43000 Federal Register / Vol. 62, No. 154 / Monday, August 11, 1997 / Notices

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 proposal.

3. The willingness to commit best

effort and demonstrated resources to the

research, development and

commercialization of this technology.

4. The demonstration of expertise in

the commercial development,

production, marketing and sales of

products related to this area of

technology.

5. The level of financial support the

CRADA Collaborator will provide for

CRADA-related Government activities.

6. The willingness to cooperate with

the National Cancer Institute in the

timely publication of research results.

7. 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.

8. 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 that is the employer of the

inventor, with (1) the grant of a license

for research and other Government

purposes to the Government when the

CRADA Collaborator’s employee is the

sole inventor, or (2) the grant of an

option to elect an exclusive or

nonexclusive license to the CRADA

Collaborator when the Government

employee is the sole inventor.

Dated: July 21, 1997.

Kathleen Sybert,

Acting Director, Office of Technology

Development, National Cancer Institute,

National Institutes of Health.

[FR Doc. 97–21148 Filed 8–8–97; 8:45 am]

BILLING CODE 4140–01–P

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.

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:

CL21R@NIH.GOV. 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 oxygenrich environment; however, the farther

tumor cells are away from the blood
Federal Register / Vol. 62, No. 154 / Monday, August 11, 1997 / Notices 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 OxideReleasing 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 oxidereleasing 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 oxidereleasing 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 nitricoxide 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 oxidereleasing 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 Nsubstituted 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
43002 Federal Register / Vol. 62, No. 154 / Monday, August 11, 1997 / Notices

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

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Institutes of Health

Prospective Grant of Exclusive

License: New Brefeldin a Derivatives

AGENCY: National Institutes of Health,

Public Health Service, DHHS.

ACTION: Notice.

SUMMARY: This is notice in accordance

with 35 U.S.C. 209(c)(1) and 37 CFR

404.7(a)(1)(i) that the National Institutes

of Health (NIH), Department of Health

and Human Services, is contemplating

the grant of an exclusive world-wide

license to practice the inventions

embodied in U.S. Patent Application

Serial Number 08/267,525, entitled

‘‘New Brefeldin A Derivatives And

Their Utility In The Treatment Of

Cancer,’’ and corresponding U.S. and

foreign patent applications to Allelix

Biopharmaceuticals, Inc. of Mississauga,

Ontario, Canada. The patent rights of

the NIH inventors in these inventions

have been assigned to the United States

of America.

DATES: Only written comments and/or

applications for a license which are

received by NIH on or before October

10, 1997, will be considered.

ADDRESSES: Requests for copies of the

patent applications, inquiries,

comments and other materials relating

to the contemplated licenses should be

directed to: Raphe Kantor, Ph.D.,

Technology Licensing Specialist, Office

of Technology Transfer, National

Institutes of Health, 6011 Executive

Boulevard, Suite 325, Rockville,

Maryland 20852–3804; Telephone: (301)

496–7056 ext. 247; Facsimile: (301)

402–0220. A signed Confidentiality

Agreement will be required to receive

copies of the patent applications.

SUPPLEMENTARY INFORMATION: This

invention relates to a new class of

compounds which can be characterized

as breveldin A derivatives, e.g., 4-O-

(N,N-dimethylglycyl) breveldin A; 7-O-

(N-N-dimethylglycyl) breveldin A.

These breveldin A analogs are more

water soluble than the parent

compound. These analogs appear to

have reduced toxicities which limited

the clinical utility of the parent

compound. These compounds exhibit

activity against a wide variety of

cancers, including colon cancer,

melanoma, leukemia, ovarian, prostate,

breast and renal tumors. However,

recently performed toxicity studies on

one breveldin A analog (breflate) found

that it still retained an unacceptable

toxicity profile.

The prospective exclusive license will

be royalty-bearing and will comply with

the terms and conditions of 35 U.S.C.

209 and 37 CFR 404.7. The prospective

exclusive license may be granted unless

within sixty (60) days from the date of

this published notice, NIH receives

written evidence and argument that

establishes that the grant of the license

would not be consistent with the

requirements of 35 U.S.C. 209 and 37

CFR 404.7.

Applications for a license filed in

response to this notice will be treated as

objections to the grant of the

contemplated licenses. Comments and

objections submitted to this notice will

not be made available for public

inspection and, to the extent permitted

by law, will not be released under the

Freedom of Information Act, 5 U.S.C.

552.

Dated: August 1, 1997.

Barbara M. McGarey,

Deputy Director, Office of Technology

Transfer.

[FR Doc. 97–21093 Filed 8–8–97; 8:45 am]

BILLING CODE 4140–01–P

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

National Institutes of Health

Prospective Grant of Exclusive

License: Diagnostic Methods Derived

From the Human Metastasis

Suppressor Gene KAI1

AGENCY: National Institutes of Health,

Public Health Service, DHHS.

ACTION: Notice.

SUMMARY: This notice in accordance

with 35 U.S.C. 209(c)(1) and 37 CFR

404.7(a)(1)(i) that the National Institutes

of Health, Department of Health and

Human Services, is contemplating the

grant of an exclusive world-wide license

to practice the inventions embodied in

U.S. Patent Applications SN 08/430,225

and corresponding foreign patent

applications entitled, ‘‘Diagnostic

Methods and Gene Therapy Using

Reagents Derived From the Human

Metastasis Suppressor Gene KAI1’’ to

Centocor, Inc. of Malvern, PA. The

patent rights in these inventions have

been assigned to the United States of