Referring to FIG. 12 , the control system 14 comprises the pilot valve system 250 , a microprocessor 254 coupled with a control panel 255 for defining and conducting the test protocol, test result indicator lights 256 a display screen 257 , for denoting passing or failing of the test connected to a suitable power supply 258 . The microprocessor 254 contains the protocols for the various parts, preferably programmed through an external computer port 260 . The desired protocol is accessed at control panel 255 through menu button 264 , start button 266 and scroll buttons 268 .
The operation of the leak detector is illustrated in the truth table of FIG. 11 and taken in conjunction with the schematic of FIG. 2 .
A part to be tested in mounted in the test fixture, the control system initialized and the test protocol selected. Thereafter, the test is initiated by actuating the start button 266 . As a first condition, the high and low pressure lines are pressurized with the accompanying pilot valves 40 , 42 in the normally open positions with the solenoids deenergized. This applies pilot pressure to the associated poppets to close and seal the high pressure and low pressure valve units 50 , 52 . Correspondingly, the normally closed exhaust pilot is deenergized and the exhaust valve 54 is in the open position. The normally closed isolation pilot is deenergized and the isolation valve unit 56 is in the open position.
Thereafter the high pressure pilot 40 is energized, venting the high pressure poppet whereby inlet high pressure air raises the high pressure valve unit 50 to the open position. Concurrently, the exhaust solenoid is energized admitting pilot pressure to the exhaust poppet piston chamber and shifting the exhaust valve unit 54 to the closed position and air flowing past the high pressure poppet pressurizes the exhaust chamber 144 through the distribution channel and past the isolation valve unit 56 to pressurize the test part with high pressure air. Thereafter, the isolation pilot is energized applying pilot pressure to the isolation piston chamber and closing the isolation poppet. Thereafter, the flow sensor 16 monitors pressure transients and through the microprocessor interface denotes pass or fail conditions at the indicator lights.
Upon completion of the test, the isolation pilot solenoid is deenergized pressurizing the high pressure piston and sealing the high pressure valve seat, thereby ceasing inlet flow. Concurrently, the isolation and exhaust pilot solenoids are deenergized allowing exhaust chamber and part pressure to shift the exhaust and isolation valves to the open position for completion of the test. In the event of excessive pressure lost at the test part, a light biasing spring may be provided at the isolation poppet to ensure movement to the open position.
For testing under low pressure conditions, the exhaust poppet is closed and the low pressure valving sequenced in similar fashion to the high pressure test detailed above. More particularly, a part to be tested in mounted in the test fixture, the control system initialized and the test protocol selected. Thereafter, the test is initiated by actuating the start button 266 . As a first condition, the high and low pressure lines are pressurized with the accompanying pilot valves in the normally open positions with the solenoids deenergized. This applies pilot pressure to the associated poppets to close and seal the later. Correspondingly, the normally closed exhaust pilot is deenergized and the exhaust poppet is in the open position. The normally closed isolation pilot is denergized and the isolation poppet is in the open position.
Thereafter the low pressure pilot 42 is energized, venting the low pressure valve whereby inlet low pressure air raises the low pressure valve unit 52 to the open position. Concurrently, the exhaust pilot is energized admitting pilot pressure to the exhaust poppet piston chamber and shifting the exhaust valve unit 54 to the closed position and air flowing past the low pressure poppet pressurizes the exhaust chamber through the distribution channel 150 and past the isolation poppet to pressurize the test part with high pressure air. Thereafter, the isolation pilot solenoid is energized applying pilot pressure to the isolation piston chamber and closing the isolation poppet. Thereafter, the flow sensor monitors pressure transients and through the microprocessor interface denotes pass or fail conditions at the indicator. Upon completion of the test, the isolation pilot is deenergized pressurizing the low pressure piston and sealing the low pressure valve seat, thereby ceasing inlet flow. Concurrently, the isolation and exhaust pilot solenoids are deenergized allow exhaust chamber and part pressure to shift the exhaust and isolation poppets to the open position for completion of the test.
Referring to FIG. 13 , a fully integrated package is illustrated for a leak detection valve 280 as described above. The valve 280 comprises an extruded metallic valve body 282 having four valve assemblies 284 , as described above. The valve assemblies are controlled by solenoids 286 carried on a top horizontal surface. The valve body 280 has an isolation port 288 in the illustrated rear wall thereof, and high and low pressure ports, and an exhaust port in the front wall thereof, which are not shown and function as above described. The control lines for the valve assemblies 284 are routed through a distribution bracket 290 . The interior pressure sensors are coupled at pin connector 292 on the top surface of the valve body 280 for operative connection to associated instrumentation.
Referring to FIGS. 14 through 17 , in another embodiment of the invention the valving is incorporated into a control valve manifold 300 . The manifold 300 includes an extruded lower valve body 302 carrying on a top surface a plurality of longitudinally spaced control modules 304 for operatively controlling conventional fluidic devices, not shown, coupled at a longitudinal series of associated outlet ports 306 exiting at a longitudinal side wall of the valve body. An inlet port 310 and an exhaust port 312 extend longitudinally through the valve body 302 in parallel spaced relationship for interconnection with the valving as described in greater detail below.
The ports 310 and 312 terminate at internally threaded ends. At the remote end, the ports are suitably sealed with a stop member, such as a threaded plug (not shown), or coupled with a succeeding manifold. The inlet port 310 is coupled with a supply line for supplying inlet fluid under pressure for control by the valving and controlled operation of the associated fluidic devices. The exhaust port 312 is coupled with an exhaust line for routing to an appropriate location the exhaust fluid.
A pair of upwardly opening laterally spaced longitudinal channels 320 are formed in the top surface of the valve body 302 . Solenoids 322 are carried in the channels 320 and operatively associated with the control modules 304 for controlling pilot pressure to the valving at pilot lines 324 . The modules 304 are connected to a suitable power source via multiple-pin socket connector 326 carried on the front lateral side wall of the valve body 302 . The valve modules 304 control the flow between the ports 310 , 312 and the operative outlet ports 306 of the manifold 300 . If certain of the ports are not required for an application, the outlet ports may be plugged or capped, and additionally the associated control module deleted. Any ports associated with the inactive outlet ports are also deleted or plugged.
It will also be apparent that the length of the valve body may be tailored to the devices to be controlled and may be coupled in series or parallel with other valving manifolds.
The manifold in controlled formats may be advantageously employed to replicate the functionality of various conventional valving configurations, such as two-way, three-way, four-way, five-way valves. In such configurations, the manifold operates with lower control pressures within a substantially smaller envelope.
More particularly, as shown in FIG. 1-8 , each control module 304 is associated with a pair of laterally spaced valves 340 , 342 in Valve A and valves 344 and 346 in Valve B. The valves are operatively disposed in the valve body 302 as referenced in FIG. 9 above.
The inlet valves 340 , 344 are disposed in upwardly opening vertical bores in the valve body normal to the inlet port 310 . Each valve includes a slidably stem supported inlet valve member 360 downwardly moveable by a floating piston 362 from a raised position communicating with the inlet port 310 and a closed position engaging an annular valve seat downstream of the inlet port.
The exhaust valves 342 , 346 are disposed in upwardly opening vertical bodes in the valve body normal to the exhaust port 312 . Each valve includes a slidably stem supported outlet valve member 370 downwardly moveable by a floating piston 372 from a lowered position engaging an annular valve seat upstream of the exhaust port 312 and a raised position communicating with the exhaust port.
An exhaust plenum chamber 380 is formed in the valve body 302 below the exhaust valve seat and in the open position communicates with the exhaust port. The exhaust plenum chamber 380 is sealed by a circular cover member 382 and sealed as described with reference to the prior embodiment. Referring to FIG. 19 , a cross passage 384 is formed at the outer periphery of the exhaust plenum chamber and established a fluid path extending serially from the outlet port 306 to the cross passage to the exhaust plenum chamber 380 to the exhaust port.
Each piston is carried in a valve cap threadedly connected in a bore extending from the top surface of the valve body coaxial with the exhaust valve seat. The valve caps are fluidly connected with branch pilot lines 323 above the piston.
Referring to Valve A in FIG. 18 illustrating a three way valve functionality, the exhaust valve 370 is connected at the branch pilot line with a normally open solenoid valve 400 connected with the main pilot line 402 . The inlet valve 360 is connected at the branch pilot line with a normally closed solenoid valve 404 connected with the main pilot line.
The outlet port 306 is formed in the side of the valve body 302 and intersects the inlet valve bore above the inlet valve seat. The device port is fluidly connected by line to one side of a single acting actuator 410 , including return spring biased piston 411 , by lines 412 and 414 .
In operation, the inlet valve member 360 is moved upwardly to an open position by inlet pressure on the lower surface thereby shifting the piston to a raised position, establishing a fluid path through outlet port 306 and lines 412 , 414 and extending actuator piston 411 . The outlet valve member is shifted by the piston to the closed position sealing flow to the outlet port. To retract the piston, the solenoid valves are reversed, whereby the inlet valve member 360 is closed, the outlet pilot pressure removed allowing pressure conditions in the plenum 380 to move the exhaust valve member 370 to the open position and venting the actuator to the exhaust port 312 thereby retracting the actuator piston under the spring biasing.
For four way simulation according to the invention, Valve B is operatively coupled with Valve A. Valve B has a normally open inlet solenoid valve 420 and a normally closed exhaust solenoid valve 422 . Valve A is coupled with one end of a double acting actuator 430 , including piston 431 , by lines 412 , 432 . Valve B is couple at the outlet port with the other end of the actuator 430 by line 434 .
In operation, the extension of actuator is controlled by Valve A as above described, and Valve B is in the exhaust mode. To retract the actuator piston 431 , Valve A is conditioned for exhaust and Valve B is conditioned for pressure, thereby shifting the piston 431 to the retracted position.
Referring to FIG. 20 , the valve manifold of the present invention may also provide two way valve functionality. Therein, a valve 500 includes a valve body 502 carrying a valve assembly 504 as described above. The inlet valve member 506 is moved by piston 508 under pilot conditions controlled by normally open solenoid valve 510 between a lower closed position engaging the inlet valve seat and the illustrated raised open position. In the open position with the solenoid valve vented, the valve permits fluid flow from supply line 520 to inlet port 522 past valve member 506 to outlet port 524 to a pressure dependent device 526 . Upon reversal of the solenoid valve 510 , the pilot pressure is applied to the piston to closed the valve member and block flow therethrough. At the next actuation, the inlet pressure shifts the valve member to the open condition.
With the above constructions, it will be appreciated that the individual valve members may be independently controlled and sequenced to a desired actuation schedule. In particular for spool valve simulation, the normal crossover time between valve positions may be eliminated by concurrent actuation of the solenoids. Should staged actuation be desired, time sequencing may be used. Further the valve ports may be integrated with other flow control. Each such simulation provides the compact size afforded by the valves directly place in the manifold bodies, and the low pilot pressures required by the valves, as well as the valve opening pressures afforded by resident pressurization.
Having thus described a presently preferred embodiment of the present invention, it will now be appreciated that the objects of the invention have been fully achieved, and it will be understood by those skilled in the art that many changes in construction and widely differing embodiments and applications of the invention will suggest themselves without departing from the sprit and scope of the present invention. The disclosures and description herein are intended to be illustrative and are not in any sense limiting of the invention, which is defined solely in accordance with the following claims.
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A valve manifold includes a valve body carrying pairs of laterally spaced piston actuated valves controlled by control modules operative to selectively pressurize and exhaust an outlet port connected to a fluid device and configured in groupings permitting varying valve functionalities.
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CROSS-REFERENCE TO RELATED APPLICATION
This application claims priority to and the benefit of Korean Patent Application No. 10-2015-0065570 filed in the Korean Intellectual Property Office on May 11, 2015 and Korean Patent Application No. 10-2015-0167328 filed in the Korean Intellectual Property Office on Nov. 27, 2015, the entire contents of each of which are incorporated herein by reference.
BACKGROUND
(a) Field
The present disclosure relates to a driving test system for a moving object that detects motion characteristics of the moving object traveling along a preset route and determines how the moving object, such as a vehicle, is functioning and driving.
(b) Description of the Related Art
In general, an autonomous test vehicle is a vehicle that is forced to drive continuously to evaluate the vehicle's driving performance so that intended test results can be obtained. This vehicle is used to perform a forced driving operation on a test road such as a Belgian road with a rough surface.
Thus, the autonomous test vehicle does not require a human driver to manually test-drive the vehicle. This saves the operator the trouble and risk of test driving, allows for severe driving tests, and improves the reliability of test results. Therefore, research, development, and studies on techniques and methods for automatically controlling testing and driving are ongoing.
Conventionally, the above autonomous test vehicle self-controls its driving by enabling a vision sensor unit installed at the front of the test vehicle to recognize road lanes and detect an approaching object.
That is, the driving of the autonomous test vehicle is controlled in response to a control tower's radio control signals, which are input through an antenna and radio transmitter/receiver installed on the vehicle, and a driving control unit automatically controls the driving of the vehicle through a pedal controller in response to an approaching object and lane recognition signals, which are input from an object detector and vision sensor unit using various sensors.
However, the operator's personal subjective view may influence a vehicle driving test, the accuracy of vehicle driving may be reduced, and the cost of labor may be increased.
The above information disclosed in this Background section is only for enhancement of understanding of the background of the invention and therefore it may contain information that does not form the prior art that is already known in this country to a person of ordinary skill in the art.
SUMMARY
The present disclosure has been made in an effort to provide a driving test system for a moving object capable of increasing the accuracy of performance tests of a moving object, such as a vehicle, and reducing the cost of labor.
An exemplary form of the present disclosure provides a driving test system for a moving object including: an unmanned aircraft configured to fly at a set distance from the moving object, where the moving object is configured to drive along a set route in a set zone and the moving object comprises a vision sensor disposed on one side that is configured to detect a motion of the moving object'; and a controller configured to control the flight of the unmanned aircraft to follow the moving object and to transmit to the vision sensor and to receive from the vision sensor, detected motion characteristics of the moving object.
The unmanned aircraft may control the moving object to implement a driving function including an advanced driver assistance system (ADAS), and the advanced driver assistance system may include autonomous emergency braking (AEB), a lane departure warning system (LDWS), a lane keeping assistance system (LKAS), blind spot detection (BSD), or smart cruise control (SCC). The vision sensor may detect lanes the moving object is traveling in and an obstacle near the moving object during implementation of the driving function.
The moving object may be controlled by the unmanned aircraft and may include a detector for detecting the moving object's surroundings.
The detector may detect lanes, an obstacle near the moving object, and the distance to the obstacle.
The moving object may be controlled by the unmanned aircraft and may have an autonomous driving function for automatically controlling a steering device, an accelerator, and a braking device.
The driving test system may further include: a conveyor with the unmanned aircraft's landing and takeoff spots set therein, which is disposed to move the unmanned aircraft from the landing spot to the takeoff spot; a landing marker formed on one side of the landing spot; a proximity sensor disposed on the other side of the landing spot to detect the unmanned aircraft; and photosensors disposed on one side of the takeoff spot to detect the unmanned aircraft.
The controller may determine the moving object's information, speed, and travel distance based on information detected by the vision sensor.
The controller may detect motion characteristics of the moving object using the advanced driver assistance system.
The driving test system may further include a radio transmitter/receiver and an antenna, and the controller may control the moving object''s driving function and the unmanned aircraft by the radio transmitter/receiver and the antenna.
An exemplary form of the present disclosure provides a driving test method for a moving object including: causing the moving object to enter a preset route and driving the moving object; flying an unmanned aircraft along with the moving object; and detecting motion characteristics of the moving object by a vision sensor mounted on the unmanned aircraft and determining how the moving object is driving.
The driving test method may further include controlling, by the unmanned aircraft, the moving object to implement a driving function including an advanced driver assistance system (ADAS), and the advanced driver assistance system may include autonomous emergency braking (AEB), a lane departure warning system (LDWS), a lane keeping assistance system (LKAS), blind spot detection (BSD), or smart cruise control (SCC).
The driving test method may further include detecting the moving object's surroundings by a detector.
The detector may detect lanes, an obstacle near the moving object, and the distance to an object in front of the moving object.
The driving test method may further include performing an autonomous driving function for automatically controlling a steering device, an accelerator, and a braking device.
The testing of moving objects such as autonomous vehicles or traditional vehicles using an unmanned aircraft can improve the test accuracy and reduce the cost of labor.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 is a schematic block diagram of a driving test system of a moving object.
FIG. 2 is a table showing functions implemented by the moving object.
FIG. 3 is a schematic top plan view of a conveyer where an unmanned aircraft takes off and lands, in the driving test system for the moving object.
FIG. 4 is a partial schematic top plan view showing a path of travel of the moving object in the driving test system for the moving object.
FIG. 5 is a flowchart showing a driving test method of the moving object.
FIG. 6 is a flowchart showing an unmanned aircraft's landing and takeoff procedure in the driving test method for the moving object.
FIG. 7 is a table showing a vision sensor's functions and the moving object's functions in the driving test method of the moving object.
DETAILED DESCRIPTION
An exemplary form of the present disclosure will hereinafter be described in detail with reference to the accompanying drawings.
FIG. 1 is a schematic block diagram of a driving test system for a moving object.
Referring to FIG. 1 and FIG. 4 , the driving test system for the moving object includes an unmanned aircraft 100 , a vision sensor 110 , the moving object 120 , a detector 140 , an antenna 150 , a radio transmitter/receiver 160 , and a controller 130 .
The moving object 120 includes an autonomous vehicle or a traditional vehicle that is set to travel along a route 400 set either manually or autonomously.
The unmanned aircraft 100 is autonomously controlled by the controller 130 to move along with the moving object 120 at a set distance above the moving object 120 . For example, the moving object 120 may be controlled by the unmanned aircraft 100 .
The vision sensor 110 disposed at the unmanned aircraft 100 detects motion of the moving object 120 and checks information on the moving object 120 . Also, the vision sensor 110 may detect a lane in which the moving object is driving and an obstacle and may detect a distance between the moving object and the obstacle.
Moreover, the detector 140 installed on the moving object 120 detects lanes 420 and an obstacle 410 near the moving object, and detects the distance to the obstacle 410 .
The controller 130 may be implemented as one or more microprocessors operating by a preset program, and the preset program may include a series of commands for performing a method according to the exemplary embodiment of the present invention.
FIG. 2 is a table showing functions implemented by the moving object.
The moving object 120 may implement a driving function which includes an advanced driver assistance system (ADAS). For example, the unmanned aircraft 100 may control the moving object 120 to implement (or perform) the driving function that includes the advanced driver assistance system.
The advanced driver assistance system may include autonomous emergency braking (AEB), a lane departure warning system (LDWS), a lane keeping assistance system (LKAS), blind spot detection (BSD), or smart cruise control (SCC).
The description of the well-known art can be substituted for the description of the advanced driver assistance system, and a detailed description of the advanced driver assistance system will be omitted.
FIG. 3 is a schematic top plan view of a conveyer where an unmanned aircraft takes off and lands, in the driving test system for the moving object.
Referring to FIG. 3 , the conveyer 300 is disposed along a set route, and landing markers 310 are disposed on either side of one end of the conveyer 300 . Moreover, a first proximity sensor 312 is disposed between the landing markers 310 .
Photosensors 316 are disposed on the other end of the conveyer 300 , spaced a set distance apart in the direction the conveyor 300 moves, and a second proximity sensor 314 is disposed between the photosensors 316 .
The unmanned aircraft 100 detects the landing markers 310 by the vision sensor 110 , and lands between the landing markers 310 . Then, the first proximity sensor 312 detects the unmanned aircraft 100 .
When the unmanned aircraft 100 is detected by the first proximity sensor 312 , the conveyor 300 goes into operation and moves the unmanned aircraft 100 .
When the unmanned aircraft 100 is located between the photosensors 316 and the second proximity sensor 314 detects the unmanned aircraft 100 , the conveyor 300 stops operating and prepares for takeoff of the unmanned aircraft 100 .
FIG. 4 is a partial schematic top plan view showing a path of travel of the moving object in the driving test system of the moving object.
Referring to FIG. 4 , the moving object 120 is set to move along the route 400 , lanes 420 are formed on either side of the moving object 120 , and the obstacle 410 is disposed in a set position. The moving object 120 may be controlled either manually or autonomously.
FIG. 5 is a flowchart showing a driving test method of the moving object.
Referring to FIG. 5 , control is started at S 500 , and the moving object 120 such as the autonomous vehicle or the traditional vehicle and the unmanned aircraft 100 are on standby at S 510 and S 520 .
The moving object 120 enters the path 400 , either by the controller 130 or by the operator at S 530 , and the unmanned aircraft 100 flies along with the moving object 120 at S 540 .
The moving object 120 performs functional driving at S 550 . The functional driving may include implementing an advanced driver assistance system (ADAS), and the advanced driver assistance system may include autonomous emergency braking (AEB), a lane departure warning system (LDWS), a lane keeping assistance system (LKAS), blind spot detection (BSD), or smart cruise control (SCC).
That is, the operator or the controller 130 selectively operates the advanced driver assistance system to control the driving of the moving object 120 at S 550 , motion characteristics of the moving object 120 are detected by the unmanned aircraft 100 at S 560 , and the driving test is finished at S 570 .
Then, the moving object 120 deviates from its route at S 580 , and the flight of the unmanned aircraft 100 is finished at S 590 .
In the exemplary form of the present disclosure, the motion characteristics of the moving object detected by the vision sensor 110 of the unmanned aircraft 100 may be transmitted to the controller 130 through the radio transmitter/receiver 160 , and the controller 130 may determine how the moving object 120 is driving based on the received information.
FIG. 6 is a flowchart showing an unmanned aircraft's landing and takeoff procedure in the driving test method for the moving object.
Referring to FIG. 6 , the unmanned aircraft 100 lands at a landing spot in the conveyor 300 at S 600 . In this case, the vision sensor 110 of the unmanned aircraft 100 detects the landing markers 310 , and the unmanned aircraft 100 lands at the corresponding location.
The first proximity sensor 312 detects the unmanned aircraft 100 at S 610 , and when it is determined that the unmanned aircraft 100 is detected, the conveyor 300 operates to move the unmanned aircraft 100 at S 620 .
The photosensors 316 or a proximity sensor detect that the unmanned aircraft 100 has reached the set landing spot at S 630 , and the conveyor 300 is stopped at S 640 . Also, the unmanned aircraft 160 starts flying in response to a set takeoff signal.
FIG. 7 is a table showing a vision sensor's functions and the moving object's functions in the driving test method of the moving object.
Referring to FIG. 7 , the vision sensor 110 checks information of the moving object such as the autonomous vehicle or the traditional vehicle, detects the speed of the moving object 120 , detects the distance traveled by the moving object 120 , and transmits the results to the controller 130 .
Also, the moving object 120 drives autonomously or performs each function in response to a control signal from the controller 130 . In this case, the moving object 120 may be operated automatically by an accelerator pedal, brake pedal, and steering wheel of the moving object 120 by a set algorithm.
While forms of the present disclosure have been described in connection with what is presently considered to be practical exemplary forms, it is to be understood that the disclosure is not limited to the disclosed forms. On the contrary, it is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
DESCRIPTION OF SYMBOLS
100 : unmanned aircraft
110 : vision sensor
120 : moving object
130 : controller
140 : detector
150 : antenna
160 : radio transmitter/receiver
300 : conveyor
310 : landing marker
312 : first proximity sensor
314 : second proximity sensor
316 : photosensor
400 : route
410 : obstacle
420 : lane
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One form of a driving test system for a moving object includes: an unmanned aircraft configured to fly at a set distance from the moving object that is configured to drive along a set route in a set zone and has a vision sensor disposed on one side that is configured to detect the moving object's motion; and a controller configured to control the flight of the unmanned aircraft to follow the moving object and to transmit to the vision sensor and to receive from the vision censor, detected motion characteristics of the moving object.
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This is a continuation of PCT/NZ00/00198, filed Oct. 12, 2000 and published in English.
FIELD OF THE INVENTION
The present invention relates to a pull through and related methods of manufacture, use and dispensing. In one form such a pull through is a pull through for an endoscopic and a method for manufacturing such apparatus.
Endoscopes require frequent cleaning. It is found that endoscopes (such as those lined with, for example, a polyurethane sleeve) are perhaps best sterilised between uses by a cleaning regime that involves the pushing and/or pulling through of a brush the effect of which is to smooth the inwardly directed surface and surface deposits of the polyurethane sleeve or its equivalent. Apparently this better enables chemical cleaning and sterilisation to ensue. See for example the post Mar. 2, 2000 published content of PCT/AU99/00669 (WO 00/10476) of Novapharm Research (Australia) Pty Limited the full content of which is here included by way of reference.
SUMMARY OF THE INVENTION
The present invention is directed to any such pull through apparatus, all uses of such apparatus and methods for manufacturing such apparatus.
As used herein the term “pull through” also includes (where the circumstance allows) a “push through” device. Frequently, by way of example, where a short length conduit is to be dealt with, it is sometimes just as convenient to push the head of a pull through type device through the device rather than thread and then pull the pull through device through the short length conduit. Accordingly the term “pull through” in the present specification and in the appended claims includes within its ambit any variant capable in some circumstances of being used as a push through.
In a first aspect the invention is a pull through comprising or including
a filament having at least a thermoplastics surface, and a moulded thermoplastic mass about said filament defining a pull through profile adapted for the purpose of the pull through, wherein the filament is a monofilament (whether of the one material or otherwise) sufficiently stiff to enable its threading through the member (e.g. endoscope, fuel line, conduit, barrel, etc.) for which it is adapted or intended for use, and wherein said moulded thermoplastic mass is of a material of lower melting point than at least part of said filament.
Preferably said monofilament is of a single plastics material.
Preferably said single plastics material is polypropylene.
Preferably the moulded thermoplastics mass is of polyethylene (eg; LLDPE) and a polyolefin elastomer. Examples include SANTOPRENE™, DOWLEX™ and ENGAGE™.
Preferably said filament is round in section.
Preferably said moulded thermoplastics mass is adjacent one end of said filament.
Preferably said moulded thermoplastics mass has been injection moulded about said filament only once the thermoplastics surface of said filament onto which it is to be injection moulded has been softened and/or conditioned.
Preferably said filament is substantially straight and free of any previous spool or coil memory.
Preferably said filament is conditioned by heating prior to said mass being injection moulded.
Preferably said filament is conditioned by heating and stretching prior to said mass being injection moulded.
Preferably said filament is a monofilament of polypropylene that has been heated preferably to from 91 to 95° C. (e.g. 93 to 95° C.) for preferably from 8 to 15 seconds (e.g. about 12 seconds) whilst preferably being stretched axially preferably by from 1 to 5% of its length from a feeder spool or coil.
Preferably said polypropylene monofilament has been extruded whilst including a gas generating agent which will expand the core region thereof upon die emergence.
Preferably said gas generating agent releases CO 2 .
Preferably said gas generating agent inclusion is such as to enhance the circularity of cross-section of the monofilament from the extrusion die.
Preferably said mass is of a profile (which whilst it may differ axially with respect to the filament) is laterally preferably symmetric about said filament.
In another aspect the invention is an endoscope pull through, being a pull through as previously defined.
In yet another aspect the invention is a conduit pull through, being a pull through as previously defined.
In another aspect the invention is a method of manufacturing a pull through, said pull through comprising or including
a filament having at least a thermoplastics surface, and a moulded thermoplastic mass about said filament defining a pull through profile adapted for the purpose of the pull through, said method comprising or including providing a coil or spool feeding of a monofilament filament having at least a thermoplastic surface, conditioning the coil or spool feed filament at an elevated temperature whilst under axial tension so as to reduce coil or spool memory in the filament, and injection moulding a thermoplastic pull through profile about at least one axial zone of said filament, said injection moulding being with a molten thermoplastic capable of “keying” to the surface of the monofilament at a temperature below the melting point of the filament.
In another aspect the present invention consists in a pull through useably as an endoscope cleaning apparatus said apparatus comprising or including
an elongate member capable of being inserted in part through a conduit (e.g. an endoscope) and thereafter to be pulled fully therethrough, said elongate member being at least in part of a first plastics material or first plastics materials (hereafter “first plastics material”), and an injection moulded form carried at and/or adjacent one end of said elongate member, said form being of a second plastics material or second plastics materials (hereafter “second plastics material”) and being such as to provide a smoothing and/or cleaning effect upon its pull through of the conduit (e.g. an endoscope) of appropriate configuration and/or dimension, wherein the form of said second plastics material has been injection moulded onto said first plastics material of said elongate member, the melting point of said second plastics material being less than that of said first plastics material.
As used herein “melting point” in respect of the first plastics material and/or second plastics material includes melting of the material or, if a blend, melting of sufficient material thereof.
Preferably said elongate member is preferably a string like member.
Preferably said elongate member is at least substantially formed of a suitable plastics material.
Preferably said suitable plastics material is at least 50% PP (polypropylene).
Preferably said elongate member is a monofilament.
Preferably said monofilament is 100% PP albeit (optionally blown by a blowing agent thereby to assume a better roundness in cross-section).
Optionally said suitable plastics material for the elongate member is 50% HDPE and 50% PP by weight as a blend or a coaxial make up of a single monofilament).
Preferably said injection moulded form is of a thermoplastic material having a melting point less than that of the first plastics material or the material providing at least the axial strength region of said elongate member.
Preferably the two plastics material are such as to enable some degree of melding, the melting point differential between the two plastics materials lending themselves to that outcome.
Preferably the second plastics material in an elastomer with LLDPE.
In another aspect the present invention consists in endoscope cleaning apparatus substantially as hereinafter described with reference to the accompanying drawings.
In still a further aspect the present invention consists in a method of manufacturing endoscope cleaning apparatus in accordance with the present invention which comprises or includes taking or providing an elongate member as aforesaid and thereafter injection moulding on or adjacent (or both) one end thereof said injection moulded form, said injection moulded form being of a second plastics material of lower melting point than the plastics material of that region (at least) of said elongate member on which the moulded form is injected.
In another aspect the present invention consists in endoscope cleaning apparatus prepared by a method in accordance with the present invention.
In still a further aspect the present invention consists in use of apparatus in accordance with the present invention to clean an endoscope or endoscopes.
BRIEF DESCRIPTION OF THE DRAWINGS
Preferred form of the present invention will now be described with reference to the accompanying drawings in which;
FIG. 1 is a reduced view of a preferred form of the present invention having an injection moulded form of said second plastics material at the end of a pull through type filament of said first plastics material, said pull through elongate member being preferably flexible and being able to pull the brush like form of the injection moulded form to achieve a cleaning effect in an appropriately dimensioned endoscope,
FIG. 2 is a cross section along the longitudinal axis of the injection moulded form end of the cleaning apparatus of FIG. 1 ,
FIG. 3A , 3 B and C show some alternatives to the embodiment of FIG. 2 , and
FIG. 4 shows a preferred manufacturing sequence.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the preferred form of the present invention the pull through is a cut to length straight and threadable monofilament of a suitable polypropylene. Preferably a tempered extruded polypropylene (eg; homopolymer P.P. supplied by Fina Chemicals, Europe or Honam Petrochemical, Korea) that has a CO 2 blown section (as a result of there having been foaming agents included with the polypropylene at the extrusion stage thereof) provides the monofilament, such monofilament assuming a substantially round cross section. Whilst coaxially different materials may be used that is not a preferred option and nor is blended material owing to delamination. Delamination problems may be overcome by better compounding prior to extrusion.
PP monofilament produced on single screw extruder 5 zones reverse temperature profile.
Polymer Base—Polypropylene homopolyer MFI3.5
Additives—Hydrocerol foaming agent let down into LDPE base.
Colour fluoro red let down into LLDPE base/Food contact safe.
Processing Data
Polymer and additives are pre-mixed. Additive percentages are precise.
Processing through the extruder using the correct temperature allows a controlled Carbon Dioxide release in the centre of the extrudate when extruded through the nozzle and exposed to the pressure drop in the atmosphere for a short time before being quenched, extrudate is drawn away from the die nozzle at a precise constant speed before being reheated in hot air.
Once the extrudate has been reheated it is then pulled down many times faster than the extrusion speed thus forming molecular chains which results in the extrudate becoming strong in the longitudinal direction. In doing this, lateral strength is extensively reduced and the extrudate remains stressed. The surface of the extrudate is then heat treated under tension to biaxially orientate the surface molecules of the extrudate before being precision cross wound to a diameter of 130 mm approx on a PVC core. The product is shrink wrapped for transportation and hygiene purposes.
The most preferred plastics material is a homopolymer polypropylene supplied by Finapro Chemicals or Honan.
That product with an inclusion of hydrocerol CO 2 is extruded to provide a monofilament of density about 0.97. Extruded PP filament tempered at about 130° C. is 0.9 mm (±5%) in diameter.
Conditioning
Because the extrudate is packaged hot and stressed, it takes on a very acute memory. Annealing or reheating the extrudate below a temperature less than the softening point of the polymer under light tension allows the molecules in the extrudate to relax thus eliminating the memory. A consequence of such conditioning is that the product will shrink.
The pre-conditioning tunnel is a simple heat tunnel during which the monofilament is drawn under some degree of tension (preferably from 91 to 95° C. (most preferably 93 to 95° C.) for about 12 seconds) so as to achieve an axial extension of no greater than 5% but preferably more than 1% during such conditioning).
The monofilament itself has a pull through head profile of a suitable material injection moulded there around at a temperature not sufficient to melt the monofilament (at least in total) at that point (or those points) and preferably not at all.
Whilst ideally the surface of the polypropylene monofilament has been pre-conditioned at an elevated temperature in order to take away the memory of its spool or coil supply, such preconditioning temperature is sufficient only to soften the outer surface to ensure better keying with the material and not to detract from the prior higher temperature tempering of the monofilament to prevent “fluffiness”.
In the preferred form of the present invention the arrangement is as shown in FIG. 4 where the injection moulding is performed using any appropriate injection moulding machine (for example, a BOY™ 22AVV) and a cassette or other off take of the output product bundles.
In another embodiment of the present invention (much less preferred as less easily threaded and more prone to delamination) the elongate injection molded form 2 may be of a suitable plastics material (such as 50% HDPE and 50% P.E.). Such a HDPE/PP blend has when formed and stretched a uniaxial orientation and at that end of the filament material 1 onto which the injection molded form 2 is injection molded there is a material melting point greater than that of the injection molded form material.
The injection moulded form 2 however is of a thermoplastic capable of being injection moulded. Such materials include a combination of an elastomer and LLDPE and preferably have a melting point below that of the material 1 so as to not destroy the structure of the filament 1 and thus the integrity of the composite device.
In the preferred form of the present invention therefore preferably the monofilament is either a polypropylene or a polypropylene/high density polyethylene mix. The head is preferably a linear low density polyethylene/elastomer mix but alternative could be of elastomer alone, high density polyethylene alone or TPR.
The pull throughs thus made can have the pull through profile of any appropriate form but preferably one that is symmetric about the monofilament into which it is keyed.
To assist such moulded symmetry of the pull through head preferably the waisted region of the filament (see FIG. 2 ) is support on a pin or the like member in the mould cavity.
Whilst annular flutes or the like can be provided these need not necessarily be present. Moreover for purposes other than endoscope cleaning or smoothing purposes other forms (brush-like or not) can be prepared.
A person skilled in the art will appreciate how (as shown) injection moulded form 2 can be brush like in character (whether having continuous or discontinuous annular ridges or the like being provided to exert a cleaning or smoothing effect).
The dimensions will be as varied as are the dimensions (diameter and length) of, for example, endoscopes.
For usual endoscope purposes an ideal length of a pull through is from 30 to 220 cm with the pull through profile being of a circular cross-section at its maximum dimension with such diameter being in the range of from 0.95 to 4.5 mm.
Other uses to which such pull throughs can be put include the cleaning of fuel lines, the cleaning of firearms, etc.
In use the pull through filament 1 would be inserted into the conduit to be pulled through (e.g. an endoscope, a fuel line, etc.) and thereafter the injection molded form 2 would be pulled through using the filament material 1 .
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A pull through such as might be used for an endoscope where a thermaplastics monofilament substantially free of spool or coil memory has molded thereon a desirable thermoplastic mass profile in a material of lower melting point than at least part of the filament, such melting point differential with preferably pre-heating of the filament ensuring an appropriate keying of the profile on the filament.
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