Exhibit
10.28


 


PUBLIC
HEALTH SERVICE


 


COOPERATIVE
RESEARCH AND DEVELOPMENT AGREEMENT


 


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 Center for Advancing Translational Sciences (NCATS) an Institute or Center (hereinafter referred to as the “IC”)
of the

NIH


and


 


VIRPAX
Pharmaceuticals Inc.,

hereinafter referred to as the “Collaborator”,


having
offices at 1554 Paoli Pike, #279 | West Chester, PA 19380,

created and operating under the laws of Delaware.


 




     


     


    




 


COOPERATIVE
RESEARCH AND DEVELOPMENT AGREEMENT


 


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. Any changes to the model CRADA are set forth in Appendix
C.


 


NCATS
personnel will be working diligently to characterize the agents provided to them with the goal of making them viable clinical
candidates. In the course of that work it is likely that NCATS personnel may make patentable inventions based on the agents or
their method of use. The parties agree and understand that the NCATS/NIH as a U.S. Federal Government lab will own a sole interest
in sole inventions and a joint interest in joint inventions, where inventorship will be determined by U.S. patent law, regardless
of the collaborator’s ownership interest in the agent itself or patents directed to it.


 


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.


 


		2.1	“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.



 


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



 


		2.2.1	“Background
                                         Data and Information” means all data and information owned by or in the possession
                                         of the CRADA Collaborator that is related to the CRADA Research Plan. This may include,
                                         but is not limited to, safety, toxicity, ADME, and/or animal data.



 


		2.3	“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.



 






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		2.4	“Confidential
                                         Information” means confidential scientific, business, or financial 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.



 


		2.5	“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.



 


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



 


		2.7	“CRADA
                                         Materials” means all tangible materials first produced in the performance of
                                         the Research Plan other than CRADA Data.



 


		2.8	“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.



 


		2.9	“Effective
                                         Date” means May 06, 2020, the effective date of the Letter of Intent, which
                                         was signed by the Parties.



 


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



 


		2.11	“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.



 


		2.12	“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.



 


		2.13	“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.



 


		2.14	“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.



 


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



 






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		2.16	“Research
                                         Plan” means the statement in Appendix A of the respective research and development
                                         commitments of the Parties.



 


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 this Agreement. The PIs will be responsible
                                         for 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.



 


All
Parties acknowledge and agree that IC may share Collaborator Materials and Collaborator Confidential Information with the NCATS
Therapeutic Development Branch’s (TDB) prime contractor or its subcontractors in fulfillment of the CRADA Research Plan.
The TDB prime contractor is subject to a Determination of Exceptional Circumstances (35 U.S.C. § 202(a)(ii)) under the Bayh-Dole
Act, which obligates it to assign inventions made by its employees to the United States Government. To the extent that subcontractors
of the NCATS TDB prime contractor use Collaborator Materials, or Collaborator Background Information and/or Data or any materials
or information which is proprietary to the CRADA Collaborator in fulfillment of the CRADA Research Plan, the subcontractor is
thereby subject to a Determination of Exceptional Circumstances (35 U.S.C. § 202(a)(ii)) under the Bayh-Dole Act. Accordingly
the said subcontractor is obligated to assign inventions made by its employees arising from such use of materials or information
which is proprietary to the CRADA Collaborator, Collaborator Materials, Collaboration Background Information and/or Data to the
United States Government. For the purposes of this Agreement, such inventions will be considered jointly developed “CRADA
Subject Inventions” and will be jointly owned by Collaborator and IC.


 


		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,
                                         not to transfer these materials to third parties except in accordance with the Research
                                         Plan 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.



 






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		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 Paragraphs 2.4, 8.3, and 8.4.



 


Article
4. Reports


 


		4.1	Interim
                                         Research and Development Reports. The PIs should exchange information quarterly,
                                         in writing. This exchange may be accomplished through meeting minutes, annual reports,
                                         detailed correspondence (including e-mail), and circulation of draft manuscripts. Additionally,
                                         quarterly meeting of the PI’s will be held for the purpose of identifying new CRADA
                                         Subject Inventions and putative inventors that may have arisen from the work being conducted
                                         under the Research Plan.



 


		4.2	Final
                                         Research and Development Reports. The Parties will exchange final reports of their
                                         results within forty-five (45) days 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	Additional
                                         Reports. The Collaborator will be expected to report to the ICD certain FDA milestones
                                         it achieves (such as IND filing, Phase 1, 2 and 3 Trials, etc.) and other major business
                                         related events. Other major business related events, may include but are not limited
                                         to, third party alliances to co-develop the lead compound, change in the development
                                         of indication stated in the CRADA Research Plan.



 


		4.4	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.



 


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.



 






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		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 producing Party will retain sole
                                         ownership of and title to all CRADA Subject Inventions, 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 copies of CRADA Data 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
                                         inventorship, 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.



 






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		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. 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 [INSERT into Agency’s
                                         model as appropriate: National Institutes of Health, Food and Drug Administration, Centers
                                         for Disease Control and Prevention], 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.



 






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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. 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. 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.



 






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		7.6	Third
                                         Party License. Pursuant to 15 U.S.C. § 3710a(b)(1)(B), if PHS grants 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 the 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, before the Effective Date,
                                         PHS had filed a Patent Application and has either offered or granted a license or has
                                         executed 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.



 


		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 Collaborator agrees to share all CRADA Background Information and
                                         Data in its possession with IC. 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.



 


		(a)	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. All CRADA Data will be managed and disseminated in accordance with the NIH HEAL Data Policy
https://heal.nih.gov/about/public-access-data


 






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		(b)	CRADA
                                         Materials.



 


Collaborator
and IC will use reasonable efforts to keep descriptions of CRADA Materials confidential until published or until corresponding
Patent Applications are filed. Collaborator acknowledges that the basic research mission of PHS includes sharing with third parties
for further research those research resources made in whole or in part with NIH funding. Consistent with this mission and the
tenets articulated in “Sharing of Biomedical Research Resources: Principles and Guidelines for Recipients of NIH Research
Grants and Contracts”, December 1999, available at http://www.ott.nih.gov/policy/research_tool.aspx, following publication
either Party may make available to third parties for further research those CRADA Materials made jointly by both PHS and Collaborator.
Notwithstanding the above, if those joint CRADA Materials are the subject of a pending Patent Application or a Patent, the Parties
may agree to restrict distribution or freely distribute them. Either Party may distribute those CRADA Materials made solely by
the other Party only upon written consent from that other Party or that other Party’s designee.


 


		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 such 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.






 






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		8.5	Protection
                                         of Human Subjects’ Information. The research and development activities to
                                         be conducted under this CRADA are not intended to involve human subjects or human tissues
                                         within the meaning of 45 C.F.R. Part 46 and 21 C.F.R. Part 50. Should it become necessary
                                         to utilize human subjects or human tissues, or to provide a Party with access to information
                                         about identifiable human subjects, the Parties agree to amend this CRADA in accordance
                                         with Paragraph 13.6 to ensure that the research and development activities conducted
                                         hereunder will conform to the appropriate federal laws and regulations, including but
                                         not limited to all applicable FDA regulations and HHS regulations relating to the protection
                                         of human subjects.





 


		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 Paragraph 2.4 or three (3) years
                                         after the expiration or termination date of this CRADA. 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. Authorship and
other matters relating to publications shall be as set forth in the Uniform Requirements for Manuscripts Submitted to Biomedical
Journals of the International Committee of Major Journal Editors (http://www.icmje.org/). 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, the other Party will have thirty (30) days to review the proposed publication or disclosure 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 thirty (30) additional days as necessary to file a Patent Application. Any public disclosures in relation
to this agreement must acknowledge the support and funding of the NIH HEAL Initiative.



 


Article
9. Representations and Warranties


 


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



 


		(a)	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.



 


		(b)	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.



 






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



 


		(a)	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.







 


		(b)	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.



 


		(c)	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.



 


Article
10. Expiration and Termination


 


		10.1	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.



 


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



 


		10.3	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. Reasons for unilateral termination
                                         may include but are not limited to failure to meet or complete project milestones, failure
                                         to disclose all safety and toxicity data related to the project.



 


		10.4	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.



 


		10.5	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.



 






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Article
11. Disputes











 


		11.1	Settlement.
                                         Any dispute arising under this CRADA which is not disposed of by agreement of the 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.



 






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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 their
                                         contractors and agents to comply with, all applicable statutes, Executive Orders, HHS
                                         regulations, and all FDA, CDC, and NIH policies 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). Additional information on these subjects is available from the HHS Office
                                         for Human Research Protections or from the NIH Office of Laboratory Animal Welfare. Collaborator
                                         agrees to ensure that employees, contractors, and agents of Collaborator 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 Principal Investigators. Substantial changes to the CRADA, extensions of the term,
                                         or any changes to Appendix C 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. 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.






 






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		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 service. 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 seven (7) days prior to
                                         publication. Either Party may disclose the Summary Page 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, 4.2, 4.3, 5.3, 5.4, 6.1-9.2, 10.3-10.5, 11.1,
                                         12.1-12.3, 13.1-13.3, 13.10 and 13.14 will survive the expiration or early termination
                                         of this CRADA.



 


SIGNATURES
BEGIN ON THE NEXT PAGE


 




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Public
Health Service


Cooperative
Research and Development Agreement


 


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:	 	 
	 	 	 
	 	 	 
	Signature	 	Date
	 	 	 
	 	 	 
	Typed Name	 	 
	 	 	 
	 	 	 
	Title	 	 
	 	 	 
	FOR COLLABORTOR:	 	 
	 	 	 
	 	 	 
	Signature	 	Date
	 	 	 
	 	 	 
	Typed Name	 	 
	 	 	 
	 	 	 
	Title	 	 





 




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Research and Development Agreement




 


CONTACTS
INFORMATION PAGE


 


CRADA
Notices


 


	For IC:	For Collaborator:
	 	 
	Lili Portilla, MPA	Shana Panzarella Director of Strategic
	Alliances, NCATS	Chief of Staff
	9800 Medical Center Drive, Room 3042B	1554 Paoli Pike, PMB 279
	 	West Chester, PA 19380
	Tel:  301-827-7170	Tel/Fax:  484-880-4588
	Email: lilip@nih.gov	Email: spanzarella@virpaxpharma.com









 


Patenting
and Licensing


 


	For IC:	For Collaborator (if separate from above):
	 	 
	Tel: 301-827-4301	Tel: 484-880-4588
	Email: kenxeo@aol.com	 






 


Delivery
of Materials Identified In Appendix B (if any)


 





	For IC:	For Collaborator:
	 	 
	Junfeng Huang, PhDp	Anthony Mack, Chairman & CEO
	NCATS, NIH	1554 Paoli Pike, PMB 279
	9800 Medical Center Drive, 224W	West Chester, PA 19380
	Rockville, MD 20892-3370	 
	Tel:  301.827.7162 (JH); 301.827.0980 (SH)	Tel/Fax: 484-880-4588
	Email: Junfeng.Huang@nih.gov;	Email: amack@virpaxpharma.com
	sharie.haugabook@nih.gov	 


 










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Health Service


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Research and Development Agreement


 


SUMMARY
PAGE


 


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


 


TITLE
OF CRADA: Fast, Centrally-Acting, Non-Addicting Novel Analgesic for Chronic Non-Cancer Pain


 





	PHS [IC] Component:	NCATS
	IC Principal Investigator:	Donald Lo, Ph.D.
	 	 
	Collaborator:	Virpax Pharmaceuticals, Inc
	Collaborator Principal Investigator:  	Jeffrey Gudin, MD
	TERM OF CRADA:	Four (4) years from the Effective Date.





 


ABSTRACT
OF THE RESEARCH PLAN:


 


Americans
are faced with a dual crisis of chronic pain and an opioid abuse epidemic. The development of an effective analgesic with rapid
onset for the treatment of pain that is devoid of the common side effects that are often associated with the use of the highly
prescribed mu-opioid receptor agonists is a priority for our healthcare system. Having such an analgesic with this product profile
has the potential to alleviate suffering and reduce dependence on mu-opioid based analgesics which contribute to misuse, abuse,
and overdose related deaths due to severe respiratory depression. Another endogenous opioid system, the enkephalins, preferentially
bind to delta-opioid receptors and are able to produce analgesic benefit without the associated respiratory depression typically
noted from mu-opioid receptor binding, and as an additional benefit, is also thought to play an important role in emotional reactivity
and mood disturbance which often accompanies chronic painful disorders. Unfortunately, systemically administered enkephalins are
prevented from reaching the brain by both rapid enzymatic degradation and the blood-brain-barrier, even with the use of various
penetration enhancers, preventing their development as patient-available pain therapy. This CRADA between the NIH/NCATS and Virpax
Pharmaceuticals focuses on the characterization of NES100, a fast, centrally acting, non-addicting analgesic. In the NES100 formulation,
the active pharmaceutical ingredient is the endogenous peptide Leu Enkephalin (L-ENK) whose molecules are encapsulated utilizing
a proprietary nanoparticle “molecular envelope technology” or MET. The polymer used to make the nanoparticles confers
a positive surface charge to the nanoparticles which allows it to stick to and integrate into mucosal surfaces present in the
nasal cavity upon intranasal administration. This “mucointegration” is expected to enhance the residence time of the
nanoparticulate peptide in the nares, enabling the prolonged delivery of L-ENK. The polymer nanoparticles encapsulating L-ENK
is then able to transport L-ENK exclusively to the brain via the intranasal route with essentially no peripheral exposure. The
scope of this project plan includes studies that are focused on the pre-clinical characterization of NES100 as a novel analgesic
for acute and chronic non-cancer pain.


 




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APPENDIX
A


 


RESEARCH
PLAN


 


I. Abstract
of the Research Project – for Public Release


 


Either
party may, without further consultation or permission, release this ABSTRACT to the public.


 


Americans
are faced with a dual crisis of chronic pain and an opioid abuse epidemic. The development of an effective analgesic with rapid
onset for the treatment of pain that is devoid of the common side effects that are often associated with the use of the highly
prescribed mu-opioid receptor agonists is a priority for our healthcare system. Having such an analgesic with this product profile
has the potential to alleviate suffering and reduce dependence on mu-opioid based analgesics which contribute to misuse, abuse,
and overdose related deaths due to severe respiratory depression. Another endogenous opioid system, the enkephalins, preferentially
bind to delta-opioid receptors and are able to produce analgesic benefit without the associated respiratory depression typically
noted from mu-opioid receptor binding, and as an additional benefit, is also thought to play an important role in emotional reactivity
and mood disturbance which often accompanies chronic painful disorders. Unfortunately, systemically administered enkephalins are
prevented from reaching the brain by both rapid enzymatic degradation and the blood-brain-barrier, even with the use of various
penetration enhancers, preventing their development as patient-available pain therapy. This CRADA between the NIH/NCATS and Virpax
Pharmaceuticals focuses on the characterization of NES100, a fast, centrally acting, non-addicting analgesic. In the NES100 formulation,
the active pharmaceutical ingredient is the endogenous peptide Leu Enkephalin (L-ENK) whose molecules are encapsulated utilizing
a proprietary nanoparticle “molecular envelope technology” or MET. The polymer used to make the nanoparticles confers
a positive surface charge to the nanoparticles which allows it to stick to and integrate into mucosal surfaces present in the
nasal cavity upon intranasal administration. This “mucointegration” is expected to enhance the residence time of the
nanoparticulate peptide in the nares, enabling the prolonged delivery of L-ENK. The polymer nanoparticles encapsulating L-ENK
is then able to transport L-ENK exclusively to the brain via the intranasal route with essentially no peripheral exposure. The
scope of this project plan includes studies that are focused on the pre-clinical characterization of NES100 as a novel analgesic
for acute and chronic non-cancer pain.


 




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II. Goal(s)
of Project


 


Goals
of the project include:


		●	Project
                                         Planning / Initiation / CRADA execution



		●	Non-cGMP
                                         and cGMP manufacture of NES100 (medicinal product and device) and API stability studies



		●	Formulation
                                         development, fill / finish, and stability studies



		●	Development
                                         or optimization & qualification and/or validation of new or existing assays and associated
                                         analytical methods required for characterization of NES100



		●	Bioanalytical
                                         assay development and qualification and/or validation



		●	Pre-clinical
                                         PK studies in species planned for use in efficacy and safety evaluations



		●	PK/PD
                                         studies in efficacy models in Sprague Dawley rats



		●	IND
                                         enabling Toxicology and Safety Pharmacology studies



 


For
avoidance of doubt, the scope of the CRADA Research Plan is limited to tasks / studies that are focused on the pre-clinical development
of NES100 for the management of acute and chronic, non-cancer pain.


 


III. Background


 


Chronic
pain is among the most common reasons for seeking medical attention and is reported by 20 - 50%of patients seen in primary care.
While the CDC in their 2016 Guidelines (Dowell et al., 2016) recommends initial treatment of non-cancer chronic pain with acetaminophen
and NSAIDs, these agents feature black box warnings for serious cardiovascular and gastrointestinal adverse events, and acetaminophen
has known hepatotoxicity. Most notably, both classes of analgesics have documented limited efficacy. Opioids are effective, but
their associated tolerance, dependence and euphoria has contributed to the current abuse epidemic, and their respiratory depressant
actions contribute to significant abuse-related mortality. Development of a fast-acting, highly effective analgesic for the treatment
of non-cancer chronic pain that is devoid of the common, well- recognized side effects of opioids which act predominantly at mu
(μ)-opioid receptors, is therefore a priority to break the cycle of pain-prescription-dependence-overdose.


 


Naturally
occurring endorphins bind to μ-opioid receptors and act as a key molecular switch, triggering brain reward systems and potentially
initiating addictive behaviors. Another endogenous opioid system, i.e. the enkephalins, preferentially bind to delta (δ)-opioid
receptors (Toll et al., 1998) to produce analgesic benefits without the associated respiratory depression typically noted from
μ-opioid receptor binding. In addition, δ-opioid receptor is thought to play an important role in emotional reactivity
and mood disturbance which often accompanies chronic painful disorders. Unfortunately, systemically administered enkephalins are
prevented from reaching the brain by both rapid enzymatic degradation and the blood- brain-barrier (BBB) (Lalatsa et al., 2014),
even with the use of various penetration enhancers (Lalatsa et al., 2012), preventing their development as patient-available pain
therapy. Therefore, new methods of enkephalin delivery must be developed and investigated to devise novel, non-addictive pain-relieving
therapies.


 






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NES100
is a microparticulate dosage form of leucine-5- enkephalin (L-ENK) prepared by the encapsulation of L-ENK in an IP-protected molecular
envelope technology (MET), aka GCPQ (N-palmitoyl-N-monomethyl-N, N-dimethyl-N, N, N-trimethyl-6-O-glycolchitosan), which is a
modified amphiphilic chitosan derivative polymer that self-assembles in aqueous media. The polymer used to make the nanoparticles
confers a positive surface charge to the nanoparticles and the particles stick to and integrate into mucosal surfaces present
in the nasal cavity. This “mucointegration” is believed to enhance the residence time of the nanoparticulate peptide
in the nares, enabling the prolonged delivery of L-ENK. The polymer nanoparticles encapsulating L-ENK is then able to transport
L-ENK exclusively to the brain via the intranasal route with essentially no peripheral exposure.


 


Efficacy
studies have shown that NES100 is active in several animal models of acute and chronic pain. The collaboration is focused on investigational
new drug (IND) studies and the output of this project will be a data package suitable for an IND application to the US FDA.


 


IV. Respective
Contributions of the Parties


 


Virpax’s
Responsibilities


 


Protocols
/ Reagents for TRND:


		1.	MET
                                         GLP toxicology reports



		2.	NES100
                                         (medicinal product and device) manufacturing protocol



		3.	MET,
                                         LENK & MET L-ENK (NES100) for method development / validation, efficacy, and PK/TK
                                         studies



 


Preclinical
IND Enabling Tasks/Studies:


		1.	pIND
                                         meeting minutes



		2.	Archive
                                         preclinical data and biological samples



 


Other
Related Tasks/Studies:


		1.	Preparation
                                         of Investigator’s Brochure



		2.	Preparation
                                         of First-in-Human (i.e. SAD/MAD) clinical protocol and associated model ICF



		3.	Preparation
                                         of IND application for filing and submission



 






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Research and Development Agreement


 





NCATS
’Responsibilities


 


Preclinical
IND Enabling Tasks/Studies:


		1.	Acute
                                         and/or chronic pain efficacy study in rats



		2.	In
                                         vitro Safety screen panel for GPCRs and ion channels



		3.	Qualified
                                         Bio A method transfer for plasma (tox species) and method development for human plasma



		4.	ADA
                                         assay development in tox species and human plasma






		5.	In
                                         vitro ADME studies



		6.	GMP
                                         manufacture of MET and LENK



		7.	Formulations:
                                         Dosage form optimization /manufacturing and stability studies of NES100 and MET for intranasal
                                         administration.



		8.	GLP
                                         Toxicology / Safety Pharmacology studies of NES100 and a single arm of MET



 


Other
Related Tasks/Studies:


		1.	N/A



 


Joint
Collaborator’s NCATS’ Responsibilities


 


All
Parties will mutually agree on the CRADA Research Plan strategy for the preclinical development of NES100 as an intranasally administered
treatment for chronic, non-cancer pain.


 


The
Parties will also review and interpret the results of any in vitro and in vivo studies, biomarker research, and
mechanistic studies of these therapeutic molecules


 


V. Material
Contributed by NCATS


 


		1.	N/A



 


VI. Material
Contributed by Collaborator


 


		1.	MET,
                                         LENK & MET L-ENK (NES100) for method development / validation, efficacy, and PK/TK



 






    	PHS CRADA	Agreement Ref. No. 2020-12	MODEL ADOPTED June 18, 2009
	Page 22 of 26	Confidential	Revised August 1, 2012



     


    




 


Public
                                         Health Service


Cooperative
Research and Development Agreement



 


VII. Experimental
Plan


 


		1.	Project
Planning / Initiation









	Project Award	04/16/2020
	Gap Analysis / Project Plan Draft	Q2 2020
	Project Plan Execution/CRADA Agreement	Q3 2020





 


		2.	In
vitro Potency






	In vitro safety screen for GPCRs & ion channels on up to 125 targets	Q3 2020






 


		3.	PD-Efficacy
/ Biomarker






	PD-Efficacy studies in Sprague Dawley rats	Q3/4 2020









 


GO/No
GO Decision


No
GO: Lack of efficacy in all animal pain models.


 


		4.	Bioanalytical
Method Development (Human)









	Reagent generation	Q3 2020
	ADA Assay Development (human)	Q4 2020
	Bioanalytical method dev for LENK for human plasma	Q2 2021





 


GO/No
GO Decision


No
GO: No reliable and sensitive bioanalytical method can be developed.


 


		5.	CMC-
Process






GMP
manufacture of LENK:








	Contracting cGMP batch LENK (1 Kg) (est. 3 month	Q2 2020
	Process development, 20 g demo-batch, and qualification of analytical methods for lot release and stability studies (est.2 month)	Q4 2020
	cGMP run and delivery of 1.0 Kg LENK including Certificate of Analysis, MSDS for toxicology studies and Phase I clinical study (est. 3 month)	Q1 2021
	Initiation of stability study (3-year)	Q2 2021
	Technology Transfer for all CMC elements	Q2 2021








 


GMP
manufacture of MET (GCPQ):








	Contracting cGMP batch MET (1.5 Kg) (est. 5-months)	Q4 2020
	Tech transfer and familiarization (est. 2-months)	Q4 2020
	Process development, 50g Demo Batch, and qualification of analytical methods for lot release and stability (est. 3-months)	Q4 2020/Q1 2021
	cGMP run and delivery 1.5 Kg MET including Certificate of Analysis, MSDS for toxicology studies and Phase I clinical study, and initiation of stability study (est. 2-months)	Q2 2021
	Initiation of stability study (3-year)	Q2 2021
	Technology Transfer for all CMC elements	Q3 2021





 


GO/No
GO Decision


No
GO: Manufacturing failure due to inherent process scalability issues.


 






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	Page 23 of 26	Confidential	Revised August 1, 2012



     


    

 


Public
Health Service


Cooperative
Research and Development Agreement





 





		6.	Toxicology
/ Safety Pharmacology (IND-Enabling)



 





	BioA method transfer/val. (LENK) & MET & ADA method dev	Q3 2020
	Non GLP ADME assays	Q1/2 2021
	Non-GLP 14-day intranasal (NES100) toxicology study in adult rats	Q1/2 2021
	Non-GLP 14-day intranasal (NES100) toxicology study in adult dogs	Q1/2 2021
	GLP in-vitro genetic toxicity studies (NES100) (Ames & Chromosome aberration)	Q4 2021
	GLP 28-day repeat dose intranasal (NES100) toxicology study with a MET arm in adult rats (including Micronucleus and FOB CNS safety pharm)	Q4 2021
	GLP 28-day repeat dose (NES100) intranasal toxicology study with a MET arm in adult dogs	Q4 2021
	GLP intranasal single dose (NES100) pulmonary and cardiovascular safety pharm in adult dogs	Q4 2021
	GLP 28-day repeat dose intravenous toxicology study (NES100) in adult rats (as needed)	Q4 2021















 


GO/No
GO Decision


GO:
Acceptable toxicity profile and adequate margin of safety based on the completed work package above would help determine path
forward for the further development of NES100 for the treatment of pain.


No
GO: Unacceptable toxicity or safety profile to enable clinical dosing.


 


		7.	CMC-
Formulation






	Analytical method transfer and validation on NES-100	Q4 2020
	Process development, 50g demonstration run	Q1/2 2021
	GMP Manufacture of the NES100 intranasal dosage forms (drug product – device combination)	Q2/3 2021
	Initiation of ICH stability study on NES100 in device up to 24 months	Q3 2021








 


GO/No
GO Decision


No
GO: Inability to manufacture the NES100 dosage form.


 





		8.	Regulatory





 





	*IND Filing	Q4 2022
	*Dependent upon the successful completion of all IND-enabling studies and assumes that preclinical planning for the IND-enabling studies begins in Q2 2020.	 


 








 




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	Page 24 of 26	Confidential	Revised August 1, 2012



     


    

 


Public
Health Service


Cooperative
Research and Development Agreement



 


APPENDIX
B


 


STAFFING,
FUNDING, AND MATERIALS/EQUIPMENT CONTRIBUTIONS

OF THE PARTIES


 


Staffing
Contributions: Not Applicable


 


Funding
Contributions: No Funds are being exchanged


 


Not
applicable


 


CRADA
Travel Payments: No travel Payments are being contributed by Collaborator


 


Materials/Equipment
Contributions:


 


IC
will provide to Collaborator the following IC Materials for use under this CRADA: None


 


Collaborator
will provide to IC the following Collaborator Materials and/or capital equipment for use under this CRADA:


 


Collaborator
Materials: MET, LENK & MET L-ENK (NES100) for method development / validation, efficacy, and PK/TK.


 


Capital
Equipment: Not Applicable


 


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.


 




    	PHS CRADA	Agreement Ref. No. 2020-12	MODEL ADOPTED June 18, 2009
	Page 25 of 26	Confidential	Revised August 1, 2012



     


    




 


Public
Health Service


Cooperative
Research and Development Agreement



 


APPENDIX
C


 


MODIFICATIONS
TO THE MODEL CRADA


 


 





	PHS CRADA	Agreement Ref. No. 2020-12	MODEL ADOPTED June 18, 2009
	Page 26 of 26	Confidential	Revised August 1, 2012