[Federal Register: August 10, 1995 (Volume 60, Number 154)]



National Institutes of Health

National Cancer Institute: Opportunity for a Cooperative Research
and Development Agreement (CRADA) for the Development of New Types of
Therapeutic Compounds for Acquired Immunodeficiency Syndrome (AIDS) and
Other Human and Animal Diseases of Retroviral Etiology Identified Using
Novel Screening Assays

AGENCY: National Institutes of Health, PHS, DHHS.

ACTION: Notice.


SUMMARY: Pursuant to the Federal Technology Transfer Act of 1986 (FTTA,
15 U.S.C. Sec. 3710; Executive Order 12591 of April 10, 1987), the
National Cancer Institute (NCI) of the National Institutes

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of Health (NIH) of the Public Health Service (PHS) of the Department of
Health and Human Services (DHHS) seeks a Cooperative Research and
Development Agreement (CRADA) with a pharmaceutical or biotechnology
company to develop novel therapeutics for AIDS and other human and
animal diseases of retroviral etiology based upon a newly identified
highly conserved HIV target protein. Any CRADA for the biomedical use
of this technology will be considered. The CRADA would have an expected
duration of one (1) to five (5) years. The goals of the CRADA include
the rapid publication of research results and their timely
commercialization. The CRADA Collaborator will have an option to
negotiate the terms of an exclusive or nonexclusive commercialization
license to subject inventions arising under the CRADA.

ADDRESSES: Proposals and questions about this CRADA opportunity may be
addressed to Cindy K. Fuchs, J.D., Office of Technology Development,
National Cancer Institute-Frederick Cancer Research and Development
Center, P.O. Box B, Frederick, MD 21702-1201, Telephone: (301) 846-
5465, Facsimile: (301) 846-6820. Background information, including
abstracts and reprints, is available. In addition, pertinent
information not yet publicly disclosed may be obtained under a
confidential disclosure agreement.
Requests for copies of the patent applications, license application
form, or other questions and comments concerning the licensing of this
technology should be directed to Steven M. Ferguson, Acting Chief,
Infectious Disease Branch, Office of Technology Transfer, National
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville,
MD 20852-3804, Telephone: (301) 496-7735 ext. 266, Facsimile: (301)
402-0220. A signed confidentiality agreement will be required to
receive copies of the patent applications.

EFFECTIVE DATE: In view of the high priority for developing new drugs
for the treatment of HIV infection, interested parties should notify
the NCI Office of Technology Development in writing no later than sixty
(60) days from the date of this announcement. Respondents will then be
provided an additional ninety (90) days for submitting formal CRADA

SUPPLEMENTARY INFORMATION: Current antivirals are ineffective against
HIV-1 largely due to the emergence of drug resistant viral mutants.
HIV-1 contains regions known as CCHC zinc fingers in the retroviral
nucleocapsid protein. These CCHC zinc fingers are highly conserved
throughout nearly all retroviruses. The CCHC zinc fingers are sequences
of 14 amino acids with four invariant residues,
Cys(X)2Cys(X)4His(X)4Cys, that chelate zinc and perform
essential functions in viral infectivity. Mutations in the CCHC zinc
fingers render HIV-1 non-infectious. Many compounds that disrupt the
CCHC zinc fingers also inactivate the HIV-1 virus. HIV-1 has two zinc
fingers, both of which are necessary for infectivity. The invariant
nature of the retroviral zinc fingers and the requirement of both
fingers would make the development of drug resistant viral mutants
unlikely. HIV-1 CCHC zinc fingers exhibit a previously unrecognized
susceptibility to attack by certain types of compounds. Compounds with
this activity may be useful for developing new types of anti-retroviral
The AIDS Vaccine Program at the National Cancer Institute-Frederick
Cancer Research and Development Center (NCI-FCRDC) has developed novel
screening assays for identifying compounds capable of inactivating
retroviruses, including HIV-1. The screening assays are based on the
ability of a compound to disrupt the CCHC zinc fingers. Retroviral CCHC
zinc fingers complex with two zinc ions, each with a formal charge of
+2. Compounds that react with the CCHC zinc fingers and remove the zinc
ions cause a change in the conformation and charge of the nucleocapsid
protein, which can be detected as a change in its electrophoretic
mobility using capillary zone electrophoresis (CZE). Purified CCHC zinc
fingers may be reconstituted with radioactive zinc\65\. By monitoring
the release of radioactive zinc\65\ caused by the reaction of a test
compound with a retroviral CCHC zinc finger, it is possible to
determine the reactivity of the test compound. Changes in the intrinsic
fluorescence, fluorescence of artificial probes, or fluorescent zinc
chelators can be used to monitor the loss of zinc from the HIV-1 CCHC
zinc fingers. Reverse phase high performance liquid chromatography
(HPLC) can be used to separate CCHC zinc fingers that have been reacted
with compounds resulting in covalent changes in these proteins. Nuclear
magnetic resonance (NMR) can be used to monitor the loss of zinc from
retroviral CCHC zinc fingers. Because these assays do not utilize live
virus, special containment facilities are not required for the
screening procedures. Several of these assays are adaptable for high
through-put screening. Gel mobility shift assays also can be used to
identify and study compounds which are able to penetrate intact virus
and to induce conformational changes in the CCHC zinc fingers. These
assays can utilize HIV-1 or retroviruses that are not pathogenic for
humans. Since CCHC zinc fingers are highly conserved among nearly all
retroviruses, assays based upon these structures are suitable for
screening for drugs that would be effective against viruses for adult
T-cell leukemia, tropical spastic paraparesis caused by Human T-Cell
Leukemia Virus-I and -II (HTLV-I and HTLV-II) as well as retroviral
infections in animals such as feline leukemia virus and feline
immunodeficiency virus in cats, equine infectious virus in horses, and
lentivirus isolated from sheep, goats and cattle.
The patent portfolio for this technology includes the following
pending patent applications:

Serial Numbers: 08/312,331 and 08/379,420
Title: ``A Method for Identifying and Using Compounds that Inactivate
HIV-1 and Other Retroviruses by Attacking Highly Conserved Zinc Fingers
in the Viral Nucleocapsid Protein''
Inventors: Dr. Louis E. Henderson, Dr. Larry O. Arthur, and Dr. William
G. Rice.

The patent rights in these inventions have been assigned to the
United States of America. Parties interested in submitting a CRADA
proposal should be aware that it may be necessary to secure a license
to the foregoing patent applications in order to commercialize products
arising from the CRADA.
The role of the National Cancer Institute in this CRADA will
include but not be limited to:

1. Providing intellectual, scientific, and technical expertise and
experience to the research project.
2. Planning research studies and interpreting research results.
3. Providing screening assay reagent(s) to the CRADA Collaborator in
``start-up'' quantities.
4. Contracting, as needed, support services at the NCI-FCRDC such as
antigen and antibody production.
5. Screening candidate therapeutic compounds using the novel assays
described above.
6. Screening promising candidates in HIV viral infectivity assays.
7. Publishing research results.

The role of the CRADA Collaborator may include but not be limited

1. Providing significant intellectual, scientific, and technical
expertise or experience to the research project.
2. Planning research studies and interpreting research results.

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3. Providing support for ongoing CRADA-related research in the
development of candidate therapeutic compounds:
(a) financial support to facilitate scientific goals;
(b) technical or financial support for further design of candidate
therapeutic compounds; and
(c) financial and logistical support for clinical trials Phases I-
4. Providing and implementing plans to independently secure future
continuing supplies of candidate therapeutic compounds to assure
continued preclinical and clinical development.
5. Providing plans and supporting clinical development leading to FDA
approval of candidate therapeutic compounds.
6. Producing, packaging, marketing, and distributing successful
therapeutic compounds.
7. Using the proposed technology for other novel biopharmaceutical and/
or veterinary applications.
8. Publishing research results.

Selection criteria for choosing the CRADA Collaborator may include
but not be limited to:
1. The ability to collaborate with NCI on further research and
development of this technology. This ability can be demonstrated
through experience and expertise in this or related areas of technology
indicating the ability to contribute intellectually to ongoing research
and development.
2. The demonstration of adequate resources to perform the research,
development and commercialization of this technology (e.g. facilities,
personnel and expertise) and accomplish objectives according to an
appropriate timetable to be outlined in the CRADA Collaborator's
3. The ability to perform clinical testing or trials, and obtain
IND, NDA and FDA approval for a new drug or treatment modality.
4. The willingness to commit best effort and demonstrated resources
to the research, development and commercialization of this technology.
5. The demonstration of expertise in the commercial development,
production, marketing and sales of products related to this area of
6. The level of financial support the CRADA Collaborator will
provide for CRADA-related Government activities.
7. The willingness to cooperate with the National Cancer Institute
in the timely publication of research results.
8. The agreement to be bound by the appropriate DHHS regulations
relating to human subjects, and all PHS policies relating to the use
and care of laboratory animals.
9. The willingness to accept the legal provisions and language of
the CRADA with only minor modifications, if any. These provisions
govern the equitable distribution of patent rights to CRADA inventions.
Generally, the rights of ownership are retained by the organization
which is the employer of the inventor, with (1) the grant of a research
license to the Government when the CRADA Collaborator's employee is the
sole inventor, or (2) the grant of an option to negotiate for an
exclusive or nonexclusive license to the CRADA Collaborator when the
Government employee is the sole inventor.

Dated July 28, 1995.
Thomas D. Mays,
Director, Office of Technology Development, National Cancer Institute,
National Institutes of Health.
[FR Doc. 95-19733 Filed 8-9-95; 8:45 am]