[Federal Register Volume 70, Number 44 (Tuesday, March 8, 2005)]
[Notices]
[Pages 11253-11254]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-4488]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Prospective Grant of an Exclusive License: Novel Isosteric 
Thalidomide Analogs With Enhanced TNF-[alpha] Inhibitory Activity

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

ACTION: Notice.

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SUMMARY: This notice, in accordance with 35 U.S.C. 209(c)(1) and 37 CFR 
part 404.7(a)(1)(i), announces that the Department of Health and Human 
Services is contemplating the grant of an exclusive license to practice 
the inventions embodied in U.S. Patent Application No. 60/504,724 filed 
September 17, 2003, entitled ``Thalidomide Analogs'' (DHHS Reference E-
189-2003/0-US-01) and PCT Application No. PCT/US2004/030506 filed 
September 17, 2004, entitled ``Thalidomide Analogs'' (DHHS Ref. E-189-
2003/0-PCT-02) to Phase 2 Discovery, Inc. The patent rights in these 
inventions have been assigned to the United States of America.
    The prospective exclusive license territory may be United States, 
Denmark, Italy, Ireland, United Kingdom, Germany, France, Sweden, 
Switzerland, Spain, Czech Republic, Greece, Russia, Australia, Japan, 
Taiwan, Singapore, China, Argentina and Brazil, and the field of use 
may be limited to development and sale of a pharmaceutical product 
useful in treating Amyotrophic Lateral Sclerosis (ALS) and Attention 
Deficit Hyperactivity Disorder (ADHD).

DATES: Only written comments and/or license applications which are 
received by the National Institutes of Health on or before May 9, 2005 
will be considered.

ADDRESSES: Requests for copies of the patent and/or patent 
applications, inquiries, comments and other materials relating to the 
contemplated exclusive license should be directed to: Mojdeh Bahar, 
J.D., Technology Licensing Specialist, Office of Technology Transfer, 
National Institutes of Health, 6011 Executive Boulevard, Suite 325, 
Rockville, MD 20852-3804. Telephone: (301) 435-2950; Facsimile: (301) 
402-0220; E-mail: [email protected].

SUPPLEMENTARY INFORMATION: Inflammatory processes associated with the 
over-production of cytokines, particularly of tumor necrosis factor-
alpha (TNF-[alpha]), accompany numerous neurodegenerative diseases, 
such as Alzheimer's disease and ALS, in addition to numerous common 
systemic conditions, such as rheumatoid arthritis, septic shock, graft-
versus-host disease, Crohn's disease and erythema nodosum leprosum 
(ENL). TNF-[alpha] has been validated as a drug target with the 
development of the inhibitors Enbril and Remicade as prescription 
medications for rheumatoid arthritis. Both, however, are large 
macromolecules that are expensive to produce, require direct 
intravenous or subcutaneous injection, and have negligible brain 
access. The classical orally active drug, thalidomide (N-[alpha]-
phthalimidoglutarimide), a glutamic acid derivative, is being 
increasingly used in the clinical management of a wide spectrum of 
immunologically-mediated, infectious diseases, and cancers. Its 
clinical value in treating ENL derives from its TNF-[alpha] inhibitory 
activity. Specifically, it inhibits TNF-[alpha] protein expression at 
the post-transcriptional level by facilitating turnover of the mRNA. 
More recent research has shown similar inhibitory action of COX2 
protein expression. These actions are mediated post-transcriptionally 
via AU-rich elements found in the 3' untranslated regions (3'-UTRs) of 
each mRNA. Thalidomide's anti-angiogenesis activity derives from its 
inhibitory actions on basic fibroblast growth factor (bFGF) and 
vascular endothelial growth factor (VEGF). The agent, additionally, 
acts as an inhibitor of the transcription factor, NFkB and a co-
stimulator of both CD8+ and CD4+ T cells. However, the action of 
thalidomide to lower TNF-[alpha] levels and inhibit angiogenesis is not 
particularly potent, and it therefore represents an interesting lead 
compound for medicinal chemistry.
    Novel structural modification of thalidomide led to the discovery 
of original and potent isosteric analogues. The present invention 
relates to thalidomide analogues and, in particular, thiothalidomides 
(sulfur-containing thalidomide analogues), methods of synthesizing the 
analogues, and methods for using the analogues to modulate TNF-[alpha] 
and angiogenesis activities in a subject. Disclosed analogues potently 
inhibited TNF-[alpha] secretion, compared to thalidomide, via post-
transcriptional mechanisms that decreased TNF-[alpha] mRNA stability 
via its 3'-UTR. Actions to inhibit angiogenesis were determined in 
widely accepted ex vivo assays.
    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 part 
404.7. The prospective exclusive license may be granted unless within 
sixty (60) days

[[Page 11254]]

from the date of this published notice, the NIH receives written 
evidence and argument that establish that the grant of the license 
would not be consistent with the requirements of 35 U.S.C. 209 and 37 
CFR part 404.7.
    Applications for a license in the field of use filed in response to 
this notice will be treated as objections to the grant of the 
contemplated exclusive license. 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: February 28, 2005.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 05-4488 Filed 3-7-05; 8:45 am]
BILLING CODE 4140-01-P