Cooperative Research And Development Agreement

EXHIBIT 10.15



NIH/ADAMHA CRADA Clearance

(Cooperative Research & Development Agreement)



After the provisions of a Cooperative Research and Development Agreement (CRADA) have been negotiated, the CRADA must go through clearance procedures. This form documents the approval process.



Title of CRADA (if untitled, create one based on the purpose of the CRADA)



Development of a fully automated karyotyping system based on co-hybridization of Cy-5labeled chromosome specific repeat probes.



Was the CRADA initiated as a result of an NIH/ADAMHA-Industry Collaboration Forum? No



CRADA No. (Assigned by the BID Technology Development Coordinator



Date CRADA goes into effect 2/15/96



Term (years)



Intramural Research Project No. Z01-



NIH/ADAMHA Principal Investigator(s) (if more than one is listed, the first is the lead PI)



Name Dr. Thomas Ried



BID (Institute/Division) NCHGR/DIR/



Lab or Branch DDB



Phone No.



Collaborating Principal Investigator(s) Name Dr. Padrig S. O'Kelly



Organization (name and address) Applied Imaging 2380 Walsh Ave., Bldg. B, Santa Clara, CA 95051



Phone No. (408) 562-0250



Are any of the collaborating organizations: YES Small Business?

NO Foreign Institution?

NO Participant in any other CRADAs with NIH/ADAMHA? CRISP Keywords (At least three from the Intramural Research Index or CRISP Thesaurus) FISH CGH Imaging



Does this CRADA address: YES Patent rights? YES Exclusive license? YES Non-exclusive?



YES Rights of first negotiation? YES Sharing NIH/ADAMHA materials? YES Sharing collaborator materials?

NO AIDS research?



NO Animals?

NO Human Subjects? YES Human tissue?



Resources (If not specified in the CRADA, give best estimate).



NIH/ADAMHA (Person - Years) 0.85



Collaborator (Person - Years) 1.1



Amount of money transferred by collaborators to NIH/ADAMHA Average dollars per year $20,000



Total dollars per term of the CRADA $20,000





Routing and Approval Signatures



1. NIH/ADAMHA Principal Investigator Date

/s/ signature unreadable 1-31-96

2. NIH/ADAMHA Laboratory Chief Date

/s/ signature unreadable

3. BID Technology Development Coordinator Date

/s/ signature unreadable 2/2/96

4. Scientific Director Date

/s/ signature unreadable 4/23/96

5. OID Director (Bld, 31/BIC38) Date

/s/ signature unreadable 4/25/96 Next, the BID Technology Development Coordinator sends this form with 12 photocopies of the CRADA to the NIH Crada Subcommittee Chairman. (Call 496-0750 for address). Review Signature (CRADA Subcommittee does not have approval authority, but reviews and comments on the proposal and may recommend approval or disapproval.



6. CRADA Subcommittee Review Date

/s/ signature unreadable 4/26/96



Final Signature: Non-disapproval NIH/ADAMHA Administrator Date

/s/ signature unreadable DDIR 4/26/96



Finally, send this form and a copy of the final CRADA (signed by each collaborating party) to: NIH Office of Invention Development, Bldg. 31, Room B1C38 (496-0750)





[REFORMATTED FROM ORIGINAL] PUBLIC HEALTH SERVICE



POLICY STATEMENT ON

COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENTS

AND INTELLECTUAL PROPERTY LICENSING



This Statement sets forth the policies of the National Institutes of Health (NIH) on various aspects of cooperative research and intellectual property licensing. These policies apply to the negotiation of NIH Cooperative Research and Development Agreements (CRADAs). License agreements for Intellectual property rights to inventions developed under a CRADA or through the NIH intramural research programs, whether negotiated by NIH or the National Technical Information Service on its behalf, will also incorporate these policies. This Statement may be revised from time to time as NIH considers appropriate.*



To implement the Federal Technology Transfer Act of 1986, (FTTA, 15 U.S.C. at (S) 3710), Executive Order 12591 of April 10, 1987 orders Federal laboratories to assist universities and the private sector in broadening our national technology base by moving new knowledge from the research laboratory into the development of new products and processes. While Federal patent law (35 U.S.C. at (S)(S) 200-212) authorizes the licensing of Government-owned patent rights, the FTTA seeks to facilitate technological collaboration at an earlier stage. Thus, the FTTA authorizes Federal laboratories to enter into CRADAs and to agree to grant intellectual property rights in advance to collaborators for inventions made in whole or part by Federal employees under the CRADA. Besides assisting in the transfer of commercially useful technologies from Federal laboratories to the marketplace, CRADAs make outside resources more accessible to Federal laboratories.



NIH, on agency of the Public Health Service (PHS) within the Department of Health and Human Services (DHHS), is among the world's preeminent biomedical research organizations. Its general mission is to conduct biomedical and behavioral research that will lead to the better health of the American people. For the NIH investigator, this agency mission prescribes the exploration of ideas, the communication of ideas and information to colleagues, and a responsibility for the prompt and accurate publication of findings. Under the FTTA, 15 U.S.C. at Sec. 3710a(a)(2), technology transfer, consistent with mission responsibilities, is also a responsibility of each laboratory science and engineering professional. To support its mission, NIH has developed an interdisciplinary and synergistic research environment that promotes the free exchange of ideas and information. In order to safeguard the collegiality and integrity of, as well as public confidence in, the NIH research programs, the following cooperative research and technology transfer policies have been adopted.



1. RESEARCH FREEDOM



NIH Investigators generally are free to choose the subject matter of their research, consistent with the mission of their Institute and the research programs of their Laboratories. No CRADA or license agreement may contravene this freedom.



2. RESEARCH POLICY



NIH research results generally are disseminated freely through publication in the scientific literature and presentations at public fora. Brief delays in this dissemination of research results may be permitted under a CRADA as necessary in order to file corresponding patent or other intellectual property applications. NIH considers the filing of such applications to be an important component of its research efforts.



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*Questions or comments about this Statement and requests for updated versions should be directed to the NIH Office of Technology Transfer at (301) 496-7057. This Statement is effective on an Interim basis.



NIH Office of Technology Transfer POLICY STATEMENT ON CRADAs & INTELLECTUAL PROPERTY LICENSING 940329 - Page 1 of 5 3. COOPERATIVE RESEARCH AND DEVELOPMENT UNDER A CRADA



As defined by the FTTA, 15 U.S.C. (S) at 3710a(d)(1), a CRADA means any agreement between one or more Federal laboratories and one or more non-Federal parties, under which the Government provides personnel, services, facilities, equipment, or other resources (but not funds), and the non-Federal parties provide funds, personnel, services, facilities, equipment, or other resources toward the conduct of specified research or development efforts. Cooperative research and development activities are intended to facilitate the transfer of Federally funded research and development for use by State and local governments, universities, and the private sector, particularly small business.



4. NIH CRADAs



As adopted by NIH, a CRADA is a standardized agreement intended to provide an appropriate legal framework for, and to expedite the approval of, cooperative research and development projects. The use of CRADAs is encouraged for cooperative efforts because they permit NIH to accept, retain, and use funds, personnel, services, and property from collaborating parties and to provide personnel, services, and property to collaborating parties. NIH may permit investigators to enter into CRADAs with collaborators who will make a significant intellectual contribution to the research project undertaken or who will contribute essential research materials or technical resources not otherwise reasonably available. While NIH welcomes contributions to its gift funds for research purposes, it does not view CRADAs as a general funding source or a mechanism for sponsored research. This approach to implementing the FTTA has been chosen in order to maintain the public's confidence in NIH through maintaining an independence from reliance on industry funding.



5. SELECTION OF COLLABORATORS UNDER A CRADA



Collaborations under a CRADA may be suggested by potential collaborators or by NIH investigators. Generally, The decision to initiate the approval process for a CRADA is made by the involved NIH investigator and Laboratory Chief based on scientific considerations and the desire for the public to benefit from the commercialization of particular NIH research. For some cooperative projects, where the development and commercialization potential is more immediate relative to the basic research aspects, NIH may seek a collaborator(s) which has both scientific expertise and commercialization capabilities. In certain areas of research, e.g., where the Government has the intellectual lead or where both scientific and commercialization capabilities are deemed essential at the outset, NIH may competitively seek a collaborator through Federal Register notification. The PHS has also developed policy guidelines for ensuring fairness of access to PHS laboratories such as NIH in the process of initiating and developing CRADAs.



6. PROPRIETARY OR CONFIDENTIAL INFORMATION AND MATERIALS



NIH recognizes that on effective collaborative research program may require the disclosure of proprietary information to NIH investigators. Although agreements to maintain confidentiality are permitted under a CRADA, collaborators should limit their disclosure of proprietary information to the amount necessary to carry out the research plan of the CRADA. The mutual exchange of confidential information, e.g., patient data, should be similarly limited. NIH also recognizes that cooperative research may require the exchange of proprietary research materials. Such materials may be used only for the purposes specified in the research plan set forth in the CRADA. All parties to the CRADA will agree to keep CRADA research results confidential to the extent permitted by law until they are published in the scientific literature or presented at a public forum.



[Page Break Altered form Original] 7. TREATMENT OF DATA AND RESEARCH



Products Produced under a CRADA: The NIH investigator and the collaborator

will agree to exchange all data and research products developed in the

course of research under a CRADA whether developed solely by NIH, jointly

with the collaborator, or solely by the collaborator. In general, tangible

research products developed under a CRADA will be shared equally by the

parties to the CRADA. All parties to a CRADA will be free to utilize



NIH Office of Technology Transfer POLICY STATEMENT ON CRADAs & INTELLECTUAL PROPERTY LICENSING 940329 - Page 2 of 5

such data and research products for their own purposes. Data and research

products developed solely by the collaborator may be designated as

proprietary by the collaborator when they are wholly separable from the

data and research products developed jointly with NIH investigators;

however, except as may be afforded through intellectual property rights

that require public disclosure of the protected subject matter (e.g.,

patents), NIH will not agree to exclude others from utilizing or

commercializing the data or research products developed solely by NIH

investigators or jointly with the collaborator under a CRADA.



8. OWNERSHIP AND LICENSING OF NIH INTELLECTUAL PROPERTY RIGHTS



Pursuant to the FTTA, 15 U.S.C. at (S) 3710a(b)(2), a Federal laboratory is authorized to own and license patent rights to inventions made in whole or part by its employees under a CRADA. The term "invention" is defined at (S) 3703(9) to mean any invention or discovery which is or may be patentable or otherwise protected under Title 35 or any novel variety of plant which is or may be protectable under the Plant Variety Protection Act (PVPA), 7 U.S.C. (S) 2321 et seq. The patent law, 35 U.S.C, at (S) 207, authorizes the ownership and licensing of intramural inventions. Executive Order 12591 at (S) 1(b)(1)(B) further authorizes the transfer of Government intellectual property rights. Although the FTTA speaks broadly of the transfer. of "technology," NIH does not have statutory authority to license (or to agree to limit dissemination of) technology developed in whole or part by its investigators under a CRADA unless a patent, PVPA certificate or other intellectual property application has been filed for that technology. NIH will retain the Government ownership interest in, but not license rights to, all intellectual property rights to inventions developed solely through intramural research or developed in whole or in part by its investigators under a CRADA.



9. GENERAL LICENSING POLICY



NIH recognizes that under the FTTA and the patent licensing low to which it refers, Congress and the President have chosen to utilize the patent system as the primary mechanism for transferring Government inventions to the private sector. The importance of patents to commercialization in the biomedical field is further reflected by the Drug Price Competition and Patent Term Restoration Act of 1984 (Pub. L. 98-417). A fundamental principle of the patent system is that the owner of a patent have a time-limited "right to exclude others from making, using, or selling the [patented] invention." The reason for such a period of exclusivity is to encourage industry to invest the resources necessary to bring an invention from the discovery stage through subsequent development, clinical trials, regulatory approvals, and ultimately into commercial production. NIH accordingly is willing to grant exclusive commercialization licenses under its patent or other intellectual property rights in cases where substantial additional risks, time and costs must be undertaken by a licensee prior to commercialization. Under a CRADA, NIH is also willing to agree to grant exclusive commercialization licenses in advance to collaborators. NIH will attempt, however, to license its intramural inventions nonexclusively in cases where an invention reflects a relatively more advanced stage in commercial development, e.g., when an NIH investigator invents a patentable new therapeutic use for a known and FDA-approved compound.



Federal laboratories are authorized to negotiate license agreements for Government-owned patent rights in intramural inventions pursuant to 35 U.S.C. (S) 207. Although (S) 207 does not apply to intellectual property license agreements authorized by the FTTA for inventions mode under a CRADA, NIH has adopted the following approach of Sec. 207 for all license agreements:





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Each Federal Agency [may] .. grant nonexclusive, exclusive, a partially

exclusive licenses under Federally owned patent applications, patents, or

other forms of protection ... on such terms and conditions ... as

determined appropriate in the public interest.



NIH has determined it to be appropriate in the public interest to grant nonexclusive research licenses and either exclusive or nonexclusive commercialization licenses to DHHS-owned intellectual property rights according to the plan discussed below.



NIH Office of Technology Transfer POLICY STATEMENT ON CRADAs & INTELLECTUAL PROPERTY LICENSING 940329 - Page 3 of 5 10. GOVERNMENT INTELLECTUAL PROPERTY RIGHTS



For inventions developed wholly by NIH investigators or jointly with a collaborator under a CRADA, NIH is required by the FTTA at 15 U.S.C. Sec. 3710a(b)(2) to retain at least a nonexclusive, irrevocable, paid-up license to practice the invention or to have the invention practiced throughout the world by or on behalf of the U. S. Government. When granting exclusive or partially exclusive licenses to NIH intramural inventions, 35 U.S.C. Sec. 208, as implemented by 37 C.F.R. Sec. 404.7(2)(i), requires the reservation of similar Government rights. NIH will not assert an ownership right in inventions made solely by a collaborator under a CRADA, but will require the grant of a research license, as described below, to the Government for inventions made wholly by a collaborator under a CRADA.



11. RESEARCH LICENSES



NIH will reserve the right under any CRADA and intellectual property license to grant nonexclusive licenses to make and to use the invention for purposes of research involving the invention itself, and not for purposes of commercial manufacture or in lieu of purchase as a commercial product for use in other research. The purpose of the research license is to facilitate basic academic research. NIH intends to consult with any involved commercialization licensee(s) before granting research licenses to commercial entities.



12. COMMERCIALIZATION LICENSES



NIH is willing to consider requests for nonexclusive or exclusive commercialization licenses to intellectual property rights to inventions developed under a CRADA or in the course of intramural research, pursuant to applicable statutes and regulations. Under a CRADA, NIH generally will grant a time-limited option to negotiate, in good faith, the terms of a license that fairly reflect the relative contributions of the parties, the risks incurred by the collaborator, and the costs of subsequent research and development needed to bring the results of CRADA research to the marketplace. NIH contemplates the drafting of a model invention license to serve as the starting point for license negotiations. It is contemplated further that such a model will reduce negotiations essentially to matters of execution fees, royalty rates, and minimum annual royalties. Royalty rates will be based on product sales and the rates conventionally granted in the field identified in the CRADA's research plan for inventions with reasonably similar commercial potential. Royalty rates generally will not exceed a rate within the range of 5 - 8 % for exclusive commercialization licenses. Contingent royalty schemes based on, e.g., patent issuance or nonissuance, and clauses treating the stacking of royalties or packaging of other inventions developed under the CRADA may be provided. Exclusive licensees will be expected to reimburse NIH for intellectual property related expenses, and may be permitted to offset such reimbursement against future product royalties,



13. NONEXCLUSIVE COMMERCIALIZATION LICENSES



Unless a request for exclusive commercialization license is made under a CRADA or submitted for an intramural invention, NIH will attempt to license its inventions nonexclusively. Such nonexclusive licenses generally will follow the guidelines of 37 C.F.R. Part 404.



14. EXCLUSIVE COMMERCIALIZATION LICENSES



All NIH exclusive commercialization licenses will require the submission by a prospective licensee of an acceptable development and commercialization plan as described by 35 U.S.C. Sec. 209(a) and subsequent periodic reports on utilization of the invention as described by Sec. 209(f)(1), All such plans and reports will be treated in confidence and as privileged from disclosure under the Freedom of



[Page Break Altered form Original] Information Act. Modification provisions as described by Sec. 209(f)(2)-(4) may apply. In appropriate cases, NIH may also reserve the right to grant separate exclusive commercialization licenses in various fields of use. The remaining provisions of 35 U.S.C. Sec. 200-212 will also apply to licenses to NIH intramural inventions.



NIH also considers the following provisions for exclusive commercialization licenses to be necessary and appropriate in the public Interest:



NIH Office of Technology Transfer POLICY STATEMENT ON CRADAs & INTELLECTUAL PROPERTY LICENSING 940329 - Page 4 of 5

(i) the exclusive licensee must pledge its reasonable best efforts to

commercialize a licensed invention and the development and

commercialization plan mentioned above may serve as the measure of such

efforts;



(ii) NIH shall have the right, after notice and opportunity to cure, to

terminate or render nonexclusive any license granted: 1) If the licensee is

not reasonably engaged in research, development, clinical trials,

manufacturing, marketing, sublicensing, or other activities reasonably

necessary to the expeditious commercial dissemination of the licensed

invention; or 2) when the licensee cannot reasonably satisfy unmet health

and safety needs;



(iii) in order to maximize the commercialization of the licensed invention

in other fields of use not utilized by the exclusive licensee through

ongoing development, manufacturing or sublicensing, NIH reserves the right

to require the licensee to grant sublicenses to responsible applicants, on

reasonable terms, in such other fields of use, unless the licensee can

reasonably demonstrate that such a sublicense would be contrary to sound

and reasonable business practice and the granting of the sublicense would

not materially increase the availability to the public of the licensed

invention; and



(iv) exclusive licensees to DHHS inventions, whether developed under a

CRADA or through intramural research, must agree to not unreasonably deny

requests for sublicense or cross license rights from future CRADA

collaborators when the possibility of acquiring such derivative rights is

necessary in order to permit a proposed cooperative research project with

NIH to go forward, and the exclusive licensee has been given a reasonable

opportunity to join as a party to the proposed CRADA



15. COMPLIANCE UNDER A CRADA WITH OTHER POLICIES



For research conducted pursuant to a CRADA, collaborators must agree to comply with PHS and NIH policies and guidelines concerning, e.g., human subjects research, the use of research animals including nonwild chimpanzees, recombinant DNA and other policy statements as may be promulgated from time to time.



16. PRICING



DHHS has responsibility for funding basic biomedical research, for funding medical treatment through programs such as Medicare and Medicaid, for providing direct medical care and, more generally, for protecting the health and safety of the public. Because of these responsibilities, and the public investment in the research that contributes to a product licensed under a CRADA, DHHS has a concern that there be a reasonable relationship between the pricing of a licensed product, the public investment in that product and the health and safety needs of the public. Accordingly, exclusive commercialization licenses granted for NIH intellectual property rights may require that this relationship be supported by reasonable evidence.



17. WAIVERS



NIH will consider requests to modify any of the foregoing policies in special cases where public health exigencies or commercial situations warrant such a modification. Modifications dealing with business terms such as royalties are not decided by the NIH investigators and should be discussed with the appropriate NIH technology management personnel.







[Page Break Altered form Original] 18. SPECIAL CONSIDERATION AND PREFERENCE UNDER A CRADA



NIH will give special consideration to entering into CRADAs with small business firms and consortia involving small business firms, and will give preference to business units located in the United States which agree to manufacture substantially in the United States products which embody inventions developed in the course of research under CRADAs.



NIH Office of Technology Transfer POLICY STATEMENT ON CRADAs & INTELLECTUAL PROPERTY LICENSING 940329 - Page 5 of 5

PUBLIC HEALTH SERVICE



COOPERATIVE RESEARCH AND DEVELOPMENT AGREEMENT*



This Cooperative Research and Development Agreement, hereinafter referred to as the "CRADA," consists of this Cover Page, an attached Agreement, a Signature Page and various Appendices referenced in the Agreement. This Cover Page serves to identify the Parties to this CRADA:



(1) the following Bureau(s), Institute(s) or Division(s) of the National Institutes of Health: National Center for Human Genome Research, hereinafter singly or collectively referred to as the "NIH;" and



(2) Applied Imaging, which has offices at 2380 Walsh Ave., Bldg. B, Santa Clara, CA 95051, hereinafter referred to as the "Collaborator."







Although drafted for two Parties, the attached CRADA may also be used for any number. This Cover Page, however, should be modified by repeating block (2) to identify other Parties to the CRADA. All non-NIH Parties are hereinafter collectively referred to as the "Collaborator." Use of the terms "Collaborator," "Party" and "Parties" should be construed as appropriate for the actual number of CRADA participants.







*This Cooperative Research and Development Agreement form is effective on an interim basis. Questions or comments about this CRADA and requests for updated versions should be directed to the NIH Office of Technology Transfer at 301-496-



PHS Technology Transfer Policy Board MODEL CRADA 010395 - Page 1 of 22

COOPERATIVE RESEARCH AND DEVELOPMENT





ARTICLE 1. INTRODUCTION



This Cooperative Research and Development Agreement (CRADA) between NIH and the Collaborator will be effective when signed by all parties. By signing this CRADA, the Collaborator acknowledges that it has received and read a copy of the Policy Statement on Cooperative Research and Development Agreements and Intellectual Property Licensing which is attached as Appendix A. The research and development project(s) which will be undertaken by each of the Parties in the course of this CRADA are detailed in the Research Plan (RP) which is attached as Appendix B The funding and staffing commitments of the Parties are set forth in Appendix C. Any exceptions or changes to the CRADA are set forth in Appendix D.



ARTICLE 2. DEFINITIONS



As used in this CRADA, the following terms shall have the indicated meanings:



2.1 "Cooperative Research and Development Agreement" or "CRADA" means this

Agreement, entered into by NIH pursuant to the Federal Technology Transfer

Act of 19 ...