Cooperative Research and Development Agreement for Intramura-PhS Clinical Research

EX-10.22 46 ex10-22.htm

 

Exhibit 10.22

 

PUBLIC HEALTH SERVICE

 

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

FOR INTRAMURAL-PHS CLINICAL RESEARCH

 

This Agreement is based on the model Cooperative Research and Development Agreement (“CRADA”) adopted by the U.S. Public Health Service (“PHS”) Technology Transfer Policy Board for use by components of the National Institutes of Health (“NIH”), the Centers for Disease Control and Prevention (“CDC”), and the Food and Drug Administration (“FDA”), which are agencies of the PHS within the Department of Health and Human Services (“HHS”).

 

This Cover Page identifies the Parties to this CRADA:

 

The U.S. Department of Health and Human Services, as represented by

National Eye Institute NEI,

an Institute or Center (hereinafter referred to as the “IC”) of the

 

National Institutes of Health

 

and

 

Curative Biotechnology Holdings, Inc.

hereinafter referred to as the “Collaborator”,

having offices at

created and operating under the laws of Florida.

 

 

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT

FOR INTRAMURAL-PHS CLINICAL RESEARCH

 

Article 1. Introduction

 

This CRADA between IC and Collaborator will be effective when signed by the Parties, which are identified on both the Cover Page and the Signature Page. The official contacts for the Parties are identified on the Contacts Information Page. Publicly available information regarding this CRADA appears on the Summary Page. The research and development activities that will be undertaken by IC and Collaborator in the course of this CRADA are detailed in the Research Plan, attached as Appendix A. The staffing, funding, and materials contributions of the Parties are set forth in Appendix B. This CRADA, including but not limited to all provisions with respect to the creation and/or disposition of intellectual property, shall not alter the terms or rights granted to Collaborator under L-088-2021-0. All terms and conditions of L-088-2021-0 remain binding and in effect.

 

Article 2. Definitions

 

The terms listed in this Article will carry the meanings indicated throughout the CRADA. To the extent a definition of a term as provided in this Article is inconsistent with a corresponding definition in the applicable sections of either the United States Code (U.S.C.) or the Code of Federal Regulations (C.F.R.), the definition in the U.S.C. or C.F.R. will control.

 

“Adverse Event” or “AE” means any untoward medical occurrence associated with the use of a Test Article in humans, whether or not considered related to the Test Article (21 C.F.R §§ 312.32; see also E6(R2): Good Clinical Practice: Integrated Addendum to International Council for Harmonisation (ICH) E6(R1) Guidance for Industry, 83 Federal Register 8882 (2018).

 

“Affiliate” means any corporation or other business entity controlled by, controlling, or under common control with Collaborator at any time during the term of the CRADA. For this purpose, “control” means direct or indirect beneficial ownership of at least fifty percent (50%) of the voting stock or at least fifty percent (50%) interest in the income of the corporation or other business entity.

 

“Annual Report” means the report of progress of an IND-associated investigation that IC, as the IND Sponsor, must submit to the FDA within sixty (60) days of the anniversary of the effective date of the IND (pursuant to 21 C.F.R.§ 312.33).

 

“Background Invention” means an Invention conceived and first actually reduced to practice before the Effective Date.

 

“Certificate of Confidentiality” or “CoC” means a certificate issued by NIH pursuant to Section 301(d) of the Public Health Service Act (42 U.S.C. 241(d)), that protects the privacy of Human Subjects enrolled in the Protocol. With limited exceptions defined in 42 U.S.C. 241(d), the CoC protects from disclosure names or any information, documents or biospecimens containing ISI collected under a Protocol conducted under this CRADA.

 

 

“Clinical Investigator” means, in accordance with 21 C.F.R. § 312.3, an individual who actually conducts a clinical investigation, that is, who directs the administration or dispensation of Test Article to a subject, and who assumes responsibility for studying Human Subjects, for recording and ensuring the integrity of research data, and for protecting the welfare and safety of Human Subjects.

 

“Collaborator Materials” means all tangible materials not first produced in the performance of this CRADA that are owned or controlled by Collaborator and used in the performance of the Research Plan. The term “Collaborator Materials” does not include “Test Article” (defined below).

 

“Confidential Information” means confidential scientific, business, financial information, or Identifiable, Sensitive Information provided that the information does not include:

 

	(a)	information that is publicly known or that is available from public sources;
	(b)	information that has been made available by its owner to others without a confidentiality obligation;
	(c)	information that is already known by the receiving Party, or information that is independently created or compiled by the receiving Party without reference to or use of the provided information; or
	(d)	information that relates to potential hazards or cautionary warnings associated with the production, handling, or use of the subject matter of the Research Plan.

 

“Cooperative Research and Development Agreement” or “CRADA” means this Agreement, entered into pursuant to the Federal Technology Transfer Act of 1986, as amended (15 U.S.C. §§ 3710a et seq.), and Executive Order 12591 of April 10, 1987.

 

“CRADA Data” means all recorded information first produced in the performance of the Research Plan.

 

“CRADA Materials” means all tangible materials first produced in the performance of the Research Plan other than CRADA Data. For the avoidance of doubt, CRADA Materials do not include Collaborator Materials, IC Materials, Test Article, or specimens collected from Human Subjects.

 

“CRADA Principal Investigator(s)” or “CRADA PI(s)” means the person(s) designated by the Parties who will be responsible for the scientific and technical conduct of the Research Plan. The CRADA PI may also be a Clinical Investigator.

 

“CRADA Subject Invention” means any Invention of either or both Parties, conceived or first actually reduced to practice in the performance of the Research Plan.

 

 

“Drug Master File” or “DMF” is described in 21 C.F.R. Part 314.420. A DMF is a submission to the FDA that may be used to provide confidential detailed information about facilities, processes, or articles used in the manufacturing, processing, packaging, and storing of one or more human drugs.

 

“Effective Date” means the date of the last signature of the Parties executing this Agreement.

 

“Government” means the Government of the United States of America.

 

“Human Subject” means, in accordance with the definition in 45 C.F.R. § 46.102(e)(1), a living individual about whom an investigator (whether professional or student) conducting research (i) obtains information or biospecimens through intervention or interaction with the individual, and uses, studies, or analyzes the information or biospecimens; or (ii) obtains, uses, studies, analyzes, or generates Identifiable Private Information or identifiable biospecimens.

 

“IC Materials” means all tangible materials not first produced in the performance of this CRADA that are owned or controlled by IC and used in the performance of the Research Plan.

 

“IND” means an “Investigational New Drug Application”, filed in accordance with 21 C.F.R. Part 312 under which clinical investigation of an experimental drug or biologic (Test Article) is performed in Human Subjects in the United States or intended to support a United States licensing action.

 

“Identifiable Private Information” or “IPI” about a Human Subject means private information for which the identity of the subject is or may readily be ascertained by the investigator or associated with the information. Regulations defining and governing this information include 45 C.F.R. Part 46.

 

“Identifiable, Sensitive Information” or “ISI” means, in accordance with the definition of 42 U.S.C. 241(d)(4), information that is about an individual and that is gathered or used during the course of research as described in 42 U.S.C. 241(d)(1)(A) through which an individual is identified, or that includes IPI, or for which there is at least a very small risk, as determined by current scientific practices or statistical methods, that some combination of the information, a request for the information, and other available data sources could be used to deduce the identity of an individual.

 

“Institutional Review Board” or “IRB” means, in accordance with 45 C.F.R. Part 46, 21 C.F.R. Part 56, and other applicable regulations, an independent body comprising medical, scientific, and nonscientific members, whose responsibility is to ensure the protection of the rights, safety, and well-being of the Human Subjects involved in a study.

 

 

“Invention” means any invention or discovery that is or may be patentable or otherwise protected under Title 35 of the United States Code, or any novel variety of plant which is or may be protectable under the Plant Variety Protection Act, 7 U.S.C. §§ 2321 et seq.

 

“Investigator’s Brochure” means, in accordance with the definition in 21 C.F.R. § 312.23(a)(5), a document containing information about the Test Article, including animal screening, preclinical toxicology, and detailed pharmaceutical data, including a description of possible risks and side effects to be anticipated on the basis of prior experience with the drug or related drugs, and precautions, such as additional monitoring, to be taken as part of the investigational use of the drug.

 

“L-088-2021-0” means exclusive patent license NIH reference number L-088-2021-0 signed February 2, 2021 between the NIH-NEI and Curative Biotechnology Holdings, Inc.

 

“Patent Application” means an application for patent protection for a CRADA Subject Invention with the United States Patent and Trademark Office (“U.S.P.T.O.”) or the corresponding patent-issuing authority of another nation.

 

“Patent” means any issued United States patent, any international counterpart(s), and any corresponding grant(s) by a non-U.S. government in place of a patent.

 

“Placebo” means an inactive substance identical in appearance to the material being tested that is used to distinguish between drug action and suggestive effect of the material under study.

 

“Protocol” means the formal, detailed description of a study to be performed as provided for in the Research Plan. It describes the objective(s), design, methodology, statistical considerations, and organization of a trial. For the purposes of this CRADA, the term, Protocol, for clinical research involving Human Subjects, includes any and all associated documents, including informed consent forms, to be provided to Human Subjects and potential participants in the study.

 

“Raw Data” means the primary quantitative and empirical data first collected from experiments and clinical trials conducted within the scope of this CRADA.

 

“Research Plan” means the statement in Appendix A of the respective research and development commitments of the Parties. The Research Plan should describe the provisions for sponsoring the IND, clinical and safety monitoring, and data management.

 

“Sponsor” means, in accordance with the definition in 21 C.F.R. § 312.3, an organization or individual who assumes legal responsibility for supervising or overseeing clinical trials with Test Articles and is sometimes referred to as the IND holder.

 

“Steering Committee” means the research and development team whose composition and responsibilities with regard to the research performed under this CRADA are described in Appendix A.

 

 

“Summary Data” means any extract or summary of the Raw Data, generated either by, or on behalf of, IC or by, or on behalf of, Collaborator. Summary Data may include extracts or summaries that incorporate ISI.

 

“Suspected Adverse Reaction” or “SAR” means any Adverse Event for which there is a reasonable possibility that the drug caused the Adverse Event. For the purposes of IND safety reporting, “reasonable possibility” means there is evidence to suggest a causal relationship between the drug and the Adverse Event. Suspected Adverse Reaction implies a lesser degree of certainty about causality than adverse reaction, which means any Adverse Event caused by a drug (21 CFR 312.32(a)).

 

“Test Article” means, in accordance with 21 C.F.R. § 50.3 (j), any drug (including a biological product), medical device, food additive, color additive, electronic product, or any other article subject to regulation under the Federal Food, Drug, and Cosmetic Act that is intended for administration to humans or animals, including a drug or biologic as identified in the Research Plan and Appendix B, that is used within the scope of the Research Plan. The Test Article may also be referred to as Investigational Agent, Study Material, or Study Product.

 

“Unique Ingredient Identifier” or “UNII” means a non-proprietary, free, unique, unambiguous, non-semantic, alphanumeric identifier based on a substance’s molecular structure and/or descriptive information and generated by the Global Registration System of the FDA.

 

Article 3. Cooperative Research and Development

 

3.1

Performance of Research and Development. The research and development activities to be carried out under this CRADA will be performed solely by the Parties identified on the Cover Page, unless specifically stated elsewhere in the Agreement. The CRADA PIs will be responsible for coordinating the scientific and technical conduct of this project on behalf of their employers. Any Collaborator employees who will work at IC facilities will be required to sign an agreement appropriately modified in view of the terms of this CRADA.

 

3.2

Research Plan. The Parties recognize that the Research Plan describes the collaborative research and development activities they will undertake and that interim research goals set forth in the Research Plan are good faith guidelines. Should events occur that require modification of these goals, then by mutual agreement the Parties can modify them through an amendment, according to Paragraph 13.6.

 

3.3

Use and Disposition of Collaborator Materials and IC Materials. The Parties agree to use Collaborator Materials and IC Materials only in accordance with the Research Plan and Protocol(s), not to transfer these materials to third parties except in accordance with the Research Plan and Protocol(s) or as approved by the owning or providing Party, and, upon expiration or termination of the CRADA, to dispose of these materials as directed by the owning or providing Party.

 

 

3.4

Third-Party Rights in Collaborator’s CRADA Subject Inventions. If Collaborator has received (or will receive) support of any kind from a third party in exchange for rights in any of Collaborator’s CRADA Subject Inventions, Collaborator agrees to ensure that its obligations to the third party are both consistent with Articles 6 through 8 and subordinate to Article 7 of this CRADA.

 

3.5

Disclosures to IC. Prior to execution of this CRADA, Collaborator agrees to disclose to IC all instances in which outstanding royalties are due under a PHS license agreement and in which Collaborator had a PHS license terminated in accordance with 37 C.F.R. § 404.10. These disclosures will be treated as Confidential Information upon request by Collaborator in accordance with the definition in Article 2 and Paragraphs 8.3 and 8.4.

 

3.6

Clinical Investigator Responsibilities. The Clinical Investigator will be required to submit, or to arrange for submission of, each Protocol associated with this CRADA to the IRB. In addition to the Protocol all associated documents, including informational documents and advertisements, must be reviewed and approved by the IRB before starting the research. The research will be done in strict accordance with the Protocol(s) and no substantive changes in a finalized Protocol will be made unless mutually agreed upon, in writing, by the Parties. Research will not commence (or will continue unchanged, if already in progress) until each substantive change to a Protocol, including those required by either the FDA or the IRB, has been integrated in a way acceptable to the Parties, submitted to the FDA (if applicable) and approved by the IRB.

 

3.7	Investigational Applications.

 

3.7.1

If an IND is required, IC will be the IND Sponsor and will submit an IND. All Clinical Investigators must have completed registration documents on file (1572 forms).

 

3.7.2

When IC files the IND, Collaborator agrees to provide IC background data and information necessary to support the IND in electronic Common Technical Document (eCTD) format: Suspected Adverse Reactions; and formulation and preclinical data, including toxicology findings. Collaborator further agrees to provide a letter of cross-reference to all pertinent regulatory filings sponsored by Collaborator. Collaborator’s employees will be reasonably available to respond to inquiries from the FDA regarding information and data contained in the Collaborator’s IND, DMF, other filings, or other information and data provided to IC by the Collaborator pursuant to this Article 3.

 

3.7.3

At least annually, the Collaborator will review the Investigator’s Brochure (IB) and will provide the updated IB in eCTD format, or if necessary, confirmation that no updates were made to the IB.

 

 

3.7.4

If Collaborator supplies Confidential Information to IC in support of an IND filed by IC, this information will be protected in accordance with the corresponding confidentiality provisions of Article 8.

 

3.7.5

Collaborator may sponsor its own clinical trials and hold its own IND for studies performed outside the scope of this CRADA. These studies, however, should not adversely affect the ability to accomplish the goal of the Research Plan, for example, by competing for the same study population. All data from those clinical trials are proprietary to Collaborator for purposes of this CRADA.

 

3.8	Test Article Information and Supply.

 

3.8.1

Collaborator agrees to provide IC without charge and on a schedule that will ensure adequate and timely performance of the research, a sufficient quantity of formulated and acceptably labeled, clinical-grade Test Article (and, as required by the Protocol(s), Placebo) to complete the clinical trial(s) agreed to and approved under this CRADA. If applicable, Collaborator agrees to provide Test Article labels to the IC. Collaborator will provide a Certificate of Analysis (COA) to IC in advance of an IND filing and for each lot of the Test Article provided.

 

3.8.2

The Test Article must be received by the IC in usable condition and accompanied by specific storage and shipping instructions, Material Safety Data Sheet (MSDS), a signed and dated COA, and stability or expiration dating information for each lot of Test Article sent. If the Collaborator performs ongoing stability testing for each lot of Test Article sent, then the Collaborator will also provide updated retest or expiration dates for those respective lots to the IC in a timely manner.

 

3.8.3

If there is evidence that the Test Article that arrived at the IC has not been maintained according to the defined shipping instructions or there is evidence of damage to the Test Article container or container closure system, IC will contact the Collaborator to inform them of the condition of the received Test Article and to determine together with the Collaborator whether the Test Article is usable or if it must be replaced. During the course of the clinical studies, the same process will be used whenever there is evidence that the Test Article has not been maintained according to the Collaborator’s recommended storage conditions. If the Test Article must be replaced, the Collaborator will replace it at no cost to IC.

 

3.9

Test Article Delivery and Usage. Collaborator will ship the Test Article and, if required, Placebo to IC in containers marked in accordance with 21 C.F.R. § 312.6. IC agrees that the Clinical Investigators will keep appropriate records and take reasonable steps to ensure that the Test Article is used in accordance with the Protocol(s) and applicable FDA regulations. In addition, IC agrees that the Test Article (and all Confidential Information supplied by Collaborator relating to the Test Article) will be used solely for the conduct of the CRADA research and development activities. Furthermore, IC agrees that no analysis or modification of the Test Article will be performed without Collaborator’s prior written consent. At the completion of the Research Plan, any unused quantity of Test Article will be returned to Collaborator or disposed as directed by Collaborator. Pharmacy contacts at IC will be determined by IC and communicated to Collaborator.

 

 

3.10

Monitoring. Subject to the restrictions in the Rights of Access and Publications section and the Certificate of Confidentiality Obligations section, and with reasonable advance notice and at reasonable times, IC will permit Collaborator or its designee(s) to audit the clinical monitoring performed by the IC, as well as to audit source documents containing Raw Data, to the extent necessary to verify compliance with the Protocol(s) and E6(R2): Good Clinical Practice: Integrated Addendum to International Council for Harmonisation (ICH) E6(R1) Guidance for Industry, 83 Federal Register 8882 (2018). Concerning the review and auditing of Raw Data and the exchange of CRADA Data, Collaborator agrees to accept the data processes, timelines, and deliverables of the IC.

 

3.11	FDA Meetings/Communications.

 

(A) Formal meetings with the FDA concerning the design of the clinical studies and/or data will be discussed and agreed upon in advance by the Collaborator and the IC. The Collaborator will have the right to participate in all formal meetings with the FDA as appropriate. The Collaborator agrees not to contact the FDA independent of the IC concerning the clinical studies under this Agreement. However, the Collaborator may contact the FDA on separate product-related issues.

 

(B) The Collaborator will promptly notify the IC of the following: (1) any FDA correspondence related to the Protocol that is received by the Collaborator or its Affiliates; and (2) any FDA enforcement actions directed toward the Collaborator or its Affiliates related to the Protocol.

 

(C) The Collaborator will also promptly notify the IC of any action taken by the FDA regarding manufacturing of the Test Article that would impact the safety of Human Subjects participating in the study.

 

Article 4. Reports

 

4.1

Interim Research and Development Reports. The CRADA PIs should exchange information regularly, in writing. This exchange may be accomplished through meeting minutes, detailed correspondence, circulation of draft manuscripts, Steering Committee reports, copies of Annual Reports and any other reports updating the progress of the CRADA research. However, the Parties must exchange updated Investigator’s Brochure, formulation and preclinical data, and toxicology findings, as they become available these data and documents will be provided in eCTD format, except for IC’s preclinical data that will be provided in standard laboratory data format.

 

4.2

Final Research and Development Reports. The Parties will exchange final reports of their results within six (6) months after the expiration or termination of this CRADA. These reports will set forth the technical progress made; any publications arising from the research; and the existence of invention disclosures of potential CRADA Subject Inventions and/or any corresponding Patent Applications.

 

 

4.3

Fiscal Reports. If Collaborator has agreed to provide funding to IC under this CRADA and upon the request of Collaborator, then concurrent with the exchange of final research and development reports according to Paragraph 4.2, IC will submit to Collaborator a statement of all costs incurred by IC for the CRADA. If the CRADA has been terminated, IC will specify any costs incurred before the date of termination for which IC has not received funds from Collaborator, as well as for all reasonable termination costs including the cost of returning Collaborator property or removal of abandoned Collaborator property, for which Collaborator will be responsible.

 

4.4	Safety Reports.

 

4.4.1 In accordance with FDA requirements IC, as the IND Sponsor, will establish and maintain records and submit safety reports to the FDA, as required by 21 C.F.R. § 312.32 and 21 C.F.R. § 812.150(b)(1), or other applicable Federal regulations. In the conduct of research under this CRADA, the Parties will comply with specific IC guidelines and policies for reporting AEs. IC must provide Collaborator with copies of all Safety Reports concurrently with their submission to the FDA, and with any other information affecting the safety of Human Subjects in research conducted under this CRADA.

 

4.4.2 During and for a period of two years after the completion of a Protocol, the Collaborator shall promptly provide to the IC any information that Collaborator has reasonably determined could directly affect the health or safety of past or current Human Subjects or influence the conduct of the Protocol. Such information may arise from any source, for example, Safety Reports provided to the FDA, study results, information in site monitoring reports or data safety monitoring committee reports. IC shall be free to communicate the relevant safety information to each Human Subject and the IRB.

 

4.5	Annual Reports. IC will provide Collaborator a copy of the Annual Report concurrently with the submission of the Annual Report to the FDA. Annual Reports will be kept confidential in accordance with Article 8.

 

Article 5. Staffing, Financial, and Materials Obligations

 

5.1

IC and Collaborator Contributions. The contributions of any staff, funds, materials, and equipment by the Parties are set forth in Appendix B. The Federal Technology Transfer Act of 1986, 15 U.S.C. § 3710a(d)(1) prohibits IC from providing funds to Collaborator for any research and development activities under this CRADA.

 

5.2

IC Staffing. No IC employees will devote 100% of their effort or time to the research and development activities under this CRADA. IC will not use funds provided by Collaborator under this CRADA for IC personnel to pay the salary of any permanent IC employee. Although personnel hired by IC using CRADA funds will focus principally on CRADA research and development activities, Collaborator acknowledges that these personnel may nonetheless make contributions to other research and development activities, and the activities will be outside the scope of this CRADA.

 

 

5.3

Collaborator Funding. Collaborator acknowledges that Government funds received by Collaborator from an agency of the Department of Health and Human Services may not be used to fund IC under this CRADA. If Collaborator has agreed to provide funds to IC, then the payment schedule appears in Appendix B and Collaborator will make payments according to that schedule. If Collaborator fails to make any scheduled payment, IC will not be obligated to perform any of the research and development activities specified herein or to take any other action required by this CRADA until the funds are received. IC will use these funds exclusively for the purposes of this CRADA. Each Party will maintain separate and distinct current accounts, records, and other evidence supporting its financial obligations under this CRADA and, upon written request, will provide the other Party a Fiscal Report according to Paragraph 4.3, which delineates all payments made and all obligated expenses, along with the Final Research Report described in Paragraph 4.2.

 

5.4

Capital Equipment. Collaborator’s commitment, if any, to provide IC with capital equipment to enable the research and development activities under the Research Plan appears in Appendix B. If Collaborator transfers to IC the capital equipment or provides funds for IC to purchase it, then IC will own the equipment. If Collaborator loans capital equipment to IC for use during the CRADA, Collaborator will be responsible for paying all costs and fees associated with the transport, installation, maintenance, repair, removal, or disposal of the equipment, and IC will not be liable for any damage to the equipment.

 

Article 6. Intellectual Property

 

6.1

Ownership of CRADA Subject Inventions, CRADA Data, and CRADA Materials. Subject to the Government license described in Paragraph 7.5, the sharing requirements of Paragraph 8.1 and the regulatory filing requirements of Paragraph 8.2, the inventing Party will retain sole ownership of and title to all CRADA Subject Inventions invented solely by its employee(s), and the producing Party will retain all copies of CRADA Data, and all CRADA Materials produced solely by its employee(s). The Parties will own jointly all CRADA Subject Inventions invented jointly and all CRADA Materials developed jointly.

 

6.2

Reporting. The Parties will promptly report to each other in writing each CRADA Subject Invention reported by their respective personnel, and any Patent Applications filed thereon, resulting from the research and development activities conducted under this CRADA. Each Party will report all CRADA Subject Inventions to the other Party in sufficient detail to determine inventor ship, which will be determined in accordance with U.S. patent law. These reports will be treated as Confidential Information in accordance with Article 8. Formal reports will be made by and to the Patenting and Licensing Offices identified on the Contacts Information Page herein.

 

 

6.3

Filing of Patent Applications. Each Party will make timely decisions regarding the filing of Patent Applications on the CRADA Subject Inventions made solely by its employee(s) and will notify the other Party in advance of filing. Collaborator will have the first opportunity to file a Patent Application on joint CRADA Subject Inventions and will notify PHS of its decision within sixty (60) days of an Invention being reported or at least thirty (30) days before any patent filing deadline, whichever occurs sooner. If Collaborator fails to notify PHS of its decision within that time period or notifies PHS of its decision not to file a Patent Application, then PHS has the right to file a Patent Application on the joint CRADA Subject Invention. Neither Party will be obligated to file a Patent Application. Each Party will provide the other Party with a final draft of any Patent Application on the CRADA Subject Invention thirty (30) days before filing so that the other Party can review and ensure protection of its Confidential Information unless a rush filing is necessary. A rush filing means the filing of a Patent Application, due to an impending, enabling disclosure, e.g., publication of a journal article or a presentation at a public event, the timing of which may not allow for the thirty (30) day review period. In the case of a rush filing where a thirty-day review period is not available, each Party will use reasonable efforts to discuss such Patent Application with the other Party reasonably in advance of the rush filing of such Patent Application. Neither Party’s Confidential Information shall be included or disclosed in any Patent Application without the other Party’s express prior written consent. Collaborator will place the following statement in any Patent Application it files on a CRADA Subject Invention: “This invention was created in the performance of a Cooperative Research and Development Agreement with the National Institutes of Health, an Agency of the Department of Health and Human Services. The Government of the United States has certain rights in this invention.” If either Party files a Patent Application on a joint CRADA Subject Invention, then the filing Party will include a statement within the Patent Application that clearly identifies the Parties and states that the joint CRADA Subject Invention was made under this CRADA.

 

6.4

Patent Expenses. Unless agreed otherwise, the Party filing a Patent Application will pay all preparation and filing expenses, prosecution fees, issuance fees, post issuance fees, patent maintenance fees, annuities, interference expenses, and attorneys’ fees for that Patent Application and any resulting Patent(s). If a license to any CRADA Subject Invention is granted to Collaborator, then Collaborator will be responsible for all expenses and fees, past and future, in connection with the preparation, filing, prosecution, and maintenance of any Patent Applications and Patents claiming exclusively licensed CRADA Subject Inventions and will be responsible for a pro-rated share, divided equally among all licensees, of those expenses and fees for non-exclusively licensed CRADA Subject Inventions. Collaborator may waive its exclusive option rights at any time and incur no subsequent financial obligation for those Patent Application(s) or Patent(s).

 

6.5

Prosecution of Patent Applications. The Party filing a Patent Application will provide the non-filing Party with a copy of any official communication relating to prosecution of the Patent Application within thirty (30) days of transmission of the communication. Each Party will also provide the other Party with the power to inspect and make copies of all documents retained in the applicable Patent Application or Patent file. The Parties agree to consult with each other regarding the prosecution of Patent Applications directed to joint CRADA Subject Inventions. If Collaborator elects to file and prosecute Patent Applications on joint CRADA Subject Inventions, then Collaborator agrees to use the U.S.P.T.O. Customer Number Practice and/or grant PHS a power(s) of attorney (or equivalent) necessary to assure PHS access to its intellectual property rights in these Patent Applications. PHS and Collaborator will cooperate with each other to obtain necessary signatures on Patent Applications, assignments, or other documents.

 

 

Article 7. Licensing

 

7.1

Background Inventions. Other than as specifically stated in this Article 7, nothing in this CRADA will be construed to grant any rights in one Party’s Background Invention(s) to the other Party, except to the extent necessary for the Parties to conduct the research and development activities described in the Research Plan

 

7.2

Collaborator’s License Option to CRADA Subject Inventions. With respect to Government rights to any CRADA Subject Invention made solely by an IC employee(s) or made jointly by an IC employee(s) and a Collaborator employee(s) for which a Patent Application was filed, PHS hereby grants to Collaborator an exclusive option to elect an exclusive or nonexclusive commercialization license. The license will be substantially in the form of the appropriate model PHS license agreement and will fairly reflect the nature of the CRADA Subject Invention, the relative contributions of the Parties to the CRADA Subject Invention and the CRADA, a plan for the development and marketing of the CRADA Subject Invention, the risks incurred by Collaborator, and the costs of subsequent research and development needed to bring the CRADA Subject Invention to the marketplace. The field of use of the license will not exceed the scope of the Research Plan.

 

7.3

Exercise of Collaborator’s License Option. To exercise the option of Paragraph 7.2 Collaborator must submit a written notice to the PHS Patenting and Licensing Contact identified on the Contacts Information Page (and provide a copy to the IC Contact for CRADA Notices) within three (3) months after either (i) Collaborator receives written notice from PHS that the Patent Application has been filed or (ii) the date on which Collaborator files the Patent Application. The written notice exercising this option will include a completed “Application for License to Public Health Service Inventions” and will initiate a negotiation period that expires nine (9) months after the exercise of the option. PHS and Collaborator will negotiate in good faith during the nine (9) month negotiation period. If PHS has not responded in writing to the last proposal by Collaborator within this nine (9) month period, the negotiation period will be extended to expire one (1) month after PHS so responds, during which month Collaborator may accept in writing the final license proposal of PHS. In the absence of Collaborator’s exercise of the option, or upon election of a nonexclusive license, PHS will be free to license the CRADA Subject Invention to others. In the event that Collaborator elects the option for an exclusive license, but no such license is executed during the negotiation period, PHS agrees not to make an offer on more favorable terms to a third party for a period of nine (9) months without first offering Collaborator the same terms to be offered to the third party, in which case Collaborator shall have a period of thirty (30) days in which to accept or reject the offer. These time periods may be extended at the sole discretion of PHS upon good cause shown in writing by Collaborator.

 

 

7.4

Government License in IC Sole CRADA Subject Inventions and Joint CRADA Subject Inventions. Pursuant to 15 U.S.C. § 3710a(b)(1)(A), for CRADA Subject Inventions owned solely by IC or jointly by IC and Collaborator, and licensed pursuant to the option of Paragraph 7.2, Collaborator grants to the Government a nonexclusive, nontransferable, irrevocable, paid-up license to practice the CRADA Subject Invention or have the CRADA Subject Invention practiced throughout the world by or on behalf of the Government. In the exercise of this license, the Government will not publicly disclose trade secrets or commercial or financial information that is privileged or confidential within the meaning of 5 U.S.C. § 552(b)(4) or which would be considered privileged or confidential if it had been obtained from a non-federal party.

 

7.5

Government License in Collaborator Sole CRADA Subject Inventions. Pursuant to 15 U.S.C. § 3710a(b)(2), for CRADA Subject Inventions made solely by an employee of Collaborator, Collaborator grants to the Government a nonexclusive, nontransferable, irrevocable, paid-up license to practice the CRADA Subject Invention or have the CRADA Subject Invention practiced throughout the world by or on behalf of the Government for research or other Government purposes.

 

7.6

Third Party License. Pursuant to 15 U.S.C. § 3710a(b)(1)(B), if PHS grants Collaborator an exclusive license to a CRADA Subject Invention made solely by an IC employee or jointly with a Collaborator employee, the Government will retain the right to require Collaborator to grant to a responsible applicant a nonexclusive, partially exclusive, or exclusive sublicense to use the CRADA Subject Invention in Collaborator’s licensed field of use on terms that are reasonable under the circumstances; or, if Collaborator fails to grant a license, to grant a license itself. The exercise of these rights by the Government will only be in exceptional circumstances and only if the Government determines (i) the action is necessary to meet health or safety needs that are not reasonably satisfied by Collaborator, (ii) the action is necessary to meet requirements for public use specified by federal regulations, and such requirements are not reasonably satisfied by Collaborator; or (iii) Collaborator has failed to comply with an agreement containing provisions described in 15 U.S.C. § 3710a(c)(4)(B). The determination made by the Government under this Paragraph is subject to administrative appeal and judicial review under 35 U.S.C. § 203(b).

 

7.7

Third-Party Rights In IC Sole CRADA Subject Inventions. For a CRADA Subject Invention conceived prior to the Effective Date solely by an IC employee that is first actually reduced to practice after the Effective Date in the performance of the Research Plan, the option offered to Collaborator in Paragraph 7.2 may be restricted if, prior to the Effective Date, PHS had filed a Patent Application and has either offered or granted a license in the CRADA Subject Invention to a third party. Collaborator nonetheless retains the right to apply for a license to any such CRADA Subject Invention in accordance with the terms and procedures of 35 U.S.C. § 209 and 37 C.F.R. Part 404.

 

 

Article 8. Rights of Access and Publication

 

8.1

Right of Access to CRADA Data and CRADA Materials. IC and Collaborator agree to exchange all CRADA Data and to share all CRADA Materials. If the CRADA is terminated, both Parties agree to provide CRADA Materials in quantities needed to complete the Research Plan. Such provision will occur before the termination date of the CRADA or sooner, if required by the Research Plan. If Collaborator possesses any human biological specimens from clinical trials under the CRADA, the specimens must be handled as described in the Protocol or as otherwise directed by IC before the termination date of the CRADA.

 

8.2

Use of CRADA Data and CRADA Materials. The Parties will be free to utilize CRADA Data and CRADA Materials internally for their own purposes, consistent with their obligations under this CRADA. The Parties may share CRADA Data or CRADA Materials with their Affiliates, agents or contractors provided the obligations of this Article 8.2 are simultaneously conveyed.

 

8.2.1

CRADA Data.

 

Collaborator and IC will use reasonable efforts to keep CRADA Data confidential until published or until corresponding Patent Applications are filed. To the extent permitted by law, each Party will have the right to use any and all CRADA Data in and for any regulatory filing by or on behalf of the Party.

 

8.2.2

CRADA Materials.

 

Collaborator and IC do not anticipate that CRADA Materials will be generated in performance of the CRADA Research Plan. Biospecimens will be handled in accordance with the Protocol.

 

8.3

Confidential Information. Each Party agrees to limit its disclosure of Confidential Information to the amount necessary to carry out the Research Plan and will place a confidentiality notice on all this information. A Party orally disclosing Confidential Information to the other Party will summarize the disclosure in writing and provide it to the other Party within fifteen (15) days of the disclosure. Each Party receiving Confidential Information agrees to use it only for the purposes described in the Research Plan. Either Party may object to the designation of information as Confidential Information by the other Party.

 

8.4

Protection of Confidential Information. Confidential Information will not be disclosed, copied, reproduced or otherwise made available to any other person or entity without the consent of the owning or providing Party except as required by a court or administrative body of competent jurisdiction, or federal law or regulation. Each Party agrees to use reasonable efforts to maintain the confidentiality of Confidential Information, which will in no instance be less effort than the Party uses to protect its own Confidential Information. Each Party agrees that a Party receiving Confidential Information will not be liable for the disclosure of that portion of the Confidential Information which, after notice to and consultation with the disclosing Party, the receiving Party determines may not be lawfully withheld, provided the disclosing Party has been given a reasonable opportunity to seek a court order to enjoin disclosure.

 

 

8.5

Human Subject Protection. The research to be conducted under this CRADA involves Human Subjects or human tissues within the meaning of 45 C.F.R. Part 46, and all research to be performed under this CRADA will conform to applicable federal laws and regulations. Additional information is available from the HHS Office for Human Research Protections (http://www.hhs.gov/ohrp/).

 

8.6

Duration of Confidentiality Obligation. The obligation to maintain the confidentiality of Confidential Information will expire at the earlier of the date when the information is no longer Confidential Information as defined in Article 2 or five (5) years after the expiration or termination date of this CRADA, except for ISI, for which the obligation to maintain confidentiality will extend indefinitely. Collaborator may request an extension to this term when necessary to protect Confidential Information relating to products not yet commercialized.

 

8.7

Publication. The Parties are encouraged to make publicly available the results of their research and development activities. Before either Party submits a paper or abstract for publication or otherwise intends to publicly disclose information about a CRADA Subject Invention, CRADA Data, or CRADA Materials, including, without limitation, in a written publication, public presentation, or other public disclosure, the other Party will have thirty (30) days to review such proposed disclosure (or ten (10) days for an abstract) to assure that Confidential Information is protected. Either Party may request in writing that the proposed publication or other disclosure be delayed for up to forty-five (45) additional days as necessary to file a Patent Application. Neither Party’s Confidential Information shall be included or disclosed in any publication or other public disclosure without the providing Party’s express prior written consent.

 

8.8

Certificate of Confidentiality Obligations. Any ISI that Collaborator receives from NIH is covered by a CoC and therefore all copies of ISI are immune from the legal process, and will not, without the consent of the Human Subject, be admissible as evidence or used for any purpose in any action, suit, or other judicial, legislative, or administrative proceeding.

 

Notwithstanding the forgoing, Collaborator will be permitted to disclose ISI:

 

a.

If required by Federal, State, or local laws (e.g., as required by the Federal Food, Drug, and Cosmetic Act, or state laws requiring the reporting of communicable diseases to State and local health departments), excluding instances of disclosure in any Federal, State, or local civil, criminal, administrative, legislative, or other proceeding;

 

b.

If the consent of the Human Subject to whom the information, document, or biospecimen pertains obtained by the IC allowed for such disclosure.

 

Prior to making any permitted disclosures above, Collaborator will ensure that any recipient of ISI protected by a CoC is aware of its confidential nature and the requirement to comply with the CoC (see https://humansubjects.nih.gov/coc/background).

 

 

Article 9. Representations and Warranties

 

9.1	Representations of IC. IC hereby represents to Collaborator that:

 

9.1.1

IC has the requisite power and authority to enter into this CRADA and to perform according to its terms, and that IC’s official signing this CRADA has authority to do so.

 

9.1.2

To the best of its knowledge and belief, neither IC nor any of its personnel involved in this CRADA is presently subject to debarment or suspension by any agency of the Government which would directly affect its performance of the CRADA. Should IC or any of its personnel involved in this CRADA be debarred or suspended during the term of this CRADA, IC will notify Collaborator within thirty (30) days of receipt of final notice.

 

9.2	Representations and Warranties of Collaborator. Collaborator hereby represents and warrants to IC that:

 

9.2.1

Collaborator has the requisite power and authority to enter into this CRADA and to perform according to its terms, and that Collaborator’s official signing this CRADA has authority to do so.

 

9.2.2

Neither Collaborator nor any of its personnel involved in this CRADA, including Affiliates, agents, and contractors are presently subject to debarment or suspension by any agency of the Government. Should Collaborator or any of its personnel involved in this CRADA be debarred or suspended during the term of this CRADA, Collaborator will notify IC within thirty (30) days of receipt of final notice.

 

9.2.3

Subject to Paragraph 12.3, and if and to the extent Collaborator has agreed to provide funding under Appendix B, Collaborator is financially able to satisfy these obligations in a timely manner.

 

9.2.4

The Test Article provided has been produced, or will be produced if not already produced, in accordance with the FDA’s current Good Manufacturing Practice set out in 21 C.F.R. §§ 210-211 and ICH QA7, and meets the specifications cited in the Certificate of Analysis and Investigator’s Brochure provided.

 

Article 10. Contingency, Expiration and Termination

 

10.1	Contingency. Parties will review results of preclinical pharmacology and toxicology testing of the ocular metformin formulation. Only after the IC concludes that clinical studies can be safely commenced, will the clinical safety studies commence.

 

10.2	Expiration. This CRADA will expire on the last date of the term set forth on the Summary Page. In no case will the term of this CRADA extend beyond the term indicated on the Summary Page unless it is extended in writing in accordance with Paragraph 13.6.

 

 

10.3	Termination by Mutual Consent. IC and Collaborator may terminate this CRADA at any time by mutual written consent.

 

10.4

Unilateral Termination. Either IC or Collaborator may unilaterally terminate this CRADA at any time by providing written notice at least sixty (60) days before the desired termination date. IC may, at its option, retain funds transferred to IC before unilateral termination by Collaborator for use in completing the Research Plan. If Collaborator terminates this Agreement before the completion of all approved or active Protocol(s), then Collaborator will supply enough Test Article (and Placebo, if applicable) necessary to complete these Protocol(s) unless termination is for safety concerns.

 

10.5

Funding for IC Personnel. If Collaborator has agreed to provide funding for IC personnel and this CRADA is mutually or unilaterally terminated by Collaborator before its expiration, then Collaborator agrees that funds for that purpose will be available to IC for a period of six (6) months after the termination date or until the expiration date of the CRADA, whichever occurs sooner. If there are insufficient funds to cover this expense, Collaborator agrees to pay the difference.

 

10.6

New Commitments. Neither Party will incur new expenses related to this CRADA after expiration, mutual termination, or a notice of a unilateral termination and will, to the extent feasible, cancel all outstanding commitments and contracts by the termination date. Collaborator acknowledges that IC will have the authority to retain and expend any funds for up to one (1) year subsequent to the expiration or termination date to cover any unpaid costs obligated during the term of the CRADA in undertaking the research and development activities set forth in the Research Plan.

 

10.7

Collaborator Failure to Continue Development. If Collaborator suspends development of the Test Article without the transfer of its active development efforts, assets, and obligations to a third party within ninety (90) days of discontinuation, Collaborator agrees that IC may continue developing the Test Article. In that event, the following will apply:

 

10.7.1

Collaborator agrees to transfer to IC all information necessary to enable IC to contract for the manufacture of the Test Article and, unless abandoned for reasons relating to safety as determined by the data safety monitoring board, to provide the Test Article (and Placebo, if any) in Collaborator’s inventory to IC.

 

10.7.2

Further, Collaborator hereby grants to IC a nonexclusive, irrevocable, world- wide, paid-up license to practice, or have practiced for or on behalf of the Government, any Background Invention that Collaborator may currently have or will obtain on the Test Article, its manufacture, or on any method of using the Test Article for the indication(s) described in the Research Plan, including the right to sublicense to third parties.

 

 

Article 11. Disputes

 

11.1

Settlement. Any dispute arising under this CRADA which is not disposed of by agreement of the CRADA Principal Investigators will be submitted jointly to the signatories of this CRADA. If the signatories, or their designees, are unable to jointly resolve the dispute within thirty (30) days after notification thereof, the Assistant Secretary for Health (or his/her designee or successor) will propose a resolution. Nothing in this Paragraph will prevent any Party from pursuing any additional administrative remedies that may be available and, after exhaustion of such administrative remedies, pursuing all available judicial remedies.

 

11.2	Continuation of Work. Pending the resolution of any dispute or claim pursuant to this Article 11, the Parties agree that performance of all obligations will be pursued diligently.

 

Article 12. Liability

 

12.1

NO WARRANTIES. EXCEPT AS SPECIFICALLY STATED IN ARTICLE 9, THE PARTIES MAKE NO EXPRESS OR IMPLIED WARRANTY AS TO ANY MATTER WHATSOEVER, INCLUDING THE CONDITIONS OF THE RESEARCH OR ANY INVENTION OR MATERIAL, WHETHER TANGIBLE OR INTANGIBLE, MADE OR DEVELOPED UNDER OR OUTSIDE THE SCOPE OF THIS CRADA, OR THE OWNERSHIP, MERCHANTABILITY, OR FITNESS FOR A PARTICULAR PURPOSE OF THE RESEARCH OR ANY INVENTION OR MATERIAL, OR THAT A TECHNOLOGY UTILIZED BY A PARTY IN THE PERFORMANCE OF THE RESEARCH PLAN DOES NOT INFRINGE ANY THIRD-PARTY PATENT RIGHTS.

 

12.2

Indemnification and Liability. Collaborator agrees to hold the Government harmless and to indemnify the Government for all liabilities, demands, damages, expenses and losses arising out of the use by Collaborator for any purpose of the CRADA Data, CRADA Materials or CRADA Subject Inventions produced in whole or part by IC employees under this CRADA, unless due to the negligence or willful misconduct of IC, its employees, or agents. The Government has no statutory authority to indemnify Collaborator. Each Party otherwise will be liable for any claims or damages it incurs in connection with this CRADA, except that IC, as an agency of the Government, assumes liability only to the extent provided under the Federal Tort Claims Act , 28 U.S.C. Chapter 171.

 

12.3

Force Majeure. Neither Party will be liable for any unforeseeable event beyond its reasonable control and not caused by its own fault or negligence, which causes the Party to be unable to perform its obligations under this CRADA, and which it has been unable to overcome by the exercise of due diligence. If a force majeure event occurs, the Party unable to perform will promptly notify the other Party. It will use its best efforts to resume performance as quickly as possible and will suspend performance only for such period of time as is necessary as a result of the force majeure event.

 

 

Article 13. Miscellaneous

 

13.1

Governing Law. The construction, validity, performance and effect of this CRADA will be governed by U.S. federal law, as applied by the federal courts in the District of Columbia. If any provision in this CRADA conflicts with or is inconsistent with any U.S. federal law or regulation, then the U.S. federal law or regulation will preempt that provision.

 

13.2

Compliance with Law. IC and Collaborator agree that they will comply with, and advise any contractors, grantees, or agents they have engaged to conduct the CRADA research and development activities to comply with, all applicable Executive Orders, statutes, and HHS regulations relating to research on human subjects (45 C.F.R. Part 46, 21 C.F.R. Parts 50 and 56) and relating to the appropriate care and use of laboratory animals (7 U.S.C. § 2131 et seq.; 9 C.F.R. Part 1, Subchapter A). IC and Collaborator will advise any contractors, grantees, or agents they have engaged to conduct clinical trials for this CRADA that they must comply with all applicable federal regulations for the protection of Human Subjects, which may include the Standards for Privacy of Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. Collaborator agrees to ensure that its employees, contractors, and agents who might have access to a “select agent or toxin” (as that term is defined in 42 C.F.R. §§ 73.4-73.5) transferred from IC is properly licensed to receive the “select agent or toxin”.

 

13.3

Waivers. None of the provisions of this CRADA will be considered waived by any Party unless a waiver is given in writing to the other Party. The failure of a Party to insist upon strict performance of any of the terms and conditions hereof, or failure or delay to exercise any rights provided herein or by law, will not be deemed a waiver of any rights of any Party.

 

13.4	Headings. Titles and headings of the articles and paragraphs of this CRADA are for convenient reference only, do not form a part of this CRADA, and will in no way affect its interpretation.

 

13.5	Severability. The illegality or invalidity of any provisions of this CRADA will not impair, affect, or invalidate the other provisions of this CRADA.

 

13.6

Amendments. Minor modifications to the Research Plan may be made by the mutual written consent of the CRADA Principal Investigators. Substantial changes to the CRADA or extensions of the term will become effective only upon a written amendment signed by the signatories to this CRADA or by their representatives duly authorized to execute an amendment. A change will be considered substantial if it directly expands the range of the potential CRADA Subject Inventions, alters the scope or field of any license option governed by Article 7, or requires a significant increase in the contribution of resources by either Party.

 

 

13.7

Assignment. Neither this CRADA nor any rights or obligations of any Party hereunder shall be assigned or otherwise transferred by either Party without the prior written consent of the other Party, which consent shall not be unreasonably withheld, delayed or conditioned. For the avoidance of doubt, the foregoing limitations shall not apply to the assignment or transfer of this Agreement by Collaborator to an Affiliate in connection with an internal reorganization, and Collaborator will notify IC of such assignment in advance of such reorganization. The Collaborator acknowledges the applicability of 41 U.S.C. § 15, the Anti Assignment Act, to this Agreement. The Parties agree that the identity of the Collaborator is material to the performance of this CRADA and that the duties under this CRADA are nondelegable.

 

13.8

Notices. All notices pertaining to or required by this CRADA will be in writing, signed by an authorized representative of the notifying Party, and delivered by first class, registered, or certified mail, or by an express/overnight commercial delivery service, prepaid and properly addressed to the other Party at the address designated on the Contacts Information Page, or to any other address designated in writing by the other Party. Notices will be considered timely if received on or before the established deadline date or sent on or before the deadline date as verifiable by U.S. Postal Service postmark or dated receipt from a commercial carrier. Notices regarding the exercise of license options will be made pursuant to Paragraph 7.3. Either Party may change its address by notice given to the other Party in the manner set forth above.

 

13.9	Independent Contractors. The relationship of the Parties to this CRADA is that of independent contractors and not agents of each other or joint venturers or partners. Each Party will maintain sole and exclusive control over its personnel and operations.

 

13.10

Use of Name; Press Releases. By entering into this CRADA, the Government does not directly or indirectly endorse any product or service that is or will be provided, whether directly or indirectly related to either this CRADA or to any patent or other intellectual- property license or agreement that implements this CRADA by Collaborator, its successors, assignees, or licensees. Collaborator will not in any way state or imply that the Government or any of its organizational units or employees endorses any product or services. Each Party agrees to provide proposed press releases that reference or rely upon the work under this CRADA to the other Party for review and comment at least five (5) business days before publication. Either Party may disclose the Title and Abstract of the CRADA to the public without the approval of the other Party.

 

13.11

Reasonable Consent. Whenever a Party’s consent or permission is required under this CRADA, its consent or permission will not be unreasonably withheld.

 

13.12

Export Controls. Collaborator agrees to comply with U.S. export law and regulations. If Collaborator has a need to transfer any CRADA Materials made in whole or in part by IC, or IC Materials, or IC’s Confidential Information to a person located in a country other than the United States, to an Affiliate organized under the laws of a country other than the United States, or to an employee of Collaborator in the United States who is not a citizen or permanent resident of the United States, Collaborator will acquire any and all necessary export licenses and other appropriate authorizations.

 

13.13

Entire Agreement. This CRADA constitutes the entire agreement between the Parties concerning the subject matter of this CRADA and supersedes any prior understanding or written or oral agreement.

 

13.14

Survivability. The provisions of Paragraphs 3.3, 3.4, 3.8, 4.2, 4.3, 4.4.2, 5.3, 5.4, 6.1- 9.2, 10.4-10.7, 11.1, 11.2, 12.1-12.3, 13.1-13.3, 13.7, 13.10 and 13.14 will survive the expiration or early termination of this CRADA.

 

SIGNATURES BEGIN ON THE NEXT PAGE

 

 

 

SIGNATURE PAGE

 

ACCEPTED AND AGREED

 

BY EXECUTING THIS AGREEMENT, EACH PARTY REPRESENTS THAT ALL STATEMENTS MADE HEREIN ARE TRUE, COMPLETE, AND ACCURATE TO THE BEST OF ITS KNOWLEDGE. COLLABORATOR ACKNOWLEDGES THAT IT MAY BE SUBJECT TO CRIMINAL, CIVIL, OR ADMINISTRATIVE PENALTIES FOR KNOWINGLY MAKING A FALSE, FICTITIOUS, OR FRAUDULENT STATEMENT OR CLAIM.

 

FOR IC:

 

/s/ Santa Tumminia -S
Santa Tumminia, Ph.D.		Date
Deputy Director, NEI

 

FOR CURATIVE BIOTECHNOLOGY HOLDINGS, INC. (“COLLABORATOR”):

 

/s/ Paul Michaels
Paul Michaels, Chairman		Date
Curative Biotechnology Holdings, Inc.

 

 

CONTACTS INFORMATION PAGE

 

CRADA Notices

 

For NEI:		For Collaborator:
Technology Transfer Specialist		Curative Biotechnology Holdings, Inc.
National Eye Institute		1825 NW Corporate Blvd #110
9609 Medical Center Drive		Boca Raton FL 33431
Room 1-E530		Email: ***@***
Bethesda, MD 20892-9702 MSC 9702		Tel: (240 ###-###-####)
Rockville, MD 20850-9702 (express mail)
Tel: 240 ###-###-####
Fax: 240 ###-###-####

 

Patenting and Licensing

 

For IC:		For Collaborator (if separate from above)
Technology Transfer Center		Curative Biotechnology Holdings, Inc.
National Cancer Institute		1825 NW Corporate Blvd #110
9609 Medical Center Drive		Boca Raton FL 33431
Room 1-E530, MSC 9702		Email: ***@***
Rockville, MD 20892-9702		Tel: (240 ###-###-####)
Tel: 240 ###-###-####
Fax: 240 ###-###-####

 

Delivery of Materials Identified in Appendix B (if any)

 

For IC:		For Collaborator:
National Institutes of Health		Curative Biotechnology Holdings, Inc.
10 Center Drive, MSC 1196, Building 10		1825 NW Corporate Blvd #110
Bethesda, MD 20892-1196		Boca Raton FL 33431
Tel: 301 ###-###-####		Email: ***@***
Email:		Tel: (240 ###-###-####)

 

 

Finances

 

CRADA Funds, Budget Officer, NEI

Building 31 - Claude D. Pepper Building, 6A16 31

Center Dr., MS2510. Bethesda, MD

Phone: 301 ###-###-#### Fax: 301 ###-###-#### E-mail: ***@***

Clinical and Safety Reporting Contacts (as needed for Article 4.4)

 

For IC:

 

National Eye Institute

9609 Medical Center Drive, Room 2W330, MSC 9716

Rockville, MD 20850 (for USPS mail)

Bethesda, MD 20892-9716 (for couriers)

 

 

SUMMARY PAGE

 

EITHER PARTY MAY, WITHOUT FURTHER CONSULTATION OR PERMISSION,
RELEASE THIS SUMMARY PAGE TO THE PUBLIC.

 

TITLE OF CRADA:		Clinical Evaluation of Curative Biotechnology Holdings,
		Inc.’s Proprietary Ocular Metformin Formulation
PHS IC:		National Eye Institute
IC Principal Investigator:		Emily Chew, M.D.
Collaborator:		Curative Biotechnology, Inc.
Collaborator Principal Investigator		Steering committee lead representative Dr. Catherine Sohn
TERM OF CRADA:		Three (3) years from the Effective Date.

 

ABSTRACT OF THE RESEARCH PLAN:

 

Under a Cooperative Research and Development Agreement (CRADA), the National Eye Institute and Curative Biotechnology, Inc. (Curative) will collaborate to evaluate Curative’s proprietary ocular metformin formulation in clinical studies for the treatment of intermediate and late-stage Age-Related Macular Degeneration (AMD) disease.

 

 

APPENDIX A

 

RESEARCH PLAN

 

Title of the CRADA:

 

Clinical Evaluation of Curative Biotechnology, Inc.’s, Proprietary Ocular Metformin Formulation in Age-Related Macular Degeneration

 

National Eye Institute (NEI), National Institutes of Health (NIH) Principal Investigator Emily Chew, M.D., Senior Investigator, and members of the Division of Epidemiology and Clinical Applications (DECA) - Clinical Trials Branch

 

Curative Biotechnology, Inc., Principal Investigator (Steering committee lead representative) Dr. Catherine Sohn.

 

Term of CRADA

Three (3) Years

 

GOAL AND SCOPE OF THIS CRADA

 

The principal goal of this CRADA is to evaluate Curative Biotechnology, Inc.’s (Curative) proprietary ocular metformin formulation (“Test Article”), in a Phase 1 safety trial in patients with Age-related macular degeneration (AMD).

 

The scope of this CRADA, including any clinical studies conducted by Dr. Emily Chew, Senior Investigator, and members of the Division of Epidemiology and Clinical Applications (DECA)- Clinical Trials Branch within the National Eye Institute (NEI), is strictly limited to the development of Curative’s proprietary ocular metformin formulation for the treatment retinal degenerative diseases in humans.

 

INTRODUCTION

 

Numerous diseases cause degeneration of the macular tissue in the retina resulting in vision loss or blindness. Age-related macular degeneration (AMD) is a leading cause of vision loss and blindness in the United States and world-wide. As AMD advances through early to intermediate and late stage (Geographic Atrophy, “GA”) progressive degeneration of macular cells may lead to loss of central vision in one or both eyes. There is no cure for AMD and currently very little that can be done to slow its progression. Potential treatments, such as the metformin therapy proposed under this CRADA study, are being tested to address the unmet need for AMD therapies and possibly other retinal degenerative disease.

 

 

Therapeutic inhibition of progressive cellular dysfunctions might slow retinal degradation in AMD and other disease. Research done at NEI demonstrates that metformin may inhibit RPE epithelial to mesenchymal cell transition, improve RPE differentiation, reduce sub-RPE deposits and ameliorate RPE senescence. However, the approved and available formulations of metformin are for systemic dosage, which carries risks of associated systemic side effects. Metformin is not available in an ocular delivery formulation. Direct ocular delivery of metformin might minimize side effects and more effectively target retinal tissues therapeutically. However, questions remain regarding whether an ocular metformin formulation can be developed that effectively reaches the posterior retinal tissues to produce a therapeutic effect. Curative has developed the only known ocular metformin formulation under a license application with NEI. The availability of the ocular metformin formulation might allow clinical study to determine if the observed effects in the NEI research models of will translate into treatment effects in AMD patients and potentially other retinal disease.

 

EXPERTISE OF THE PARTIES

 

Dr. Emily Chew is a Senior Investigator in Clinical Trials Branch of the Division of Epidemiology and Clinical Applications. Dr. Chew has analyzed, designed, or chaired numerous clinical trials. She is the author of more than 200 research articles based on her studies of retinal disease.

 

Curative Biotechnology Holdings, Inc. (“Curative”), is a publicly traded development-stage biomedical company focusing on novel treatments for rare diseases. Curative has expertise in drug formulation and regulatory approval for commercial drug products. Curative is an exclusive licensee under NIH technology (NIH ref. No E ###-###-####) under License No. L-088-2021-0.¹

 

This CRADA will leverage the expertise and strengths of both Parties to advance the development of Curative’s ocular metformin formulation for the benefit of patients with AMD- related vision loss and potentially other retinal disease.

 

EXPERIMENTAL PLAN

 

The experimental details that follow are approximate and may be changed upon mutual agreement of the NEI and Curative. Any substantive change to the Research Plan will be by mutual agreement and written Amendment to this CRADA.

 

Parties will work together to review and discuss preclinical pharmacology and toxicology data for the ocular metformin formulation. Under guidance of Dr. Chew, the Parties will coordinate and plan activities for clinicals safety studies.

 

Curative will supply ocular metformin drug to the NEI in amounts sufficient to complete a clinical safety trial lead by Dr. Chew. Curative will be responsible for any coordination of manufacture of the ocular metformin to supply for the trials. Dr. Chew will be responsible for study design and study activities. The supply of metformin for the studies is generally anticipated to be formulated as follows: [***]

 

1 Note: Curative was formerly doing business as Connectyx Technologies Holdings Group, Inc. before changing names to Curative in 2020.

 

 

The Active Product Ingredient (API) are expected to be sourced from [***] and to comply with quality attributes for metformin hydrochloride USP monograph and the documented certificate of analysis with a drug master file registration [***].

 

NEI will conduct any clinical studies in accordance with NIH policies and NIH Internal Review Board approved protocols, as may be amended from time-to-time. It is expected that the clinic safety study may consist of up to [***] patients diagnosed with intermediate and Geographic Atrophy disease. Dosing is expected to be [***], with [***] of observation. Blood samples may be collected for from the patients for testing and analysis.

 

DESCRIPTION OF THE CONTRIBUTIONS AND RESPONSIBILITIES OF THE PARTIES

 

NEI

 

	●	[***]
	●	[***]
	●	[***]
	●	[***]
	●	[***]

 

COLLABORATOR

 

	●	[***]
	●	[***];
	●	[***]

	○	[***]
	○	[***]

●

[***]

 

COLLABORATOR AND NEI

 

	●	[***]
	●	[***]
	●	[***]

 

 

RELATED, ACTIVE NIH AND COLLABORATOR AGREEMENTS

 

Exclusive patent license No. L-088-2021-0

 

RELATED INTELLECTUAL PROPERTY OF THE PARTIES

 

Collaborator Patents and Patent Applications:

 

●

(Curative – as licensee under L-088-2021-0)

 

NEI Patent Applications

 

●

Licensed under L-088-2021-0:

 

	○	US provisional patent application 62/899,899 “Druggable Target to Treat Retinal Degeneration” [NIH Ref. No. E ###-###-####-0-US-01]
	○	PCT/US2020/050540 “Druggable Target to Treat Retinal Degeneration” filed September 11, 2021 [NIH Ref. No. E ###-###-####-0-PCT-02]

 

 

APPENDIX B

 

STAFFING, FUNDING AND MATERIALS/EQUIPMENT CONTRIBUTIONS OF THE PARTIES

 

Staffing Contributions

 

IC will provide scientific staff and other support necessary to conduct the research and other activities described in the Research Plan. IC’s scientific staff will include IC’s Principal Investigator and technical staff.

 

IC estimates that [***] of effort per year will be required to complete the CRADA research.

 

Collaborator estimates that [***] of effort per year will be required to complete the CRADA research.

 

Funding Contributions

 

Collaborator agrees to provide research support of up to twenty-three thousand US dollar ($23,000) per patient, not to exceed one-hundred and fifteen thousand dollars ($115,000) in total funding under this CRADA, to cover research activities under the CRADA including but not limited to:

 

	○	Required patient travel and recruitment
	○	Patient blood sample storage,
	○	Project support personnel

 

Funding payment to NEI will be due within thirty (30) days from invoice received from the NEI.

 

CRADA PAYMENTS:

All CRADA payments will be made via wire transfer and will reference “CRADA 03434

CRADA title: “Clinical Evaluation of Curative Biotechnology, Inc.’s, Proprietary Ocular Metformin Formulation in Age-Related Macular Degeneration and Collaborator will provide notice of payment to:

 

CRADA Funds, Budget Officer, NEI

Building 31 - Claude D. Pepper Building, 6A16 31

Center Dr., MS2510. Bethesda, MD

Phone: 301 ###-###-#### Fax: 301 ###-###-#### E-mail: ***@***

 

CRADA TRAVEL PAYMENTS:

 

Travel arrangements for all Government staff will be made in accordance with the Federal Travel Rules and Regulations, whether arranged by IC and funded using either appropriated funds or CRADA funds or arranged and funded directly by Collaborator.

 

Materials/Equipment Contributions

 

IC will provide the following IC Materials for use under this CRADA: [***].

 

Collaborator will provide the following [***] for use under this CRADA:

 

Test Article: [***]

 

Collaborator Materials: [***]

 

Capital Equipment: [***]

 

If either Party decides to provide additional Materials for use under this CRADA, those Materials will be transferred under a cover letter that identifies them and states that they are being provided under the terms of the CRADA.