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[Federal Register Volume 62, Number 154 (Monday, August 11, 1997)]
[Notices]
[Pages 43000-43002]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-21149]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health

Government-Owned Inventions; Availability for Licensing

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

ACTION: Notice.

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SUMMARY: The inventions referenced below are owned by agencies of the 
U.S. Government and are available for licensing in the U.S. in 
accordance with 35 U.S.C. 207 to achieve expeditious commercialization 
of results of federally-funded research and development. Foreign patent 
applications are filed on selected inventions to extend market coverage 
for U.S. companies and may also be available for licensing.

ADDRESSES: Licensing information and copies of the issued U.S. patents 
and the U.S. patent applications referenced below may be obtained by 
contacting Carol Lavrich, Technology Licensing Specialist, Office of 
Technology Transfer, National Institutes of Health, 6011 Executive 
Boulevard, Suite 325, Rockville, Maryland 20852-3804; telephone: 301/
496-7057 ext. 287; fax: 301/402-0220; e-mail: [email protected] A signed 
Confidential Disclosure Agreement will be required to receive copies of 
the patent applications.

SUPPLEMENTARY INFORMATION: The National Institutes of Health is seeking 
licensees and/or CRADA collaborators for the further development, 
evaluation, and commercialization of nitric oxide (NO) compounds and 
subsequent drug delivery strategies for the treatment of a variety of 
medical disorders. Published elsewhere in this issue of the Federal 
Register is a notice describing the CRADA opportunities available from 
the National Cancer Institute for these NO technologies. A complete 
listing of these technologies may be found in the CRADA notice; 
abstracts for some of them appear below.

Complexes of Nitric Oxide With Polyamines

LK Keefer, JA Hrabie (NCI)
Serial No. 07/585,793 filed 20 Sep 90; U.S. Patent 5,155,137 issued 13 
Oct 92

    Novel complexes of nitric oxide and polyamines are potentially 
useful in treating a variety of clinical disorders. These nitric oxide/
polyamine complexes release nitric oxide under physiological conditions 
in a sustained and controllable fashion and possess long-lived 
pharmacological effects.
    Related cases: Serial No. 07/906,479 filed 30 Jun 92 (DIV), which 
issued as U.S. Patent 5,250,550 on 05 Oct 93; Serial No. 08/522,405 
filed 02 Feb 96 (CIP of 07/906,479)

Oxygen Substituted Derivatives of Nucleophile-Nitric Oxide Adducts as 
Nitric Oxide Donor Products

LK Keefer, TM Dunams, JE Saavedra (NCI)
Serial No. 07/950,637 filed 23 Sep 92; U.S. Patent 5,366,997 issued 22 
Nov 94

    A novel class of compounds that release nitric oxide (NO) in vivo 
offers to improve the treatment of many clinical disorders. This new 
class of compounds is stable to acidic conditions of the stomach and in 
the blood stream but releases nitric oxide at sites of metabolic 
activation. Thus, they provide organ-selective NO release and can be 
advantageously administered orally.

Polymer-Bound Nitric Oxide/Nucleophile Adduct Compositions, 
Pharmaceutical Compositions Incorporating Same, and Methods of Treating 
Biological Disorders

LK Keefer, JA Hrabie (NCI)
Serial No. 07/935,565 filed 24 Aug 92; U.S. Patent 5,405,919 issued 11 
Apr 95

    A polymeric composition capable of releasing nitric oxide including 
a polymer and a nitric oxide-releasing N2O2-
functional group bound to the polymer; pharmaceutical compositions 
including the polymeric composition; and methods for treating 
biological disorders in which dosage with nitric oxide is beneficial. 
The compositions can be used as and/or incorporated into implants, 
injectables, condoms, prosthesis coatings, patches, and the like for 
use in a wide variety of medical applications.

Nitric Oxide-Releasing Compounds for the Sensitization of Hypoxic Cells 
in Radiation Therapy

JB Mitchell, MC Krishna, D Wink, JE Liebmann, A Russo (NCI)
Serial No. 08/319,888 filed 07 Oct 94; U.S. Patent 5,650,442 issued 22 
Jul 97

    A novel method has been developed for sensitizing oxygen-poor, or 
hypoxic, tumor cells, which will increase the effectiveness of 
radiation treatment. It has long been known that ionizing radiation is 
more effective in killing cancer cells if the cells are in an oxygen-
rich environment; however, the farther tumor cells are away from the 
blood

[[Page 43001]]

supply, the more hypoxic they are and the more resistant they are to 
radiation therapy. Current methods for delivering oxygen to hypoxic 
cells have limitations because they are toxic to normal tissue, require 
oxygen for their activity, or have too short a half-life. This 
development overcomes such problems by employing a nitric oxide (NO)-
containing compound that spontaneously releases NO under physiologic 
conditions without requiring oxygen. This compound--which has a 
relatively long half-life and is nontoxic to normal cells--has the dual 
advantages of being able to sensitize hypoxic tumor cells to ionizing 
radiation while protecting normal cells from the effects of radiation.

Use of Nitric Oxide-Releasing Agents for Reducing Metastasis Risk

RJ Korthuis, L Kong, LK Keefer (NCI)
Serial No. 08/344,341 filed 22 Nov 94

    Metastasis, which involves the release of cancerous cells from a 
tumor into the circulatory or lymphatic system, is a major problem in 
tumor therapy. Current methods to prevent metastasis from occurring 
include chemotherapy and immunotherapy. However, chemotherapeutic 
methods currently in use employ inhibitors of nucleic acid or protein 
synthesis that cause serious side effects. This invention relates to 
the use of compounds that generate nitric oxide (NO) to reduce 
metastases. It is not known at the present whether NO in fact does 
reduce metastases, although it is known that tumor cells that 
synthesize NO appear to be less metastatic than those that do not. 
Specifically, the claims relate to a series of novel compounds that 
contain a nitric oxide-releasing N2O2-functional 
group. These compounds are useful for inhibiting tumor cell adherence 
at sites at risk.

Biopolymer-Bound Nitric Oxide-Releasing Compositions, Pharmaceutical 
Compositions Incorporating Same and Methods of Treating Biological 
Disorders Using Same

JE Saavedra, LK Keefer, PP Roller, M Akamatsu (NCI) Serial No. 08/
344,157 filed 22 Nov 94; U.S. Patent 5,632,981 issued 27 May 97

    Nitric oxide (NO) has recently been implicated in a variety of 
bioregulatory processes, including normal physiological control of 
blood pressure, macrophage-induced cytostasis and cytotoxicity, and 
neurotransmission. A number of compounds have been developed which are 
capable of delivering nitric oxide, including compounds which release 
nitric oxide upon being metabolized and compounds which release nitric 
oxide spontaneously in aqueous solution. Nitric oxide in its pure form, 
however, is a highly reactive gas having limited solubility in aqueous 
media. Nitric oxide, therefore, is difficult to introduce reliably into 
most biological systems without premature decomposition. The invention 
provides a polymeric-bound composition (biopolymer) capable of 
spontaneously releasing nitric oxide under physiological conditions. A 
biopolymer would include any biological polymer, such as peptides, 
polypeptides, proteins, oligonucleotides, and nucleic acids, including 
those that contain naturally occurring and/or nonnaturally occurring 
subunits. Specific examples include antibodies or fragments thereof and 
peptide hormones, proteins, and growth factors for which the target 
cell type has a high population of receptors.

Incorporation of N2O2 Functional Group Into 
Polymeric Drug Delivery Systems for Treatment of Impotence

LK Keefer (NCI), JE Saavedra (NCI), M Hanamoto (Vivus), PC Doherty 
(Vivus), V Place (Vivus)
Serial No. 08/419,044 filed 10 Apr 95

    Impotence is a major problem in the urology clinic with 
approximately 10-20 million men with moderate to severe forms of 
erectile dysfunction. This invention relates to a method of treating 
impotency in males through the use of nitric oxide-releasing agents. As 
nitric oxide is a mediator of penile erection, this method comprises 
the administration of a nitric oxide-releasing agent which is capable 
of providing a penile erection-inducing amount of nitric oxide to the 
male animal and which includes a nitric oxide-releasing functional 
group. Thus the invention provides a method of administering nitric 
oxide by using: compounds comprising nitric oxide-releasing functional 
groups, polymers to which a nitric oxide-releasing functional group is 
bound, as well as a nitric oxide delivery means for use in the method 
which delivers such a compound or polymer. The delivery means may be 
biodegradable or nonbiodegradable. The invention provides a method in 
which the nitric-oxide releasing agent provides nitric oxide to the 
penis of an impotent male animal in sufficient quantity to create a 
penile erection.

Polysaccharide-Bound Nitric Oxide/Nucleophile Adducts

DJ Smith, D Chakravarthy, LK Keefer (NCI)
Serial No. 08/419,424 filed 10 Apr 95

    The present invention relates to compositions comprising a number 
of nitric oxide/nucleophile adducts capable of releasing nitric oxide 
in a physiological environment, pharmaceutical compositions comprising 
such nitric oxide/nucleophile adduct compositions, and methods of their 
use to treat biological disorders for which the administration of 
nitric oxide is indicated. The spontaneous generation of nitric oxide 
by these compounds has proven advantageous for many applications in 
which only one tissue is to be targeted among the many that could be 
affected by systemic administration. The invention details the 
compounds which eventually provides a composition capable of releasing 
nitric oxide which includes a nitric oxide-releasing 
N2O2 functional group bound to a polymer, 
specifically a polysaccharide. This permits modulation of the time 
course of nitric oxide release in a controllable way as well as 
limiting nitric oxide exposure to selected sites within the body 
through the use of incorporating the N2O2 
functional group into a variety of polymeric matrices. It also provides 
a pharmaceutical composition which includes a pharmaceutically 
acceptable carrier and a polymer, specifically a polysaccharide, having 
a nitric oxide-releasing N2O2 functional group 
bound to the polymer. The invention provides for a method of treatment 
of disorders which comprises administering a composition comprising a 
polymer and a nitric oxide-releasing N2O2 
functional group bound to the polymer in an amount sufficient to 
release a therapeutically effective amount of nitric oxide.

N-Substituted Piperazine NONOates

LK Keefer, JE Saavedra, JA Hrabie (NCI)
Serial No. 08/475,732 filed 07 Jun 95

    A frequent problem in nitric oxide research is the delivery of 
nitric oxide to a specific organ or cell type needed without adversely 
affecting other nitric oxide sensitive parts of the body. This 
invention overcomes this problem by the synthesis of a number of N-
substituted piperazine NONOate compounds which are potent nitric oxide 
releasing compounds without activation at physiological pH. The 
invention's N-substituted piperazine NONOates, when tagged to 
polypeptides and proteins, can become an effective tissue-selective 
potent nitric oxide releasing protein. Thus, the invention may achieve 
specific cellular interactions unique to the proteins to be adducted 
allowing for exquisite

[[Page 43002]]

targeting even though the adduct is systemically administered and 
nitric oxide release is spontaneous.

Selective Prevention of Organ Injury in Sepsis and Shock Using 
Selective Release of Nitric Oxide in Vulnerable Organs

JF Saavedra, TR Billiar, LK Keefer (NCI)
Serial No. 08/509,558 filed 31 Jul 95

    The invention provides a method of treating mammalian tissue which 
is injured or is at risk of injury during sepsis or shock, including 
septic shock, hemorrhagic stock, and cardiogenic shock. In the 
suggested method, nitric oxide is delivered to target tissue or cells 
in a controlled and predictable manner through the administration of a 
nitric oxide containing compound (diazeniumdiolate) which is protected 
from the systemic release of nitric oxide under physiological 
conditions, and/or that is concentrated in at risk organs before 
releasing its nitric oxide. The diazeniumdiolate is capable of 
releasing at the targeted tissue a therapeutically effective amount of 
nitric oxide, sufficient to protect tissue from sepsis or shock-induced 
injury.

O2-aryl Substituted Diazeniumdiolates

JE Saavedra, A Srinivasan, LK Keefer (NCI)
Serial No. 60/026,816 filed 27 Sep 96

    Diazeniumdiolates, wherein the N1 position is 
substituted by an organic moiety and the O2-oxygen is bound 
to a substituted or unsubstituted aromatic group, are provided. The 
O2-aryl diazeniumdiolates are stable with respect to the 
hydrolytic generation of nitric oxide in neutral to acidic solutions. 
These novel compounds generate nitric oxide in basic or nucleophilic 
environments or microenvironments. Also provided are compositions, 
including pharmaceutical compositions, comprising such compounds and 
methods of using such compounds.

Encapsulated and Non-Encapsulated Nitric Oxide Generators Used as 
Antimicrobial Agents

SJ Green, LK Keefer (NCI)
Serial No. 08/428,632 filed 24 Apr 95

    This invention relates to compositions capable of releasing nitric 
oxide and therapeutic methods of use thereof for the treatment of 
microorganism-related disease states. The composition comprises one or 
more nitric oxide generators, preferably encapsulated in vesicles, such 
as liposomes. The compositions are used therapeutically by 
administration to humans and animals via different routes for the 
treatment of infectious diseases caused by pathogenic microbes.

    Dated: August 4, 1997.
Barbara M. McGarey,
Deputy Director, Office of Technology Transfer.
[FR Doc. 97-21149 Filed 8-8-97; 8:45 am]
BILLING CODE 4140-01-P
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