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(c) is subsequently received by the Receiving Party from a Third Party who is not bound by any obligation of confidentiality with respect to such information; |
(d) has been published by a Third Party or otherwise enters the public domain through no fault of the Receiving Party in breach of this Agreement; or |
(e) can be demonstrated by documentation or other competent evidence to have been independently developed by or for the Receiving Party without reference to the Disclosing Party's Confidential Information; provided that the foregoing exception shall not apply with respect to Product Information. |
Specific aspects or details of Confidential Information shall not be deemed to be within the public domain or in the possession of the Receiving Party merely because the Confidential Information is embraced by more general information in the public domain or in the possession of the Receiving Party. Further, any combin... |
9.2. Permitted Disclosures. The Receiving Party may use and disclose Confidential Information of the Disclosing Party to the extent that such disclosure is: |
9.2.1. made in response to a valid order of an arbitral tribunal, court of competent jurisdiction or other Governmental Authority of competent jurisdiction or, if in the reasonable opinion of the Receiving Party's legal counsel, such disclosure is otherwise required by Applicable Law or the rules of a stock exchange on... |
9.2.2. made by or on behalf of the Receiving Party to a patent authority as may be reasonably necessary or useful for purposes of obtaining or enforcing a Patent under this Agreement; provided, however, that reasonable measures shall be taken to assure confidential treatment of such information, to the extent such prot... |
9.3. Additional Permitted Disclosures and Use by AbbVie. After the License Option Effective Date, AbbVie and its Affiliates and its and their Sublicensees may disclose and use Confidential Information of Cugene as may be necessary or reasonably useful in connection with the Exploitation of the Licensed Therapeutic and ... |
9.4. Additional Permitted Disclosures and Use by Cugene. Cugene and its Affiliates may disclose and use Confidential Information of AbbVie as may be necessary or reasonably useful for Cugene to exercise its rights or fulfill its obligations under this Agreement, including in connection with any filing or submission to ... |
9.5. Use of Name. Except as expressly provided herein, neither Party shall mention or otherwise use the name, logo or other Trademarks of the other Party or any of its Affiliates or any of its or their (sub)licensees (or any abbreviation or adaptation thereof) in any publication, press release, marketing and promotiona... |
9.6. Public Announcements. The Parties have agreed upon the content of a press release that shall be issued by AbbVie substantially in the form attached hereto as Schedule 9.6, the release of which the Parties shall coordinate in order to accomplish such release promptly upon a date to be mutually agreed by the Parties... |
9.7. Publications. The Parties recognize the desirability of publishing and publicly disclosing the results of and information regarding the activities under this Agreement. |
9.7.1. Cugene Publications. During the Term of this Agreement, Cugene shall not, and shall cause each of its Affiliates and its and their licensees and (sub)licensees not to, make any publications or public disclosures regarding Product Information without AbbVie's prior written consent in its sole discretion. For clar... |
9.7.2. AbbVie Publications. From and after the License Option Effective Date until termination of this Agreement, AbbVie may publicly disclose the results of and information regarding activities under this Agreement with respect to any Licensed Therapeutic or any Licensed Products, subject to prior review and complianc... |
9.8. Return of Confidential Information. Upon the effective date of the termination of this Agreement for any reason, at the written request of a Party, the non-requesting Party shall either, at the requesting Party's election: (a) promptly destroy all copies of the requesting Party's Confidential Information in the po... |
Notwithstanding the foregoing, the non-requesting Party shall be permitted to retain such Confidential Information (x) to the extent necessary or useful for purposes of performing any continuing obligations or exercising any ongoing rights hereunder and, in any event, a single copy of such Confidential Information for ... |
ARTICLE 10 REPRESENTATIONS AND WARRANTIES |
10.1. Mutual Representations and Warranties. Each Party represents and warrants to the other Party, as of the Effective Date: |
10.1.1. it is duly organized, validly existing and in good standing under the Applicable Law of the jurisdiction of its incorporation and has full corporate power and authority to enter into this Agreement and to carry out the provisions hereof; |
10.1.2. the execution and delivery of this Agreement and the performance by it of the transactions contemplated hereby have been duly authorized by all necessary corporate action and do not violate: (a) such Party's charter documents, bylaws or other organizational documents; (b) in any material respect, any agreement,... |
10.1.3. this Agreement is a legal, valid and binding obligation of such Party enforceable against it in accordance with its terms and conditions, subject to the effects of bankruptcy, insolvency or other laws of general application affecting the enforcement of creditor rights, judicial principles affecting the availabi... |
10.2. Additional Representations, Warranties and Covenants of Cugene. |
10.2.1. Cugene additionally represents and warrants to AbbVie (a) as of the Effective Date that except as set forth in the disclosure schedules delivered by Cugene on the Effective Date (the "Initial Disclosure Schedules") and (b) as of each Bring Down Date, except as set forth in the Updated Disclosure Schedules, in e... |
(a) All Existing Patents (i) are listed on the Existing Patents Schedule, (ii) to Cugene's Knowledge, with respect to issued Existing Patents (if any), are subsisting and are not invalid or unenforceable, in whole or in part, (iii) are being diligently prosecuted in the respective patent offices in the Territory in acc... |
(b) There are no claims, judgments, or settlements against, or amounts with respect thereto, owed by Cugene or any of its Affiliates relating to the Existing Regulatory Documentation, the Existing Patents, or the Cugene Know-How. No claim or litigation has been brought or, to Cugene's Knowledge, threatened by any Perso... |
AbbVie will be able to provide a tool tau cargo upon commencing the partnership for use in capsid screening and to begin DNA optimization as described below. The final tau cargo is estimated to be completed and transferred to Capsida by 4Q2021, as described in the timeline below. |
10.2.2 Dose β Efficacy Relationship in Mice |
Dose ranging studies in tau disease models will be conducted by AbbVie for the purpose of establishing a relationship between dose β cargo expression β target engagement - efficacy (i.e., clearance of tau pathology). Disease proof-of-concept can be established using already developed and efficient CNS-targeting rodent ... |
10.2.3 Additional NHP Studies for Target Engagement |
AbbVie will work to translate the rodent efficacy model to NHP to incorporate tau aggregate deposition with PET imaging and biomarker detection. Based on the dose response results in mice, AbbVie will do limited dose response in the NHP models to establish target engagement and develop a model for estimating human dose... |
10.2.4 Tau Cargo β Capsid Optimization: Selection of Research Product |
Vector optimization will be finalized as described in Section 3.3.1 Tau Cargo Development, with AbbVie providing data relating to various vector compositions to efficacy in mouse models at the time of finalizing the gene therapy modules (4Q2021). These elements will be incorporated into the Final Individual Capsid β Ca... |
10.2.5 Tau Capsid β Cargo Program (Research Product) Data Package: Reports and Deliverables |
Upon completion of the tau capsid β cargo studies, all data sets outlined in Appendix 6 and corresponding reports for the top performing capsid variants (i.e., Reserved Capsids, Primary Capsid and Back-Up Capsids) will be provided to AbbVie. These include: |
β’ Cell-type distribution in NHPs and rodents, after peak expression is established (e.g., IHC, RNA scope or preferred method) |
β’ DNA MOI data in tissues (CNS cells and selected peripheral tissues) in NHPs and / or rodents |
β’ Bulk RNA and / or protein data in targeted tissues and in selected peripheral tissues in NHPs and / or rodents |
β’ Acceptable immunogenicity profile (e.g., nADA) in NHP and low prevalence of preexisting antibodies (<50%) in the target patient population (sufficient sample size to estimate nADA in AD/PD serum sample, but no more 50 samples) |
β’ Toxicity profiles in adult cynomolgus monkey, including clinical pathology and histopathology at peak expression and later (e.g., look at later timepoints for recovery) |
β’ Sequence of the Research Product, Primary and Back-Ups capsids, including patentability and FTO assessment |
The Target Product Profile for the Research Product for the tau program has the following attributes. |
Meets TCP criteria as agreed by the JGC. |
In vivo activity established with evidence of on-target and sustained effect (e.g., clearance of tau aggregates) in a preclinical model (preferably tauopathy model). |
Projected human efficacious dose with appropriate preclinical safety profile (acceptable therapeutic window) and feasible dosing regimen for IV administration in human. |
Data supportive of translational biomarkers to enable dose selection, target engagement and mode of action in clinical studies. |
Packaging efficiency and scalability supportive of generating a suitable dosing regimen for human use via the intended route of administration (i.v.) |
Acceptable neutralizing antibody prevalence data in the intended patient population and plan for widespread use in the general population; data supportive of advancement to IND enabling studies. |
Manufacturing executable plan in place including process, scalability, analytical methods etc. |
10.3 Ξ±-Synuclein Capsid β Cargo Development |
10.3.1 Ξ-SYNUCLEIN CARGO DEVELOPMENT |
Ξ±-synuclein cargo development will be led by AbbVie and is generally outside of the scope of this research plan with the exception of the vector optimization strategy which will be designed jointly between AbbVie and Capsida. Vector optimization will include assessment of the efficacy of various promoter elements (e.g.... |
10.3.2 Dose β Efficacy Relationship in Mice |
Dose ranging studies in Ξ±-synuclein disease models will be conducted by AbbVie for the purpose of establishing a relationship between dose β therapeutic protein expression β efficacy (i.e., clearance of Ξ±-synuclein pathology). Disease proof-of-concept can be established using already characterized and efficient CNS-tar... |
10.3.3 Additional NHP Studies for Target Engagement |
In addition, AbbVie will work to translate the rodent efficacy model to NHP to incorporate Ξ±-synuclein aggregate deposition with biomarker detection. A PET imaging approach may be considered upon availability of the -synuclein PET ligand. Based on the dose response results in mice, AbbVie will do limited dose response ... |
10.3.4 Ξ±-synuclein Cargo β Capsid Optimization: Selection of Research Product |
Vector optimization will be finalized as described in Section 3.4.1 -synuclein Cargo Development, with AbbVie providing data relating various vector compositions to efficacy in mouse models at the time of finalizing the gene therapy modules (4Q2022). These elements will be incorporated into the Final Individual Capsid ... |
10.3.5 Ξ±-synuclein Capsid β Cargo Program (Research Product) Data Package: Reports and Deliverables |
Upon completion of the Ξ±-synuclein capsid β cargo studies all data sets outlined in Appendix 6 and corresponding reports for the top performing capsids (i.e., Reserved Capsids, Primary Capsid and Back-Up Capsids) will be provided to AbbVie. These include: |
β’ Cell-type distribution in NHPs and rodents, after peak expression is established (e.g., IHC, RNA scope or preferred method) |
β’ DNA MOI data in tissues (CNS cells and selected peripheral tissues) in NHPs and / or rodents |
β’ Bulk RNA and / or protein data in the targeted tissues and in selected peripheral tissues in NHPs and / or rodents |
β’ Acceptable immunogenicity profile (e.g, nADA) in NHP and low prevalence of preexisting antibodies (<50%) in the target patient population (sufficient sample size to estimate nADA in AD/PD serum samples, but not to exceed 50 samples) |
β’ Toxicity profiles in adult cynomolgus monkeys, including clinical pathology and histopathology at peak expression and later (e.g., later timepoints for recovery) |
β’ Sequence of the Research Product, Primary and Back-Ups capsids, including patentability and FTO assessment |
The Target Product Profile for the Research Product for the -synuclein program has the following attributes: |
Meets TCP criteria as agreed by the JGC. |
In vivo activity established with evidence of on-target and sustained effect (e.g., clearance of -synuclein aggregates) in a preclinical model (preferably synucleinopathy model). |
Projected human efficacious dose with appropriate preclinical safety profile (acceptable therapeutic window) and feasible dosing regimen for IV administration in human. |
Data supportive of translational biomarkers to enable dose selection, target engagement and mode of action in clinical studies. |
Packaging efficiency and scalability supportive of generating a suitable dosing regimen for human use via the intended route of administration (i.v.) |
Acceptable neutralizing antibody data in the intended patient population and plan for widespread use in the general population supportive of advancement to IND enabling studies. |
Manufacturing executable plan in place including process, scalability, analytical methods etc. |
11.0 Process and Analytical Development, Scale up, and Supply. |
Capsida will provide non-GLP supply (research grade material) for discovery and preclinical research. Upon opt-in, Capsida will initiate process development activities shown below in preparation for GLP-tox material generation and clinical supply. |
The FDA guidelines on potency testing for cellular and gene therapy products recommends multiple CMC-related activities to characterize product quality and manufacturing controls, to assure identity, purity, strength (potency), sterility and stability of products to certify lot release and establish product dating and ... |
The cargo sequence will be transferred to the process development team and synthesized in a plasmid backbone suitable for manufacturing. Positive control material will be generated using the selected capsid and cargo to serve as a reference control for analytical development activities and evaluate process fit in each ... |
Some analytical methods, specifically the in vitro potency assay, are known to be complicated for AAV gene therapy products. Regarding the potency assay (used to quantify the transducibility and efficacy of the protein produced from a specific lot of product), AbbVie will develop this assay format for tau andsynuclein.... |
12.0 Budget (Amounts shown are in '000s) |
CAPSID Program Research Plan (Tau and Alpha Syn) |
Year 1 Year 2 Year 3 GRAND TOTAL |
% of Team Time by Function Research Total 6% 17% 7% Technology 33% 33% 14% Process Development 20% 20% 20% All Other (Excluding Manufacturing) 6% 7% 3% |
FTE Costs by Function Research 249 888 397 1,533 Technology 904 972 416 2,293 Process Development 689 854 947 2,489 All Other (Excluding Manufacturing) 394 490 229 1,113 TOTAL FTE COST 2,236 3,204 1,989 7,428 |
Supplies Cost by Function Research 106 391 165 662 Technology 1,144 1,217 513 2,875 Process Development 1,147 1,255 1,255 3,656 TOTAL SUPPLIES COST 2,397 2,863 1,933 7,193 |
Outside Spend NHP Experiments Shared Cost Abbvie Ratio 33% 33% 33% Shared NHP Experiments 119 7 - 126 Abbvie Only NHP Characterizations 289 1,010 136 1,435 TOTAL NHP COSTS 408 1,017 136 1,561 |
Overhead Allocations Travel % 13% 13% 8% Consulting % 23% 23% 13% Rent % 23% 23% 13% IT Expense % 33% 33% 19% All Other % 7% 7% 4% |
Travel $ 13 28 18 59 Consulting $ 408 314 178 899 Rent $ 715 985 567 2,267 IT $ 319 361 232 912 All Other $ (Legal, Finance, Other) 125 120 73 318 Total Overhead 1,580 1,807 1,069 4,456 |
GRAND TOTAL 6,621 8,891 5,126 20,638 10% of Grand Total 2,064 |
Memo: Per Program 3,310 4,445 2,563 10,319 10% Per Program 1,032 |
Appendix A |
** solid (blue) color represents key data available at various stages of the Capsid Generation, Screening & Optimization process (Section 3.2.1) |
TCP Criteria - Data deliverables 1. Initial Library Screening 2. Variant Optimization 3. Pooled Screening 4. Preliminary Individual Capsid Characterization 5. Final Capsid Optimization 6. Pooled Screening 7. Final Individual Capsid - Cargo Characterization 1st Round 2nd Round 1st Round 2nd Round 1st Round 2nd Round |
Targeted Cell Type Gross neuronal transduction Quantified neuronal transduction (all targets) Quantified oligodendrocyte transduction (A-syn only) Quantified motor neuron transduction (TDP43only) |
Targeted Tissue NGS DNA level Benchmarked vector genome residence DNA MOI |
Route of Administration IV delivery |
Expression Level Bulk RNA level Bulk protein level Durability |
Tissue De-targeting (including liver and DRG) Benchmarked vector genome residence DNA MOI Bulk RNA level Bulk protein level |
Projected Human Dose Immunogenicity of capsid Immunogenicity of cargo Toxicity Histopathology Estimated Therapeutic Window (single dose) Estimated Therapeutic Window (multi dose) |
Manufacturing Packaging efficiency |
Immunogenicity Immunogenicity of capsid Immunogenicity of cargo Neutralization by human patient serum |
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