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17 Primary cellular assay cycle 6 102,000 |
18 Data & chemistry analysis cycle 6 75,000 |
19 DESIGN-Make-ADME x cycle 7 196,000 |
20 Primary cellular assay cycle 7 102,000 |
21 Data & chemistry analysis cycle 7 75,000 |
22 DESIGN-Make-ADME cycle 8 196,000 |
23 Primary cellular assay cycle 8 102,000 |
24 Data & chemistry analysis cycle 8 75,000 |
25 Disease relevant cellular assay cycle #1 193,000 |
26 Disease relevant cellular assay cycle #2 193,000 |
27 Disease relevant cellular assay cycle #3 193,000 |
28 Disease relevant cellular assay cycle #4 193,000 |
29 Disease relevant cellular assay cycle #5 193,000 |
30 MOA (Proteomics and transcriptomics) 217,000 |
31 MOA (Pixcell - Translation) 186,000 |
32 MOA (Pixcell - TranscriptLight) 186,000 |
33 Chemical proteomics (ABPP and/or CETSA) 194,000 |
34 Cellular safety study – cycle #1 112,000 |
35 Cellular safety study – cycle #2 112,000 |
36 Cellular safety study – cycle #3 112,000 |
37 Cellular safety study – cycle #4 112,000 |
38 Kinase Panels 85,000 |
39 Safety panels 44 55,000 |
40 PK (single and repeated) 122,000 |
41 Animal model cluster 1 186,000 |
42 Animal model cluster 2 186,000 |
43 Animal model cluster 3 186,000 |
Lead Generation total budget 6,000,000 |
*The cost of unperformed activities as described in Section 7.3.2 (Collaboration Target Substitution Fee) will be calculated as the difference between the Lead Generation total budget ($6,000,000) and the sum of the budgeted costs of all tasks completed in the Lead Generation stage. |
Exhibit C-1 Success Criteria for Option Exercise Data Package Prior to Payment of License Option Period Extension Fee |
High Throughput Screening System Development Primary, Translationlight assay development • Validation of a tRNA-candidate pair for intended target in a disease-relevant cell line and stimuli, as defined in the research plan |
Assay transfer to HCS • S/N is maintained after assay miniaturization to a format that enables library screening. Criteria used routinely at Anima: reproducibility >0.7; CV < 20%; SNR >3; Z' > 0.4; signal window >2. |
Secondary assay development • Identification and validation of at least 2 disease-relevant cell lines per target that can be utilized for MoA deconvolution assays (historical or novel data to confirm) • Identification and validation of a non-diseased cell line that expresses the target of interest to demonstrate tissue... |
Translationlight Screen Screen • Complete screening of Library 5 along with image and data analysis in timelines defined in the research plan |
Hit Confirmation and Hit Validation Hit confirmation • Confirmed actives from powder reduce signal by ≥40% in secondary target-specific assay (for example, immunofluorescence), demonstrate dose response (IC50 <10 µM), do not alter general translation (bulk tRNA, metabolic labeling), have minimal effect (<30%) on viabil... |
Hit validation and expansion (including SAR) • Establishment of clusters of compounds around HTS actives • Concentration-response demonstrated in secondary assays (potency IC50 <10µM; maximum reduction of signal >50%; Hill slope between 0.7 and 2; <30% inhibition of metabolic labeling) within each hit cluster / chemoty... |
Activity determination • Demonstrate dose-dependent inhibition of target-specific mRNA and/or protein in disease-appropriate cells +/- stimulus as defined in the research plan |
Cytotoxicity assays • ONC: Demonstrate >10X increased CTG potency in target dependent cell lines versus non-target dependent cell lines • IMM: Demonstrate >10X increased potency for modulation of target protein/RNA as compared with CTG in disease-appropriate cells, and no activity in independent cell lines |
MoA: target timing • Demonstrate dose-dependent modulation of target or PD biomarker in disease-relevant cells/conditions as defined in the research plan |
Exhibit C-2 Success Criteria for Option Exercise Data Package Following Payment of License Option Period Extension Fee |
Lead Generation Compound re-synthesis and activity validation • Validated and expanded hits exhibit dose-dependent inhibition (potency < 3µM, max effect >80%) of target specific assay identified • Confirmed target expression profile (such as in vivo target engagement) |
Mode of action and target ID • Hypothesis defined from validation of insights generated from transcriptomics and proteomics analysis, RNA sequencing, polyA analysis and Anima's target deconvolution methods with at least 2 MOAs per nominated target; at least 1 candidate target for each MOA, and follow-on characterizatio... |
Chemistry design • At end of LG, dynamic range of activities demonstrated within lead series, >30X improvement in potency compared with initial hits • LEAD compounds: within Ro5, LLE (Lipophilic Ligand Efficiency, pIC50-cLogP) 3-5. Chemically tractable (<10 steps) • Analysis to show that there are no obvious impediment... |
In vitro ADMET and activity • LEAD compounds: RLM/MLM Clint, u <100 µL/min/mg, Kinetic solubility >10 µM, PAMPA >1.5 x10-6 cm/sec • Ability to prioritize lead series based on ADME characteristics, liability assessment, IVIVC evaluation, and physiochemical properties with potential for oral administration in rodent PK s... |
Translation, cellular and general in vitro safety • Availability of in vitro and in vivo assay funnel relevant to MoA of lead series • LEAD compounds: modulation of target protein/mRNA or functional disease endpoint or PD marker IC50 < 100 nM in disease-relevant cells and >100X higher IC50 in independent cells; Evidenc... |
In vivo PK study; rodent PKPD • LEAD: %F (po) > 25% with exposure sufficient to support in vivo PD or efficacy evaluation • Demonstrate on-target PD response consistent with exposure data in at least one appropriate animal model via oral administration |
Acute in vivo efficacy • Demonstrate dose-dependent efficacy following oral administration in an acute efficacy model as defined in the research plan; efficacy is consistent with PD and exposure |
Lead Optimization (LO) Chemistry design (synthesis cycles, SAR analysis, in vitro and in vivo ADME) • Successful completion of key chemistry objective(s) identified for LO • At least one compound meets core candidate nomination (CN) criteria with additional compounds closely behind • CN criteria: modulation of target p... |
Compound SAR studies • Clear SAR understanding on lead series allows to address potency/selectivity/DMPK property/safety/tox issues |
MoA and pathway analysis • Demonstration that candidate molecule exhibits expected biological activity via proposed MoA with pathway analysis in disease-relevant cell lines |
In vitro and in vivo efficacy studies in commercially available disease models • Candidate molecule exhibits IC50s < 100nM in at least 3 disease-relevant cell-based PD models/measures as defined for each target in the research plan; >100X potency in non-dependent cell lines. • Robust efficacy consistent with target kno... |
In vivo mini safety study • Rat CV window >10X (Onc) or >20X (Imm) compared to efficacious Cmax • Dog CV window >10X (Onc) or >20X (Imm) compared to efficacious Cmax • 5 or 7-day rodentexploratory safety study with histopath did not reveal unmonitorable severe tox. Preliminary assessment suggests TI>2 (Onc) or >20 (Imm... |
In vitro safety panel • No safety liability identified in CEREP bioprofiling • AMES/MN negative (confirm negative in vivo if positive in vitro) • hERG >100X target mRNA/protein modulation in Disease-relevant cells as defined by the research plan |
Schedule 1.13 Existing Patents |
Country Patent No. Application No. Filing Date Issue Date Status |
Patent Family: PROTEIN SYNTHESIS MONITORING (PSM) |
1. PCT PCT/IL2003/001011 WO 2004/050825 27-Nov-2003 17-Jun-2004 expired |
2. USA US 7807349 10/537071 27-Nov-2003 05-Oct-2010 granted |
3. USA-1 CIP US 8442773 12/872736 31-Aug-2010 14-May-2013 granted |
Patent Family: METHODS FOR EVALUATING RIBONUCLEOTIDE SEQUENCES |
4. Australia 2005248167 2005248167 26-May-2005 10-Mar-2011 granted |
5. Canada 2567749 2567749 26-May-2005 23-Jul-2013 granted |
6. Europe 1751299 05743440.9 26-May-2005 27-Jan-2010 granted |
7. France 1751299 05743440.9 26-May-2005 27-Jan-2010 granted |
8. Germany 1751299 05743440.9 26-May-2005 27-Jan-2010 granted |
9. Israel 179421 179421 26-May-2005 29-Sep-2012 granted |
10. PCT WO2005/116252 PCT/IL2005/000540 26-May-2005 08-Dec-2005 granted |
11. UK 1751299 05743440.9 26-May-2005 27-Jan-2010 granted |
12. USA 9012150 11/569476 26-May-2005 21-Apr-2015 granted |
Patent Family: SYSTEMS AND METHODS FOR MEASURING GENERAL TRANSLATION ACTIVITY IN VIABLE CELLS |
13. Australia 2008309146 2008309146 07-Oct-2008 25-Sep-2014 granted |
14. Canada 2702007 2702007 07-Oct-2008 21-Mar-2017 granted |
15. Europe 2188383 08808123.7 07-Oct-2008 18-Jan-2017 granted |
16. France 2188383 08808123.7 07-Oct-2008 18-Jan-2017 granted |
17. Germany 2188383 08808123.7 07-Oct-2008 18-Jan-2017 granted |
18. Ireland 2188383 08808123.7 07-Oct-2008 18-Jan-2017 granted |
19. Israel 204755 204755 07-Oct-2008 31-Jul-2014 granted |
20. Netherlands 2188383 08808123.7 07-Oct-2008 18-Jan-2017 granted |
21. PCT WO2009/047760 PCT/IL2008/001328 07-Oct-2008 16-Apr-2009 granted |
22. Switzerland 2188383 08808123.7 07-Oct-2008 18-Jan-2017 granted |
23. UK 2188383 08808123.7 07-Oct-2008 18-Jan-2017 granted |
24. US Prov. 60/978420 09-Oct-2007 expired |
25. US Prov. 61/086165 05-Aug-2008 expired |
26. USA 9012171 12/682212 07-Oct-2008 21-Apr-2015 granted |
Patent Family: SYSTEMS AND METHODS FOR MEASURING TRANSLATION ACTIVITY OF TARGET PROTEINS IN VIABLE CELLS |
27. Australia 2010299444 2010299444 21-Sep-2010 23-Mar-2016 granted |
28. Canada 2775231 2775231 21-Sep-2010 05-Jun-2018 granted |
29. Europe 2480890 10818500.0 21-Sep-2010 28-Feb-2018 granted |
30. France 2480890 10818500.0 21-Sep-2010 28-Feb-2018 granted |
31. Germany 2480890 10818500.0 21-Sep-2010 28-Feb-2018 granted |
32. Israel 218507 218507 21-Sep-2010 22-Jul-2016 granted |
33. Netherlands 2480890 10818500.0 21-Sep-2010 28-Feb-2018 granted |
34. PCT WO2011/036666 PCT/IL2010/000792 21-Sep-2010 31-Mar-2011 granted |
35. Switzerland 2480890 10818500.0 21-Sep-2010 28-Feb-2018 granted |
36. UK 2480890 10818500.0 21-Sep-2010 28-Feb-2018 granted |
37. US Prov. 61/245313 21-Sep-2010 expired |
38. USA 9034576 13/497273 21-Sep-2010 19-May-2015 granted |
Schedule 1.72 Existing In-License Agreements |
1. Patent License Agreement by and between The Trustees of the University of Pennsylvania and Anima Cell Metrology, Inc., dated June 25, 2010, as amended by that certain First Amendment to Patent License Agreement dated September 13, 2011. |
Schedule 10.5 Public Announcement |
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