Document:

ALLONGE
      TO SERIES A CONVERTIBLE NOTE

     

    This
      Allonge (the “Allonge”), dated August 8, 2006, attached to and forming a part of
      the Series A Convertible Note, dated February 15, 2006 (collectively, the
“Note”), made by NEW CENTURY COMPANIES, INC., a Delaware corporation (the
“Company”), payable to the order of MOTIVATED MINDS, LLC, an Arizona limited
      liability company (the “Holder”), in the original principal amount of
      $300,000.

    

    1.
      Paragraph 3 of the Note is hereby amended and restated in its entirety as
      follows:

    

    3.
      Pre-Payments and Maturity Date. This Note shall be due and payable, including
      all accrued Interest thereon, as follows: (i) $150,000 on August 16, 2006 and
      (ii) $150,000 on October 16, 2006. Each of these dates is referred to as the
      “Maturity Date.” At any time on or prior to the Maturity Date, the Company shall
      have the right to prepay this Note, in whole or in part without penalty, on
      ten
      (10) days’ advance notice to Holder and subject to the right of Holder to
      convert in advance of such prepayment date and provided that on such prepayment
      date, the Company will pay in respect of the redeemed Note cash equal to the
      face amount plus accrued Interest on the Note (or portion thereof) redeemed
      at
      that point. The Company will pay this Note to the extent of the proceeds of
      the
      next debt or equity financing that the Company closes after the Issue Date,
      including but not limited to any financing arranged by Ascendiant Securities,
      LLC.

    

    2.
      The
      following is hereby added as subparagraph 4.3 to Paragraph 4, “Fees,” of 
the
      Note:

    

    4.3
      Extension Fees and Expenses. The Company will issue 45,000 restricted shares
      of
      its Common Stock to Holder as an extension fee for Holder to extend the original
      maturity date of May 16, 2006 to the new Maturity Date set forth in this
      Allonge. The Company shall also pay Source Capital Group, Inc. a fee of $3,000
      and shall reimburse $500 of legal fees of Holder (payable to Quarles & Brady
      Streich Lang LLP) in connection with the extension of the original maturity
      date
      on the date of this Allonge.

    

    3.
      The
      term “Maturity Date” in Paragraph 23, “Definitions,” is amended and restated in
      its entirety as follows:

     

    The
      “Maturity Date” means each of the dates set forth in Paragraph 3, “Pre-payments
      and Maturity Date.” 

    

    4.
      In all
      other respects, the Note is confirmed, ratified, and approved and, as amended
      by
      this Allonge, shall continue in full force and effect.

     

    
      
        
        

      

      
        
        

        
          

        

      

      
        
        

      

    

     

    IN
      WITNESS WHEREOF, the Company and Holder have caused this Allonge to be executed
      and delivered by their respective duly authorized officers as of the date and
      year first above written. 

     

    
      	
              NEW
                CENTURY COMPANIES, INC.

            	 	 	 
	 	 	 	 
	
              /s/ David
                Duquette

            	 	 	 
	
              
By:
              David Duquette	 	 	
            
	Its: President	 	 	 

    

    
       

      
        Accepted
          and agreed to:

         

      

      
        	
                
                  MOTIVATED
                    MINDS, LLC

                

              	 	 	 
	 	 	 	 
	
                /s/ Ira
                  Gaines

              	 	 	 
	
                
By:
                Ira Gaines	 	 	
              
	Its: President	 	 	 

      

       

      
        
          
          

        

          -2-AMENDMENT
      TO REGISTRATION RIGHTS AGREEMENT

    

    This
      Amendment (the “Amendment”) is made and entered into effective as of August 8,
      2006, between New Century Companies, Inc., a Delaware corporation (the
“Company), and Motivated Minds, LLC., an Arizona limited liability company
      (“Motivated Minds”). All capitalized terms in this Amendment shall have the same
      meanings as such terms have in the Registration Rights Agreement, dated as
      of
      February 15, 2006, between the foregoing parties (the “Agreement”).

    

    RECITALS

    

    WHEREAS,
      the Company desires to amend the Agreement in accordance with the terms set
      forth in this Amendment.

    

    NOW
      THEREFORE, in consideration of the foregoing and of the mutual promises and
      conditions set forth, the parties agree as follows:

    

    AGREEMENT

    

    1.
      The
      following subparagraph 1.5 is added to Paragraph 1, “Piggyback Registration,”of
      the Agreement as follows:

    

    1.5
      The
      Company has filed a Piggyback Registration under this Paragraph 1, “Piggyback
      Registration,” in which it has included the Registrable Securities of the
      Holders. The Company shall amend such Piggyback Registration within a reasonable
      period of time of its being declared effective to include an additional 45,000
      restricted shares of Common Stock it issued to Motivated Minds in connection
      with an extension of the Note and the Warrant Shares of Richard Kelly, a
      designee of Source Capital Group, Inc. The Company will use its best efforts
      to
      cause such amendment to become effective. If such Registration Statement cannot
      be amended for any reason, the Company will file a new Registration Statement
      with the Securities and Exchange Commission within a reasonable period of time
      of its first Piggyback Registration being declared effective. Such new
      Registration Statement will be treated as a “Piggyback Registration” for
      purposes of this Agreement. The Company will use its best efforts to cause
      such
      new Registration Statement to become effective. 

    

    2.
      This
      Amendment shall become effective on the date written above. 

     

    3.
      The
      Agreement shall be deemed amended to the extent set forth in this Amendment.
      The
      Agreement, as amended by the Amendment, shall constitute one agreement. All
      other terms and provisions of the Agreement shall remain in full force and
      effect. If there is any inconsistency with the terms of the Agreement and the
      Amendment, the terms of the Amendment shall govern over the Agreement. This
      Amendment is intended to be a final expression of the parties’ agreement to
      amend the Agreement and is intended to
      be a
      complete and exclusive statement of their agreement and understanding with
      respect to such amendment.

     

    
      
        
        

      

      
        1

        
          

        

      

      
        
        

      

    

    

    IN
      WITNESS WHEREOF, this Amendment has been entered into as of the day and year
      first above written.

     

    
      	
              NEW
                CENTURY COMPANIES, INC.

            	 	 	 
	 	 	 	 
	
              /s/ David
                Duquette

            	 	 	 
	
              

              By:
                David Duquette

            	 	 	
            
	Its: President	 	 	 

       

      
        	
                
                  MOTIVATED
                    MINDS, LLC

                

              	 	 	 
	 	 	 	 
	
                /s/ Ira
                  Gaines

              	 	 	 
	
                

                By:
                  Ira Gaines

              	 	 	
              
	Its: President	 	 	 

      

    

    

    
      
        
        

      

        2Exhibit
      10.1

     

    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
      Institute of Neurological Disorders and Stroke

    an
      Institute, Center, or Division (hereinafter referred to as the “ICD”)
      of
      the

    the
      National Institutes of Health

     

    and
      

     

    Lixte,
      Inc.

    hereinafter
      referred to as the “Collaborator”,

    having
      offices at 6 Tinker Lane, East Setatuket, New York 11733

    created
      and operating under the laws of Delaware. 

     

    
      
         

      

      
         

        
          

        

      

      
         

      

    

    

    COOPERATIVE
      RESEARCH AND DEVELOPMENT AGREEMENT

     

    Article
      1. Introduction
      

     

    This
      CRADA between ICD and Collaborator will be effective when signed by the Parties,
      which are identified on both the Cover Page and the Signature Page (page 16).
      The official contacts for the Parties are identified on the Contacts Information
      Page (page 17). Publicly available information regarding this CRADA appears
      on
      the Summary Page (page 18). The research and development activities that will
      be
      undertaken by ICD 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. 

     

    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. 

            

    

     

    
      	2.3	
              “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. 

            

    

     

    
      	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

            

    

     

    
      
         

      

      
        2

        
          

        

      

      
         

      

    

     

    
      	
            	(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 I 986. 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 the date of the last signature of the Parties executing this
                Agreement. 

            

    

     

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

            

    

     

    
      	2.11	
              “ICD
                Materials”
                means all tangible materials not first produced in the performance
                of this
                CRADA that are owned or controlled by ICD 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. .
                

            

    

     

    
      	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 ICD
                facilities will be required to sign a Guest Researcher or Special
                Volunteer Agreement appropriately modified in view of the terms of
                this
                CRADA. 

            

    

     

    
      
         

      

      
        3

        
          

        

      

      
         

      

    

     

    
      	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 ICD
                Materials.
                The Parties agree to use Collaborator Materials and ICD 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. 

            

    

     

    
      	3.5	
              Disclosures
                to ICD.
                Prior to execution of this CRADA, Collaborator agrees to disclose
                to ICD
                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 regularly, in writing. This exchange
                may be accomplished through meeting minutes, annual reports, detailed
                correspondence, and circulation of draft manuscripts.
                

            

    

     

    
      	4.2	
              Final
                Research and Development Reports.
                The Parties will exchange final reports of their results within four
                (4)
                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 ICD 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,
                ICD
                will submit to Collaborator a statement of all costs incurred by
                ICD for
                the CRADA. If the CRADA has been terminated, ICD will specify any
                costs
                incurred before the date of termination for which ICD 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

        
          

        

      

      
         

      

    

     

    Article
      5. Staffing,
      Financial, and Materials Obligations 

     

    
      	5.1	
              ICD
                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, l5 U.S.C. § 37l0a(d)(1) prohibits ICD from providing funds to
                Collaborator for any research and development activities under this
                CRADA.
                

            

    

     

    
      	5.2	
              ICD
                Staffing.
                No ICD employees will devote 100% of their effort or time to the
                research
                and development activities under this CRADA. ICD will not use funds
                provided by Collaborator under this CRADA for ICD personnel to pay
                the
                salary of, any permanent ICD employee. Although personnel hired by
                ICD
                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 ICD under this CRADA. If Collaborator has agreed to
                provide
                funds to ICD 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, ICD 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. ICD 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 ICD with capital equipment
                to enable the research and development activities under the Research
                Plan
                appears in Appendix B. If Collaborator transfers to ICD the capital
                equipment or provides funds for ICD to purchase it, then ICD will
                own the
                equipment. If Collaborator loans capital equipment to ICD 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 ICD 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.

            

    

     

    
      
         

      

      
        5

        
          

        

      

      
         

      

    

     

    
      	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.
                

            

    

     

    
      	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
                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

        
          

        

      

      
         

      

    

     

    
      	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 ICD employee(s) or made jointly by an ICD 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 ICD 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

        
          

        

      

      
         

      

    

     

    
      	7.4	
              Government
                License in ICD 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 ICD or jointly by ICD 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 an exclusive license
                to a CRADA Subject Invention made solely by an ICD 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(2).
                

            

    

     

    
      	7.7	
              Third-Party
                Rights In ICD Sole CRADA Subject Inventions.
                For a CRADA Subject Invention conceived prior to the Effective Date
                solely
                by an ICD 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.
                

            

    

     

    
      
         

      

      
        8

        
          

        

      

      
         

      

    

     

    
      	7.8	
              Joint
                CRADA Subject Inventions Not Exclusively Licensed by
                Collaborator.
                If Collaborator does not acquire an exclusive commercialization license
                in
                a joint CRADA Subject Invention in all fields of use then, for those
                fields of use not exclusively licensed to Collaborator, each Party
                will
                have the right to use the joint CRADA Subject Invention and to license
                its
                use to others, and each Party will cooperate with the other, as necessary,
                to fulfill international licensing requirements. The Parties may
                agree to
                a joint licensing approach for any remaining fields of use.
                

            

    

     

    Article
      8. Rights
      of Access and Publication 

     

    
      	8.1	
              Right
                of Access to CRADA Data and CRADA Materials.
                ICD 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 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 ICD 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. 

     

    
      	
            	(b)	
              CRADA
                Materials. 

            

    

     

    Collaborator
      and ICD 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://ott.od.nih.gov/NewPages/RTguide_final.html, 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. 

     

    
      
         

      

      
        9

        
          

        

      

      
         

      

    

     

    
      	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.
                

            

    

     

    
      	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. 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.
                

            

    

     

    
      
         

      

      
        10

        
          

        

      

      
         

      

    

     

    Article
      9. Representations
      and Warranties 

     

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

            

    

     

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

            

    

     

    
      	
            	(b)	
              To
                the best of its knowledge and belief, neither ICD 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 ICD or any of its personnel involved in this
                CRADA be
                debarred or suspended during the term of this CRADA, ICD 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 ICD 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 ICD 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.
                ICD and Collaborator may terminate this CRADA at any time by mutual
                written consent. 

            

    

     

    
      	10.3	
              Unilateral
                Termination.
                Either ICD or Collaborator may unilaterally terminate this CRADA
                at any
                time by providing written notice at least sixty (60) days before
                the
                desired termination date. ICD may, at its option, retain funds transferred
                to ICD before unilateral termination by Collaborator for use in completing
                the Research Plan. 

            

    

     

    
      
         

      

      
        11

        
          

        

      

      
         

      

    

     

    
      	10.4	
              Funding
                for ICD Personnel.
                If Collaborator has agreed to provide funding for ICD 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 ICD 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
                ICD 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.
                

            

    

     

    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
                ICD employees under this CRADA, unless due to the negligence or willful
                misconduct of ICD, 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 ICD, 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

        
          

        

      

      
         

      

    

     

    
      	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.
                ICD 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 ICD 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

        
          

        

      

      
         

      

    

     

    
      	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
                will be assigned or otherwise transferred by either Party without
                the
                prior written consent of the other Party.

            

    

     

    
      	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 ICD, or ICD Materials, or ICD’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.
                

            

    

     

    
      
         

      

      
        14

        
          

        

      

      
         

      

    

     

    
      	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.l-9.2,
                l0.3,
                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

     

    
      
         

      

      
        15

        
          

        

      

      
         

      

    

    SIGNATUREPAGE
      

     

    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
                NINDS:

               

              /s/
                Story Landis 

            	 	
               

               

              3/20/06 

            
	
              Story
                Landis, Ph.D.

            	 	
              Date

            
	
              Director,
                National Institute of Neurological Disorders and Stroke

            	 	 
	 	 	 
	 	 	 
	
              FOR
                COLLABORATOR:

               

              /s/
                John S. Kovach 

            	 	
               

               

              3/22/06 

            
	
              Dr.
                John S. Kovach

            	 	
              Date

            
	
              President,
                Lixte, Inc.

            	 	 

    

    

    
      
         

      

      
        16

        
          

        

      

      
         

      

    

    CONTACTS
      INFORMATION PAGE 

     

    

    
      	
              CRADA
                Notices

            
	 	 
	
              For
                ICD: 

            	
              For
                Collaborator:

            
	
              Dr.
                Martha Lubet

            	
              Dr.
                John S. Kovach

            
	
              6120
                Executive Blvd 

            	
              6
                Tinker Lane

            
	
              Suite
                450

            	
              East
                Setatuket, NY 11733

            
	
              Rockville,
                MD 20892 

            	 

    

    
 

    
      	
              Patenting
                and Licensing

            
	 	 
	
              For
                ICD:

            	
              For
                Collaborator (if separate from above):

            
	
              Division
                Director, Division of Technology

            	
              Same
                as above

            
	
              Development
                and Transfer

            	     

	
              NIH
                Office of Technology Transfer

            	       

	
              6011
                Executive Boulevard, Suite 325

            	       

	
              Rockville,
                Maryland 20852-3804

            	        

	
              Tel:
                301-496-7057

            	 
	
              Fax:
                301-402-0220

            	 

    

    

    

    
      	
              Delivery
                of Materials Identified In Appendix B (if any)

            
	 	 
	
              For
                ICD:

            	
              For
                Collaborator:

            
	
              Dr.
                Zhengping Zhuang 

            	
              N.A.

            
	
              Bldg
                10 Room 4N244

            	 
	
              10
                Center Drive

            	 
	
              Bethesda,
                MD 20892

            	 

    

    

    
      
         

      

      
        17

        
          

        

      

      
         

      

    

    

    SUMMARY
      PAGE 

     

    

    EITHER
      PARTY MAY, WITHOUT FURTHER CONSULTATION OR PERMISSION.

     

    RELEASE
      THIS SUMMARY PAGE TO THE PUBLIC.

     

    TITLE
      OF
      CRADA: Identification of agents regulating Nuclear Receptor Corepressor (N-CoR)
      pathway for glioma tumor cell differentiation 

     

    

    
      	
              PHS[ICD]
                Component:

            	 	
              National
                Institute of Neurological Disorders and Stroke 

            
	
              ICD
                Principal Investigator: 

            	 	
              Dr.
                Edward Oldfield 

            
	
              ICD
                Co-Principal Investigator: 

            	 	
              Dr.
                Zhengping Zhuang 

            
	
              Collaborator:
                

            	 	
              Lixte,
                Inc. 

            
	 	 	 
	
              Collaborator
                Principal Investigator: 

            	 	
              Dr.
                John S.Kovach 

            
	 	 	 
	
              TERM
                OF CRADA: 

            	 	
              2
                (Two) years from the Effective Date 

            

    

    

    

    ABSTRACT
      OF THE RESEARCH PLAN: 

     

    The
      National Institute of Neurological Disorders and Stroke (“NINDS”) in Bethesda,
      Maryland, and Lixte, Inc. will collaborate in the identification and evaluation
      of agents that target the Nuclear Receptor CoRepressor (N-CoR) pathway for
      glioma tumor cell differentiation. NINDS and Lixte, Inc. will also conduct
      research to determine if expression of N-CoR correlates with prognosis in glioma
      patients. 

    

    
      
         

      

      
        18

        
          

        

      

      
         

      

    

    PUBLIC
      HEALTH SERVICE

    COOPERATIVE
      RESEARCH AND DEVELOPMENT AGREEMENT

     

    APPENDIX
      A

     

    RESEARCH
      PLAN 

     

    Scope
      of this CRADA 

     

    The
      subject of this CRADA is limited to identifying agents that act synergistically
      with retinoic acid (RA) or okadaic acid to inhibit proliferation of Glioblastoma
      multiforme (GBM) cells and to determine if expression of Nuclear Receptor
      Corepressor (N-CoR) correlates with prognosis in glioma patients. 

     

    Background
      

     

    N-CoR
      binds to unliganded nuclear receptors such as retinoid acid receptor (RAR)
      and
      thyroid hormone receptor. When N-CoR forms a complex with Silencing Mediator
      of
      Retinoid and Thyroid Hormone Receptors (SMRT), Histone Deacetylase 3 (HDAC3)
      and
      RAR, transcription of RAR specific target genes is repressed resulting in
      increased cell proliferation. Using 2-D gel technology, the SNB/NINDS has
      discovered that Nuclear Receptor Corepressor (N-CoR) is overexpressed in
      Glioblastoma multi forme (GBM) glioma cells. Phosphastase-1 inhibitors such
      as
      okadaic acid are known to inhibit N-CoR activity (Hermanson et al. Nature
      419:934, 2002). SNB/NINDS has also discovered that okadaic acid acts
      synergistically with retinoic acid (RA) to inhibit GBM cell growth and increase
      cell differentiation. Okadaic acid is not specifically targeted to N-CoR and
      consequently is likely to have significant side-effects. SNB/NINDS seeks to
      identify other agents that inhibit N-CoR activity, especially agents that
      preferentially or specifically target N-CoR. 

     

    Glial
      Fibrillary Acidic Protein (GFAP) is expressed in astrocytes and is used as
      a
      marker to measure the degree of astroglial differentiation in GBM cell lines.
      Its expression is up-regulated in GBM cell lines cultured in retinoic acid
      and
      okadaic acid. Up-regulation of GF AP expression will be used as an additional
      confirmatory assay to characterize agents positive in anti-GBM proliferation
      assay. 

     

    A
      Confidentiality Disclosure Agreement (CDA) between Lixte and NTNDS for
      discussions regarding the N-CoR technology was executed in September, 2005.
      Lixte has recently submitted a patent application naming NINDS employees Dr.
      Zhuang, Dr. Oldfield, Dr. Deric Park. Dr. Jie Li, and Dr. Irina Lubensky
      and Lixte employee Dr. Kovach as inventors. The application includes methods
      of
      identifying compounds that affect cell growth of glioblastoma, methods of
      inhibiting tumor growth by administering one or more of the following: a RAR
      inhibitor, a phosphataseinhibitor or histone deacetylase inhibitor, and methods
      of measuring of N-CoR in tumor samples, cerebrospinal fluid (CSF) and serum
      as a
      means to confirm diagnosis, to determine response to treatment, or to determine
      recurrence of GBM in patients.

     

    
      
         

      

      
        A-1

        
          

        

      

      
         

      

    

     

    Background
      of the Parties

     

    SNB/NINDS

     

    Dr.
      Oldfield has had more than 20 years of experience leading a research effort
      in
      brain tumors that has examined the biology and pathophysiology of brain tumors,
      drug delivery to Central Nervous System (CNS) tumors and in developing novel
      approaches for treating them. As the Chief of the Surgical Neurology Branch,
      NTNDS, he leads a multi-dimensional research effort focused on the understanding
      and treatment of tumors of the CNS.

     

    Dr.
      Zhuang has worked in the field of cancer genetics and cancer biology for many
      years. Recently he has developed a novel approach of integrating tissue
      microdissection into genomic and proteomic research. Successful application
      of
      this technique has led to the identification of several genetic and protein
      targets, such as N-CoR in brain tumors, for diagnostic and therapeutic
      use.

     

    LIXTE,
      INC.

     

    John
      S.
      Kovach, M.D., founded Lixte, Inc. in 2005. The company seeks to apply recent
      advances in the molecular characterization of human tissue and in assay
      technology to improve diagnostics, prognostics, and therapy for common
      cancers.

     

    Dr.
      Kovach has more than 30 years experience in cancer research. He has extensive
      experience in anti-cancer drug evaluation and biomarkers of cancer
      cells.

     

    Objectives
      of this CRADA 

     

    NINOS
      and
      Lixte will work together to identify agents that act synergistically with
      retinoic acid or okadaic acid to inhibit CNS tumor cell growth, especially
      agents that inhibit N-CoR pathway activity. Lixte will provide approximately
      50
      compounds of known pharmacologic activity to SNB/NINOS to be evaluated in an
      in
      vitro
      screening assay. If licenses are required to use the compounds in the research
      plan, Lixte is responsible for obtaining any necessary licenses. Some of these
      compounds will be tested to determine if they act synergistically with retinoic
      acid and mutually agreed upon functional analogues of retinoic acid in
      inhibiting the growth of GBM cells. Some of these, compounds will be tested
      to
      determine if they act synergistically with okadaic acid and mutually agreed
      upon
      functional analogues of okadaic acid in inhibiting the growth of GBM cells.
      

     

    SNB/NINOS
      has also observed that a percentage of glioma cells localize N-CoR in the
      nuclear compartment, whereas in normal cells N-CoR is predominantly localized
      to
      the cytoplasmic compartment or is completely degraded. Therefore, the CRAOA
      research will determine if localization of N-CoR correlates with prognosis
      in
      glioma patients. An assay to determine if N-CoR can be detected in the serum
      or
      CSF from patients with GBM will also be developed. This assay will be used
      to
      determine if N-CoR levels in serum or CSF are useful in the diagnosis of GBM
      or
      the prognosis of disease in GBM patients. 

     

    
      
         

      

      
        A-2

        
          

        

      

      
         

      

    

     

    Samples
      from patients will be obtained under an appropriate IRB approved protocol.
      All
      samples will be labeled with code numbers and no Identifiable Patient
      Information (IPI) will be released to the Parties. 

     

    Work
      Scope:

     

    1)    Development
      of a high throughput in vitro screening assay for agents that act
      synergistically with retinoic acid or okadaic acid to inhibit proliferation
      of
      GBM cell lines. 

     

    The
      assay
      to determine if agents act synergistically with retinoic acid or okadaic acid
      to
      inhibit GBM cell growth in
      vitro
      currently used by SNB/NINOS will be modified so that large numbers of agents
      can
      be screened. The assay will be sufficiently robust so that assessment of the
      activity of several hundreds of different compounds and combinations of
      compounds at several concentrations can be made over a four to six month
      period.

     

    2)    Screening
      of compounds for activity in GBM assay. 

     

    Initial
      experiments will be done with chemicals (primarily phosphatase inhibitors)
      of
      known toxicologic and pharmacologic properties in humans. These chemicals have
      been identified and claimed in the patent application. Lixte will supply these
      chemicals and other known inhibitors of N-CoR/SMRT complex to identify agents
      that act synergistically with retinoic acid or okadaic acid in the GBM assays.
      

     

    3)    Development
      of an assay for cellular localization and levels of expression of the N-CoR
      in
      tissue and body fluids. 

     

    Lixte
      and
      SNBININDS will develop an assay to assess the potential value of N-CoR
      expression as a tool for diagnosis and for assessing the regression and/or
      progression of the cancer during medical management. Preliminary experiments
      will focus on the ability to detect the presence of N-CoR in brain tumor tissue,
      serum and CSF. 

     

    Responsibilities
      of the Parties 

     

    SNB/NINDS
      Laboratory will: 

     

    1)    Adapt
      the assay currently used in SNBININDS to a high throughput assay for the
      identification of agents active against GBMs. 

     

    2)    Screen
      agents for anti-proliferative activity against GBMs. 

     

    3)    Screen
      selected agents that are positive in the anti-proliferative assay in Glial
      Fibrillary Acidic Protein (OF AP) confirmatory assay. 

     

    4)    Analyze
      samples from GBM patients to determine if level of and localization of
      expression of N-CoR in tumor samples, serum or CSF correlates with prognosis
      of
      patients with OBM. 

     

    5)    Conduct
      preliminary animal studies of selected agents, if mutually agreed upon.

     

    
      
         

      

      
        A-3

        
          

        

      

      
         

      

    

     

    Lixte
      will 

     

    1)    Provide
      drugs and other chemicals selected for screening in in
      vitro
      assays. 

     

    2)    If
      a candidate agent is identified for further testing, Lixte will provide the
      agent in sufficient quantities to conduct in
      vivo
      animal studies. 

     

    Shared
      Responsibilities of Lixte and SNB/NINDS 

     

    1)    Mutually
      select agents to test in in
      vitro
      screening assays. 

     

    2)    Evaluate
      results of the initial in vitro screening assay to mutually select agents for
      further testing.

     

    3)    Mutually
      select up to six (6) agents for further evaluation in in
      vitro
      and, if appropriate, animal models.

     

    4)    Develop
      assays for N-CoR in biopsies of CNS tumors and in serum and
      CSF.

     

    5)    Design
      and evaluate studies to determine if N-CoR assays are useful in differential
      diagnosis of GBM or assessment of regression or progression of CNS tumors during
      medical management.

     

    6)    Provide
      tumor samples, serum and spinal fluid from GBM patients. Lixte will execute
      a
      contract to obtain samples. SNB/NINDS samples will be obtained under an NIH
      IRB
      approved protocol. 

     

    CRADAs
      AND OTHER AGREEMENTS BETWEEN THE PARTIES

     

    CRADAs:
      None 

     

    CTAs:
      None 

     

    CDAs:
      Confidential Disclosure Agreement 04765 between NINDS and Lixte, Inc. effective
      9/7/2005 

     

    INTELLECTUAL
      PROPERTY: 

     

    Sole
      NINDS:
      None

     

    Sole
      Lixte:
      None

     

    Joint
      NINDS and Lixte:
      Provisional Patent Application filed February 6,2006, entitled “Use of
      Phosphatases to Treat Glioblastomas. Inventors: NINDS employees Zhuang,
      Oldfield, D. Park, J. Li, J. Lubensky and Lixte employee, J. S.
      Kovach. 

     

    References:
      

     

    1.
      Hermansonet al. Nature 419:934, 2002. 

     

    
      
         

      

      
        A-4

        
          

        

      

      
         

      

    

    APPENDIX
      B

     

    STAFFING,
      FUNDING AND MA TERIALS/

    EQUIPMENT
      CONTRIBUTIONS OF THE PARTIES

     

    Staffing
      Contributions:

     

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

     

    ICD
      estimates that 2.2 person-years of effort per year will be required to complete
      the CRAOA research. 

     

    Although
      personnel hired by PHS using CRAOA funds shall focus principally on CRAOA
      research, such personnel nonetheless shall be free to participate in other,
      non-CRADA research in the laboratory, and such activities shall be outside
      the
      scope of this CRAOA. No funds provided under this CRADA by Collaborator will
      be
      used by the PHS to pay the salary of any tenured or tenure-track employee.
      

     

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

     

    Collaborator
      estimates that 0.20 person-years of effort per year will be required to complete
      the CRADA research. 

     

    Funding
      Contributions:

     

    Collaborator
      agrees to provide funds in the amount of two hundred thousand dollars ($200,000)
      per year of the CRADA for ICD to use to acquire technical, statistical, and
      administrative support for the research activities, as well as to pay for
      supplies and travel expenses. Collaborator will provide funds in equal annual
      installments. The first installment will be due within one hundred eighty (180)
      days of the Effective Date. Each subsequent installment will be due within
      thirty (30) days of each anniversary of the Effective Date. Collaborator agrees
      that ICD can allocate the funding between the various categories in support
      of
      the CRADA research as ICD’s PI sees fit. 

     

    CRADA
      PAYMENTS: 

     

    Collaborator
      will make checks payable to the National Institute of Neurological Disorders
      and
      Stroke, will reference the CRADA number 02165 entitled “Identification of agents
      regulating Nuclear Receptor Corepressor (N-CoR) pathway for glioma tumor cell
      differentiation” on each check, and will send them via trackable mail or courier
      to: 

     

    
      
         

      

      
        B-1

        
          

        

      

      
         

      

    

     

    
      National
        Institute of Neurological Disorders and Stroke, 

      Financial
        Management Branch Building 31, Room8A34 

      31
        Center
        Drive, MSC2540 

      Bethesda,
        MO 20892-2540 

    

     

     

    CRADA
      Travel Payments:

     

    In
      order
      to foster research under the CRADA, NINDS staff may travel to Lixte or make
      presentations of data at scientific meetings. At the mutual consent of NlNDS
      and
      Lixte, Collaborator may provide for transportation and lodging costs for such
      activities. In such cases, both Parties must agree that1) the activities would
      be appropriate under this CRAOA and 2) selection of participating NINOS
      staff must be based on mutually acceptable criteria. Such travel is subject
      to
      NIH Manual Chapter 1500 and other applicable federal travel rules and
      regulations, whether paid for by government funds or private
      companies

     

    Materials/Equipment
      Contributions: 

     

    ICD
      will
      transfer to the Collaborator the following ICD Materials for use under this
      CRADA: None 

     

    If
      ICD
      decides to provide additional ICD 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. 

     

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

     

    Collaborator
      Materials: Lixte will provide compounds used in the Research Plan. These
      compounds are not proprietary to Lixte, Inc. 

     

    Capital
      Equipment: None 

     

    
      
         

      

      
        B-2

        
          

        

      

      
         

      

    

    APPENDIX
      C 

     

    MODIFICATIONS
      TO THE MODEL CRADA

     

    Text
      to
      be added to the Model PHS CRADA (2005 version) is indicated by underlining
      and text
      to be deleted is indicated by strikethrough.

     

    Add
      new Article 2.17 

     

    2.17 “Human
      Subject” means in accordance with the definition in 45 C.F.R. § 46.102 (f),
      a living individual about whom an investigator conducting research obtains:
      

     

    (a) data
      through intervention or interaction with the individual;: or 

     

    (b) Identifiable
      Private Information. 

     

    Add
      new Article 2.18 

     

    2.18 “Identifiable
      Private Information” or “IPI” about a Human Subject means private information
      from which the identity of the subject is or may readily be ascertained.
      Regulations defining and governing this information include 45 C.F.R. Part
      46
      and 21 C.F.R. Part 50.

     

    Modify
      Article 3.2 as follows: 

     

    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. Any protocol
      for research in animals must, in addition to other laws, comply with the
      provisions of 9 C.F.R. Part I Subchapter A., including review and approval
      of
      the proposed research by an Independent Animal Care and Use Committee.

     

    Add
      new Article 3.6 as follows: 

     

    3.6 Third-Party
      Contractors.
      If
      Collaborator elects to conduct a portion of the Research Plan through a third
      party (e.g., as a contractor of Collaborator), then Collaborator agrees to
      notify ICD and to ensure that the agreement between Collaborator and the third
      party will be consistent with Collaborator’s obligations under this CRADA. In
      particular, to the extent any Invention the third party may make would be a
      CRADA Subject Invention if it had been made by an employer of Collaborator,
      then
      Collaborator shall secure a commitment by the third party to assign its related
      Inventions to Collaborator, and any such Invention shall thereafter be treated
      as a CRADA Subject Invention in all respects. Further, the agreement between
      Collaborator and third party shall require that the third party will comply
      with
      all local rules and regulations for protection of human subjects.

     

    
      
         

      

      
        C-1

        
          

        

      

      
         

      

    

     

    Modify
      Article 8.5 as follows: 

     

    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. Collaborator shall,
      under no circumstances, receive information about or linked to identifiable
      Human Subjects in any form. Collaborator may receive samples of human tissue
      or
      data derived from identifiable private information, but only if all of the
      samples or data have first been rendered completely untraceable to any human
      subject.

     

    Modify
      Article 13.13 as follows: 

     

    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. The CDA executed between the Parties on or about
      September 7, 2005 is hereby superseded and succeeded by the terms of this
      CRADA. Specifically, the confidential data exchanged between the Parties under
      that CDA shall be governed by the terms of this CRADA as if they had been
      exchanged after execution of this CRADA, and not by the terms of the
      CDA.

     

    Modify
      Article 13.14 as follows:

     

    13.14 Survivability.
      The
      provisions of Paragraphs 3.3,3.4,4.2,4.3,5.3,5.4,6.1-9.2,10.310.5, 11.1,
      12.1-12.3, 13.1-13.3, 13.10, 13.l3
      and
      13.14 will survive the expiration or early termination of this CRADA.

     

    
      
         

      

      
        C-2

        
          

        

      

      
         

      

    

    AMENDMENT 1

     

    Current
      CRADA TERMS: 

     

    
      	
              CRADA
                # 2165 

            	
              Nih
                Pls: Dr. Edward Oldfield

            
	
              Effective
                Date: 3/22/2006 

            	
              Dr.
                Zhengping Zhuang

            
	
              Executed
                Date: 3/22/2006 

            	
              Institute:
                NINDS

            
	
              Original
                Term: 24 months 

            	
              Collaborator
                PI: Dr. John Kovach

            
	
              Expiration
                Date: 3/22/2008 

            	
              Collaborator:
                Lixte Biotechnology, Inc.

            

    

    

    NEW
      CRADA
      TERMS: 

     

    The
      purpose of this amendment is to change certain terms of the above referenced
      Cooperative Research and Development Agreement (CRADA). These changes are
      reflected below and except for these changes all other provisions including
      the
      research plan of the original CRADA remain in full force and effect. Each
      signatory will receive an original of this amendment. Text to be added to
      Appendices A and B of the original CRADA is indicated by underlining
      and text
      to be deleted is indicated by strikethrough.

     

    1.    Change
      the name of the Collaborator from Lixte, Inc. to Lixte Biotechnology, Inc.
      

     

    2.    Amend
      the
      Research Plan, Appendix A, on page 22 as follows: 

     

    2)
      Screening of compounds for activity in GBM assay.
      Initial
      experiments will be done with chemicals (primarily phosphatase inhibitors)
      of
      known toxicologic and pharmacologic properties in humans. These chemicals have
      been identified and claimed in the patent application. Lixte will supply these
      chemicals and other known inhibitors of N-CoR/SMRT complex to identify agents
      that act synergistically with retinoic acid or okadaic acid in the GBM
      assays.

     

    GBM
      assays have shown that some of these compounds are active in the assays. Analogs
      of up to five compounds that are active in the in
      vitro
      GBM
      assay will be provided by Lixte and will be tested in the in
      vitro
      GBM
      assay. Compounds selected for analog activity studies will be mutually agreed
      upon. The exact number of analogs that will be tested for the selected compounds
      will be agreed upon in writing by the Principle Investigators prior to the
      start
      of testing of the analogs. The analogs provided by the Lixte will be transferred
      to NINDS under a cover letter that identifies them and states that they are
      being provided under the terms of the CRADA.

     

    3.    Amend
      Appendix B on page 26 as follows: 

     

    Collaborator
      Materials: Lixte will provide compounds used in the Research Plan. Some
      of tThese
      compounds are proprietary to Lixte Biotechnology,
      Inc.

     

    
      
         

      

      
         

        
          

        

      

      
         

      

    

     

    Capital
      Equipment: None 

    

    

    SIGNATURES
      BEGIN ON NEXT PAGE 

     

    
      
         

      

      
         

        
          

        

      

      
         

      

    

    SIGNATURE
      PAGE 

     

    ACCEPTED
      AND AGREED TO 

     

    
      	
              FOR
                NINDS:

               

              /s/
                Story Landis 

            	 	
               

               

              10/19/06 

            
	
              Story
                Landis, Ph.D.

            	 	
              Date

            
	
              Director,
                National Institute of Neurological Disorders and Stroke

            	 	 
	 	 	 
	 	 	 
	
              FOR
                COLLABORATOR:

               

              /s/
                John S. Kovach 

            	 	
               

               

              10/26/06 

            
	
              Dr.
                John S. Kovach

            	 	
              Date

            
	
              President,
                Lixte Biotechnology, Inc.

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