[Federal Register Volume 59, Number 245 (Thursday, December 22, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-31395]


[[Page Unknown]]

[Federal Register: December 22, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
 

National Institute of Child Health and Human Development; 
Licensing Opportunity and/or Opportunity for a Cooperative Research and 
Development Agreement (CRADA) for the Use of Orally Active Derivatives 
of 1,3,5(10)-estratriene and Pharmaceutical Compositions Thereof

AGENCY: National Institutes of Health, Public Health Service, DHHS.

ACTION: Notice.

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SUMMARY: The National Institutes of Health is seeking licensees and/or 
CRADA partners for the further development, evaluation, and 
commercialization of novel esters of estradiol and pharmaceutical 
compositions thereof. The invention claimed in U.S. Patent Application 
Serial No. 08/122,853 entitled ``Orally Active Derivatives of 
1,3,5(10)-estratriene'' (Kim, H.K., Blye, R.P., and Bialy, G.), filed 
August 17, 1993, is available for either exclusive or non-exclusive 
licensing (in accordance with 35 U.S.C. 207 and 37 CFR Part 404) and/or 
further development under a CRADA for clinical and research 
applications described below in Supplementary Information.
    To expedite the research, development, and commercialization of 
this new class of drugs, the National Institutes of Health is seeking 
one or more license agreements and/or CRADAs with pharmaceutical or 
biotechnology companies in accordance with the regulations governing 
the transfer of Government-developed agents. Any proposal to use or 
develop these drugs will be considered.

ADDRESSES: CRADA proposals and questions about this opportunity should 
be addressed to: Dr. Gordon Guroff, Deputy Scientific Director, 
National Institute of Child Health and Human Development, Building 49, 
Room 5A64, Bethesda, Maryland 20892 (301/496-4751).
    Licensing proposals and questions about this opportunity should be 
addressed to: Ms. Carol Lavrich, Technology Licensing Specialist, 
Office of Technology Transfer, National Institutes of Health, 6011 
Executive Boulevard, Rockville, Maryland 20852-3804 (301/496-7735, ext. 
287).
    Information about the patent application and pertinent information 
not yet publicly described can be obtained under a Confidential 
Disclosure Agreement. Respondees interested in licensing the 
invention(s) will be required to submit an Application for License to 
Public Health Service Inventions. Respondees interested in submitting a 
CRADA proposal should be aware that it may be necessary to secure a 
license to the above patent rights in order to commercialize products 
arising from a CRADA.

DATES: There is no deadline by which license applications must be 
received. CRADA proposals must be received on or before March 22, 1995.

SUPPLEMENTARY INFORMATION: One facet of oral contraceptive technology 
which has received little attention over the last three decades is the 
development of new orally active estrogens with attractive 
pharmacologic profiles. These would include hormones with fewer side 
effects than those associated with the currently available estrogens, 
ethynylestradiol and its 3-methyl ether (mestranol), notably nausea, 
vomiting, alterations in liver function, and histopathology and 
clotting disorders. Some clinicians have suggested that the presence of 
the 17-ethynyl moiety, which protects the steroid from rapid metabolism 
by the liver (so-called ``first-pass'' effect) and thus confers oral 
activity, is also responsible for many of the side effects observed 
with these drugs.
    In an effort to develop nonethynylated estrogens, NICHD has 
synthesized several estradiol nitrate esters which exhibit potent 
estrogenic activity in rats and rhesus monkeys following both oral, 
subcutaneous, and percutaneous administration. Using an increase in the 
uterine weight of immature rats (rat uterotropic test) as an endpoint, 
two of these esters were more than five times as potent as 
ethynylestradiol following oral administration. They also induce 
estrogen withdrawal bleeding in ovariectomized rhesus monkeys following 
both oral and percutaneous administration. They are very potent 
postcoital agents following oral administration to rats on days 0-4 of 
gestation.
    The superiority of these esters to ethynylestradiol or its methyl 
ether as the estrogenic component of oral contraceptive tablets will 
depend upon clinical and histopathological findings from toxicity 
studies in animals and/or clinical observations in Phase I and II human 
studies. The estradiol nitrate esters also have considerable potential 
clinical utility as replacement estrogens in menopausal women. The most 
widely used therapeutic regimens involve oral administration of 
ethynylestradiol, estradiol or conjugated estrogens (principally 
estrone sulfate) either continuously or cyclically, with or without 
addition of a progestin, much of which depends on the presence or 
absence of the uterus.
    Compounds of this series have been studied for estrogenic potency 
following oral, subcutaneous and topical administration and 
pharmacokinetic data are available on several analogs utilizing 
radioimmunoassays developed by the Government. Relative binding 
affinities to the rat and rabbit uterine estrogen receptor are 
currently being studied.
    In an effort to expedite research, development, and 
commercialization of the novel estradiol esters, the National Institute 
of Child Health and Human Development seeks a CRADA partner(s) for 
joint exploration and possible commercialization. Any CRADA proposed 
for these purposes will be considered.
    The CRADA aims will include the rapid publication of research 
results consistent with protection of proprietary information and 
patentable inventions as well as the timely exploitation of commercial 
opportunities. The CRADA partner will enjoy the benefits of first 
negotiation for licensing Government rights to any inventions arising 
under the agreement and will advance funds payable upon signing the 
CRADA to help defray Government expenses for patenting such inventions 
and other CRADA-related costs.
    The role of the National Institute of Child Health and Human 
Development will be as follows:
    1. Provide the collaborator with all biological data on 
compositions of matter covered by the agreement.
    2. Provide samples of compositions of matter covered by the 
agreement.
    3. Provide chemical data on compositions of matter covered by the 
agreement including synthetic routes, analytical methods employed, and 
purity.
    4. Provide conformational analysis of compositions of matter 
covered by the agreement where possible.
    5. Continue studies on the pharmacokinetics and biological activity 
of compositions of matter covered by the agreement.
    6. Conduct studies to optimize formulations for administration of 
the compositions of matter covered by the agreement by various routes 
in rodents and primates.
    7. Conduct Ames Test and other genetic toxicology on compositions 
of matter covered by the agreement scheduled for clinical evaluation.
    8. Participate in meetings with the Food and Drug Administration 
for establishment of the drug safety studies required for Phase I, II, 
and III clinical investigations of any of the compositions of matter 
covered by the agreement and provide liaison with that Agency.
    The role of the collaborator will be as follows:
    1. Undertake studies to identify any unique properties of the 
compositions of matter covered by the agreement including 
pharmacological differences from ethynylestradiol and mestranol 
(ethynylestradiol-3-methyl ether) which might favor their use as the 
estrogenic component of combined oral contraceptives.
    2. Undertake a broad spectrum of estrogen receptor binding studies.
    3. Undertake acute, subacute, chronic, carcinogenicity, and 
reproductive toxicology studies necessary to proceed with the orderly 
evaluation of selected compositions of matter covered by the agreement 
in human subjects.
    4. Undertake an orderly sequence of clinical investigations of 
selected compositions of matter covered by the agreement for their 
safety and efficacy as estrogens for employment in combined oral 
contraceptives, postcoital contraceptives and for therapeutic use in 
gynecic medicine.
    Selection criteria for choosing the CRADA partner(s) will include 
but are not limited to the following:
    1. The collaborator must present in their proposal a clear 
statement of their capabilities and experience with respect to the 
tasks to be undertaken. This would include experience in drug 
development, regulatory affairs, and marketing.
    2. The proposal must contain a clear and concise outline of the 
work to be undertaken, a schedule of significant events, and outline of 
objectives to be accomplished in a timely manner, and such experimental 
details as will provide a basis for evaluation of competing 
submissions.
    3. The proposal must contain the level of financial support the 
collaborator will supply for CRADA-related Government activities.
    4. A willingness to cooperate with the NICHD in publication of 
research results consistent with the protection of proprietary 
information and patentable inventions which may arise during the period 
of the agreement.
    5. Agreement to be bound by DHHS rules and regulations regarding 
the use of human subjects in clinical investigations, patent rights, 
ethical treatment of animals, and randomized clinical trials.
    6. Agreement with provisions for equitable distribution of patent 
rights to any inventions developed under the CRADA(s). Generally, the 
rights of ownership are retained by the organization which is the 
employer of the inventor, with an irrevocable, non-exclusive, royalty-
free license to the Government (when a company employee(s) is the sole 
inventor) or an option to negotiate an exclusive or non-exclusive 
license to the company on terms that are appropriate (when the 
Government employee(s) is the sole inventor).

    Dated: December 14, 1994.
Barbara M. McGarey,
Deputy Director, Office of Technology Transfer.
[FR Doc. 94-31395 Filed 12-21-94; 8:45 am]
BILLING CODE 4140-01-P