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12.11 Remedies. Except as otherwise expressly provided herein, termination of this Agreement (either in its entirety or with respect to one (1) or more country(ies) or other jurisdiction(s)) in accordance with the provisions hereof shall not limit remedies that may otherwise be available in law or equity. |
12.12 Accrued Rights; Surviving Obligations. |
12.12.1 Termination or expiration of this Agreement (either in its entirety or with respect to one (1) or more country(ies) or other jurisdiction(s)) or one or more Product(s) for any reason shall be without prejudice to any rights that shall have accrued to the benefit of a Party prior to the effective date of such te... |
12.12.2 Notwithstanding the termination of AbbVie's licenses and other rights under this Agreement or with respect to a particular country or other jurisdiction or a particular Product, as the case may be, AbbVie shall have the right for one (1) year after the effective date of such termination with respect to each cou... |
ARTICLE 13 MISCELLANEOUS |
13.1 Force Majeure. Neither Party shall be held liable or responsible to the other Party or be deemed to have defaulted under or breached this Agreement for failure or delay in fulfilling or performing any term of this Agreement when such failure or delay is caused by or results from events beyond the reasonable contro... |
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13.2 Change in Control of Heptares. |
13.2.1 Heptares (or its successor) shall provide AbbVie with written notice of any Change in Control of Heptares within five (5) Business Days following the closing date of such transaction. |
13.2.2 In the event of a Change in Control of Heptares, then (a) Heptares shall comply with the terms of Section 6.9.1, and (b) AbbVie shall have the right, in its sole and absolute discretion, by written notice delivered to Heptares (or its successor) at any time during the one hundred eighty (180) days following the ... |
13.3 Export Control. Agreement is made subject to any restrictions concerning the export of products or technical information from the United States or other countries that may be imposed on the Parties from time to time. Each Party agrees that it will not export, directly or indirectly, any technical information acqui... |
13.4 Assignment. |
13.4.1 Without the prior written consent of the other Party, such consent not to be unreasonably withheld, conditioned, or delayed, neither Party shall sell, transfer, assign, delegate, pledge, or otherwise dispose of, whether voluntarily, involuntarily, by operation of law or otherwise, this Agreement or any of its ri... |
13.5 Severability. If any provision of this Agreement is held to be illegal, invalid, or unenforceable under any present or future law, and if the rights or obligations of either Party under this Agreement will not be materially and adversely affected thereby, (a) such provision shall be fully severable, (b) this Agree... |
13.6 Governing Law, Jurisdiction and Service. |
13.6.1 Governing Law. This Agreement and the performance, enforcement, breach and termination hereof shall be interpreted, governed by and construed in accordance with the laws of the State of New York, United States excluding any conflicts or choice of law rule or principle that might otherwise refer construction or i... |
13.6.2 Service. Each Party further agrees that service of any process, summons, notice or document by registered mail to its address set forth in Section 13.8.2 shall be effective service of process for any action, suit, or proceeding brought against it under this Agreement in any such court. |
13.7 Dispute Resolution. Other than for disputes resolved by the procedures set forth in Section 2.2.3, 7.15 or 13.11, if a dispute arises between the Parties in connection with or relating to this Agreement or any document or instrument delivered in connection herewith (a "Dispute"), it shall be resolved pursuant to t... |
13.7.1 General. Any Dispute shall first be referred to the Senior Officers of the Parties, who shall confer in good faith on the resolution of the issue. Any final decision mutually agreed to by the Senior Officers shall be conclusive and binding on the Parties. If the Senior Officers are not able to agree on the resol... |
13.7.2 Intellectual Property Disputes. If a Dispute arises with respect to the validity, patentability, enforceability or inventorship of any Patent, Trademark or other intellectual property rights, and such Dispute cannot be resolved in accordance with Section 13.7.1, unless otherwise agreed by the Parties in writing,... |
13.7.3 ADR. Any ADR proceeding under this Agreement shall take place pursuant to the procedures set forth in Schedule 13.7.3. |
13.7.4 Adverse Ruling. Any determination pursuant to this Section 13.7 that a Party is in material breach of this Agreement shall specify a (non-exclusive) set of actions to be taken to cure such material breach, if feasible. |
13.7.5 Interim Relief and Tolling. Notwithstanding anything herein to the contrary, nothing in this Section 13.7 shall preclude either Party from seeking interim or provisional relief from any court of competent jurisdiction, including a temporary restraining order, preliminary injunction or other interim equitable rel... |
13.8 Notices. |
13.8.1 Notice Requirements. Any notice, request, demand, waiver, consent, approval, or other communication permitted or required under this Agreement shall be in writing, shall refer specifically to this Agreement and shall be deemed given only if (a) delivered by hand, or (b) by internationally recognized overnight de... |
13.8.2 Address for Notice. |
If to AbbVie, to: 4th Floor, Washington House 16 Church Street Hamilton HM 11, Bermuda Attention: AbbVie Ireland Unlimited Company with a copy (which shall not constitute notice) to: AbbVie Inc. 1 North Waukegan Road North Chicago, IL 60064 Attention: Vice Chairman, External Affairs, Chief Legal Officer and Corporate S... |
If to Heptares, to: Heptares Therapeutics Ltd, The Steinmetz Building, Granta Park, Great Abington, Cambridge, Cambridgeshire, CB21 6DG, UK Attention: The Executive Vice President and Chief R&D Officer |
with a copy (which shall not constitute notice) to the same address, Attention: The Company Secretary |
13.9 Entire Agreement; Amendments. This Agreement, together with the Schedules attached hereto, sets forth and constitutes the entire agreement and understanding between the Parties with respect to the subject matter hereof and all prior agreements, understandings, promises, and representations, whether written or oral... |
13.10 English Language. This Agreement shall be written and executed in, and all other communications under or in connection with this Agreement shall be in, the English language. Any translation into any other language shall not be an official version thereof, and in the event of any conflict in interpretation between... |
13.11 Equitable Relief. Each Party acknowledges and agrees that the restrictions on the Parties set forth in Section 6.9, ARTICLE 8 and ARTICLE 9 are reasonable and necessary to protect the legitimate interests of the non-breaching Party and that such Party would not have entered into this Agreement in the absence of s... |
13.12 Waiver and Non-Exclusion of Remedies. Any term or condition of this Agreement may be waived at any time by the Party that is entitled to the benefit thereof, but no such waiver shall be effective unless set forth in a written instrument duly executed by or on behalf of the Party waiving such term or condition. Th... |
13.13 No Benefit to Third Parties. Except as provided in ARTICLE 11, covenants and agreements set forth in this Agreement are for the sole benefit of the Parties hereto and their successors and permitted assigns, and they shall not be construed as conferring any rights on any other Persons. |
13.14 Further Assurance. Each Party shall duly execute and deliver, or cause to be duly executed and delivered, such further instruments and do and cause to be done such further acts and things, including the filing of such assignments, agreements, documents, and instruments, as may be necessary or as the other Party m... |
13.15 Relationship of the Parties. It is expressly agreed that Heptares, on the one hand, and AbbVie, on the other hand, shall be independent contractors and that the relationship between the Parties shall not constitute a partnership, joint venture, or agency, including for all tax purposes. Neither Heptares, on the o... |
13.16 Performance by Affiliates. Each Party may use one (1) or more of its Affiliates to perform its obligations and duties hereunder and such Affiliates are expressly granted certain rights herein; provided that each such Affiliate shall be bound by the corresponding obligations of the relevant Party and, subject to a... |
13.17 Counterparts; Execution. This Agreement may be executed in two (2) or more counterparts, each of which shall be deemed an original, but all of which together shall constitute one (1) and the same instrument. This Agreement may be executed by electronically transmitted signatures and such signatures shall be deeme... |
13.18 References. Unless otherwise specified, (a) references in this Agreement to any Article, Section or Schedule shall mean references to such Article, Section or Schedule of this Agreement, (b) references in any Section to any clause are references to such clause of such Section, and (c) references to any agreement,... |
13.19 Schedules. In the event of any inconsistencies between this Agreement and any schedules or other attachments hereto, the terms of this Agreement shall control. |
13.20 Construction. Except where the context otherwise requires, wherever used, the singular shall include the plural, the plural the singular, the use of any gender shall be applicable to all genders and the word "or" is used in the inclusive sense (and/or). Whenever this Agreement refers to a number of days, unless o... |
[SIGNATURE PAGE FOLLOWS.] |
[SIGNATURE PAGE TO COLLABORATION AND OPTION TO LICENSE AGREEMENT] |
THIS AGREEMENT IS EXECUTED by the duly authorized representatives of the Parties as of the Effective Date. |
HEPTARES THERAPEUTICS LIMITED |
By: |
Name: |
Title: |
Malcolm Weir |
Executive Vice Chairman |
[SIGNATURE PAGE TO COLLABORATION AND OPTION TO LICENSE AGREEMENT] |
THIS AGREEMENT IS EXECUTED by the duly authorized representatives of the Parties as of the Effective Date. |
HEPTARES THERAPEUTICS LIMITED |
By: |
Name: |
Title: |
Schedule 1.58 |
Corporate Names |
Heptares Therapeutics Limited |
Sosei Group Corporation |
Schedule 1.180 |
Research Plans |
GPR65 RESEARCH PLAN |
CONFIDENTIAL: CONTAINS HEPTARES PLATFORM CONFIDENTIAL INFORMATION |
I) Outline of research plan |
General information & Deliverables |
Sosei Heptares will enter into a research collaboration agreement with AbbVie with the aim of developing an oral GPR65 small molecule agonist IND-ready Clinical Candidate for the treatment of IBD. |
II) GPR65 Agonist Program |
Research Program Details |
Sosei Heptares' in-house work will concentrate on computational chemistry, medicinal chemistry, in vitro pharmacology, DMPK, stabilised GPCR (StaR protein) generation and structural biology to enable the generation of one Clinical Candidate. |
Primary screening (native conformation GPCR expressed by a cell, StaR protein binding and functional assays) and appropriate secondary screening (selectivity assays, etc.) will be performed by Sosei Heptares. Other activities outlined in this research plan will be outsourced through existing vendors or identification o... |
Estimated Timeline of Research Activities Performed by Sosei Heptares and Abbvie |
[Timeline chart showing activities across 20 quarters including Platform activities, Discovery, and Preclinical Development with milestones for StaR, Lead Gen, Lead Op, Cand Nom, Cand Sel, GLP Tox, and IND] |
Platform |
a) StaR protein generation |
Thermostability assays will be established for the GPR65 receptor consistent with their use for agonist discovery, and Sosei Heptares will use its proprietary StaR protein and SABRE technology to identify thermostabilising mutations. These will be combined in an iterative way to shift the GPR65 receptor gradually to an... |
Deliverable: The sequences of stabilised receptors suitable for biophysical screening and structure determination with increased thermostability by ≥ 10C. |
b) StaR protein expression and purification |
GPR65 StaR proteins will be expressed in insect cells using a baculovirus system. A variety of approaches, such as a range of tags, codon optimisation, additives, enzyme cleavage and further mutagenesis, will be investigated to optimise the levels of receptor expression and to obtain homogeneous protein. For crystallis... |
Deliverable: Stabilised GPR65 receptor (>90% purity) suitable for biophysical screening and structure determination. QC by SDS PAGE, gel filtration and mass spec. |
c) Biophysics |
The primary platform for biophysical studies at Sosei Heptares will be Surface Plasmon Resonance (SPR) in which the GPR65 StaR protein or SuperStaR protein is immobilised to a sensor chip through a His tag. The affinities and kinetics of binding of tool agonists (or antagonists), and agonists (or antagonists) generated... |
Deliverable: Information on the affinities, kinetics and binding poses of compounds used to refine models of binding to the receptor and assist with compound optimisation, along with homology models used to propose experiments and interpret results. |
d) Structure determination |
The GPR65 SuperStaR protein will be utilised for structure determination. Crystallisation trials will be set up for several constructs using a wide range of detergent conditions. These will include standard crystallisation screens as well as proprietary Sosei Heptares screens designed for GPCR crystallisation. Crystall... |
A crystal structure of the receptor should meet the following criteria: Data Statistics/Resolution: Maximum resolution of greater than, or equivalent to, 3.5Ä; where this is defined as a CC1/2 of not less than 0.5 with an I/σ (Mean((I)/sd(I)) equivalent to, or greater than, 1.0 in the outer (highest) resolution shell. ... |
A Cryo-EM structure of the GPR65 receptor should meet the following criteria: Resolution in the region of the ligand binding site of at least 3.80 Å at an FSC figure of 0.143, in line with the principles described in Rosenthal P.B. & Henderson, R. J. Mol. Biol. (2003), 333: 721-745. The structure maps should be as good... |
Deliverable: Raw data, coordinates, mtz files for structures (x-ray and Cryo-EM). |
Drug Discovery |
a) Computational Chemistry: Modelling of GPR65 receptor structure |
Homology models of the GPR65 receptor with a range of different literature agonists (Appendix F) bound will be generated based on the published X-ray structures of analogous receptors and in-house data on relevant structures, guided by SAR, receptor mutation data, structural chemogenomics analyses and previously propos... |
Structural cheminformatics and chemogenomics databases and analysis tools (e.g. de Graaf et al. ChemMedChem, 2018, 13, Tr Pharmacol Sci 2018, 39) will be used to: i) combine public and proprietary GPCR structure and ligand bioactivity data to enable the identification of structure-activity/function/selectivity relation... |
The models and ligand docking poses will be refined based on reported literature tools/SAR for GPR65, covering different chemotypes and modalities (Roth et al. Nature (2015) 527: 477), Onozawa et al. E J Pharm 683 (2012) 325–331) (Appendix F) and any putative GPR65 binding site data reported (Ishii et al. PNAS (2010) 1... |
The receptor homology models will be evaluated, prioritised, challenged, and optimised in an iterative manner based on: 1. Their ability to rationalise and predict ligand SAR (e.g. explain importance of specific chemical groups, conformational properties, enable the discrimination of active/inactive molecules), and/or ... |
Models of the agonist form of the receptor will be used to perform in silico screens of compound databases. Hits from screening will be docked into the models to help guide medicinal chemistry to elaborate hits. Sosei Heptares has developed and successfully applied combined energy-based and structural interaction finge... |
Molecular interaction field (GRID) and water interaction network (waterFLAP, waterMAP) based binding site analysis methods, Free Energy Perturbation (FEP+), and advanced MD methods/MetaMD have been developed at Sosei Heptares (in collaboration with Molecular Discovery and Schrodinger) to identify and prioritise druggab... |
To identify ligand induced and/or cryptic/transient allosteric binding pockets in GPR65, combined Molecular Dynamics (MD) and druggable binding site analysis methods have been developed at Sosei Heptares to identify (cryptic) druggable allosteric ligand binding pockets. These druggable allosteric GPR65 binding pockets ... |
Deliverable: Models of the GPR65 receptor with the hits of the ≥ 2 chemical series including lead compounds bound consistent with known SAR. WaterMaps, MD trajectories, FEP+ maps with output G correlations. |
b) Stage 1: Hit identification |
The aim of the hit identification phase will be to use models of the structure of GPR65 to generate new chemical matter to identify structurally distinct hit series. The ≥ 2 chemically distinct series will have Tanimoto similarity values (based on ECFP4 fingerprint) of less than 0.4 to potentially de-risk off target as... |
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