Document:

Exhibit 10.14

 

AGREEMENT

 

 

Between

 

 

NEW YORK UNIVERSITY

 

 

and

 

 

COLLATERAL THERAPEUTICS, INC.

 

 

NYU/COLLATERAL THERAPEUTICS

Research & License Agreement

 

 

INDEX

 

	
  Section 1

  	
  Definitions

  	
  page 1

  
	
  Section 2

  	
  Effective Date

  	
  page 4

  
	
  Section 3

  	
  Performance of the NYU
  Research Project

  	
  page 4

  
	
  Section 4

  	
  Funding of the NYU
  Research Project

  	
  page 5

  
	
  Section 5

  	
  Title

  	
  page 5

  
	
  Section 6

  	
  Patents and Patent
  Applications

  	
  page 6

  
	
  Section 7

  	
  Grant of License

  	
  page 8

  
	
  Section 8

  	
  Payments for License

  	
  page 9

  
	
  Section 9

  	
  Method of Payment

  	
  page 12

  
	
  Section 10

  	
  Development and
  Commercialization

  	
  page 13

  
	
  Section 11

  	
  Confidential Information

  	
  page 15

  
	
  Section 12

  	
  Publication

  	
  page 15

  
	
  Section 13

  	
  Liability and
  Indemnification

  	
  page 16

  
	
  Section 14

  	
  Security for
  Indemnification

  	
  page 17

  
	
  Section 15

  	
  Expiry and Termination

  	
  page 18

  
	
  Section 16

  	
  Representations and
  Warranties by CORPORATION

  	
  page 19

  
	
  Section 17

  	
  Representations and
  Warranties by NYU

  	
  page 20

  
	
  Section 18

  	
  No Assignment

  	
  page 21

  
	
  Section 19

  	
  Use of Name

  	
  page 21

  
	
  Section 20

  	
  Miscellaneous

  	
  page 22

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  Appendix I       Pre Existing Inventions 

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  Appendix II      Research Program

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
  Appendix III     Development Plan

  	
   

  

 

 

RESEARCH AND  LICENSE  AGREEMENT

 

This
Agreement, effective as of March 24, 1997 (the “Effective Date”), is by and
between NEW YORK UNIVERSITY (hereinafter “NYU”), a corporation organized and
existing under the laws of the State of New York and having a place of business
at 70 Washington Square South, New York, New York 10012 and COLLATERAL
THERAPEUTICS, INC. (hereinafter “CORPORATION”), a corporation organized and
existing under the laws of the State of California, having its principal office
at 9360 Towne Centre Drive, San Diego, California 92121.

 

RECITALS

 

WHEREAS,
Dr. Claudio Basilico of NYU (hereinafter “the NYU Scientist”), together with
other co-inventors, has made certain inventions all as more particularly
described in an issued U.S. patent and U.S. patent applications and foreign
patent applications owned by NYU, in each case identified in annexed Appendix I
and forming an integral part hereof (hereinafter “the Pre-Existing Inventions”);

 

WHEREAS, NYU is willing to perform the NYU Research
Project (as hereinafter defined);

 

WHEREAS, CORPORATION is prepared to sponsor the NYU
Research Project;

 

WHEREAS, subject to the terms and conditions hereinafter set forth, NYU
is willing to grant to CORPORATION and CORPORATION is willing to accept from
NYU the License (as hereinafter defined);

 

NOW,
THEREFORE, in consideration of the mutual promises and agreements contained
herein, the parties hereto hereby agree as follows:

 

1.             Definitions.

 

(a)          “Calendar Year” shall mean any consecutive
period of twelve months commencing on the first day of January of any year.

 

(b)         “Corporation Entity” shall mean any company
or other legal entity which controls, or is controlled by, or is under common
control with, CORPORATION; control means the holding of fifty percent (50%) or more
of (i) the capital and/or (ii) the voting rights and/or (iii)
the right to elect or appoint directors.

 

 

(c)          “Date of First Commercial Sale” shall have
the meaning set forth in Section 7(b) hereof.

 

(d)         “FGF-4” shall mean Fibroblast Growth Factor 4
the amino acid sequence of which is provided in Figure 1 in the article by P.
Delli Bovi, A.M. Curatola, F. G. Kern, A. Greco, M. Ittmann, and C. Basilico published
in Cell, Volume 50, pages 729-737, August 28, 1987.

 

(e)          “Field” shall mean gene therapy for coronary
artery disease, congestive heart failure, and peripheral vascular disease.

 

(f)          “GI Agreement” shall mean, collectively (i)
the Agreement, dated as of February 6, 1989, between NYU and Genetics
Institute, Inc. (“GI”), as amended by the Amendment, dated February 25, 1997,
and (ii) the Settlement
Agreement, dated August 22, 1996, between NYU and GI.

 

(g)         “License” shall mean the exclusive worldwide
license to practice the Research Technology (as hereinafter defined) for the
development, manufacture, use and
sale of the Licensed Products (as hereinafter defined) in the Field and the
exclusive worldwide right to sublicense such rights in accordance with Section
7(c).

 

(h)         “Licensed Products” shall mean products
comprising a nucleic acid sequence encoding FGF-4 or fragments or analogs
thereof, in each case which are covered by a claim of any unexpired patent
within the NYU Patents (as hereinafter defined) which has not been disclaimed
or held invalid by a court of competent jurisdiction from which no appeal can
be taken or of any active patent application within the NYU Patents, or which
utilize all or any portion of NYU Know-How.

 

(i)           “Net Sales” shall mean the total amount
invoiced in connection with sales of Licensed Products by CORPORATION, any
Corporation Entity or any sublicensee of CORPORATION, any Corporation Entity or
a sublicensee in accordance with Section 7(c)(iii), in each case to end users; provided
that Net Sales shall (i) not include any amounts invoiced in connection
with sales of Licensed Products for (A) transportation charges,
including insurance relating thereto, or (B) sales and excise taxes,
value-added taxes or customs duties paid by the

 

2

 

person selling or distributing any Licensed
Product or any other governmental charges imposed upon the sale or distribution
of any Licensed Product; and (ii) be adjusted to reflect any deductions
to amounts invoiced to take account of (X) distributors’ fees, rebates,
allowances or sales commissions actually granted, allowed or incurred and
credits for returns or (Y) quantity or case discounts, cash discounts or
chargebacks actually granted, allowed or incurred in the ordinary course of
business in connection with the sale or distribution of any Licensed Product; provided,
further, that Net Sales shall not include amounts invoiced by
CORPORATION to any person or entity that is a Corporation Entity or a
sublicensee of CORPORATION or a Corporation Entity under the License.

 

(j)           “NYU Know-How” shall mean the Pre-Existing
Inventions, any proprietary information or proprietary materials including, but
not limited to, pharmaceutical, chemical, biological and biochemical products,
information and trade secrets, know-how, technical and non-technical data,
materials, methods and processes and any drawings, plans, diagrams,
specifications and/or other documents containing such information, discovered,
developed or acquired by, or on behalf of students or employees of NYU during the term and in the course of
the NYU Research Project.

 

(k)          “NYU Patents” shall mean all United States
and foreign patents and patent applications, and any divisions, continuations, in whole or in part,
reissues, re-examinations, renewals and extensions thereof, and pending
applications therefor:

 

(1)           which claim Pre-Existing Inventions and which
are identified on annexed Appendix I; or

 

(2)           which claim inventions that are made, in
whole or in part, by students or employees of NYU during the term and in the
course of the NYU Research Project.

 

(l)           “Research Period” shall mean the three-year
period commencing on the Effective Date hereof and any extension thereof as to
which NYU and CORPORATION shall mutually agree in writing.

 

(m)         “NYU Research Project” shall mean the
investigations at NYU during the Research Period into the Field under the
supervision of the NYU Scientist in

 

3

 

accordance
with the research program, described in annexed Appendix II, which forms an
integral part hereof.

 

(n)         “Research Technology” shall mean all NYU
Patents and NYU Know-How.

 

(o)         “Total Net Sales” shall mean the aggregate
Net Sales of CORPORATION, any Corporation Entity and any sublicensee of
CORPORATION or any Corporation Entity to end users of Licensed Products.

 

2.             Effective Date.

 

This Agreement shall be effective as of the
date first written above and shall remain in full force and effect until it
expires or is terminated in accordance with Section 16 hereof.

 

3              Performance of the NYU Research Project.

 

(a)           In consideration of the sums to be paid to
NYU as set forth in Section 4 below, NYU undertakes to perform the NYU Research
Project under the supervision of the NYU Scientist during the Research Period,
as such Project may be amended in accordance with Section 20(f).  If, during the Research Period the NYU
Scientist shall cease to supervise the NYU Research Project, then NYU shall promptly so notify CORPORATION
and shall endeavor to find among the scientists of NYU a Scientist acceptable
to CORPORATION to continue the supervision of the NYU Research Project.  If NYU is unable to find such a Scientist
acceptable to CORPORATION within three months after such notice to CORPORATION,
CORPORATION shall have the option to terminate its funding of the NYU Research
Project.  CORPORATION shall promptly
advise NYU in writing if CORPORATION so elects. 
Such termination of funding pursuant to this Section 3(a) shall not
terminate this Agreement or the License granted herein.  Nothing herein contained shall be deemed to
impose an obligation on NYU to find a replacement for the NYU Scientist.

 

(b)           Nothing contained in this Agreement shall be construed as a warranty on
the part of NYU that any results or inventions will be achieved by the NYU
Research Project, or that the Research Technology and/or any other results or
inventions achieved by the NYU Research Project, if any, are or will be
commercially exploitable and furthermore, NYU makes

 

4

 

no
warranties whatsoever as to the commercial or scientific value of the Research
Technology and/or as to any results which may be achieved in the NYU Research
Project.

 

(c)           NYU will have full authority and
responsibility for the NYU Research Project. All students and employees of NYU
who work on the NYU Research Project will do so as employees or students of
NYU, and not as employees of CORPORATION.

 

(d)           NYU shall provide to CORPORATION a report on
the NYU Research Project within ninety (90) days following the end of each
twelve-month period occurring during the Research Period.

 

4.             Funding of the NYU Research Project.

 

(a)           As compensation to NYU for work to be
performed on the NYU Research Project during the Research Period, subject to
any earlier termination of the Research Project pursuant to Section 3(a)
hereof, CORPORATION will pay NYU the total sum of $600,000, payable in six
equal consecutive installments of $100,000, on the Effective Date and at six
month intervals following such Date.

 

(b)           Nothing in this Agreement shall be
interpreted to prohibit NYU (or the NYU Scientist) from obtaining additional
financing or research grants for the NYU Research Project from government
agencies, which grants or financing may render all or part of the NYU Research
Project and the results thereof subject to the patent rights of the U.S.
Government and its agencies, as set forth in Title 35 U.S.C.§200 et  seq.

5.             Title.

 

(a)           Subject to the License granted to CORPORATION
hereunder, it is hereby agreed that all right, title and interest, in and to
the Research Technology, and in and to any drawings, plans, diagrams,
specifications, and other documents containing any of the Research Technology
shall vest solely in NYU.  At the request
of NYU, CORPORATION shall take all steps as may be necessary to give full
effect to said right, title and interest of NYU including, but not limited to,
the execution of any documents that may be required to record such right, title
and interest with the appropriate agency or government office.

 

5

 

(b)           Subject to the License granted to CORPORATION
hereunder, for so long as the NYU Scientist is employed by NYU, any and all
inventions made by such NYU Scientist and relating to the Field shall be owned
solely by NYU.

 

6.             Patents and Patent Applications.

 

(a)           NYU will promptly disclose to CORPORATION in
writing any inventions which constitute potential NYU Patents developed in the
course of the NYU Research Project.

 

(b)           At the initiative of CORPORATION or NYU, the
parties shall consult with each other regarding the prosecution of all patent
applications within NYU Patents (excluding any Pre-Existing Invention).  Such patent applications shall be filed,
prosecuted and maintained by the law firm of Darby & Darby or by other
patent counsel jointly selected by NYU and CORPORATION.  Copies of all such patent applications and
patent office actions shall be forwarded to each of NYU and CORPORATION.

 

NYU
and CORPORATION shall each also have the right to have such patent applications
and patent office actions independently reviewed by other patent counsel
separately retained by NYU or CORPORATION, upon prior notice to and consent of
the other party, which consent shall not unreasonably be withheld.

 

(c)           All applications and proceedings with respect
to NYU Patents (other than those relating to any Pre-Existing Invention) shall
be filed, prosecuted and maintained by NYU at the expense of CORPORATION. Against
the submission of invoices, CORPORATION shall reimburse NYU for all costs and
fees incurred by NYU during the term of this Agreement, in connection with the
filing, maintenance, prosecution, protection and the like of such patents.

 

(d)           NYU and CORPORATION shall assist, and cause
their respective employees and consultants to assist each other, in assembling
inventorship information and data for the filing and prosecution of patent
applications on inventions pertaining to the Research Technology.

 

6

 

(e)           If at any time during the term of this
Agreement CORPORATION decides that it is undesirable, as to one or more
countries, to prosecute or maintain any patents or patent applications within
the NYU Patents (other than those relating to any Pre-Existing Invention), it
shall give prompt written notice thereof to NYU, and upon receipt of such
notice CORPORATION shall be released from its obligations to bear all of the
expenses to be incurred thereafter as to such countries in conjunction with
such patent(s) or patent application(s) and such patent(s) or application(s)
shall be deleted from the Research Technology and NYU shall be free to grant
rights in and to the Research Technology in such countries to third parties,
without further notice or obligation to CORPORATION, and the CORPORATION shall
have no rights whatsoever to exploit the Research Technology in such countries.

 

(f)            Under the GI Agreement, provisions exist to
determine the circumstances under which patent protection will be obtained by
NYU with respect to any Pre-Existing Invention. 
For patent applications with respect to Pre-Existing Inventions, copies
of such applications and office actions shall be forwarded to CORPORATION who
may consult with NYU with regard thereto. 
CORPORATION agrees, upon presentation of supporting documentation, to
reimburse NYU for one quarter (1/4) of the expenses incurred by NYU as of the
Effective Date in connection with obtaining such patent protection.  In the event that such separate provisions
result in a situation where patent protection in any country is not pursued by
NYU because of a lack of funding pursuant to such provisions, then NYU shall
notify CORPORATION thereof and CORPORATION shall have the option to pay NYU to
pursue such patent protection.

 

(g)           Nothing herein contained shall be deemed to be a warranty by NYU that

 

(i)            NYU can or will be able to obtain any patent or patents on any patent application
or applications in the NYU Patents or any portion thereof, or that any of the
NYU Patents will afford adequate or commercially worthwhile protection, or

 

7

 

(ii)           that the manufacture, use, or sale of any element of the Research
Technology or any Licensed Product will not infringe any patent(s) of a third
party.

7.             Grant of License.

 

(a)           Subject to the terms and conditions
hereinafter set forth, and subject to any rights of the U.S. Government
pursuant to Title 35 of the United States Code §200 et  seq., NYU
hereby grants to CORPORATION and CORPORATION hereby accepts from NYU the License.

 

(b)           The License granted to CORPORATION in Section
7(a) hereto shall commence upon the Effective Date and shall remain in force on
a country-by-country basis, if not previously terminated under the terms of
this Agreement, for fifteen (15) years from the Date of First Commercial Sale
in such country or until the expiration date of the last patent within the NYU
Patents in any such country to expire, whichever shall be later.  CORPORATION shall inform NYU in writing of
the Date of First Commercial Sale with respect to each Licensed Product in each
country as soon as practicable after the making of each such first commercial
sale.

 

(c)           CORPORATION shall be entitled to grant
sublicenses under the License on terms and conditions in compliance and not
inconsistent with the terms and conditions of this Agreement (except that the
rate of royalty may be at higher rates than those set forth in this Agreement)
(i) to a Corporation Entity or (ii) to other third parties for
consideration and in an arms-length transaction. All sublicenses shall only be
granted by CORPORATION under a written agreement, a copy of which shall be provided
by CORPORATION to NYU as soon as practicable after the signing thereof.  Each sublicense granted by CORPORATION
hereunder shall be subject and subordinate to the terms and conditions of this License
Agreement and shall contain (inter-alia) the following provisions:

 

(1)           the sublicense shall expire automatically on the
termination of the License;

 

(2)           the sublicense shall not be assignable, in whole
or in part;

 

8

 

(3)           the sublicensee shall not grant further sublicenses,
except that a sublicensee may grant a further sublicense solely for purposes of
effecting distribution of Licensed Products to end users on the same terms
required for sublicenses under this Section 7(c);

 

(4)           both during the term of the sublicense and thereafter
the sublicensee shall agree to a confidentiality obligation similar to that imposed
on CORPORATION in Section 11 below, and that the sublicensee shall impose on
its employees, both during the terms of their employment and thereafter, a
similar undertaking of confidentiality; and

 

(5)           the sublicense agreement shall include the text
of Sections 13 and 14 of this Agreement and shall state that NYU is an intended
third party beneficiary of such sublicense agreement for the purpose of
enforcing such indemnification and insurance provisions.

 

8.             Payments for License.

 

(a)           In consideration for the grant and during the term of the License with
respect to each Licensed Product, CORPORATION shall pay to NYU:

 

(1)           On the Effective Date, a non-refundable,
non-creditable license issue fee of one hundred thousand dollars ($100,000);

 

(2)           On the first anniversary of the Effective Date
and on each subsequent anniversary thereof, a non-refundable, non-creditable license
maintenance fee of twenty-five thousand dollars ($25,000); provided that
such fee shall cease to be payable on the first anniversary of the Effective
Date following the completion by CORPORATION of one full year of sales of
Licensed Products in accordance with the terms of this Agreement;

 

(3)           Upon the achievement of the following technical
milestones with respect to any Licensed Product, the payments as indicated
below:

 

9

 

	
  Milestone

  	
   

  	
  Payments

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  Upon the filing of an initial
  Investigational New Drug Application (or foreign equivalent thereof) for each
  new Licensed Product

  	
   

  	
  $

  	
  250,000

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  Upon the filing of a Product License
  Application (or foreign equivalent thereof) for each Licensed Product

  	
   

  	
  $

  	
  500,000

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  Upon the approval of a Product License
  Application (or foreign equivalent thereof) for each Licensed Product

  	
   

  	
  $

  	
  1,000,000

  	
   

  

 

provided that only one payment shall be made at each
milestone for each separate Licensed Product notwithstanding the number of
applications that may be filed and approved in various countries for each such
separate Licensed Product.

 

(4)           With respect to sales of Licensed Products a royalty
of 3% of Total Net Sales during each calendar year.

 

(b)           For the purpose of computing the royalties due to NYU hereunder, the
year shall be divided into two parts ending on June 30 and December 31.  Not later than one hundred thirty (130) days
after each December and June in each Calendar Year during the term of the
License, CORPORATION shall submit to NYU a full and detailed report of
royalties or payments due NYU under the terms of this Agreement for the
preceding half year (hereinafter “the Half-Year Report”), setting forth the
Total Net Sales and Net Sales of each of CORPORATION, each Corporation Entity
and each sublicensee of CORPORATION, any Corporation Entity or sublicensee
permitted under Section 7(c)(iii) and/or lump sum payments and all other payments
or consideration from sublicensees upon which such royalties are computed and
including at least:

 

(i)            the quantity of Licensed Products used, sold,
transferred or otherwise disposed of on a country-by-country basis;

 

10

 

(ii)           the
selling price of each Licensed Product;

 

(iii)          the
deductions permitted under subsection l(i) hereof to arrive at Net Sales; and

 

iv)           the royalty
computations and subject of payment.

 

If no royalties or other payments are due, a statement shall be sent to
NYU stating such fact. Payment of the full amount of any royalties or other
payments due to NYU for the preceding half year shall accompany each Half-year
Report on royalties and payments. 
CORPORATION shall keep for a period of at least six (6) years after the
date of entry, full, accurate and compete books and records consistent with
sound business and accounting practices and in such form and in such detail as
to enable the determination of the amounts due to NYU from CORPORATION pursuant
to the terms of this Agreement.

 

(c)           Within
ninety (90) days after the end of each Calendar Year, commencing on the Date of
First Commercial Sale CORPORATION shall furnish NYU with a report (hereinafter
the “Annual Report”), certified
by an independent certified public accountant, relating to the royalties and
other payments due to NYU pursuant to this Agreement in respect of the Calendar
Year covered by such Annual Report and containing the same details as those
specified in Section 8(b) above in respect of the Half-Year Report.

 

(d)           On
reasonable notice and during regular business hours, NYU or the authorized
representative of NYU shall each have the right to inspect the books of
accounts, records and other relevant documentation of CORPORATION or of
Corporation Entity and the sublicensees of CORPORATION, Corporation Entity and
any sublicensee insofar as they relate to the production, marketing and sale of
the Licensed Products, in order to ascertain or verify the amount of royalties
and other payments due to NYU hereunder, and the accuracy of the information
provided to NYU in the aforementioned reports. 
NYU shall also have the right, not more than once each calendar year, to
audit CORPORATION’s books and financial records for the purpose of verifying
full

 

11

 

payment by CORPORATION of
its royalty obligations hereunder. Such audits shall be conducted during normal
business hours and shall not interfere with CORPORATION’s conduct of its
business. Each such audit shall be at NYU’s expense, unless a particular audit
reveals an underpayment of ten percent (10%) or more of the amount that should
have been paid to NYU for the period audited, in which case CORPORATION shall
bear the expense of such audit.  In the
event of any underpayment of royalties, CORPORATION shall promptly remit to NYU
all amounts due.

 

(e)           Beginning
in the year in which CORPORATION completes one full year of sales of Licensed
Products and continuing thereafter until this Agreement shall terminate or
expire, CORPORATION agrees that if the total royalties paid to NYU under
subsection 8 (a) (4) hereof do not amount to five hundred thousand dollars
($500,000) in each Calendar Year, CORPORATION will pay to NYU within one
hundred thirty (130) days after the end of each such Calendar Year, as
additional royalty, the difference between the amount of the total royalties
paid to NYU by CORPORATION in such Calendar Year and five hundred thousand
dollars ($500,000), failing which NYU shall have the right solely at its
election, upon written notice to CORPORATION, to either terminate this
Agreement for cause or to declare the License granted herein to CORPORATION to
be non-exclusive.

 

(f)            CORPORATION
shall, and shall cause each Corporation Entity and sublicensee of CORPORATION,
Corporation Entity or a sublicensee, to effect sales of Licensed Products to
third parties on commercially reasonable, arm’s length terms.

 

9.             Method
of Payment.

 

(a)           Royalties
and other payments due to NYU hereunder shall be paid to NYU in United States
dollars. Any such royalties on or other payments relating to transactions in a
foreign currency shall be converted into United States dollars based on the
closing buying rate of the Morgan Guaranty Trust Company of New York applicable
to transactions under exchange regulations for the particular currency on the
last business day of the accounting period for which such royalty or other payment
is due.

 

12

 

(b)           CORPORATION
shall be responsible for payment to NYU of all royalties due on sale, transfer
or disposition of Licensed Products by Corporation Entity or by the
sublicensees of CORPORATION, Corporation Entity or a sublicensee.

 

10.           Development
and Commercialization.

 

(a)           It
shall be within the judgment of CORPORATION in what manner to proceed with the
development of Licensed Products for commercialization; provided that
CORPORATION shall use efforts, consistent with its sound and reasonable
business practices and technical judgment, to effect introduction of Licensed
Products into the commercial market. CORPORATION shall be deemed to satisfy the
due diligence requirements of this Section 10(a) by: (i) preparing and
filing an Investigational New Drug Application for a Licensed Product within
three (3) years following the Effective Date; (ii) preparing and filing
an application for marketing approval of a Licensed Product in the United
States, Canada, or a country within the European Union within six (6) years
following the Effective Date; and (iii) obtaining marketing approval of
a Licensed Product in the United State, Canada, or a country within the
European Union within eight (8) years following the Effective Date.  Corporation’s Development Plan is annexed
hereto as Appendix III.

 

(b)           Provided
that applicable laws, rules and regulations require that the performance of the
tests, trials, studies and other activities required by subsection (a) above
shall be carried out in accordance with FDA current Good Laboratory Practices,
current Good Manufacturing Practices and current Good Clinical Practices and in
a manner acceptable to the relevant health authorities, CORPORATION shall carry
out such tests, trials, studies and other activities in accordance with such
Practices and in a manner acceptable to the relevant health authorities.  Furthermore, the Licensed Products shall be
produced in accordance with FDA current Good Manufacturing Practice procedures
in a facility which has been licensed by the FDA to manufacture such Licensed
Products, provided that applicable laws, rules and regulations so require.

 

(c)           CORPORATION
undertakes to begin the regular commercial production, use, and sale of the Licensed

 

13

 

Products in each country
in which approval has been received (as described in Section 10(a)) and to
continue diligently thereafter to commercialize the Licensed Products in each
such country in a manner consistent with sound and reasonable business
practices.

 

(d)           CORPORATION
shall provide NYU with written reports on all activities and actions undertaken
by CORPORATION to develop and commercialize the Licensed Products; such reports
shall be made within sixty (60) days after each six (6) months of the duration
of this Agreement, commencing six months after the Effective Date.

 

(e)           If
CORPORATION shall not satisfy the requirements set forth in Section 10(a)
(unless such delay or failure is necessitated by FDA or other regulatory agencies or unless NYU and
CORPORATION have mutually agreed to amend the Development Plan because of
unforeseen circumstances) NYU shall notify CORPORATION in writing of
CORPORATION’S failure and shall allow CORPORATION sixty (60) days to cure such
failure.  Upon receiving such notice,
CORPORATION may elect to extend such diligence period and all subsequent
diligence periods relating to such Licensed Product for one twelve (12) month
period upon written certification to NYU that CORPORATION is continuing product
development work with respect to a Licensed Product and payment to NYU of a fee
equal to $100,000. After the expiration of any such twelve-month period,
CORPORATION may elect to further extend its diligence obligations under Section
10(a) with respect to such Licensed Product for successive one-year periods
upon (i) written notice to NYU, (ii) certification by CORPORATION that it is
continuing to diligently develop such Licensed Product and, together with its
sublicensee(s), will spend no less than three million dollars ($3,000,000) in
each Calendar Year on development of such Product and (iii) payment to NYU
prior to the beginning of such year of an amount equal to $500,000,
representing minimum annual royalties with respect to such Product.  CORPORATION’s failure to cure a delay in the
diligence requirements to NYU’s reasonable satisfaction or elect and satisfy
the requirements of one of the options set forth above within such 60-day
period shall be a material breach of this Agreement.

 

14

 

11.           Confidential
Information.

 

(a)           Except
as otherwise provided in Section 11(b) and 11(c) below CORPORATION shall
maintain any and all of the Research Technology in confidence and shall not
release or disclose any tangible or intangible component thereof to any third
party without first receiving the prior written consent of NYU to said release
or disclosure; provided that CORPORATION may, without NYU’s consent,
disclose Research Technology to sublicensees pursuant to Section 7, CORPORATION
Entities and consultants engaged by CORPORATION, in each case pursuant to a
confidentiality agreement requiring such party to maintain any and all of the
Research Technology in confidence and not release or disclose any tangible or
intangible component thereof to any third party without first receiving the
prior written consent of NYU to said release or disclosure.

 

(b)           The
obligations of confidentiality set forth in Section 11(a) shall not apply to
any component of the Research Technology which was part of the public domain
prior to the Effective Date of this Agreement or which becomes a part of the
public domain not due to some unauthorized act by or omission of CORPORATION
after the effective date of this Agreement or which is disclosed to CORPORATION
by a third party who has the right to make such disclosure.

 

(c)           The
provisions of Section 11(a) notwithstanding, CORPORATION may disclose the
Research Technology to third parties who need to know the same in order to
secure regulatory approval for the sale of Licensed Products.

 

12.           Publication.

 

(a)           Prior
to submission for publication of a manuscript describing the results of any
aspect of the NYU Research Project, NYU shall
send CORPORATION a copy of the manuscript to be submitted by overnight mail or
facsimile transmission, and shall allow CORPORATION thirty (30) days from the
date of such mailing to determine whether the manuscript contains such subject
matter for which patent protection should be sought prior to publication of
such manuscript, for the purpose of protecting an invention made by the NYU
Scientist during the course and within the term of the NYU Research Project.

 

15

 

Should CORPORATION believe
the subject matter of the manuscript contains a patentable invention, then,
prior to the expiration of such 30-day period from the mailing date of such
manuscript to CORPORATION by NYU, CORPORATION shall give written notification
to NYU of:

 

(i)            its determination
that such manuscript contains patentable subject matter for which patent
protection should be sought; and

 

(ii)           the
countries in which such patent protection should be sought.

 

(b)           After
the expiration of such 30-day period from the date of mailing such manuscript
to CORPORATION, unless NYU has received the written notice specified above from
CORPORATION, NYU shall be free to submit such manuscript for publication to
publish the disclosed research results in any manner consistent with academic,
standards.

 

(c)           Upon
receipt of such written notice from CORPORATION, NYU will thereafter delay
submission of the manuscript for an additional period of up to sixty (60) days
to permit the preparation and filing in accordance with Section 6 hereof of a
U.S. patent application by NYU on, the subject matter to be disclosed in such
manuscript.  After expiration of such
60-day period, or the filing of a patent application on each such invention,
whichever shall occur first, NYU shall be free to submit the manuscript and to
publish the disclosed results.

 

13.           Liability
and Indemnification.

 

(a)           CORPORATION
shall indemnify, defend and hold harmless NYU and its trustees, officers,
medical and professional staff, employees, students and agents and their
respective successors, heirs and assigns (the “Indemnitees”) , against any
liability, damage, loss or expense (including reasonable attorneys’ fees and
expenses of litigation) incurred by or imposed upon the Indemnitees or any one
of them in connection with any claims, suits, actions, demands or judgments (i)
arising out of the design, production, manufacture, sale, use in commerce or in
human clinical trials, lease, or promotion by CORPORATION, a Corporation Entity
or an agent of CORPORATION, or by a sublicensee of CORPORATION, a

 

16

 

Corporation Entity or a sublicensee,
of any Licensed Product, process or service relating to, or developed pursuant
to, this Agreement or (ii) arising out of any other activities to be carried
out pursuant to this Agreement.

 

(b)           With
respect to an Indemnitee, CORPORATION’S indemnification under subsection (a)(i)
of this Section 13 shall apply to any liability, damage, loss or expense
whether or not it is attributable to the negligent activities of such
Indemnitee, CORPORATION’s indemnification obligation under subsection (a)(ii)
of this Section 13 shall not apply to any liability, damage, loss or expense to
the extent that it is attributable to the negligent activities of any such
Indemnitee.

 

(c)           CORPORATION
agrees, at its own expense, to provide attorneys reasonably acceptable to NYU
to defend against any actions brought or filed against any Indemnitee with
respect to the subject of indemnity to which such Indemnitee is entitled
hereunder, whether or not such actions are rightfully brought.

 

14.           Security
for Idemnification.

 

(a)           At
such time as any Licensed Product, process or service relating to, or developed
pursuant to, this Agreement is being commercially distributed or sold (other
than for the purpose of obtaining regulatory approvals) by CORPORATION or by a
sublicensee, Corporation Entity or agent of CORPORATION, CORPORATION shall at
its sole cost and expense procure and maintain, or cause, a sublicensee,
Corporation Entity or agent of CORPORATION to procure and maintain, policies of
comprehensive general liability insurance in amounts not less than
$5,000,000.00 per incident and $10,000,000.00 annual aggregate and naming the
Indemnitees as additional insureds.  Such
comprehensive general liability insurance shall provide (i) product liability
coverage and (ii) broad form contractual liability coverage for CORPORATION’s
indemnification under Section 13 of this Agreement.  If CORPORATION elects to self-insure all or
part of the limits described above (including deductibles or retentions which
are in excess of $250,000 annual aggregate) such self-insurance program must be
acceptable to NYU.

 

17

 

The minimum amounts of
insurance coverage required under this Section 14 shall not be construed to
create a limit of CORPORATION’s liability with respect to its indemnification
under Section 13 of this Agreement.

 

(b)           CORPORATION
shall provide NYU with written evidence of such insurance upon request of NYU.  CORPORATION shall provide NYU with written
noticed at least sixty (60) days prior to the cancellation, non-renewal or
material change in such insurance; if CORPORATION does not obtain replacement
insurance providing comparable coverage within such sixty (60) day period, NYU
shall have the right to terminate this Agreement effective at the end of such
sixty (60) day period without notice or any additional waiting periods.

 

(c)           CORPORATION
shall maintain such comprehensive general liability insurance beyond the expiration
or termination of this Agreement during (i) the period that any product,
process or service, relating to, or developed pursuant to, this Agreement is
being commercially distributed or sold (other than for the purpose of obtaining
regulatory approvals) by CORPORATION or by a sublicensee, Corporation Entity or
agent of CORPORATION and (ii) a reasonable period after the period referred to
in (c)(i) above which in no event shall be less than fifteen (15) years.

 

15.           Expiry
and Termination.

 

(a)           Unless
earlier terminated pursuant to this Section 15 or Section 8(e), hereof, this
Agreement shall expire upon the expiration of the period of the License in all
countries as set forth in Section 7(b) above.

 

(b)           At
any time prior to expiration of this Agreement, either party may terminate this
Agreement forthwith for cause, as “cause” is described below, by giving written
notice to the other party.  Cause for
termination by one party of this Agreement shall be deemed to exist if the
other party materially breaches or defaults in the performance or observance of
any of the provisions of this Agreement and such breach or default is not cured
within sixty (60) days or, in the case of failure to pay

 

18

 

any amounts due
hereunder, thirty (30) days (unless otherwise specified herein) after the
giving of notice by the other party specifying such breach or default, or if
either NYU or CORPORATION discontinues its
business or becomes insolvent or bankrupt.

 

(c)           In
the event that CORPORATION determines, at any time following the end of the
Research Period, to cease all development or commercialization of all Licensed
Products covered by this Agreement, CORPORATION may terminate this Agreement by
notifying NYU in writing thereof no less than one hundred twenty (120) days
prior to the date of termination.

 

(d)           Any
amount payable hereunder by one of the parties to the other, which has not been
paid by the date on which such payment is due, shall bear interest from such
date until the date on which such payment is made, at the rate of two percent
(2%) per annum in excess of the prime rate prevailing at the Citibank, N.A., in
New York, during the period of arrears and such amount and the interest thereon
may be set off against any amount due, whether in terms of this Agreement or
otherwise, to the party in default by any non-defaulting party.

 

(e)           Upon
termination of this Agreement for any reason and prior to expiration as set
forth in Section 15(a) hereof, all rights in and to the Research Technology
shall revert to NYU, and CORPORATION shall not be entitled to make any further
use whatsoever of the Research Technology.

 

(f)            Termination
of this Agreement shall not relieve either party of any obligation to the other
party incurred prior to such termination.

 

(g)           Sections
5, 11, 13, 14, 15 and 19 hereof shall survive and remain in full force and
effect after any termination, cancellation or expiration of this Agreement.

 

16.           Representations
and Warranties by CORPORATION.

 

CORPORATION hereby represents and warrants to NYU as follows:

 

(1)           CORPORATION
is a corporation duly organized, validly existing and in good standing under
the laws of the State of California. 
CORPORATION has been granted all requisite power and authority to carry

 

19

 

on its business and to
own and operate its properties and assets. 
The execution, delivery and performance of this Agreement have been duly
authorized by the Board of Directors of CORPORATION;

 

(2)           There
is no pending or, to CORPORATION’s knowledge, threatened litigation involving
CORPORATION which would have any effect on this Agreement or on CORPORATION’s
ability to perform its obligations hereunder;

 

(3)           There
is no indenture, contract, or agreement to which CORPORATION is a party or by
which CORPORATION is bound which prohibits or would prohibit the execution and
delivery by CORPORATION of this Agreement or the performance or observance by
CORPORATION of any term or condition of this Agreement; and

 

(4)           CORPORATION
has received and reviewed copies of the GI Agreement (with the exception of
those sections of the February 6, 1989 Agreement following section 4.1) and
understands and accepts the terms thereof that it has received and reviewed.

 

17.           Representations
and Warranties by NYU.

 

NYU hereby represents and warrants to CORPORATION as follows:

 

(1)           NYU
is a corporation duly organized, validly existing and in good standing under
the laws of the State of New York.  NYU
has been granted all requisite power and authority to carry on its business and
to own and operate its properties and assets. The execution, delivery and
performance of this Agreement have been duly authorized by the Board of
Trustees of NYU.

 

(2)           There
is no pending or, to NYU’s knowledge, threatened litigation involving NYU which
would have any effect on this Agreement or on NYU’s ability to perform its
obligations hereunder; and

 

(3)           There
is no indenture, contract, or agreement to which NYU is a party or by which NYU
is bound which prohibits or would prohibit the execution and delivery by NYU of
this Agreement or the performance or observance by NYU of any term or condition
of this Agreement.

 

20

 

(4)           As
of the Effective Date, NYU is not aware of any prior art that would invalidate
any patent or patent claim, or that would prevent from issuing any patent
application covered by the NYU Patents.

 

18.           No
Assignment.

 

Neither CORPORATION nor
NYU shall have the right to assign, delegate or transfer at any time to any
party, in whole or in part, any or all of the rights, duties and interest
herein granted without first obtaining the written consent of the other to such
assignment, which consent shall not be unreasonably withheld; provided that
(i) CORPORATION may, without the prior consent of NYU, assign all of its rights
and obligations under this Agreement to a third party in connection with a
merger or corporate restructuring of CORPORATION or a sale of all or
substantially all of its assets, following written notice thereof and execution
by the third party with NYU of an agreement to be bound by the terms of this
Agreement and (ii) NYU may assign its interest in this Agreement in whole or in
part without the consent of CORPORATION if such assignee (A) is a parent,
subsidiary, affiliate or related entity to NYU or (B) is an entity that
acquires substantially all of the ownership interests or assets of NYU or New
York University Medical Center (or any successor to the foregoing) or (C) is an
entity formed by NYU or New York
University Medical Center (or any successor to the foregoing) and other
institutions, one of the purposes of which is to perform the activities for
which NYU is obligated pursuant to this Agreement.

 

19.           Use
of Name.

 

Without the prior written
consent of the other party, neither CORPORATION nor NYU shall use the name of
the other party or any adaptation thereof or of any staff member, employee or
student of the other party:

 

(i)            in any
product labeling, advertising, promotional or sales literature;

 

(ii)           in
connection with any public or private offering or in conjunction with any
application for regulatory approval, unless disclosure is otherwise required by
law, in which case either party may make factual statements concerning the
Agreement or file copies of the Agreement after providing the other party with
an opportunity

 

21

 

to comment and reasonable
time within which to do so on such statement in draft.

 

Except as provided
herein, neither NYU nor CORPORATION will issue public announcements about this
Agreement or the status or existence of the NYU Research Project without prior
written approval of the other party.

 

20.           Miscellaneous.

 

(a)           In
carrying out this Agreement the parties shall comply with all local, state and
federal laws and regulations including but not limited to, the provisions of
Title 35 United States Code §200 et  seq. and 15 CFR §368 et
seq.

 

(b)           If
any provision of this Agreement is determined to be invalid or void, the
remaining provisions shall remain in effect.

 

(c)           This
Agreement shall be deemed to have been made in the State of New York and shall
be governed and interpreted in all respects under the laws of the State of New
York.

 

(d)           Any
dispute arising under this Agreement shall be resolved in an action in the
courts of New York State or the federal courts located in New York State, and
the parties hereby consent to personal jurisdiction of such courts in any
action.

 

(e)           All
payments or notices required or permitted to be given under this Agreement
shall be given in writing and shall be effective when either personally
delivered or deposited, postage prepaid, in the United States registered or
certified mail, addressed as follows:

 

To NYU:                New
York University Medical Center

550 First Avenue

New York, NY       10016

 

Attention:              Isaac
T. Kohlberg

Vice President for

    Industrial Liaison

 

and

 

22

 

Office of Legal Counsel

New York University

Bobst Library

70 Washington Square South

New York, NY  10012

 

Attention:              Kathy
L. Schulz

Associate General Counsel

 

To CORPORATION:

 

Collateral Therapeutics,
Inc.

9360 Towne Centre Drive

San Diego, California 92121

 

Attention:              Jack
W. Reich, PhD

President and Chief

Executive Officer

 

or such other address or
addresses as either party may hereafter specify by written notice to the
other.  Such notices and communications
shall be deemed effective on the date of delivery or fourteen (14) days after
having been sent by registered or certified mail, whichever is earlier.

 

(f)            This
Agreement (and the annexed Appendices) constitute the entire Agreement between
the parties and no variation, modification or waiver of any of the terms or
conditions hereof shall be deemed valid unless made in writing and signed by
both parties hereto.  This Agreement
supersedes any and all prior agreements or understandings, whether oral or
written, between CORPORATION and NYU.

 

(g)           No
waiver by either party of any non-performance or violation by the other party
of any of the covenants, obligations or agreements of such other party
hereunder shall be deemed to be a waiver of any subsequent violation or
non-performance of the same or any other covenant, agreement or obligation, nor
shall forbearance by any party be deemed to be a waiver by such party of its
rights or remedies with respect to such violation or non-

performance.

 

(h)           The
descriptive headings contained in this Agreement are included for convenience
and reference only and shall not be held to expand, modify or aid

 

23

 

in the interpretation, construction or meaning of this Agreement.

 

(i)            It
is not the intent of the parties to create a partnership or joint venture or to
assume partnership responsibility or liability. 
The obligations of the parties shall be limited to those set out herein
and such obligations shall be several and not joint.

 

IN WITNESS WHEREOF, the parties hereto have executed this Agreement
effective as of the date and year first above written.

 

	
   

  	
  NEW YORK UNIVERSITY

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  By:

  	
  /s/ Isaac T. Kohlberg

  	
   

  
	
   

  	
   

  	
  Isaac T. Kohlberg

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Title:

  	
  Vice President for Industrial Liaison

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Date:

  	
  3/24/97

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Collateral Therapeutics, Inc.

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  By:

  	
  /s/ Christopher J. Reinhard

  	
   

  
	
   

  	
   

  	
  Christopher J. Reinhard

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Title

  	
  Chief Operating Officer

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
   

  	
  Date:

  	
  3-21-97

  	
   

  

 

24

 

Appendix I

 

Pre-existing NYU Patent and Patent Applications:

 

US patent 5,459,250 entitled “Truncated Mammalian
Growth Factor DNA Sequence” and US patent applications Serial No. 08/056,482
filed May 3, 1993, Serial No. 08/478,485 filed June 7, 1995, Serial No. 08/478,486 filed June 7, 1995, Rule 60
continuing patent application filed December 31, 1996 and US divisional patent application
filed February 13, 1997.

 

PCT filing /US90/06702 filed November 15, 1990

Serial No. 91900453 Europe filed June 12, 1992

Serial No, 2,068,871  Canada filed May
15, 1992

Serial No, 501065/1991 Japan filed August 19, 1992

Serial No, 68942/91 Australia filed November 15, 1990

 

 

APPENDIX I

 

PRE-EXISTING
NYU PATENTS AND PATENT APPLICATIONS

 

	
  U.S. APPLICATIONS

  	
   

  	
  Serial No.

  	
   

  	
  Filing Date

  	
   

  	
  Status

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Mammalian
  Growth Factor

  	
   

  	
  07/062,925

  	
   

  	
  6/16/87

  	
   

  	
  ABANDONED

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Mammalian
  Growth Factor 

  	
   

  	
  07/177,506

  	
   

  	
  4/4/88

  	
   

  	
  ABANDONED

  
	
  (CIP of 07/062,925)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Mammalian
  Growth Factor 

  	
   

  	
  07/806,771

  	
   

  	
  12/6/91

  	
   

  	
  ABANDONED

  
	
  (Cont. of 07/177,506)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Mammalian
  Growth Factor 

  	
   

  	
  07/901,705

  	
   

  	
  6/22/92

  	
   

  	
  ABANDONED

  
	
  (CIP
  of 07/806,771)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Mammalian
  Growth Factor 

  	
   

  	
  08/056,482

  	
   

  	
  5/3/93

  	
   

  	
  Allowed - Issue 

  Fee
  Paid 1/1/97

  
	
  (Cont.
  of 07/806, 771)

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Truncated
  Mammalian Growth 

  Factor
  DNA Sequence 

  (Cont. of 07/901,705)

  	
   

  	
  08/187,780

  	
   

  	
  1/25/94

  	
   

  	
  Issued -

  U.S.
  Patent No. 

  5,459,250

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Mammalian
  Growth Factor 

  (Div.
  of 08/187,780)

  	
   

  	
  08/478,485

  	
   

  	
  6/7/95

  	
   

  	
  Pending

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Mammalian
  Growth Factor 

  (Div.
  of 08/187,780)

  	
   

  	
  08/478,486

  	
   

  	
  6/7/95

  	
   

  	
  Pending

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Mammalian
  Growth Factor 

  (Cont. of 08/056,482)

  	
   

  	
  Not yet assigned

  	
   

  	
  12/31/96

  	
   

  	
  Pending

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Mammalian
  Growth Factor
 (Div. of 08/056,482) 

  	
   

  	
  Not yet assigned

  	
   

  	
  2/13/97

  	
   

  	
  Pending 

  

 

 

FOREIGN
APPLICATIONS

 

The following patents
and patent applications are based upon International Application No. PCT/US90/06702, filed November 15, 1990 and
all are entitled “NON GLYCOSYLATED FGF-4 AND COMPOSITIONS CONTAINING THE SAME”.

 

	
  Country

  	
   

  	
  Application No.

  	
   

  	
  Filing Date

  	
   

  	
  Status

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Australia

  	
   

  	
  68942/91

  	
   

  	
  11/15/90

  	
   

  	
  Issued 2/24/94

  Patent No. 642,947

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Canada

  	
   

  	
  2,068,871

  	
   

  	
  11/15/90

  	
   

  	
  Pending

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  EPC

  	
   

  	
  91900453

  	
   

  	
  11/15/90

  	
   

  	
  Pending

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Japan

  	
   

  	
  501065/1991

  	
   

  	
  11/15/90

  	
   

  	
  Pending

  

 

 

APPENDIX II

 

RESEARCH PROGRAM

 

THIRD GENERATION
FGF-4 MOLECULES

 

BACKGROUND

 

The FGFs family includes at least nine growth factors which show a
variable degree of homology within a conserved
“core” region. Although originally identified
for their growth promoting activity in fibroblasts, FGFs affect the proliferation or differentiation of a variety of
cells of mesenchymal and -neuroectodermal
origin.  Furthermore, many FGFs have been
shown to be angiogenic in vivo and in
vitro. The action of FGFs is mediated by their interaction with the high
affinity FGF receptors that also constitute a gene family of Receptor Tyrosine Kinases (RTK). (Basilico and Moscatelli,
1992)

 

The
receptors for the FGF family of growth factors are encoded by four distinct but homologous genes called FGFR-1/flg,
FGFR-2/bek, FGFR-3 and FGFR-4 These membrane-spanning
receptors have tyrosine kinase domains in their intracellular regions while their extracellular portion consists
of three immunoglobulin (Ig)-like loops.
Alternative splice variants of receptors 1, 2 and 3 have been isolated which
have alternative amino acids in the second half of Ig-loop III which are
encoded in three separate exons (IIIa,
IIIb and IIIc). This region is important in ligand-binding and variants of each receptor type have different
affinities for the various FGFs, In general,
the receptors have overlapping ligand-binding specificities with each receptor being able to bind more than one ligand
(Ornitz et al, 1996). The most restricted specificity is seen in the
case of the KGF receptor - a IIIb-splice variant of FGFR-2, which binds only FGF-7 (KGF), while the IIIc form can bind
FGF-1, FGF-2, FGF-4, FGF-5 and FGF-9 but not FGF-7. Binding of FGF to FGFR is
modulated by the

 

 

interaction of the ligand with heparin or Heparin sulfate
proteoglycans (HSPG) (Yayon
et al, 1991). While the major effect of heparin binding on the FGF-FGFR interaction is not fully clarified, it is generally
agreed that a sustained activation of FGFR signaling cannot be achieved in the
absence of heparin or HSPG. Heparin binding does not appear to alter the
conformation of FGFs, but is known to stabilize them and affect binding affinity. This could result from ligand oligomerization,
which in turn influences sustained
receptor dimerization (Roghani et al, 1994 Spivak-Kroizman et al, 1994). As mentioned above, binding of FGFs to
their receptors exhibits only partial specificity. Thus the tissue distribution
of FGFR expression, the presence and concentration of a specific ligand, and
the relative affinity of the ligand -receptor interaction will all determine
whether a specific FGF can activate
a specific FGFR in a tissue or organ.

 

FGFs (and thus FGF signaling) have been implicated
in a variety of physiological and pathological processes. As mentioned
above, many FGFs are angiogenic,
because they can interact with specific receptors (mainly FGFR-1) which are present on the surface of vascular endothelial
cells. In addition to induce proliferation
of fibroblasts and in some cases of epithelial cells, they are potent neurotrophic factors, as they increase the
survival of neurons in culture, and may influence the proliferation and differentiation of neuronal progenitor
cells (Temple and Qian, 1995). FGFs
can also induce or inhibit differentiation in a variety of cell types (e.g. of myoblasts into myotubes).
Furthermore, several FGFs have been identified as oncogenes, because their
ectopic expression can create an autocrine growth loop in cells expressing the appropriate receptors. They can also
function as tumor progression agents
by inducing tumor vascularization (Basilico and Moscatelli, 1992).

 

 

In spite of an
impressive number of publications, the roles that FGFs play vivo in tissue
homeostasis, regeneration and development are only beginning to be
understood.  Several lines of evidence
indicate that FGF signaling plays a major role in development. FGF signaling
has been shown to be important for mesoderm induction in Xenopus (Amaya et al,
1991; Amaya et al, 1993). Developmental abnormalities are associated with
knock-out of the FGF-4, FGF-8 and FGF-3 genes as well as of FGFR-1 and FGFR-2
(Mansour et al, 1993; Deng et al, 1994; Yamaguchi et al, 1994; Feldman et al, 1995) and targeting of
dominant-negative receptor molecules to various organs in transgenic mice also
results in a variety of defects in development (Werner et al, 1993; Peters et
al, 1994; Mima et al, 1995; Campochiaro et al, 1996). Furthermore, a number of
autosomally dominant genetic syndromes leading to bone malformations, including
achondroplasia, Crouzon syndrome, thanatophoric dysplasia etc., have been
linked to mutations in FGFR-1, 2 and 3 (Muenke and Schell, 1995). These
mutations, which occur in different regions of the receptor molecules, appear
to share the property of being “activating”/mutations, ie. to produce a
receptor which signals in a ligand-independent manner (Webster and Donoghue,
1996; Galvin et al 1996; Naski et al, 1996; Li et al, 1997). However, the
precise mechanism by which uncontrolled FGF signaling leads to skeletal and
skull malformations has not yet been elucidated.

 

The situation in the adult is far less clear. While
many FGFs have been shown to be angiogenic in a variety of experimental
settings, and exert other important effects on tissue homeostatis (e.g. promote
neuronal survival) (Basilico and Moscatelli, 1992; Baird, 1994), studies on
mice in which specific FGF genes which are normally expressed in the adult have
been inactivated by homologous recombination has produced somewhat surprising
results. Knock-out of FGF-5 only produces a long-hair phenotype (Hebert et al,
1994), and no defect in wound healing

 

3

 

has been associated with the knock-out of FGF-7 (Guo
et al, 1996).  Knock-out of one of the
FGF prototypes, FGF-2 (basic FGF) produces no overt phenotype, although subtle
defects have begun to emerge (Ortega S. and Basilico, C., unpublished results).
A likely explanation for these observations is that the FGF family of growth
factors exhibits a high degree of redundancy, such that one FGF can easily
fulfill the function of another (e.g. FGF-1 for FGF-2).

 

The answer to some of the questions raised
above will undoubtedly derive from the many experiments of gene knock-out,
transgenic expression etc: that are being carried out in our as well as in
other laboratories, and will certainly suggest rational and perhaps unexpected
indications for FGFs in clinical interventions. For present and future usages
of FGFs in a clinical setting it will be however desirable to create new FGF
molecules with broader spectrum of action and higher potency or stability. We plan
to create such molecules, starting from FGF-4, which is the main subject of
this research agreement FGF-4 is normally only expressed during development,
where it plays an important role in post-implantation development and limb bud
formation. It is a secreted protein which has already been shown to be a potent
mitogen for a variety of cells and to be angiogenic in vivo.

 

SPECIFIC AIMS OF THE RESEARCH PROGRAM

 

As mentioned above, FGFs exhibit only partial
specificity for binding to their receptors. For example, while at present FGF-1
appears to be the ligand capable of binding and activating with very high
affinity all known FGF receptor isoforms (Ornitz et al, 1996), FGF-1 is quite
unstable and may not be the best universal activator. Similarly, FGF-4 binds
with high affinity to FGFR-2 and with somewhat lower affinity to FGFR-1, but
does not bind with high affinity FGFR-3 and-4, FGF-2

 

4

 

binds equally well FGFR-1 and-2, but is a poor ligand
for all other receptors. It would be desirable therefore for experiments of
gene therapy or for any clinical use to develop FGF ligands which either bind
only one of the receptors, or exhibit broad specificity together with high
potency.  Furthermore, in clinical
application of molecules, such as FGF-4, immunogenicity could pose a problem.
Thus, if possible, it would be also desirable to generate a new FGF ligand with
low immunogenicity.

 

We already know from previous studies that
subtle alterations in the ligand structure can result in higher affinity
receptor binding. A case in point is the K140 truncated FGF-4 molecule
(Bellosta et al, 1993), which binds FGFR-1 and FGFR-2 (but not FGFR-3 and -4)
with higher affinity than FGF-4, and is consequently about 5 times more potent
as a mitogen in cells expressing these receptors. Preliminary studies also
indicate that K140 is more stable than FGF-4. We propose therefore to study the
possibility of creating, starting from the FGF-4 molecule, and maintaining its
secreting properties, new FGF ligands with increased binding efficiency to
specific receptors, with an emphasis on receptors expressed in cardiac myocytes
or heart endothelial cells. In addition we will try to create molecules which
are more stable and possibly less immunogenic than the ones presently
available. This investigation will require a preliminary study of exactly what
type of receptors are expressed in the heart tissues. Although the available
evidence suggests that it is mainly FGFR-1, this will have to be confirmed.
Furthermore, the design of new FGF-4 molecules would obviously benefit from the
knowledge of the tridimensional structure of FGF-4. We plan to collaborate with
a group of x-ray crystallographers to obtain this information. The crystal
structures of FGF-1 and FGF-2 are known, and some knowledge can also be derived
from those.

 

5

 

The strategy that we plan to follow will
consist of creating either N-terminally shorter FGF-4 molecules, similar to the
K140 molecule previously described, chimeric molecules between FGF-4 and other
FGFs, or specific mutations in conserved and non-conserved domains of FGF-4 (or
K140).  The receptor binding domain(s) of
FGF molecules have not yet been precisely identified, possibly because they are
conformational domains. It is however known that specific regions of these
molecules contribute to receptor binding specificity (Seddon et al, 1995) and
this knowledge will help in designing new FGF molecules. According to the most
recently published data (Ornitz et al, 1996) FGF-4 is a highly potent activator
of FGFR-1, FGFR-2 (the IIIc isoforms) and of FGFR-4. These data however are at
some variance with our binding data, which indicate a binding affinity
decreasing from FGFR-2c > FGFR-lc > FGFR4.
While these discrepancies may be explained by a variety of factors, it is clear
that FGF-4 binds to and activates poorly the FGFR-2b form. Since this receptor
is preferentially expressed in cells of ectodermal origin (e.g. keratinocytes)
it would be desirable to obtain an FGF-4 molecule capable of activating FGFR-2b
as well as the other receptors. This will be the first objective of this
program.  Mutant FGF-molecules will be
expressed in mammalian cells as secreted proteins, or in bacteria as mature
proteins, and tested in vitro for receptor activation, mitogenicity, stability,
etc. Cell lines expressing specific FGF receptors as well as a variety of
endothelial cell lines are all available in our laboratory.

 

REFERENCES

 

Amaya, E., Musci, T.J. and Kirschner, M.W. (1991) Cell
66:257-270

 

Amaya E., Stein, P.A., Musci, T.J. and Kirschner, M.W.
(1993) Development 118:477-487

 

6

 

Baird, A. (1994) Curr. Opin. Neurobiol. 4:78-86 

 

Basilico, C. and Moscatelli, D. (1992) Adv. Cancer
Res, 59:115-165 

 

Bellosta, P., Talarico, D., Rogers, D. and Basilico, C.
(1993) J of Cell Biol 121:705-713

 

Campochiaro, P.A., Chang, M., Ohsato, M., Vinores,
S.A., Nie, Z., Hjelmeland, L., Mansukhani, A., Basilico, C. and Zack, D.J.
(1996) J. Neurosci. 16:1679-1688

 

Deng, C.X., Wynshaw-Boris, A., Shen, M.M., Daugherty,
C., Ornitz, D.M. and Leder, P. (1994) Genes & Dev. 8:3045-3057

 

Feldman, B., Poureymirous, W., Papaioannou, V.E.,
DeChiara, T.M. and Goldfarb, M.(1995) Science 267:246-248

 

Galvin, B.D., Hart, K.C., Meyer, A.N., Webster, M.K.
and Donoghue, D.J. (1996) Proc. Natl. Acad. Sci. 93:7894-7899

 

Li, Y., Mangasarian, K., Mansukhani, A. and Basilico,
C. (1997) Oncogene, in press

 

Mima, T., Ueno, H., Fischman, D.A., Williams, L.T. and
Mikawa, T. (1995) Proc. Natl. Acad. Sci. 92:467-471

 

Muenke, M. and Schell V. (1995) TIGS 11:308-313

 

Naski, M.C., Wang, Q., Xu, J. and Ornitz, D.M. (1996)
Nature Genetics 13:233-237

 

7

 

Ornitz, D.M., Xu, J., Colvin, J.S., McEwen, D.G.,
MacArthur, C.A., Coulier, F., Gao, G. and Goldfarb, M. (1996) J. Biol. Chem.
271:15292-15297

 

Peters, K., Werner, S., Liao, X., Wert, S., Whitsett,
J. and Williams, L. (1994) EMBO J. 13:3296-3301

 

Roghani, M., Mansukhani, A., Dell’Era, P., Bellosta,
P., Basilico, C., Rifkin, D.B. and Moscatelli, D. (1994) J. Biol. Chem.
269:3976-3984

Seddon, A.P., Aviezer, D., Li, L.Y., Bohlen, P. and
Yayon, A. (1995) Biochemistry 34:731-736

 

Spivak-Kroizman, T., Lemmon, M.A., Dikic, I., Ladbury,
J.E., Pinchasi, D, Huang, J., Jaye, M., Crumley,
G., Schlessinger, J., and Lax L. (1994) Cell 79:1015-1024

 

Temple, S. and Qian, X. (1995) Neuron
15:249-252

 

Webster, M.K. and Donoghue, D.J. (1996) EMBOJ.
15:520-527

 

Werner, S., Weinberg, W., Liao, X., Peters, K.G.,
Blessing, M., Yuspa, S.H., Weiner, R.L. and Williams, L.T. (1993) EMBO J.
12:2635-2643

 

Yamaguchi, T.P., Kendraprasad, H., Henkemeyer, M and
Rossant, J. (1994) Genes & Dev. 8:3032-3044

 

8

 

Appendix
III. Collateral Therapeutics
Development Plan

 

Anglogenesis:
Myocardial Ischemia Draft Timeline

 

	
  Activity

  	
   

  	
  Duration

  	
   

  	
  Start

  	
   

  	
  Finish

  	
   

  	
  1997

  	
   

  	
  1998

  	
   

  	
  1999

  	
   

  	
  2000

  	
   

  	
  2001

  	
   

  	
  2002

  	
   

  	
  2003

  	
   

  	
  2004

  	
   

  
	
  Anglogensis: Myocardial Ischemia

  	
   

  	
  344w

  	
   

  	
  3/1/97

  	
   

  	
  10/3/03

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
   

  	
   

  
	
  FGF-4 gene Identified

  	
   

  	
  0w

  	
   

  	
  3/1/97

  	
   

  	
  3/1/97

  	
   

  	
  **

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  File IND 

  	
   

  	
  0w

  	
   

  	
  5/29/98

  	
   

  	
  5/29/98

  	
   

  	
   

  	
   

  	
  **

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  File PLA with FDA

  	
   

  	
  0w

  	
   

  	
  9/27/02

  	
   

  	
  9/27/02

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  **

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  PLA approval

  	
   

  	
  0w

  	
   

  	
  10/3/03

  	
   

  	
  10/3/03

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  **

  	
   

  	
   

  	
   

  

 

Project: Anglogenesis

Date: 3/3/97

 

	
  *

  	
  Task

  
	
  **

  	
  Milestone

  
	
  ***

  	
  Critical

  
	
  ****

  	
  Progress

  
	
  @

  	
  Summary

  

 

 

Anglogenesis:
Peripheral Vascular Disease Draft Timeline

 

	
  ID

  	
   

  	
  Activity

  	
   

  	
  Duration

  	
   

  	
  Start

  	
   

  	
  Finish

  	
   

  	
  1997

  	
   

  	
  1998

  	
   

  	
  1999

  	
   

  	
  2000

  	
   

  	
  2001

  	
   

  	
  2002

  	
   

  	
  2003

  	
   

  	
  2004

  	
   

  
	
  1

  	
   

  	
  Anglogensis: Peripheral Vascular Diseas

  	
   

  	
  312w

  	
   

  	
  1/1/97

  	
   

  	
  12/24/03

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2

  	
   

  	
  Pre-clinicial research

  	
   

  	
  98w

  	
   

  	
  1/1/97

  	
   

  	
  11/3/93

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  3

  	
   

  	
  Recombinant adenovirus/In vitro testi

  	
   

  	
  39w

  	
   

  	
  1/1/97

  	
   

  	
  9/30/97

  	
   

  	
  *

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  4

  	
   

  	
  In vivo studies(plg) 

  	
   

  	
  62w

  	
   

  	
  2/26/97

  	
   

  	
  6/5/98

  	
   

  	
  *

  	
   

  	
  *

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  5

  	
   

  	
  Toxcology studies

  	
   

  	
  28w

  	
   

  	
  5/6/98

  	
   

  	
  11/3/98

  	
   

  	
   

  	
   

  	
  *

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  6

  	
   

  	
  Pharmacodynamics study

  	
   

  	
  39.2w

  	
   

  	
  6/27/97

  	
   

  	
  5/27/98

  	
   

  	
  *

  	
   

  	
  *

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  7

  	
   

  	
  Formulation & stability studies

  	
   

  	
  39w

  	
   

  	
  10/1/97

  	
   

  	
  6/30/98

  	
   

  	
  *

  	
   

  	
  *

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  8

  	
   

  	
  File IND

  	
   

  	
  0w

  	
   

  	
  11/3/98

  	
   

  	
  11/3/98

  	
   

  	
   

  	
   

  	
  **

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  9

  	
   

  	
  Clinical

  	
   

  	
  221w

  	
   

  	
  10/1/97

  	
   

  	
  12/25/01

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
  @

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  10

  	
   

  	
  Pilot product manufacturing 

  	
   

  	
  70w

  	
   

  	
  10/1/97

  	
   

  	
  2/2/99

  	
   

  	
  *

  	
   

  	
  *

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  11

  	
   

  	
  Clinicial studies 

  	
   

  	
  143w

  	
   

  	
  12/16/98

  	
   

  	
  9/11/01

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  *

  	
   

  	
  *

  	
   

  	
  *

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  12

  	
   

  	
  File
  market approval with FDA

  	
   

  	
  0W

  	
   

  	
  12/25/01

  	
   

  	
  12/25/01

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  **

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  13

  	
   

  	
  Marketing

  	
   

  	
  52W

  	
   

  	
  12/26/01

  	
   

  	
  12/24/02

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  @

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  14

  	
   

  	
  Large
  scale production

  	
   

  	
  52W

  	
   

  	
  12/26/01

  	
   

  	
  12/24/02

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  *

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  15

  	
   

  	
  Product
  marketing/sales

  	
   

  	
  0W

  	
   

  	
  12/24/02

  	
   

  	
  12/24/02

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  	
  **

  	
   

  	
   

  	
   

  	
   

  	
   

  

 

Project: Peripheral Vascular Dise

Date: 3/13/97

 

	
  *

  	
  Task

  
	
  **

  	
  Milestone

  
	
  ****

  	
  Progress

  
	
  @

  	
  Summary

  

 

 

FIRST AMENDMENT TO AGREEMENT

 

This First Amendment to Agreement (hereafter “Amendment”)
is effective on April 28, 1998 by and between COLLATERAL THERAPEUTICS INC., a
corporation organized and existing under the laws of California, having a place
of business at 9360 Town Centre Drive, San Diego, California 92121 (hereafter “CORPORATION”);
and NEW YORK UNIVERSITY, a corporation organized and existing under the laws of
the State of New York, having a place of business at 70 Washington Square
South, New York, New York 10012 (hereafter “NYU”),

 

WITNESSETH:

 

WHEREAS, CORPORATION and NYU entered into a
certain agreement made and effective as of March 24, 1997 (the “Agreement”),
pursuant to which, inter alia. CORPORATION undertook to sponsor certain
research at NYU and NYU granted to CORPORATION a license to certain Research
Technology (as such term is defined in the Agreement); and

 

WHEREAS, CORPORATION and NYU desire to expand
the scope of the research under the terms and conditions of the Agreement as
specified herein; and

 

WHEREAS, NYU desires to perform such research;
and

 

WHEREAS, CORPORATION desires to provide
additional research funds to NYU for the performance of such research by NYU;

NOW, THEREFORE, in consideration of the
premises and the covenants, conditions and promises set forth below, the
parties hereto hereby agree as follows:

 

1.             Except as expressly provided for herein, all
terms and conditions of the Agreement shall remain in full force and effect.

 

2.             Terms which are defined in the Agreement shall
have the same meanings when used in this Amendment, unless a different
definition is given herein.

 

 

3.             Section 1(m) of the
Agreement shall be, and hereby is, amended in its entirety so that, as amended,
said Section 1(m) shall read as follows:

 

1(m)        “NYU Research Project” shall mean the investigations
at NYU during the Research Period into the Field under the supervision of the
NYU Scientist in accordance with the research program, described in annexed
Appendix II and in annexed Exhibit A to the Amendment, each of which forms an
integral part hereof.

 

4.             Section 4(a) of the
Agreement shall be, and hereby is, amended in its entirety so that, as amended,
said Section 4(A) shall read as follows:

 

4(a)         As compensation to NYU for work to be performed on the
NYU Research Project during the Research Period, subject to any earlier
termination of the Research Project pursuant to Section 3(a) hereof,
CORPORATION will pay NYU the total sum of $675,000, payable in six successive
semiannual installments, commencing on the Effective Date; the first three
installments shall be in the amount of $100,000 each; the fourth installment
shall be in the amount of $175,000; the fifth and sixth installments shall be
in the amount of $100,000 each.

 

IN WITNESS WHEREOF, the parties hereto have executed
this Amendment as follows:

 

	
  NEW YORK UNIVERSITY

  	
  COLLATERAL THERAPEUTICS,
  INC,

  
	
   

  	
   

  
	
  By:

  	
  /s/ [ILLEGIBLE]

  	
   

  	
  By:

  	
  /s/ [ILLEGIBLE]

  
	
   

  	
   

  
	
  Title:

  	
  Vice
  President for Industrial Liaison

  	
  Title:

  	
  COO & CFO

  
	
   

  	
   

  
	
  Date

  	
  5.1.98

  	
  Date:

  	
  April 29, 1998

  
									

 

 

EXHIBIT A

 

Specific Aims

 

Our plan is to construct a mammalian expression vector
expressing a truncated form of FGF-4 (K140, Bellosta, et al, J Cell. Biol.
121:705-713, 1993). This truncated form of FGF-4 was shown to result from the
spontaneous cleavage of unglycosylated FGF-4 molecules at position 66 of the
FGF-4 precursor protein, and was shown to have higher biological activity and
receptor binding affinity than the wild-type, mature FGF-4. Thus such a
molecule should have desirable properties in experiments aimed at inducing
collateral circulation in the myocardium of patients with coronary stenosis.

 

Research Plan

 

We have plasmids expressing the unglycosylated mutant
of FGF-4, whose protein product is cleaved in tissue culture by a cellular
protease to produce K140. However, since this protease is unknown, there is no
guarantee that it may be expressed in all tissues and operate efficiently in
vivo.  Therefore we will construct a
plasmid which should only produce directly the K140 protein. The strategy to
produce this plasmid will be as follows: We will create two deletions (see
diagram) linking the FGF-4 signal peptide to the N-terminus of K140, that
should produce three possible peptides differing only in the number of Alanines
(1, 2 or 3) at their N-terminus.
The FGF-4 signal peptide naturally causes cleavage in two positions in the
FGF-4 precursor protein, downstream of A30 or A31 and presumably this type of
cleavage will be preserved in the internally deleted molecule, which should
produce mature forms of 140 amino acids (K140, 2A at the N-terminus) 141 (3A at
the N-terminus), or 139 (1A at the N-terminus). 
We do not know whether the presence of an additional Alanine or the lack
of one will alter the properties of K140, although that seems unlikely, and
that is the reason why it may be useful to have two constructs.  The construction of these plasmids although
apparently simple is going to be laborious because of the high GC content of
the 5’ of the FGF-4 cDNA. The method which will be used is the following:

pGemKS3A (encoding
the wild type FGF-4) will be linearized with Pvul and subjected to PCR. Primers
used will be GGG GGC GCC GCC GCG GCC GTC CAG AGC GGC GCC GGC (spanning the
deletion from nt 342 to 441) and SP6. The PCR product will be cloned in the TA
vector (Invitrogen) and used as a template for two rounds of PCRs with oligos
extending the 5’ end till bp 258 of the FGF-4 cDNA (including a Eco47III site
at 281 bp). These two rounds of PCRs will be performed by preheating the
samples at 94° C for 10 minutes and PCR performed as before except that the
annealing temperature will be 65° C and include 10% DMSO. For each round the
PCR product will be gel purified. The product will be cloned into TA vector and
sequenced to verify the deletion junction. The presence of the Eco47III site
will be verified by restriction digestion. This site will be used to insert the
Eco47III fragment from pGEMKS3B containing the 281 bp 5’ end fragment of the
FGF-4 cDNA. All PCR generated mutations downstream of the deletion will be
eliminated by cloning the NgoM1 fragment containing the deletion into the
PGEMKS3B vector cut with NgOM1 in order to reconstitute the deletion-containing

 

 

full length coding sequence. Finally, the EcoRI
fragment containing the full length cDNA encoding the internally deleted FGF-4
will be isolated, and subcloned into p91023B mammalian expression vector.

 

Once
the deleted molecules are constructed, they will be inserted into a mammalian
expression vector and tested for expression, production and secretion of the
correct protein, and biological activity of the protein produced. This will be
tested in a mitogenic assay comparing it to known amounts of recombinant FGF-4,
and by testing the ability of the plasmids encoding the deleted molecule to
transform NIH3T3 cells. We will also determine the stability of the protein
produced upon thermal inactivation. If these assays prove satisfactory, the
mutated cDNA will be available for insertion into Adenovirus vectors and
testing in the pig model of
coronary stenosis.

 

2

 

	
  1

  	
   

  	
  MSGPGTAAVALLPAVLLALLAPWAGRGGAAAPTAPNGTLEAELERRWESL

  	
   

  	
  50

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  51

  	
   

  	
  VALSLARLPVAAQPKE K140AAVQSGAGDYLLGIKRLRRLYCNVGIGFHLQALP

  	
   

  	
  100

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  101

  	
   

  	
  DGRIGGAHADTRDSLLELSPVERGVVSIFGVASRFFVAMSSKGKLYGSPF

  	
   

  	
  150

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  151

  	
   

  	
  FTDECTFKEILLPNNYNAYESYKYPGMFUALSKNGKTKKGNRVSPTMKVT

  	
   

  	
  200

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  201

  	
   

  	
  HFLPRL

  	
   

  	
  206

  

 

1)      Amino acid sequence of the human K-FGF precursor
protein. The hydrophobic signal peptide is underlined. The arrows indicate the
sites of cleavage of the mature, secreted form of K-FGF. Asterisks indicate the
glycosylation signal. The bracket indicates the sites of cleavage which
generates the 15-kD K140 protein.

 

MSGPGTAAVALLPAVLLALLAPWAGRGGAAAAAVQSGAGD

 

MSGPGTAAVALLPAVLLALLAPWAGRGGAAAAVQSGAGD

 

2)      Sequence encoded in the deleted molecules. The arrows
indicate the expected sites of cleavage downstream of the signal peptide.

 

3

 

SECOND AMENDMENT TO AGREEMENT

 

This Second Amendment to Agreement (hereafter “Second
Amendment”) is effective on March 24, 2000 by and between COLLATERAL
THERAPEUTICS INC., a corporation organized and existing under the laws of
Delaware, having a place of business at 11622 El Camino Real, San Diego,
California 92130 (hereafter “CORPORATION”); and NEW YORK UNIVERSITY, a
corporation organized and existing under the laws of the State of New York,
having a place of business at 70 Washington Square South, New York, New York
10012 (hereafter “NYU”).

 

WITNESSETH:

 

WHEREAS, CORPORATION and NYU entered into a
certain agreement made and effective as of March 24, 1997 and First Amendment
to Agreement effective as of April 28, 1998 (together the “Agreement”),
pursuant to which, inter alia, CORPORATION undertook to sponsor certain
research at NYU and NYU granted to CORPORATION a license to certain Research
Technology (as such term is defined in the Agreement); and

 

WHEREAS, CORPORATION and NYU desire to extend the term
of the research period and expand the scope of the research under the terms and
conditions of the Agreement as specified herein; and

 

WHEREAS, NYU desires to perform such research;
and

 

WHEREAS, CORPORATION desires to provide
additional research funds to NYU for the performance of such research by NYU;

 

NOW, THEREFORE, in consideration of the
premises and the covenants, conditions and promises set forth below, the
parties hereto hereby agree as follows:

 

1.             Except as expressly
provided for herein, all terms and conditions of the Agreement shall remain in
full force and effect.

 

2.             Terms which are
defined in the Agreement shall have the same meanings when used in this Second
Amendment, unless a different definition is given herein.

 

3.             Section 1(1) of the
Agreement shall be, and hereby is, amended in its entirety so that, as amended,
said Section 1(1) shall read as follows:

 

1(1)        “Research Period” shall mean the six-year
period commencing on the Effective Date hereof and any extension thereof as to
which NYU and CORPORATION shall mutually agree in writing.

 

4.             Section 1(m) of the
Agreement shall be, and hereby is, amended in its entirety so that, as amended,
said Section 1(m) shall read as follows:

 

1(m)        “NYU Research Project” shall mean the
investigations at NYU during the Research Period into the Field under the
supervision of the NYU Scientist in accordance with the research program,
described in annexed Appendix II, in annexed Exhibit A to the First Amendment,
and in annexed Exhibit A to the Second Amendment each of which forms an
integral part hereof.

 

 

5.           Section 4(a) of the
Agreement shall be, and hereby is, amended in its entirety so that, as amended,
said Section 4(A) shall read as follows:

 

4(a)        As compensation to
NYU for work performed on the NYU Research Project during the Research Period,
subject to any earlier termination of the Research Project pursuant to Section
3(a) hereof, CORPORATION will pay NYU (i) the sum of $675,000, payable in six
successive semiannual installments, commencing on the Effective Date; the first
three installments shall be in the amount of $100,000 each; the fourth
installment shall be in the amount of $175,000; the fifth and sixth
installments shall be in the amount of $100,000 each; NYU acknowledges that as
of September 28, 1999, CORPORATION has paid this amount in full; and (ii) the
sum of $396,000 payable in six, equal, successive semiannual installments, the
first of which shall be due within fifteen (15) days after the signature of this
Second Amendment by the last party to sign (the “Execution Date”).

 

IN WITNESS WHEREOF, the parties hereto have executed
this Amendment as follows:

 

	
  NEW
  YORK UNIVERSITY

  	
  COLLATERAL THERAPEUTICS, INC.

  
	
   

  	
   

  
	
  By:

  	
  /s/ [ILLEGIBLE]

  	
   

  	
  By:

  	
  /s/ [ILLEGIBLE]

  
	
   

  	
  Vice Dean for Industrial Liaison

  	
   

  	
   

  	
  President and Chief Operating Officer

  
	
   

  	
  and Research Administration

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  
	
  Date:

  	
  7/24/00

  	
   

  	
  Date:

  	
  07-05-00

  	
   

  
									

 

 

EXHIBIT A

to the Second
Amendment

 

Structural and biological analysis of the
interaction of FGF4 with FGF receptors

 

INTRODUCTION

 

The family of fibroblast growth factors (FGF)
is one of the largest family of growth factors with a multiplicity of
biological functions which impact on a variety of biological processes. FGFs
can affect the proliferation and differentiation of a variety of cells of
mesenchymal and neuro-ectodermal origin, and it has become evident that,
clearly the most important role of FGF signaling is during development (1,2).

 

FGF signaling has been shown to play a major
role in a number of developmental processes, including embryonic mesoderm
induction and post-implantation blastocyst development. FGF signaling is also
essential for the development of limb and lungs and unregulated FGF signaling
leads to a variety of human bone morphogenic disorders, including dwarfism and
craniosynostosis syndromes. FGFs are also potent angiogenic factors; the
sprouting of new blood vessels from a pre-existing one is an essential
physiological process in development, but also plays a major role in human
diseases, such as diabetic retinopathy, arteriosclerosis, and cancer (2).

 

The FGF family includes at present twenty-two
members including four (FGF11-  14, FHF) which may not be bonafide FGFs. Ten
(FGF1-10) are best characterized (1,2). FGFs action is mediated by their interaction
with high affinity receptors. FGF receptors (FGFR) also constitute a family of four
related, membrane spanning tyrosine kinases, with a conserved structure, including three
Ig-like loops in the extracellular domain, and a split cytoplasmic tyrosine kinase domain
(1-3). The FGFR genes produce m-RNAs which can undergo alternative splicing to
produce different FGFR isoforms. 
Splicing alternatives which result in modification of the sequence of the third
Ig loop are biologically important, as they can alter the binding specificity of the
receptor. Binding

 

1

 

of FGFs to their receptors shows only partial and
overlapping specificity, such that one receptor can bind multiple ligands with
variable affinity (3,4).

 

This complex system of ligand-receptor
specificity is also characterized by the fact that FGFs need to interact with
the so called low-affinity receptors, which consist of cell surface Heparan
sulfate proteoglycans (HSPG) and can be replaced by soluble heparin, in order
to activate FGFRs (5). Receptor activation requires interaction of FGFs with
HSPG or heparin. These molecules simultaneously interact with the receptor
forming a trimeric receptor-heparin-ligand structure (6,7). Heparin oligosaccharides
also exhibit considerable specificity in ligand/receptor interaction (8). Thus
the interaction of FGFs with their receptors is regulated at a variety of
levels, including growth factor expression, specificity of receptor binding and
interaction with HSPG.

 

FGFs range in molecular weight from 18 to 29
kDa and show 13-71% aminoacid identity. All members share a conserved,
centrally located, “core” region, of about 100 aminoacids, common to all FGFs
(1,2). Outside of this “core” structure, their sequences diverge considerably.

 

The FGFR family includes four identified genes
and numerous subtypes of alternative spliced isoforms, particularly within the
FGFR1 and FGFR2 genes (3,9). FGFRs have an extracellular domain which binds the
ligand, a transmembrane segment and a cytoplasmic tyrosine kinase domain, which
can be activated by phosphorylation. The extracellular portion comprises three
Ig-like domains, Dl, D2, and D3, with an acidic stretch of approximately 30
residues, between Dl and D2. Isoforms generated by alternative splicing include
receptors that lack Ig-like domain D1 or both D1 and the acidic box, as well as
variants having two alternative sequences, called IIIb and IIIc for the
C-terminal half of the third Ig-like D3 domain (3,9). As alluded to above,
these latter splice forms alter ligand specificity, in agreement with the
finding that D3 is an

 

2

 

important site for ligand binding (see below).
Furthermore, the IIIc forms of FGFR1 and FGFR2 are expressed exclusively in
mesenchymally derived cells, while the IIIb forms are expressed in cells of
epithelial origin. Members of the FGFs family bind FGFRs with varying
affinities. FGF1 binds with high affinity to the four receptors and to all the
known isoforms. FGF4 binds FGFR1 and FGFR2 with high affinity, and FGFR3 and
FGFR4 with a lower affinity. FGF3, FGF7 and FGF10 only interact with the IIIb
splice variant form of FGFR2, (also known as the KGFR)(4).

 

Experiments of gene knock-out in mice have
revealed considerable redundancy in the FGF gene family, perhaps not surprising
since multiple FGFs can activate the same receptor (2). This could be one of
the reasons why so far an angiogenic phenotype has not been demonstrated in any
single FGF knock-out mice. Nevertheless, a considerable body of evidence
indicates that most of the FGFs are potent angiogenic agents in a variety of
experimental animal models. The most important FGFs for angiogenesis are
probably those which can interact with FGFR1 and FGFR2 (IIIc), which are the
major FGFRs expressed by endothelial cells, FGF4, on which we have concentrated
most of our studies, is angiogenic in mice, rabbit and pig hearts.

 

Recently the crystal structures of FGF2 bound to the
extracellular domain of FGFR1, and that of FGF1 bound to FGFR2 have been
determined (6,7). The crystal structure of the extracellular ligand binding
domain of FGFRl (D2 and D3) in complex with FGF2 at 2.8 A resolution shows two
FGF2 molecules (residues 16-144), two D2-3 molecules (residues 149-359) in 1:1
complex, and four sulfate ions (6). The structure of the FGF1/FGFR2 complex is
very similar (7). The dimeric structure is stabilized by direct
receptor-receptor interaction (D2-D2) and interaction between FGF2 and D2 of
the other receptor in the dimer. The two FGF2 molecules are on opposite sides
of the dimer and are not in contact. A positively charged canyon is formed
between the two

 

3

 

D2 domains of FGFR, extending onto the heparin binding
sites of the ligand. This canyon is likely to make-up the heparin binding site
of the receptor. A ternary structure is formed, probably occurring first by
binding of FGF to FGFR in a 1:1 complex, which then associate into signaling
dimers in the presence of heparin (6). Thus the specificity of FGF interaction
with FGFR depends on a variety of factors: 1) Binding of the ligand to the D2
and D3 domains and intervening sequences. 2) Binding of the ligand as well as
of the receptor to heparin or specific heparin sulfate proteoglycans. 3)
Interaction between the D2 domains of dimerizing receptor molecules.
Modification of any of these parameters would alter the ability of each ligand
to interact with specific FGER, suggesting that a structural and mutational
analysis of the precise contact points between ligand and receptor, and/or
ligand and heparin could be fruitful for the creation of novel FGF molecules.

 

SPECIFIC AIMS

 

1.       To obtain the crystal structure of FGF4 bound to its
highest affinity receptor, FGFR2.

 

2)      To identify the FGF4 residues that contact FGFR and
mediate its activation.

 

3)      To utilize the knowledge generated by the studies
described above to create FGF4 mutants with novel or broader affinity to FGFR
and possibly FGFR antagonists.

 

PRELIMINARY REULTS

 

In order to obtain a detailed insight into the
three-dimensional structure of FGF4, we determined its crystal structure at
2.8A resolution (Figure 1). For these studies we used a cDNA encoding only a
truncated FGF4 molecule missing the first 43 N-terminal

 

4

 

aminoacids of the mature protein. The protein
expressed and purified from bacteria has full biological activity, in line with
the observation that a truncated FGF4 molecule lacking the 35 N-terminal residues
(32-67; residues 1-31 encode for the signal peptide) retains potent biological
activity and displays higher receptor binding affinity compared to that of full
length FGF4 (10). Based on the crystal structure, we predicted that residues
F129, FF135/136, FF15Q/151, Y172, that are exposed to the surface of the
molecule, could be relevant for FGF4 receptor binding. However, when FGF4
molecules in which these residues had been mutated were tested for biological
activity, some of these predictions turned out not to be correct, since
mutation of these residues did not affect the biological activity of FGF4 (see
Table 1). Because of the similarity between FGF2 and FGF4, we thus superimposed
the structure of FGF4 on that of FGF2 in complex with FGFR1 (Figures 2 and 3).
By analyzing the data of the complex, we identified residues Y87, Y166, E159,
L203, R205 as possible primary interacting sites between FGF4 and D2 and D3 of
FGFR1. Some of these predictions are in agreement with previous studies on the
importance of these FGF residues in receptor binding. Replacement of Y24 and
Y103 by alanine in FGF2, which correspond to residues 87 and166 in FGF4,
resulted in a dramatic decrease in FGFR1 binding. Substitution of E96 with
alanine in FGF2, corresponding to E196 in FGF4, also results in more than 100
fold reduction in receptor binding (11).

 

We
have created a series of FGF4 mutants by site directed mutagenesis (Table 1).
We have expressed and produced the mutants in a mammalian system using COS
cells and subsequently analyzed the biological activity of these mutants in a
DNA synthesis assay, using NIH3T3 cells (Figure 4). The results of these
experiments are summarized in Table 1. Unfortunately, many of the mutants
constructed appear not to be efficiently produced in COS cells. Thus we plan to
express these mutants in bacteria, purify these

 

5

 

factors and determine their ability to bind and
activate FGF receptors in comparison to that of wild type FGF4 (see below). It
should also be mentioned that the use of bacterially produced, recombinant FGF4
molecules will allow us much more precise determination of their receptor
affinity, interaction with heparin, etc. than is possible using supernatants
from transfected COS cells.

 

AIM 1. Crystal structure of FGF4 bound to FGFR2.

 

As discussed above, a number of predictions on
the FGF4 domains which interact and play a role in the activation of FGFR were
made on the basis of the crystal structure of this growth factor in isolation,
but these predictions are not always correct, as clearly conformational changes
occur during receptor-ligand interaction or interaction of the ligand/receptor
with heparin. The superimposition of FGF4 on the known structure of FGF2 bound
to FGFR1 allows more accurate predictions, but still suffers from the problem
of relying on the conservation of FGF structure and is unlikely to highlight
unique features of FGF4 or of its interaction with FGFR (Figures 2 and 3). We
plan therefore to obtain the crystal structure of FGF4 bound to FGFR2, its
highest affinity receptor. We will use the FGF4 construct described above
(missing the 43 N-terminal aminoacids) because it has full biological activity
and easier to express and purify to high concentration. Similarly we will use
FGFR2 molecules containing only D2 and D3 as previously used for the structure
of the FGF2/FGFR1 complex. Proteins will be expressed in E. Coli and we will
follow the strategy described in ref. (6).

 

Another interesting aspect of the interaction between
FGF and FGFR is the role and sites of interaction of heparin with the receptor
and the ligand (Figure 3). The two structures recently described were obtained
in the absence of heparin. Thus the heparin sites of interaction were inferred
from the position of sulfate ions on the structure. It

 

6

 

should be very interesting to verify whether these
hypotheses are correct, and whether they also apply to FGF4, and therefore we
will attempt to obtain the structure of FGF4/FGFR2 complex in the presence or
absence of specific heparin oligosaccharides (classical heparin preparations
are too heterogeneous for crystallographic studies). This will be important for
future studies and possible modification of the heparin binding sites on the
ligand or the receptor.

 

AIM 2. Identification of residues
that are relevant for the binding of FGF4 with its high affinity receptors.

 

Since the mutants, FF150/151GG, FF135/136AA,
Y166A and N167A are not produced and/or secreted in COS cells (see Table 1), we
have decided to change our strategy and to produce all mutants in
bacteria.  As described under Preliminary
Results we superimposed the structure of FGF4 with that of FGF2 in complex with
D2 and D3 of FGFR1 (Figure 2). Based on the model that was generated, we have
identified residues Y87, Y166, E159, L203, R205 of the FGF4 as likely to be
directly involved in high affinity receptor binding. By molecular dynamics
calculations however, we have determined that the residues F129, F136 and F151
could also be relevant for the stability of the binding of FGF4 with the
receptor.

 

Switch aminoacid mutagenesis has and will be carried
out following the Quick Change TM site directed mutagenesis kit (Strategene)
using the pET15b-FGF4 vector as a template. This plasmid was used for the
production of FGF4 used for the crystal structure. In the pET15b vector the
FGF4 cDNA was cloned under the LacZ T7 inducible promoter (Novagene). The
presence of the mutation in the cDNA will be analyzed by sequencing and the
production and purification of the mutant protein will be done according to the
protocol described in Plotnikov et al (6), The biological activity

 

7

 

of
the purified proteins will be tested in a DNA synthesis assay using NIH3T3
cells and compared to that of wild-type FGF4. Studies on the affinity of the
FGF4 mutants with its high receptors will be performed by Scatchard analysis on
a CHO cell line expressing FGFR2. Briefly, the purified protein will be
iodinated using the 125-1 labeled Bolton-Hunter reagent. Scatchard assays will
be performed as described in (10). Relatives dissociation constants (Kd) of the
mutants will be calculated and compared with that of wt-FGF4. These results
will be confirmed also by competition experiments for binding to FGFR2, using
iodinated FGF4 or FGF2 as the ligand (10). As previously described, FGF2 binds
FGFR2 with the same high affinity as FGF4 (4). In order to study if binding of
the FGF4 mutants with its high affinity receptor results in weaker receptor
activation, we will also analyze the ability of the mutants to phosphorylate
FGFRs. These experiments will be performed by conventional receptor
phosphorylation assays using CHO cells expressing FGFR2. Briefly, CHO-FGFR2
cells will be serum starved for 24 hours and treated for 10 minutes with 100 ng
of either wt FGF4 or the mutants. Cells will be lysed in 1% Triton buffer and
subjected to immunoprecipitation using anti-FGFR2 antiserum. Immunoprecipitates
will be resolved in SDS-PAGE and proteins blotted on a nitrocellulose membrane.
Immunoblotting will be performed using anti phosphoytyrosine and anti FGFR2
antisera.

 

While
these experiments are in progress, we should be able to obtain the crystal
structure of FGF4 bound to FGFR2, As discussed above, this is likely to provide
more precise information on the FGF4/FGFR2 interaction, that should complement,
extend or correct some of the predictions made on the basis of superimposing
FGF4 on the FGF2/FGFR1 complex. In particular, the results of the experiments
in the presence of heparin should be very useful. Thus, similarly to what is
described above, we will

 

8

 

generate new mutants of FGF4 and test their ability to
interact with the receptor, and with heparin.

 

Taken together, these experiments should
provide a comprehensive description of the mechanisms determining the
interaction of FGF4 with its receptor and suggest strategies to design mutated
forms of FGF4 with increased, decreased, or broader binding of FGFRs.

 

AIM 3. Creation of FGF4 mutants with novel or broader binding
specificity to FGFR.

 

Structure-based site directed mutagenesis in FGFs identified two
putative receptor binding sites: a primary site that contributes to most of the
high affinity interaction of FGFs with FGFRs, and a secondary site that
exhibits low receptor binding affinity but is required for receptor activation.
It was suggested that the secondary binding site may confer to FGFs the ability
to bind the FGFRs with different affinities (12). FGF7 is ideal for this type
of study since it only recognizes the FGFR2bIII isoform, or KGFR (13). Since
FGF4 does not bind KGFR with appreciable affinity (4), it is possible to study
if substitution of particular residues of the FGF7 molecule into the FGF4
increases binding of the new chimeric FGF4/FGF7 for KGFR. Based on the model
that was generated with the crystal structure of FGF7 (14), we believe that the
b4/b5 loop from aminoacid 103 to 107 (RTVAV) of FGF7 is probably relevant
for its biological activity and for its receptor binding affinity to KGFR.
Based on subsequent studies of this and other models, we also predict that the
substitution of A106 of FGF7 with valine would increase the probability of binding
of the new chimera to KGFR. We will substitute the residues SRVER from
aminoacid 119 to 123 of FGF4 with the aminoacid RTVVV from aminoacid 103 to 107
of FGF7.

 

9

 

Switch aminoacids mutagenesis will be carried out by
site directed mutagenesis as described above, using the pET15b-FGF4 vector as a
template. The protein will be expressed in bacteria and purified as described
(6). The chimeric FGF4/FGF7 will be tested for its ability to bind and activate
KGFR. We will initially express the KGFR in CHO-DG44 cells which do not express
any of the member of the FGFR family (1). The plasmid encoding for the KGFR
cDNA will be transfected into the CHO cells together with an excess of a
plasmid encoding for the resistance for Neomycin. Positive clones will be
selected and expression of the receptor will be tested in western blot analysis
using an antibody that recognizes the KGFR. Affinity of the chimera FGF4/FGF7
for KGFR will be calculated and compared with that of wt-FGF7. Schatchard
analysis and competition experiments will be performed using CHO expressing
KGFR or FGFR2, for which FGF4 has high affinity (4). We will also analyze the
ability of the chimeric FGF4/FGF7 ligand to activate the KGFR receptor in
phosphorylation experiments. Briefly, CHO cells expressing either the KGFR or
the FGFR2 will be serum starved for 24 hours and increasing concentration of
FGF4/FGF7 will be added to the cells for 10 minutes. KGFR will be
immunoprecipitated from total cell lysates and its level of phosphorylation
will be analyzed by immunoblot experiments using antiphosphotyrosine antiserum.
As a positive control we will use wt-FGF4 and wt-FGF7 for FGFR2 and KGFR
phosphorylation.

 

While these studies will provide useful information on
the possibility of designing new FGF4 molecules, it is not clear whether the
chimeric FGF4/FGF7 molecule will have practical uses. We will therefore construct new mutants of FGF4 based on
the structure of FGF4 complexed with FGFR2, compared to that of the FGFR2/FGFR1
complex. It is very difficult at this moment to indicate which mutations we
will perform; as the choice will dependent on identifying the critical sites of
FGF4

 

10

 

interaction with its receptor and heparin. The
goal would be that of creating FGF4 molecules with tighter “fit” for the
receptors, or perhaps capable of a more stable association. In the long run,
although it is again difficult
to outline a precise strategy at the moment, we would like to create FGFR
antagonists, i.e. ligands which will bind FGFR with high affinity, but will not
activate signal transduction. These ligands would therefore compete with FGF4
(or other FGFs) and inhibit receptor activation. Such ligands could in principle
be truncated FGF polypeptides which only interact with the D2 or D3 domain of
the receptor or molecules which are incapable of binding the heparin “bridge”
spanning the heparin binding canyon of the receptor.

 

REFERENCES

 

1)      Basilico C., and Moscatelli, D. 1992. The FGF family
of growth factors and oncogenes. Adv. Cancer Res. 59:115-165.

 

2)      Goldfarb, M. 1996. Functions of fibroblast growth
factors in vertebrate development. Cytokine & Growth Rev. 7:311-325

 

3)      Johnson, D.E., and Williams, L.T. 1993. Structural and
functional diversity in the FGF receptor multigene family. Adv. Cancer Res.
60:1-41.

 

4)      Ornitz, D.M., Xu, J., Colvin, J.S., McEwen, D.G.,
MacArthur, C.A., Coulier, F., Gao, G., and Goldfarb, M. 1996. Receptor
specificity of the fibroblast growth factor family. J. Biol. Chem.
271:15292-15297.

 

5)      Yayon, A., Klagsbrun, M., Esko, J.D., Leder, P., and Ornitz, D.M. 1991. Cell
surface, heparin-like molecules are required for binding of basic fibroblast
growth factor to its high affinity receptor. Cell 64:841-848.

 

6)      Plotnikov, A.N., Schlessinger, J., Hubbard, S.R., and Mohammadi,
M. 1999. Structural basis for FGF receptor dimerization and activation. Cell
98:641-650.

 

7)      Stauber, D.J., DiGabriele, A.D., and Hendrickson, W.A.
2000. Structural interactions of fibroblast growth factor receptor with its
ligands. Proc. Natl. Acad. Sci. USA 97:49-54.

 

11

 

8)      Ornitz, D.M. 20000. FGFs, heparan sulfate and FGFRs:
complex interactions essential for development. Bioessays 22:108-112.

 

9)      McKeehan, W.L., Wang, F., and Kan, M. 1998. The heparan
sulfate-fibroblast growth factor family: diversity of structure and function.
Prog. Nucleic Acid Res. Mol. Biol. 59:135-176.

 

10)    Bellosta, P., Talarico, D., Rogers, D., and Basilico, C. 1993.  Cleavage of K-FGF produces a truncated
molecule with increased biological activity and receptor binding affinity. J
Cell Biol. 121:705-713.

 

11)    Zhu, H., Ramnarayan, K. Anchin, J., Miao, W.Y., Sereno, A., Millman, L.,
Zheng, J., Balaji, V.N., and Wolff, M.E. 1995. Glu-96 of basic fibroblast
growth factor is essential for high affinity receptor binding. Identification
by structure-based site-directed mutagenesis. J. Biol. Chem. 270:21869-21874.

 

12)    Sher, I., Weizman, A., Lubinsky-Mink, S., Lang, T., Adir, N.,
Schomburg, D., and Ron, D. 1999. Mutations uncouple human fibroblast growth
factor (FGF)-7 biological activity and receptor binding and support broad
specificity in the secondary receptor binding site of FGFs. J. Biol. Chem.
274:35016-35022.

 

13)    Werner, S. 1998.
Keratinocyte growth factor: a unique playaer in epithelial repair processes.
Cytokine Growth Factor Rev. 9:153-165.

 

14)        Osslund, T.D., Syed, R., Singer, E., Hsu, E.W.,
Nybo, R., Chen, B.L., Harvey, T., Arakawa, T., Narhi, LO., Chirino, A., and
Morris, C.F. 1998. Correlation between the 1.6 A crystal structure and
mutational analysis of keratinocyte growth factor. Protein Sci. 7:1681-1690.

 

12

 

figures

 

Figure 1.       Ribbon diagram of the FGF4 structure. The amino and
carboxyl termini are indicated by NT and CT. The  b strands of FGF4 are
labeled from 1 to 12, starting from the N-terminus.

 

Figure 2.        Superimposition of the FGF4 molecule in place of FGF2
binding to the D2 (green) and D3 (blue) domains of FGFRl. As can be seen by
comparison with ref (6), although the “fit” is quite good, three regions of
FGF4 (marked in red) clash with the receptor structure, highlighting the
limitations of this “superimposition” approach.

 

Figure 3.       A. Molecular surface representation of the putative
FGF4-FGFR1 complex, viewed from the top. FGF4 is in orange, the D2 domains of
FGFRl are in green.

B.     Surface
change distribution of the complex, also viewed from the top. Blue and red
represent positive or negative electrostatic potential, respectively. The
positively charged canyon, i.e. the putative heparin binding site, runs between
the two D2 domains in the dimer extending to the adjoining ligands. Sulfate
ions are marked.

 

Figure 4.       Mitogenic activity in quiescent NIH3T3 cells of FGF4
mutants. Cells were serum starved in 0.5% serum for 48 hrs. Supernatant from
COS cells containing the secreted proteins was added to the medium at the
relative concentration of 1:100, 1:250 and 1:1000 as indicated. Cells were labeled
after 16 hrs. with 1 μCi of 3H-Thymidine
for 6 hrs. and radioactivity incorporated into DNA was counted after TCA
precipitation.

 

13

 

Table 1.
BIOLOGICAL ACTIVITY OF FGF4 MUTATIONS

 

	
  FGF4 WT

  	
  +++

  
	
   

  	
   

  
	
  Y87A

  	
  -

  
	
   

  	
   

  
	
  F129A (the F129 residue is
  unique to FGF4)

  	
  -

  
	
   

  	
   

  
	
  F135A

  	
  +/-

  
	
   

  	
   

  
	
  F136A

  	
  NT

  
	
   

  	
   

  
	
  FF135/136AA

  	
  not
  expressed/secreted

  
	
   

  	
   

  
	
  F150A

  	
  +++

  
	
   

  	
   

  
	
  F151A

  	
  NT

  
	
   

  	
   

  
	
  FF150/151GG

  	
  not expressed/secreted

  
	
   

  	
   

  
	
  E159A

  	
  NT

  
	
   

  	
   

  
	
  Y166A

  	
  not expressed/secreted

  
	
   

  	
   

  
	
  N167A

  	
  not expressed/secreted

  
	
   

  	
   

  
	
  Y172A

  	
  +++

  
	
   

  	
   

  
	
  L203A

  	
  NT

  
	
   

  	
   

  
	
  R205A (unique to FGF4)

  	
  NT

  

 

Mitogenic activity of the FGF4 mutants was calculated
by Thymidine incorporation assays as described in Figure 4 +++ high activity;
+/- low activity (less than 20,000 cpm at 1:100 conc.); - no activity (no
increase in cpm over background); NT = not tested.

 

14Exhibit 10.15

 

Exclusive
License Agreement

 

 

between

 

 

The
Regents of the University of California

 

 

and

 

 

Collateral
Therapeutics.

 

 

for

 

 

Angiogenesis
Gene Therapy

 

 

U.C. Case No. 94-161-1,-3

 

 

	
   

  	
  U.C. AGREEMENT

  
	
   

  	
  CONTROL NUMBER

  
	
   

  	
  96-04-0203

  

 

 

Table
of Contents

 

	
  Article
  No.

  	
   

  	
  Title

  	
   

  	
  Page

  
	
   

  	
   

  	
   

  
	
   

  	
  Recitals

  	
  1

  
	
  1.

  	
  Definitions

  	
  4

  
	
  2.

  	
  Grant

  	
  7

  
	
  3.

  	
  License Issue Fee

  	
  9

  
	
  4.

  	
  Royalties

  	
  9

  
	
  5.

  	
  Due Diligence.

  	
  13

  
	
  6.

  	
  Progress and Royalty Reports

  	
  15

  
	
  7.

  	
  Books and Records

  	
  17

  
	
  8.

  	
  Life of the Agreement

  	
  18

  
	
  9.

  	
  Termination by The Regents

  	
  19

  
	
  10.

  	
  Termination by Licensee

  	
  20

  
	
  11.

  	
  Disposition of Patent Products on Hand Upon
  Termination

  	
  20

  
	
  12.

  	
  Use of Names and Trademarks

  	
  21

  
	
  13.

  	
  Limited Warranty

  	
  22

  
	
  14.

  	
  Patent Prosecution and Maintenance

  	
  23

  
	
  15.

  	
  Patent Marking

  	
  27

  
	
  16.

  	
  Patent Infringement

  	
  27

  
	
  17.

  	
  Indemnification

  	
  29

  
	
  18.

  	
  Notices

  	
  31

  
	
  19.

  	
  Assignability

  	
  32

  
	
  20.

  	
  Late Payments

  	
  32

  
	
  21.

  	
  Waiver

  	
  33

  
	
  22.

  	
  Failure to Perform

  	
  33

  
	
  23.

  	
  Governing Laws

  	
  33

  
	
  24.

  	
  Government Approval or Registration

  	
  34

  
	
  25.

  	
  Export Control Laws

  	
  34

  
	
  26.

  	
  Force Majeure

  	
  34

  
	
  27.

  	
  Confidentiality

  	
  35

  
	
  28.

  	
  Miscellaneous

  	
  37

  

 

 

U.C.
Case No. 94-161-1,-3

Revised:
7/13/95 (SH)

Draft
date:  September 25, 1995

 

Exclusive
License Agreement

for

Angiogenesis
Gene Therapy

 

This license agreement (“Agreement”) is effective this 27th
day of September, 1995, by and
between The Regents of the University of California (“The Regents”), a
California corporation, having its statewide administrative offices at 300
Lakeside Drive, 22nd Floor, Oakland, California   94612-3550 and Collateral Therapeutics (“Licensee”),
a California corporation, having a principal place of business at 9360 Towne
Centre Drive, San Diego, California 
92121.

 

Recitals

 

Whereas, certain inventions, relating to “Angiogenesis Gene Therapy” (“Invention”),
useful for angiogenesis, were made at the University of California, San Diego (“UCSD”)
and are described and claimed in certain patent applications, naming Drs. H.
Kirk Hammond, Frank Giordano, and

 

 

Wolfgang
Dillmann as co-inventors, identified in the below defined Patent Rights;

 

Whereas, Licensee entered into a Letter of Intent (“Letter of Intent”),
having U.C. Agreement Control No. 95-30-0891, effective March 27, 1995, that
provided the Licensee with a time-limited exclusive right to negotiate for a
license to the Patent Rights;

 

Whereas, under 35 USC 200-212, The Regents may elect to retain title to
any invention (including the Invention) made by it, in whole or in part, under
U.S. Government funding;

 

Whereas, if The Regents elects to retain title to the Invention, then
the law requires that The Regents grant to the U.S. Government a
nontransferable, paid-up, nonexclusive, irrevocable license to use the
Invention by or on behalf of the U.S. Government throughout the world;

 

Whereas, The Regents elected on September 19, 1995, to retain title to
the Invention and granted the required licenses to the U.S. Government;

 

Whereas, H. Kirk Hammond, M.D., is an employee of the Veterans
Administration Medical Center (“VA”);

 

Whereas, 37 CFR §501.6(a)(2) allows the VA to release the Invention to
Dr. Hammond, under certain conditions;

 

2

 

Whereas, Dr. Hammond, also an employee of The Regents, is under
obligation to assign to The Regents the rights in the Invention that were
released to him by the VA;

 

Whereas, Licensee is a “small entity” as defined in 37 CFR Section 1.9
and a “small-business concern” defined at 15 U.S.C. §632;

 

Whereas, both parties recognize that royalties due under this Agreement
will be paid on issued patents and pending patent applications that are being
prosecuted diligently and in good faith;

 

Whereas, Licensee requested an exclusive license to the Patent Rights
from The Regents; and

 

Whereas, The
Regents wish to grant an exclusive license to the Patent Rights to Licensee so
that products and other benefits derived from the Invention can be enjoyed by
the general public.

 

The parties agree as follows:

 

3

 

1.  Definitions

 

As used in this Agreement, the following terms will have the meaning
set forth below:

 

1.1        “Patent Rights” means all U.S. patents and
patent applications and foreign patents and patent applications assigned to The
Regents, and in the case of foreign patents and patent applications those
requested under Paragraph 14.4 herein, including any reissues, extensions,
substitutions, continuations, divisions, and continuations-in-part applications
(only to the extent, however, that claims in the continuations-in-part
applications are entitled to the priority filing date of the parent patent
application) based on and including the following:

 

1.1.1        any subject matter claimed in or described according to the
requirements of 35 USC Section 112 in U.S. Patent Application Serial Number
08/396,207, entitled “Gene Therapy for Myocardial Ischemia,” filed February 28,
1995, by Dr. H. Kirk Hammond, et al., and assigned to The Regents; and

 

1.1.2        any subject matter claimed in or described according to the
requirements of 35 USC Section 112 in U.S. Patent Application Serial Number
[ILLEGIBLE], entitled “Gene
Therapy for Myocardial Ischemia”, filed June 7, 1995, by Dr. H. Kirk Hammond,
et al., and assigned to The Regents.

 

1.2        “Patent Products” means:

 

1.2.1        any kit, composition of matter, material, or product;

 

4

 

1.2.2        any kit, composition of matter, material, or product to be used in a
manner requiring the performance of the Patent Method; or

 

1.2.3        any kit, composition of matter, material, or product produced by the
Patent Method;

 

to the extent that the manufacture, use, or sale of such kit,
composition of matter, material, or product, in a particular country, would
fall within the scope of (1) an unexpired claim of a patent under Patent Rights
in that country or (2) a pending claim of a pending patent application that is
being prosecuted diligently and in good faith in that country, were it issued
as a claim in a patent under Patent Rights in that country in which such
application is pending.   This definition
of Patent Products also includes a service either used by Licensee or provided
by Licensee to its customers when such service requires the practice of the
Patent Method.

 

1.3        “Patent Method” means any process or method,
the use or practice of which in a country would fall within the scope of (1) an
unexpired claim of a patent under Patent Rights in that country or (2) a
pending claim of a pending application that is being prosecuted diligently and
in good faith in that country, were it issued as a claim in a patent under
Patent Rights in that country in which such application is pending.

 

1.4        “Net Sales” means the gross invoice prices
from the sale of Patent Products by Licensee, an Affiliate, a Joint Venture, or
a sublicensee

 

5

 

to
independent third parties for cash or other forms of consideration in
accordance with Generally Accepted Accounting Principles limited to the
following deductions (if not already deducted from the gross invoice price and
at rates customary within the industry): 
(a) allowances (actually paid and limited to rejections, returns, and
prompt payment and volume discounts
granted to customers of Patent Products, whether in cash or Patent Products in
lieu of cash); (b) freight, transport packing, insurance charges associated
with transportation; and (c) taxes, tariff, or import/export duties based on
sales when included in gross sales, but not value-added taxes or taxes assessed
on income derived from such sales.

 

1.5        “Affiliate(s)” of Licensee means any entity
which, directly or indirectly, controls Licensee, is controlled by Licensee, or
is under common control with Licensee (“control” for these purposes being
defined as the actual, present capacity to elect a majority of the directors of
such affiliate, or if not, the capacity to elect the members that control fifty
percent (50%) of the outstanding stock or other voting rights entitled to elect
directors) provided, however, that in any country where the local law will not
permit foreign equity participation of a majority, then an “Affiliate” will
include any company in which Licensee will own or control, directly or
indirectly, the maximum percentage of such outstanding stock or voting rights
permitted by

 

6

 

local
law.   Each reference to Licensee herein
will be meant to include its  Affiliates.

 

1.6        “Joint Venture” means any separate entity
established pursuant to an agreement between a third party and Licensee to
constitute a vehicle for commercializing patent products, in which the separate
entity manufactures, uses, purchases, sells, or acquires Patent Products from
Licensee.   Each reference to Licensee
herein will be meant to include its Joint Venture(s).

 

2.  Grant

 

2.1        Subject to the terms of this Agreement,
subject to the licenses granted to the U.S. Government as set forth in the
Recitals above, and subject to the obligations of Section 2.5 below, The
Regents hereby grants to Licensee exclusive licenses under Patent Rights to
make, use, sell, offer for sale, and import Patent Products and to practice the
Patent Method where Patent Rights exist.

 

2.2        The Regents also grants to Licensee the
exclusive right to issue sublicenses to third parties to make, use, sell, offer
for sale, and import Patent Products and to practice the Patent Method,
provided Licensee retains current exclusive rights thereto under this
Agreement.  To the extent applicable,
such sublicenses will include all of the rights of and obligations

 

7

 

due
to The Regents (and, if applicable, the U.S. Government, including 35 USC
Sections 200-21 2 and the implementing regulations), including the payment of
royalties in Article 4, (Royalties) that are contained in this Agreement,

 

2.3        Licensee will notify The Regents of each
sublicense granted hereunder and provide The Regents with a copy of each
sublicense. Licensee will collect and pay all royalties due The Regents as set
forth in Paragraph  4.1 below (and
guarantee all such payments due from sublicensees).   Licensee will require sublicensees to
provide it with progress and royalty reports in accordance with the provisions
herein, and Licensee will collect and deliver to The Regents all such reports
due from sublicensees.

 

2.4        Upon termination of this Agreement for any
reason, The Regents, at its sole discretion, will determine whether any or all
sublicenses will be canceled or assigned to The Regents.

 

2.5        Nothing in this Agreement will be deemed to
limit the right of The Regents to publish any and all technical data resulting
from any research performed by The Regents relating to the Invention and to
make and use Patent Product(s), Patent Method(s), and associated technology
solely for educational and noncommercial research purposes.

 

8

 

3.   License Issue Fee

 

3.1        As partial consideration for all the rights
and licenses granted to Licensee, Licensee will pay to The Regents a license
issue fee of Five Hundred and Fifty Thousand Dollars ($550,000) according to
the following schedule:

 

3.1.1        Seventy-Five Thousand Dollars ($75,000)
within thirty (30) days after the execution of this Agreement by both parties;

 

3.1.2        Seventy-Five Thousand Dollars ($75,000) on or
before June 30, 1997;

 

3.1.3        Fifty Thousand Dollars ($50,000) on or before
December 31, 1998;

 

3.1.4        One Hundred Thousand Dollars ($100,000) on orbefore June 30, 2000; and

 

3.1.5        Two Hundred and Fifty Thousand Dollars
($250,000) on or before December
31, 2001.

 

3.2        The fees set forth in Paragraph 3.1 above are
non-refundable, non-creditable, and not an advance against royalties.

 

4.   Royalties

 

4.1        As further consideration for all the rights
and licenses granted to Licensee, Licensee also will pay to The Regents an
earned royalty at the rate of two percent (2%) based on the Net Sales of Patent
Products.

 

9

 

4.2        Paragraphs 1.1, 1.2, and 1.3 define Patent
Rights, Patent Product, and Patent Method so that royalties will be payable
only on Patent Products covered by either a pending patent application that is
being prosecuted diligently and in good faith in a relevant country or by an
issued patent in a relevant country.  
Earned royalties will accrue in each country for the duration of any
issued patent within Patent Rights in that country and wilt be payable to The
Regents when Patent Products are invoiced, or if not invoiced, when delivered
to a third party for the purpose of patient administration for purposes other
than clinical trials.   Licensee, its
Affiliates, Joint Ventures, and sublicensees will not use Patent Products or
Patent Methods for administration to patients in any business of the Licensee,
or of its Affiliates, Joint Ventures, and sublicensees without payment of
applicable royalty on Net Sales to be calculated on retail sales prices as if
the sales transaction had occurred at arm’s-length to an unrelated third party.

 

4.3        Royalties accruing to The Regents will be
paid to The Regents quarterly on or before the following dates of each calendar
year:

 

February 28 for the calendar
quarter ending December 31

 

May 31 for the calendar
quarter ending March 31

 

August 31 for the calendar
quarter ending June 30

 

November 30 for the calendar
quarter ending September 30

 

10

 

Each such payment will be for royalties which
accrued up to the most recently completed calendar quarter of Licensee.

 

4.4        Beginning in the year 2003, Licensee will pay
to The Regents a minimum annual royalty in the amounts and at the times set
forth below:

 

	
  2003

  	
  -

  	
   

  	
  $

  	
  100,000

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2004

  	
  -

  	
   

  	
  $

  	
  250,000

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2005

  	
  -

  	
   

  	
  $

  	
  400,000

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2006

  	
  -

  	
   

  	
  $

  	
  650,000

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  2007

  	
  -

  	
   

  	
  $

  	
  750,000

  	
   

  

 

In each succeeding calendar year after The year 2007, Licensee will pay a
minimum annual royalty of Seven Hundred and Fifty Thousand ($750,000) for the
life of this Agreement.  Each minimum
annual royalty payment must be paid to The Regents by February 28 of each year
fallowing the calendar year in which royalties accrued.   Royalties paid during the prior calendar
year will be credited against the minimal annual royalty payment due and owing
for the prior calendar year.

 

4.5        All monies due The Regents will be payable in
United States funds collectible at par in San Francisco, California.  When Patent Products are sold for monies
other than United States dollars, the earned royalties will first be determined
in the foreign currency of the country in which such Patent Products were sold
and then converted into equivalent United States

 

11

 

funds.  The exchange rate will be that rate quoted in
the Wall Street Journal on the last business day of the reporting period.

 

4.6        Earned royalties on sales of Patent Products
occurring in any country outside the United States will not be reduced by any
taxes, fees, or other charges imposed by the government of such country except
those taxes, fees, and charges allowed under the provisions of Paragraph 1.4
(Net Sales).   Licensee will be
responsible for all bank transfer charges.

 

4.7        Notwithstanding the provisions of
Article 26. (Force Majeure), if at any time legal restrictions prevent
prompt remittance of part or all royalties owed to The Regents by Licensee with
respect to any country where a Patent Product is sold or distributed, Licensee
will convert the amount owed to The Regents into United States funds and will
pay The Regents directly from another source of funds for the amount impounded.

 

4.8        In the event that any patent or any claim
thereof included within the Patent Rights is held invalid or unenforceable in a
final decision by a court of competent jurisdiction and last resort and from
which no appeal has or can be taken, all obligation to pay royalties based on
such patent or claim or any claim patentably indistinct therefrom will cease as
of the date of such final decision.  
Licensee will not, however, be relieved from paying any royalties that
accrued before such decision or that are based on another patent or claim that
has not expired or that is not involved in such decision.

 

12

 

4.9        No royalties will be collected or paid
hereunder to The Ragents on Patent Products sold to the account of the U.S.
Government.  Licensee and its sublicensee
will reduce the amount charged for Patent Products distributed to the United
Stares Government by an amount equal to the royalty for such Patent Products
otherwise due The Regents as provided herein.

 

5.   Due Diligence

 

5.1        Licensee, upon execution of this Agreement,
will diligently proceed with the development, manufacture and sale of Patent
Products.  In this regard, The Regents
acknowledges that the technology covered by this Agreement has only recently
been invented and that substantial additional effort, expense and time, as well
as regulatory approval, will be required before manufacture and sales of any
Patent Products will be possible. Meeting the requirements of Section 5.3
below shall be deemed to satisfy the due diligence requirements of this
Article 5.

 

5.2        Licensee will be entitled to exercise prudent
and reasonable business judgment in the manner in which it meets its due
diligence obligations hereunder, including under Section 5.3 below.   In no case, however, will Licensee be wholly
relieved of its obligations to meet
each of the due diligence provisions of Paragraph 5.3 below.

 

13

 

5.3        If Licensee is unable to
perform any of the following:

 

5.3.1        begin Phase I Clinical Trials in the United
States for Patent Products on or before June 30, 1997; and

 

5.3.2        enter pivotal clinical trials (a combination
of Phase II and Phase III Clinical Trials) in the United States for said Patent
Products on or before December 31, 1998; and

 

5.3.3        file far marketing approval in the United
States for said Patent Product on or before December 31, 2001; and

 

5.3.4        market Patent Products in the United States
within six (6) months after receiving marketing approval of such Patent
Products from the U.S. Food and Drug Administration; and

 

5.3.5        diligently and earnestly fill the market
demand for Patent Products following commencement of marketing at any time
during the exclusive period of this Agreement;

 

then The Regents will have the right and option to
terminate this Agreement or reduce the exclusive licenses granted to Licensee
to non-exclusive licenses in accordance with Paragraph 5.4 hereof.   The exercise of this right and option by The Regents supersedes the rights
granted in Article 2. (Grant).

 

5.4        To exercise either the right to terminate
this Agreement or reduce the exclusive licenses granted to Licensee to
non-exclusive licenses for lack of diligence required in this Article 5.
(Due Diligence), The Regents will give Licensee written notice of the
deficiency.   Licensee thereafter has

 

14

 

60 (sixty) days to cure the deficiency. Licensee shall be entitled to a
one-time extension of each of the dates set forth in Subparagraphs 5.3.1
through 5.3.4 (which have not been met) by one (1) additional year to cure
the deficiency upon payment of One Hundred Thousand Dollars ($100,000) to The
Regents, provided that such payment is received by The Regents within sixty
(60) days of receipt of written notice by The Regents of Licensee’s
deficiency.  The One Hundred Thousand
Dollar ($100,000) payment has the effect of extending the subject date and all
subsequent dates by one (1) year.  
If The Regents has not received the One Hundred Thousand Dollar
($100,000) payment by the end of the sixty (60)-day period, or written tangible
evidence satisfactory to The Regents that the deficiency has been cured by the
end of the sixty (60)-day period, then The Regents may, at its option,
terminate this Agreement or reduce the exclusive licenses granted to Licensee
to non-exclusive licenses by giving written notice to Licensee. These notices
will be subject to Article 18, (Notices).

 

6. Progress and Royalty
Reports

 

6.1        Beginning February 28, 1996, and
semi-annually thereafter, Licensee will submit to The Regents a progress report
covering activities by Licensee related to the development, including clinical
trials and testing, of all Patent Products and the obtaining of the
governmental approvals necessary

 

15

 

for marketing.  These progress
reports will be provided to The Regents to cover the progress of the research
and development of the Patent Products until their first commercial sale in the
United States.

 

6.2        The progress reports submitted under
Paragraph 6.1 will include, but
not be limited to, the following topics so that The Regents may be able to
determine the progress of the development of Patent Products:

 

•              summary of work completed;

 

•              summary of work in progress;

 

•              current schedule of anticipated events
or milestones specified in Paragraph 5.3 and the datas when said milestones
have been met or will be met, as of the time of the report;

 

•              market introduction date of Patent Products;
and

 

•              activities of sublicensees, if any.

 

6.3        Licensee will also report to The Regents in
its immediately subsequent progress and royalty report the date of first
commercial sale of a Patent Product(s) in each country where the Licensee has
sought marketing approval.

 

6.4        After the first commercial sale of a Patent
Product, Licensee will provide The Regents with quarterly royalty reports to
The Regents on or before each February 28, May 31, August 31,
and November 30 of each year.   Each
such royalty report will cover the most recently completed

 

16

 

calendar quarter of Licensee (October through December, January through
March, April through June, and July through September) and will show:

 

6.4.1        the gross sales and Net Sales of Patent
Products sold by Licensee and reported to Licensee as sold by its sublicensees
during the most recently completed calendar quarter;

 

6.4.2        the number of Patent Products sold or
distributed by Licensee and reported to Licenses as sold or distributed by its
sublicensees;

 

6.4.3        the royalties, in U.S. dollars, payable
hereunder with respect to Net Sales; and

 

6.4.4        the exchange rates used, if any.

 

6.5        If no sales of Patent Products have been made
during any reporting period after the first commercial sale of a Patent
Product, then a statement to this effect is required.

 

7.   Books and Records

 

7.1        Licensee will keep books and records
accurately showing all Patent Products manufactured, used, and/or sold under
the terms of this Agreement.   Such books and records will be preserved for
at least four (4) years after the date of the royalty payment to which
they pertain and will be open to inspection by representatives or agents of The
Regents at reasonable times to determine the accuracy of the books and records
and to determine compliance by Licenses with the terms of this Agreement.

 

17

 

7.2        The fees and expenses of representatives of
The Regents performing such an examination will be borne by The Regents.   However, if an error in royalties of more
than five percent (5%) of the total royalties due for any year is discovered,
then the fees and expenses of these representatives will be borne by Licensee.

 

8.   Life of the Agreement

 

8.1        Unless otherwise terminated by operation of
law or by acts of the parties in accordance with the terms of this Agreement,
this Agreement will be in force from the effective date recited on page one
and will remain in effect for the life of the last-to-expire patent licensed
under this Agreement, or until the last patent application licensed under this
Agreement is abandoned.

 

8.2        Any termination of this Agreement will not
affect the rights and obligations set forth in the following Articles:

 

	
  Article

  	
   

  	
  3

  	
   

  	
  License
  Issue Fee

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Article

  	
   

  	
  7

  	
   

  	
  Books
  and Records

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Article

  	
   

  	
  11

  	
   

  	
  Disposition
  of Patent Products on Hand Upon Termination

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Article

  	
   

  	
  12

  	
   

  	
  Use
  of Names and Trademarks

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Paragraph

  	
   

  	
  14.6

  	
   

  	
  Patent
  Prosecution and Maintenance

  

 

18

 

	
  Article

  	
   

  	
  17

  	
   

  	
  Indemnification

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Article

  	
   

  	
  22

  	
   

  	
  Failure
  to Perform

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Article

  	
   

  	
  27

  	
   

  	
  Confidentiality

  

 

9.  Termination by The Regents

 

9.1        If Licensee should violate or fail to perform
any material term or covenant of this Agreement, then The Regents may give
written notice of such default (“Notice of Default”) to Licensee.   If Licensee should fail to repair such
default within sixty (60) days after the date of such notice takes effect, The
Regents will have the right to terminate this Agreement and the licenses herein
by a second written notice (“Notice of Termination”) to Licensee.   If a Notice of Termination is sent to
Licensee, this Agreement will automatically terminate on the date such notice
takes effect.   Such termination will not
relieve Licensee of its obligation to pay any royalty or license fees owing at
the time of such termination and will not impair any accrued right of The
Regents.  These notices will be subject
to Article 18. (Notices).

 

19

 

10.   Termination by Licensee

 

10.1      Licensee will have the right at any time to
terminate this Agreement in whole or as to any portion of Patent Rights by
giving notice in writing to The Regents.  Such Notice of Termination will be subject to Article 18.
(Notices) and termination of this Agreement will be effective sixty (60) days
after the effective date thereof.

 

10.2      Any
termination pursuant to the above paragraph will not relieve The Regents or
Licensee of any obligation or liability accrued hereunder prior to such
termination or rescind anything done by The Regents or Licenses or any payments
made to The Regents hereunder prior to the time such termination becomes
effective, and such termination will not affect in any manner any rights of The
Regents or Licensee arising under this Agreement prior to such termination.

 

11.   Disposition of Patent Products on Hand Upon
Termination

 

11.1      Upon termination of this Agreement, Licensee
will have the privilege of disposing of all previously made or partially made
Patent Products, but no more, within a period of one hundred twenty (120) days,
provided, however, that the sale of such Patent Products will be subject to the
terms of this Agreement including, but not limited to the payment of fees and
reimbursement for patent costs and the payment of royalties based on

 

20

 

the Net Sales of Patent Products at the rates and at the times provided
herein and the rendering of reports in connection therewith.

 

12.   Use of Names and Trademarks

 

12.1      Nothing contained in this Agreement will be
construed as conferring any right to use in advertising, publicity, or other
promotional activities any name, trade name, trademark, or other designation of
either party hereto by the other (including contraction, abbreviation or simulation
of any of the foregoing).   Unless
required by law, the use by Licensee of the name “The Regents of the University
of California” or the name of any campus of the University of California for
use in advertising, publicity, or other promotional activities is expressly
prohibited.

 

12.2      It is understood that The Regents will be
free to release to the inventors and senior administrative officials employed
by The Regents the terms of this Agreement upon their request.   If such release is made, The Regents will
request that such terms will be kept in confidence in accordance with the
provisions of Article 27. (Confidentiality) and not be disclosed to
others.   It is further understood that
should a third party inquire whether a license to Patent Rights is available,
The Regents may disclose the existence of this Agreement and the Extent of the
grant in Article 2. (Grant) to such third party, but will not disclose the
name of Licensee, except where The

 

21

 

Regents is
required to release such information under either the California Public Records
Act or other applicable law.

 

13.  Limited
Warranty

 

13.1      The Regents warrants to Licensee that it has
the lawful right to grant this license, and that it has not granted any rights
or licenses to Patent Rights, other than to the U.S. Government, in derogation
of this Agreement.

 

13.2      This license and the associated Invention are
provided WITHOUT WARRANTY OF MERCHANTABILITY OR FITNESS FOR A PARTICULAR
PURPOSE OR ANY OTHER WARRANTY, EXPRESSED OR IMPLIED.   THE REGENTS MAKES NO REPRESENTATION OR
WARRANTY THAT THE INVENTION, PATENT PRODUCTS, OR PATENT METHOD WILL NOT
INFRINGE ANY PATENT OR OTHER PROPRIETARY RIGHT.

 

13.3      IN NO EVENT WILL THE REGENTS BE LIABLE FOR
ANY INCIDENTAL, SPECIAL OR CONSEQUENTIAL DAMAGES RESULTING FROM EXERCISE OF
THIS LICENSE OR THE USE OF THE INVENTION, PATENT METHOD, OR PATENT PRODUCTS.

 

13.4      Nothing in this Agreement will be construed
as:

 

13.4.1      a
warranty or representation by The Regents as to the validity, enforceability,
or scope of any Patent Rights; or

 

22

 

13.4.2      a warranty or representation that anything
made, used, sold or otherwise disposed of under any license granted in this
Agreement is or will be free from infringement of patents of third parties; or

 

13.4.3      an obligation to bring or prosecute actions
or suits against third parties for patent infringement except as provided in
Article 16. (Patent Infringement); or

 

13.4.4      conferring by implication, estoppel, or
otherwise any license or rights under any patents of The Regents other than
Patent Rights as defined herein, regardless of whether such patents are
dominant or subordinate to Patent Rights; or

 

13.4.5      an obligation to furnish any know-how not
provided in Patent Rights.

 

14.   Patent Prosecution and Maintenance

 

14.1      The Regents will diligently prosecute and
maintain the United States and foreign patents comprising Patent Rights using
counsel of its choice.   The Regents will
promptly provide Licensee with copies of all relevant documentation so that
Licensee may be currently and promptly informed and apprised of the continuing
prosecution, and may comment upon such documentation sufficiently in advance of
any initial deadline for filing a response, provided, however, that if Licensee
has not commented upon such documentation prior to the initial deadline for filing a
response with the relevant government patent office or The Regents must act to
preserve Patent Rights, The Regents will be free to respond appropriately

 

23

 

without consideration of comments by Licensee, if any.  Both parties hereto will keep this
documentation in confidence in accordance with the provisions of Article 27.
(Confidentiality) herein.  The Regents’
counsel will take instructions only from The Regents.

 

14.2      The Regents will use all reasonable efforts
to amend any patent application to include claims requested by Licensee and
required to protect the Patent Products contemplated to be sold or Patent
Method to be practiced under this Agreement.

 

14.3      The Regents and Licensee will cooperate in
applying for an extension of the term of any patent included within Patent
Rights, if appropriate, under the Drug Price Competition and Patent Term
Restoration Act of 1 984, Licensee will prepare all such documents, and The
Regents will execute such documents and will take such additional action as
Licensee may reasonably request in connection therewith.

 

14.4      The Regents will, at the request of Licensee,
file, prosecute, and maintain patent applications and patents covered by Patent
Rights in foreign countries if available. 
Licensee must notify The Regents within nine (9) months of the
filing of the corresponding United States application of its decision to
request The Regents to file foreign counterpart patent applications.  This notice concerning foreign filing must be
in writing and must identify the countries desired.   The absence of such a notice from

 

24

 

Licensee to The Regents within the nine (9)-month period will be
considered an election by Licensee not to request The Regents to secure foreign
patent rights an behalf of Licensee.  The
Regents wilt have the right to file patent applications at its own expense in
any country Licensee has not included in its list of desired countries, and
such applications and resultant patents, if any, will not be included in the
licenses granted under this Agreement unless Licensee agrees in writing to pay
all costs associated with any such patent application(s) and provided the
rights of said patent application(s) are available at the time Licensee agrees
to pay the associated costs.

 

14.5      All past, present and future costs of
preparing, filing, prosecuting and maintaining all United States and foreign
patent applications and all costs and fees relating to the preparation and
filing of patents covered by Patent Rights in Paragraph 1.1 will be borne by
Licensee.   This includes all patent preparation
and prosecution costs incurred by The Regents prior to the execution of this
Agreement.  Such costs will be due upon
execution of this Agreement and will be payable at the time that the license
issue fee is payable.   The costs of all
interferences and oppositions will be considered prosecution expenses and also
will be borne by Licensee.   Licensee
will reimburse The Regents for all costs and charges within thirty (30) days
following receipt of an itemized invoice from The Regents for same.

 

25

 

14.6      The obligation of Licenses to underwrite and
to pay patent preparation, filing, prosecution, maintenance, and related costs
will continue for such costs as may be incurred during the three (3)-month period
after receipt by either party of a Notice of Termination for ail non-cancelable
obligations made prior to the receipt of said Notice of Termination,  Licensee will reimburse The Regents for all
patent costs incurred during the term of the Agreement and for three (3) months
thereafter whether or not invoices for such costs are received during the three
(3)-month period after receipt of a Notice of Termination.   Licensee may with respect to any particular
patent application or patent terminate its obligations with the patent
application or patent in any or ail designated countries upon three months
written notice to The Regents.  The
Regents may continue prosecution and/or maintenance of such application(s) or
patent(s) at its sole discretion and expense, provided, however, that Licensee
will have no further right or licenses thereunder.

 

14.7      Licensee will have a continuing
responsibility to keep The Regents informed of its large/small entity status
(as defined by the United States Patent and Trademark Office) of itself and its
sublicensees.

 

26

 

15.  Patent
Marking

 

15.1   Licensee will mark all Patent Products made,
used or sold under the terms of this Agreement, or their containers, in
accordance with the applicable patent marking laws.

 

16.  Patent
Infringement.

 

16.1   In the event that Licensee learns of the
substantial infringement of any patent licensed under this Agreement, Licensee
will call the attention of The Regents thereto in writing and will provide The
Regents with reasonable evidence of such infringement.  Both parties to this Agreement acknowledge
that during the period and in a jurisdiction where Licensee has exclusive
rights under this Agreement, neither will notify a third party of the
infringement of any of Patent Rights without first obtaining consent of the
other party, which consent will not be unreasonably withheld.   Both parties will use their best efforts in
cooperation with each other to terminate such infringement without litigation.

 

1 6.2  Licensee may request that The Regents take
legal action against the infringement of Patent Rights.  Such request must be made in writing and must
include reasonable evidence of such infringement and damages to Licensee.   If the infringing activity has not been
abated within ninety (90)

 

27

 

days
following the effective date of such request, The Regents will have the right
to elect to:

 

16.2.1      commence suit on its own account; or

 

16.2.2      refuse to participate in such suit

 

and
The Regents will give notice of its election in writing to Licensee by the end
of the one hundredth (100th) day after receiving notice of such request from
Licensee.  Licensee may thereafter bring
suit for patent infringement if and only if The Regents elects not to commence
suit and if the infringement occurred during the period and in a jurisdiction
where Licensee had exclusive rights under this Agreement.  However, in the event Licensee elects to
bring suit in accordance with this paragraph, The Regents may thereafter join
such suit at its own expense, but the Licensee will control the lawsuit.

 

16.3   Such
legal action as is decided upon will be at the expense of the party on account
of whom suit is brought and all recoveries recovered thereby will belong to
such party, provided, however, that legal action brought jointly by The Regents
and Licensee and participated in by both will be at the joint expense of the
parties and all recoveries will be allocated in the following order:  a) to each party reimbursement in equal
amounts of the attorney’s costs, fees, and other related expenses to the extent
each party paid for such costs, fees, and expenses until all such costs, fees,
and

 

28

 

expenses
are consumed for each party; and b) any remaining amount shared jointly by them
in proportion to the share of expenses paid by each party.

 

16.4   Each party will cooperate with the other in
litigation proceedings instituted hereunder but at the expense of the party on
account of whom suit is brought.   Such
litigation will be controlled by the party bringing the suit, provided,
however, that The Regents may be represented by counsel of its choice in any
suit brought by Licensee.

 

17.  
Indemnification

 

17.1   Licensee will (and will require its
sublicensees to) indemnify, hold harmless, and defend The Regents, its
officers, employees, and agents; the sponsors of the research that led to the
Invention; the inventors of any invention covered by Patent Rights (including
the Patent Products and Patent Method contemplated thereunder) and their
employers against any and all claims, suits, losses, damage, costs, fees, and
expenses resulting from or arising out of exercise of this license or any
sublicense.   This indemnification will
include, but will not be limited to, any product liability.

 

17.2   Licensee, at its sole cost and expense, will
insure its activities in connection with the work under this Agreement and
obtain, keep in force, and maintain insurance as follows: (or an equivalent
program of self insurance)

 

29

 

At the initiation of
clinical trials, Comprehensive or Commercial Form General Liability
Insurance (contractual liability included) with limits as follows up to and
until Licensee enters Phase III Clinical Trials:

 

	
  (a)

  	
   

  	
  Each
  Occurrence

  	
   

  	
  $

  	
  3,000,000

  	
   

  
	
  (b)

  	
   

  	
  Products/Completed
  Operations Aggregate

  	
   

  	
  $

  	
  3,000,000

  	
   

  
	
  (c)

  	
   

  	
  Personal and
  Advertising injury

  	
   

  	
  $

  	
  3,000,000

  	
   

  
	
  (d)

  	
   

  	
  General
  Aggregate (commercial form only)

  	
   

  	
  $

  	
  3,000,000

  	
   

  

 

Comprehensive or Commercial Form General
Liability Insurance (contractual liability included) with limits as follows
after Licensee enters

 

Phase
III Clinical Trials:

 

	
  (a)

  	
   

  	
  Each Occurrence

  	
   

  	
  $

  	
  5,000,000

  	
   

  
	
  (b)

  	
   

  	
  Products/Completed
  Operations Aggregate

  	
   

  	
  $

  	
  5,000,000

  	
   

  
	
  (c)

  	
   

  	
  Personal and Advertising
  Injury

  	
   

  	
  $

  	
  5,000,000

  	
   

  
	
  (d)

  	
   

  	
  General Aggregate
  (commercial form only)

  	
   

  	
  $

  	
  5,000,000

  	
   

  

 

It should be expressly
understood, however, that the coverages and limits referred to under the above
will not in any way limit the liability of Licensee.   Licensee will furnish The Regents with
certificates of insurance evidencing compliance with all requirements.  Such certificates will:

 

(a)           Provide for thirty (30)-day advance written
notice to The Regents of any modification;

 

(b)           Indicate that The Regents has been endorsed
as an additional Insured under the coverages referred to under the above; and

 

(c)           Include a provision that the coverages will
be primary and will not participate with nor will be excess over any valid and
collectable insurance or program of self-insurance carried or maintained by The
Regents.

 

30

 

17.3 The Regents will
immediately notify Licensee in writing of any claim or suit brought against The
Regents in respect of which The Regents intends to invoke the provisions of
this Article 17. (Indemnification). 
Licensee will keep The Regents informed as appropriate and necessary on
a current basis of its defense of any claims pursuant to this Article 17.
(Indemnification).

 

18.  Notices

 

18.1   Any notice or payment required to be given
to either party will be deemed to have been properly given and to be effective (a) on
the date of delivery if delivered in person or (b) five days after mailing
if mailed by first-class certified mail, postage paid, to the respective addresses
given below, or to another address as it may designate by written notice given
to the other party.

 

	
  In the case of Licensee:

  	
   

  	
  COLLATERAL THERAPEUTICS

  
	
   

  	
   

  	
  9360 Towne Centre Drive

  
	
   

  	
   

  	
  San Diego, CA  92121

  
	
   

  	
   

  	
  Tel:  (619) 622-4100

  
	
   

  	
   

  	
  Fax:  (619) 587-3518

  
	
   

  	
   

  	
  Attention: Jack Reich,
  Ph.D.

  

 

31

 

	
  In the case of The
  Regents:

  	
   

  	
  THE REGENTS OF THE
  UNIVERSITY

  	
   

  	
   

  
	
   

  	
   

  	
  OF CALIFORNIA

  	
   

  	
   

  
	
   

  	
   

  	
  1320 Harbor Bay Parkway,
  Suite 150

  	
   

  	
   

  
	
   

  	
   

  	
  Alameda, California 94502

  	
   

  	
   

  
	
   

  	
   

  	
  Tel: (510) 743-6600

  	
   

  	
   

  
	
   

  	
   

  	
  Fax: (510) 748-6639

  
	
   

  	
   

  	
  Attention:

  	
   

  	
  Terence A. Feuerborn

  
	
   

  	
   

  	
   

  	
   

  	
  Executive Director

  
	
   

  	
   

  	
   

  	
   

  	
  Research Administration
  and

  
	
   

  	
   

  	
   

  	
   

  	
  Technology Transfer

  
	
   

  	
   

  	
  Referring to: U.C. Case No.
  94-161-1,-3

  
							

 

19.  Assignability

 

19.1   This Agreement is binding upon and will
inure to the benefit of The Regents, its successors and assigns, but will be
personal to Licensee and assignable by Licensee only with the written consent
of The Regents, which consent shall not be unreasonably withheld.

 

20.   Late
Payments

 

20.1   In the event royalty payments or fees or
patent prosecution costs are not received by The Regents when due, Licensee
will pay to The Regents interest charges at a rate of ten percent (10%) simple
interest per annum. Such interest will be calculated from the date payment was
due until actually received by The Regents. 
Acceptance by The Regents of any late payment interest from Licensee
under this Paragraph 20 will in no way affect the provision of Article 21.
(Waiver) herein.

 

32

 

21.   Waiver

 

21.1  It is agreed that no waiver by either party
hereto of any breach or default of any of the covenants or agreements herein
set forth will be deemed a waiver as
to any subsequent and/or similar breach or default.

 

22.   Failure to Perform

 

22.1   In the event of a failure of performance due
under the terms of this Agreement and if it becomes necessary for either party
to undertake legal action against the other on account thereof, then the
prevailing party will be entitled to reasonable attorney’s fees in addition to
casts and necessary disbursements.

 

23.   Governing Laws

 

23.1   THIS AGREEMENT WILL BE INTERPRETED AND
CONSTRUED IN ACCORDANCE WITH THE LAWS OF THE STATE OF CALIFORNIA, excluding any
choice of law rules that would direct the application of the laws of
another jurisdiction, but the scope and validity of any patent or patent
application will be governed by the applicable laws of the country of such
patent or patent application.

 

33

 

24.  
Government Approval or Registration

 

24.1  If this Agreement or any associated
transaction is required by the law of any nation to be either approved or
registered with any governmental agency, Licensee will assume all legal obligations
to do so.   Licensee will notify The
Regents if it becomes aware that this Agreement is subject to a United States
or foreign government reporting or approval requirement. Licensee will make all
necessary filings and pay all costs including fees, penalties, and all other
out-of-pocket costs associated with such reporting or approval process.

 

25.   Export
Control Laws

 

25.1   Licensee will observe all applicable United
States and foreign laws with respect to the transfer of Patent Products and
related technical data to foreign countries, including, without limitation, the
International Traffic in Arms Regulations (1TAR) and the Export Administration
Regulations.

 

26.   Force Majeure

 

26.1  The parties to this Agreement will be excused
from any performance required hereunder if such performance is rendered
impossible or unfeasible due to any acts of God, catastrophes, or other major
events

 

34

 

beyond
their reasonable control, including, without limitation, war, riot, and
insurrection; laws, proclamations, edicts, ordinances, or regulations; strikes,
lock-outs, or other serious labor disputes; and floods, fires, explosions, or
other natural disasters.  However, any
party to this Agreement will have the right to terminate this Agreement upon
thirty (30) days’ prior written notice if either party is unable to fulfill its
obligations under this Agreement due to any of the causes mentioned above and
such inability continues for a period of one year.   Notices will be subject to Article 18.
(Notices).

 

27.  
Confidentiality

 

27.1   Licensee and The Regents respectively will
treat and maintain the proprietary business, patent prosecution, software,
engineering drawings, process and technical information, and other proprietary
information of the other party (“Proprietary Information”) in confidence using
at least the same degree of care as that party uses to protect its own
proprietary information of a like nature for a period from the date of
disclosure until five (5) years after the date of termination of this
Agreement.

 

27.2   Proprietary Information will be labeled or
marked confidential or as otherwise similarly appropriate by the disclosing
party, or if the Proprietary Information is orally disclosed, it will be reduced
to writing or some other physically tangible form, marked and labeled as set
forth above

 

35

 

by
the disclosing party and delivered to the receiving party within thirty (30)
days after the oral disclosure as a record of the disclosure and the
confidential nature thereof. 
Notwithstanding the foregoing, Licensee and The Regents may use and
disclose Proprietary Information to its employees, agents, consultants, and
contractors having a need to know the Proprietary Information and, in the case
of Licensee, its sublicensees, provided that any such parties are bound by a
like duty of confidentiality.

 

27.3  Nothing contained herein will in any way
restrict or impair the right of Licensee or The Regents to use, disclose, or
otherwise deal with any Proprietary Information:

 

27.3.1      that recipient can demonstrate by written
records was previously known to it;

 

27.3.2      that is now, or becomes in the future, public
knowledge other than through acts or omissions of recipient;

 

27.3.3      that is lawfully obtained without
restrictions by recipient from sources independent of the disclosing party;

 

27.3.4      that is required to be disclosed to a
governmental entity or agency in connection with seeking any governmental or
regulatory approval, or pursuant to the lawful requirement or request of a
governmental entity or agency;

 

27.3.5      that is furnished to a third party by the
recipient with a need to know and with similar confidentiality restrictions
imposed on such third party, as evidenced in writing, or

 

36

 

27.3.6      that The Regents is required to disclose
pursuant to the California Public Records Act or other applicable law.

 

27.4   Upon termination of this Agreement, Licensee
and The Regents will destroy or return to the disclosing party proprietary
information received from the other in its possession within fifteen (15) days
following the effective date of termination. 
Licensee and The Regents will provide each other, within thirty (30)
days following termination, with a written notice that Proprietary Information
has been returned or destroyed.  Each
party may, however, retain one copy of Proprietary Information for archival
purposes in nonworking files.

 

28.  
Miscellaneous

 

28.1   The headings of the several sections are
inserted for convenience of reference only and are not intended to be a part of
or to affect the meaning or interpretation of this Agreement.

 

28.2   The licenses and any sublicenses granted
hereunder will be subject to any legal obligations to the U.S. Government
including those set forth in 35 U.S.C. 200-212 and applicable governmental
implementing regulations.   Because this
Agreement grants the exclusive right to use or sell the Patent Products in the
United States, Licensee acknowledges that

 

37

 

Patent
Products will be manufactured substantially in the United States as required
under 35 USC Section 204.

 

28.3   The manufacture of Patent Products will be
in accordance with any applicable government importation laws and regulations
of a particular country on Patent Products made outside the particular country
in which such Patent Products are to be used or sold.

 

28.4  Licensee will obtain all necessary governmental
approvals in each country where it intends to sell or manufacture and use
Patent Products or permit others to manufacture, use, or sell Patent Products.

 

28.5  This Agreement will not be binding upon the
parties until it has been signed below on behalf of each party, in which event,
it will be effective as of the date recited on page one.

 

28.6  No amendment or modification hereof will be
valid or binding upon the parties unless made in writing and signed on behalf
of each party.

 

28.7  This Agreement embodies the entire
understanding of the parties and will supersede all previous communications,
representations or understandings, either oral or written, between the parties
relating to the subject matter hereof.  The
Letter of intent specified in the Recitals in this Agreement is hereby
terminated.

 

28.8  In case any of the provisions contained in
this Agreement are held to be invalid, illegal, or unenforceable in any
respect, such invalidity,

 

38

 

illegality,
or unenforceability will not affect any other provisions hereof, but this
Agreement will be construed as if such invalid or illegal or unenforceable
provisions had never been contained herein.

 

The Regents and Licensee
execute this Agreement in duplicate originals by their respective, authorized
officers on the date indicated.

 

 

	
  Collateral Therapeutics:

  	
  The Regents of the University 

  of California:

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  By

  	
  /s/ Jack W.
  Reich Ph.D.

  	
   

  	
  By

  	
  /s/ Terence
  A. Feuerborn

  	
   

  	
   

  
	
   

  	
  (Signature)

  	
   

  	
   

  	
  (Signature)

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Name

  	
    JACK
  W. REICH, Ph.D.

  	
   

  	
  Name 

  	
  Terence A. Feuerborn

  	
   

  
	
   

  	
  (Please Print)

  	
   

  	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Title

  	
    PRESIDENT AND C.E.O.

  	
   

  	
  Title

  	
  Executive Director

  	
   

  
	
   

  	
   

  	
   

  	
  Research Administration
  and

  	
   

  
	
   

  	
   

  	
   

  	
  Technology Transfer

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Date

  	
      Sept.
  27, 1995

  	
   

  	
  Date

  	
       9-28-95

  	
   

  	
   

  
										

 

 

	
  Approval as to legal form:

  	
  /s/ ILLEGIBLE

  	
   

  	
  9//24/95

  	
   

  
	
   

  	
  [SEAL]

  	
   

  	
  Date

  	
   

  
	
   

  	
   

  	
   

  	
   

  

 

39

 

1st Amendment

to the Exclusive License Agreement

 

between

 

The Regents of the University of California

 

and

 

Collateral Therapeutics, Inc.

 

for

 

“Angiogenesis Gene Therapy”

 

UC Case No. 94-161-1, -3

 

 

 

1st Amendment to the Exclusive License Agreement

for “Angiogenesis Gene Therapy”

 

This Amendment is made and
is effective this 19th day of Sept.,1996, by and between The Regents
of the University of California (“The Regents”), a California corporation,
having its statewide administrative offices at 300 Lakeside Drive, 22nd Floor,
Oakland, California 94612-3550, and Collateral Therapeutics, Inc. (“Licensee”),
a California corporation, have a principal place of business at 9360 Towne
Centre Drive, San Diego, California 92121.

 

RECITALS

 

WHEREAS, Licensee and The
Regents entered into a license agreement entitled “Exclusive License Agreement
for Angiogenesis Gene Therapy,” effective on September 27, 1995, having
U.C. Agreement Control Number 96-04-0203 (“License Agreement”), and covering
licensure to Licensee by The Regents of rights in certain inventions developed
by Dr. H. Kirk Hammond, et al. (“Inventor”) at the University of
California, San Diego (“UCSD”) and claimed in U.S. Patent Application Serial
Nos. 08/396,207 and 08/485,472;

 

	
   

  	
  U.C. AGREEMENT

  
	
   

  	
  CONTROL NUMBER

  
	
   

  	
  96-04-0203 B

  

 

1

 

Whereas, in accordance with
Paragraph 2.3 of the License Agreement, Licensee has notified The Regents of
its intent to enter into a sublicense agreement with Schering
Aktiengesellschaft (“Schering AG”);

 

Whereas, Schering AG will
use its resources to further develop the Patent Products so that the technology
licensed under the sublicense agreement may be developed, utilized, and
marketed and the products therefrom and other benefits may be enjoyed by the
general public;

 

Whereas, Licensee desires to
amend the License Agreement to reflect that, upon termination of the License
Agreement, any sublicenses to Schering AG will be assigned to The Regents;

 

Whereas, Licensee and The
Regents desire to amend the License Agreement to redefine Patent Rights to
exclude two continuing patent applications entitled “Gene Therapy for
Myocardial Ischemia” filed in the names of Dr. Wolfgang Dillmann, Dr. Ruben
Mestril, and Dr. Frank Giordano and any continuing patent applications
thereof;

 

Whereas, Licensee and The
Regents desire to amend the License Agreement to reflect the above changes;

 

Now, Therefore, in
consideration of the foregoing and the mutual promises and covenants contained
herein, the parties hereto agree as follows:

 

2

 

1.             Paragraph 1.1 (Definitions) of the License Agreement
shall be replaced in its entirety with the following Paragraphs 1.1a and 1.1b: 

 

1.1a   “Patent
Rights” means all U.S. patents and patent applications and foreign patents and
patent applications assigned to The Regents, and in the case of foreign patents
and patent applications those requested under Paragraph 14.4 herein, including
any reissues, extensions, substitutions, continuations, divisions, and
continuations-in-part applications (only to the extent, however, that claims in
the continuations-in-part applications are entitled to the priority filing date
of the parent patent application) based on and including the following:

 

1.1.1.       any subject matter claimed in or described
according to the requirements of 35 USC Section 112 in U.S. Patent Application
Serial Number 08/396,207, entitled “Gene Therapy for Myocardial Ischemia,”
filed February 28, 1995, by Dr. H. Kirk Hammond, et al., and assigned
to The Regents; and

 

1.1.2.       any subject matter claimed in or described
according to the requirements of 35 USC Section 112 in U.S. Patent
Application Serial Number 08/485,472, entitled “Gene Therapy for Myocardial
Ischemia,” filed June 7, 1995, by Dr. H. Kirk Hammond, Dr. Wolfgang

 

3

 

Dillmann, and Dr. Frank Giordano, and assigned to The Regents.

 

1.1b         The subject matter relating to the use of
heat-shock proteins described and claimed in U.S. Patent Application Serial
Number 08/481,122 entitled “Gene Therapy for Myocardial Ischemia,” filed June 7,
1995, by Dr. Wolfgang Dillmann, Dr. Ruben Mestril, and Dr. Frank
Giordano and U.S. Patent Application Serial Number 08/660,387 entitled “Gene
Therapy for Myocardial Ischemia,” filed June 7, 1996, by Dr. Wolfgang
Dillmann, Dr. Ruben Mestril, and Dr. Frank Giordano and any
continuing applications thereof are expressly excluded from this
Agreement.   The excluded patent
applications specified in this Paragraph 1.1b do not and will not claim any
angiogenesis gene therapy or gene therapy delivery subject matter that is described
and/or claimed in any of the patent applications referred to in Paragraph 1.1a
above.

 

2.             Paragraph 2.4 (Grant) of the License
Agreement shall be replaced in its entirety with the following:

 

2.4           Except as provided below, upon termination of
this Agreement for any reason, The Regents, at its sole discretion, will
determine whether any or all sublicenses will be canceled or assigned to The
Regents.   Notwithstanding the foregoing,
any sublicenses to

 

4

 

Schering AG will be assigned to The Regents.   The Regents will not be bound by any duties
or obligations contained in any sublicense that extend beyond the duties and
obligations of The Regents in this Agreement.

 

In Witness Whereof, both The
Regents and Licensee have executed this Amendments, in duplicate originals, by
their respective officers hereunto duly authorized, on the day and year
hereinafter written.

 

 

	
  COLLATERAL THERAPEUTICS,
  INC.

  	
  THE REGENTS OF THE UNIVERSITY

  OF CALIFORNIA

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  By

  	
  /s/ Jack W.
  Reich, Ph.D.

  	
   

  	
  By

  	
  /s/ Candace
  L. Voelker

  	
   

  	
   

  
	
   

  	
  (Signature)

  	
   

  	
   

  	
  (Signature)

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Name

  	
  JACK W.
  REICH, Ph.D.

  	
   

  	
  Name

  	
  Candace L. Voelker

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Title

  	
    PRESIDENT & C.E.O.

  	
   

  	
  Title

  	
  Associate Director

  	
   

  
	
   

  	
   

  	
   

  	
  Office of Technology
  Transfer

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Date

  	
    Sept. 19, 1996

  	
   

  	
  Date

  	
  9/19/96

  	
   

  	
   

  
										

 

 

	
  Approval as to legal form:

  	
  /s/ ILLEGIBLE

  	
   

  	
  9-19-96

  
	
   

  	
  [SEAL]

  	
   

  	
  Date

  
	
   

  	
   

  	
   

  	
   

  

 

5

 

2nd Amendment

to the Exclusive License Agreement

 

between

 

The Regents of the University of California

 

and

 

Collateral Therapeutics, Inc.

 

for

 

“Angiogenesis Gene Therapy’

 

UC Case No. 94-161-1,-3

 

 

	
   

  	
  U.C. AGREEMENT

  
	
   

  	
  CONTROL NUMBER

  
	
   

  	
  96-04-0203C

  

 

 

2nd Amendment to the Exclusive License Agreement 

for “Angiogenesis Gene Therapy”

 

This amendment (‘“Amendment’”)
is effective this 30th day of June, 1997, by and between The Regents
of the University of California (“The Regents”), a California corporation,
having its statewide administrative offices at 300 Lakeside Drive, 22nd Floor,
Oakland, California 94612-3550, and Collateral Therapeutics, Inc. (“Licensee”),
a California corporation, having a principal place of business at 9360 Towne
Centre Drive, San Diego, California 92121.

 

RECITALS

 

WHEREAS, Licensee and The
Regents entered into a license agreement entitled “Exclusive License Agreement
for Angiogenesis Gene Therapy,” effective on September 29, 1995, having
U.C. Agreement Control Number 96-04-0203 (“License Agreement”), and covering
licensure to Licensee by The Regents of rights in certain inventions developed
by Dr. H. Kirk Hammond, et al. (“Inventor”) at the University of
California, San Diego (“UCSD”) and claimed in Patent Rights (as defined in the
License Agreement);

 

Whereas, Licensee and The
Regents amended the License Agreement on September 19, 1996, to redefine
Patent Rights and to grant Licensee rights to enter into a sublicense agreement
with Schering Aktiengesellschaft;

 

Whereas, Licensee has
experienced unforeseen difficulties in obtaining rights in materials desired
for the development of the invention:

 

1

 

Whereas, Licensee desires to
amend the License Agreement to extend the diligence provisions provided in
Paragraph 5.3 in order to accommodate the above-cited unforeseen difficulties
so that it can continue development of the invention; and

 

Whereas, The Regents desires
that the invention be developed, utilized, and marketed to the fullest extent
so that the products therefrom may be enjoyed by the general public and,
therefore, is willing to amend the Agreement;

 

Now, Therefore, in
consideration of the foregoing and the mutual promises and covenants contained
herein, the parties hereto agree as follows:

 

1.             Paragraph 5.3 (Due Diligence) of the License
Agreement shall be replaced in its entirety with the following:

 

“5.3         If Licensee is unable
to perform any of the following:

 

5.3.1        begin Phase I Clinical Trials in the United
States for Patent Products on or before June 30, 1998; and

 

5.3.2        enter pivotal clinical trials (a combination
of Phase II and Phase III Clinical Trials) in the United States for said Patent
Products on or before December 31, 1999; and

 

5.3.3        file for marketing approval in the United
States for said Patent Product on or before December 31, 2002; and

 

5.3.4        market Patent Products in the United States
within six (6) months after receiving marketing approval of such Patent
Products from the U.S. Food and Drug Administration; and

 

5.3.5        diligently and earnestly fill the market
demand for Patent Products following commencement of marketing

 

2

 

at any time during the exclusive period of this Agreement;

 

then
The Regents will have the right and option to terminate this Agreement or
reduce the exclusive licenses granted to Licensee to non-exclusive licenses in
accordance with Paragraph 5.4 hereof. The exercise of this right and option by
The Regents supersedes the rights granted in Article 2. (Grant).”

 

This Amendment is not
intended to, and it is agreed that it does not, expressly or by implication,
affect in any way, any other provisions of the Exclusive License Agreement for
Angiogenesis Gene Therapy, dated September 29, 1995, which are intended to
remain in full force and effect.

 

In Witness Whereof, both The
Regents and Licensee have executed this Amendments, in duplicate originals, by
their respective officers hereunto duly authorized, on the day and year
hereinafter written.

 

 

	
  COLLATERAL THERAPEUTICS, INC.

   

  	
  THE REGENTS OF THE UNIVERSITY
OF CALIFORNIA

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  By

  	
  /s/ Jack W.
  Reich, Ph.D.

  	
   

  	
  By

  	
  /s/ Candace
  L. Voelker

  	
   

  	
   

  
	
   

  	
  (Signature)

  	
   

  	
   

  	
  (Signature)

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Name

  	
  JACK W.
  REICH, Ph.D.

  	
   

  	
  Name

  	
  Candace L. Voelker

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Title

  	
  President & CEO

  	
   

  	
  Title

  	
  Associate Director

  	
   

  
	
   

  	
   

  	
   

  	
  Office of Technology
  Transfer

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Date

  	
     6-24-97

  	
   

  	
  Date

  	
  6/30/97

  	
   

  	
   

  
										

 

 

	
  Approval as to legal form:

  	
  /s/ [ILLEGIBLE]

  	
   

  	
  [ILLEGIBLE]

  
	
   

  	
  [SEAL]

  	
   

  	
  Date

  
	
   

  	
   

  	
   

  	
   

  

 

3

 

3rd Amendment to 

the Exclusive License Agreement

 

between

 

The Regents of the University of California

 

and

 

Collateral Therapeutics

 

UC Case No. 94-161

Agreement No. 96-04-0203

 

 

3rd AMENDMENT TO THE EXCLUSIVE LICENSE AGREEMENT FOR 

ANGIOGENESIS GENE THERAPY

 

This
amendment (Amendment) is effective this 11th day of March 1999
between The Regents of the University of California (“The Regents’’), a
California corporation having its statewide administrative offices at 1111
Franklin Street, 12th Floor, Oakland, California 94607-5200, and
Collateral Therapeutics (“Licensee”), a Delaware corporation having a principal
place of business at 11622 El Camino Real, San Diego California 92130.

 

RECITALS

 

Licensee
and The Regents entered into a license agreement entitled “Exclusive License
Agreement for Angiogenesis Gene Therapy,” effective on September 27, 1995
(UC Agreement Control Number 96-04-0203). The above described license agreement
(the “Agreement”) was amended by mutual agreement of the parties on September 19,
1996 and again on June 30, 1997;

 

Licensee
has requested that some provisions of Article 5 (Due Diligence) be amended
and extended so that Licensee can remain in compliance with the Agreement and
achieve product approval under feasible diligence provisions. The Regents has
agreed to this Third Amendment so that the products licensed under the
Agreement may be developed for the benefit of the general public. 

 

The Regents and the Licensee
agree as follows:

 

Subparagraph
5.3.2 of Article 5 (Diligence) is removed in its entirely from the
Agreement and replaced with the following:

 

5.3.2    Submit a Phase III
(large scale) clinical trial protocol to the U.S. Food and Drug Administration
on or before December 31, 1999; and

 

This
Third Amendment does not, expressly or by implication, affects any other
provision of the Agreement in any way.

 

 

The
Regents and Licensee have executed this Third Amendment in duplicate originals,
by their respective and duly authorized officers on the day and year written
below.

 

 

 

	
  COLLATERAL THERAPUETICS

  	
  THE REGENTS OF THE UNIVERSITY

  OF CALIFORNIA

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  By

  	
  /s/ Jack W.
  Reich, Ph.D.

  	
   

  	
  By

  	
  /s/ Candace
  L. Voelker

  	
   

  	
   

  
	
   

  	
  (Signature)

  	
   

  	
   

  	
  (Signature)

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Name

  	
  Jack W.
  Reich

  	
   

  	
  Name

  	
  Candace L. Voelker

  	
   

  
	
  Title

  	
  President and CEO

  	
   

  	
  Title

  	
  Associate Director

  	
   

  
	
   

  	
   

  	
   

  	
  Office of Technology
  Transfer

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Date

  	
    April 8, 1999

  	
   

  	
  Date

  	
  4/23/99

  	
   

  	
   

  
										

 

 

4th Amendment to

 

the Exclusive License Agreement

 

between

 

The Regents of the University of California

 

and

 

Collateral Therapeutics

 

UC Case No. 94-161

 

Agreement Control No. 96-04-0203

 

 

	
   

  	
  U.C. AGREEMENT

  
	
   

  	
  CONTROL NUMBER

  
	
   

  	
  96-04-0203 RevH

  

 

 

4th AMENDMENT TO THE EXCLUSIVE LICENSE AGREEMENT FOR

ANGIOGENESIS GENE THERAPY

 

This amendment (Amendment)
is effective this 8th day
of February, 2000 between The Regents of the University of California (“The
Regents”), a California corporation, having its statewide administrative
offices at 1111 Franklin Street, 12’h Floor, Oakland, California
94607-5200, and Collateral Therapeutics (“Licensee”), a Delaware corporation,
having a principal place of business at 11622 El Camino Real. San Diego,
California 92130.

 

RECITALS

 

Licensee and The Regents
entered into a license agreement entitled “Exclusive License Agreement for
Angiogenesis Gene Therapy,” effective an September 27, 1995 (U.C. Agreement Control Number 96-04-0203).
The above described license agreement (the ‘‘Agreement”) was amended by mutual
agreement of the parties on September 19, 1996, on June 30, 1997, and
on March 11, 1999;

 

In response to an unforeseen
and unavoidable delay in the regulatory approval process, Licensee has asked
The Regents to extend the term of a diligence provision (Article 5) in the
Agreement;

 

Licensee so requests and the
Regents accedes to the Licensee’s request so that the Licensee can remain in
compliance with the Agreement and achieve product approval within a feasible
time period;

 

In consideration for this
Fourth Amendment, Licensee will make an early payment of the License Issue Fee
due under Subparagraph 3.1.4 of the Agreement.

 

The parties therefore agree
to amend the Agreement as follows:

 

 

1.             Subparagraph 3.1.4 of Article 3 (License
Issue Fee) is removed in its entirety and replaced with the following:

 

3.1.4        One Hundred Thousand Dollars ($100,000) on or
before January 20, 2000; and

 

2.             Subparagraph 5.3.2 of Article 5
(Diligence) is removed in its entirety from the Agreement and replaced with the
following;

 

5.3.2        Submit a Phase III (large scale) clinical
trial protocol to the U.S. Food and Drug Administration on or before July 31,
2000; and

 

This
Fourth Amendment does not, expressly or by implication, affect any other
provision of the Agreement in any way.

 

The
Regents and Licensee have executed this Fourth Amendment, in duplicate
originals, by their respective and duly authorized officers on the day and year
written below.

 

 

	
  COLLATERAL THERAPUETICS

  	
  THE REGENTS OF THE UNIVERSITY

  

  OF CALIFORNIA

  	
   

  
	
   

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  By

  	
  /s/ Jack W.
  Reich, Ph.D.

  	
   

  	
  By

  	
  /s/ Candace
  Voelker

  	
   

  	
   

  
	
   

  	
  (Signature)

  	
   

  	
   

  	
  (Signature)

  	
   

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Name

  	
  Jack W.
  Reich

  	
   

  	
  Name

  	
  Candace L. Voelker

  	
   

  
	
  Title

  	
  Chief Executive Officer

  	
   

  	
  Title

  	
  Associate Director,

  	
   

  
	
   

  	
   

  	
   

  	
   Office of Technology
  Transfer

  	
   

  
	
   

  	
   

  	
   

  	
   

  	
   

  
	
  Date

  	
    Feb. 8, 2000

  	
   

  	
  Date

  	
  2/9/00

  	
   

  	
   

  
										

 

 

	
  Approved as to legal form:

  	
  /s/ P. Martin Simpson, Jr.

  	
   

  	
  2/7/96

  
	
   

  	
  [SEAL]

  	
   

  	
  Date

Source: [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00095-of-00352.parquet"}, [{"source": "alea-institute/alea-institute/kl3m-data-edgar-agreements/train-00095-of-00352.parquet"}]]