Notice (B): Government-Owned Inventions; Availability for Licensing

Federal Register: April 17, 2008 (Volume 73, Number 75)    
                  Page 20929-20930

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

ACTION: Notice.

SUMMARY: The inventions listed below are owned by an agency 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 companies and may also be available for licensing.

ADDRESSES: Licensing information and copies of the U.S. patent 
applications listed below may be obtained by writing to the indicated 
licensing contact at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-3804; telephone: 301/496-7057; fax: 301/402-0220. A 
signed Confidential Disclosure Agreement will be required to receive 
copies of the patent applications.

Substituted 3,6-diphenyl-7H-[1,2,4] triazolo[3,4-b] [1,3,4] 
Thiadiazines as Potent Inhibitors of PDE4A, PDE4B, and PDE4D

    Description of Technology: Phosphodiesterase 4 (PDE4) is a major 
cAMP-metabolizing enzyme found in immune and inflammatory cells, airway 
smooth muscle, and pulmonary nerves. It plays a significant role within 
the inflammatory responses associated with asthma and chronic 
obstructive pulmonary disease (COPD) and its modulation has been linked 
to memory enhancement and depression. Due to its widespread therapeutic 
potential, PDE4 inhibitors are highly sought after agents for treating 
numerous disease states. While several PDE4 inhibitors have already 
advanced into clinical settings, unfavorable side effects including 
emesis, nausea, and abdominal pain emphasize the need for novel 
chemotypes with potent and selective PDE4 inhibition.
    This technology describes a series of substituted 3,6-diphenyl-7H-
[1,2,4] triazolo[3,4-b] [1,3,4] thiadiazines that act as inhibitors of 
PDE4. This core structure represents a novel chemotype within extensive 
classes of PDE4 inhibitors and the structure activity relationships of 
these PDE4 inhibitors identify key binding sites and substitutions 
critical to the functionality for potent PDE4 inhibition. Selectivity 
of this novel chemotype shows weak inhibitory potency against nine PDE 
isoforms excluding PDE4 and strong inhibitory potency against PDE4A, 
PDE4B, and PDE4D. In a selectivity comparison study, the novel 
chemotype performs better than the PDE4 inhibitor in clinical 
development. Subtype-selective PDE4 inhibitors are becoming 
increasingly more important as new research shows that independent PDE 
isoforms have differential effects on cells.
    Applications: Treatment of numerous diseases associated with PDE4 
including asthma, COPD, inflammatory bowel disease, and other anti-
inflammatory diseases with other possible treatments including 
depression and psychosis.
    Development Status: Pre-clinical.
    Publication: AP Skoumbourdis et al. Identification of a potent new 
chemotype for the selective inhibition of PDE4. Bioorg Med Chem Lett. 
2008 Feb 15;18(4):1297-1303.
    Inventors: Craig J. Thomas et al. (NHGRI).
    Patent Status: U.S. Provisional Application No. 61/020,079 filed 09 
Jan 2008 (HHS Reference No. E-055-2008/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contact: Fatima Sayyid, M.H.P.M.; 301-435-4521; 
Fatima.Sayyid@nih.hhs.gov.

[[Page 20930]]

Nitrite and Nitrite-Methemoglobin Therapy To Detoxify Stroma-Free 
Hemoglobin Based Blood Substitutes

    Description of Technology: Cell-free hemoglobin based oxygen 
carriers (HBOCs) are blood substitutes and resuscitative agents that 
can be used to replace whole blood donations, alleviate blood shortages 
and reduce the risks of infections such as HIV and hepatitis. Stroma-
free HBOCs offer the advantages of increased stability, consistency of 
supply, and reduced immunogenicity over the use of the alternative cell 
based sources. However, the side effects associated with their use, 
including vascular toxicity, pulmonary and systemic hypertension, 
myocardial infarction, inflammation, and platelet aggregation severely 
limit their scope of clinical applications. These adverse effects are 
due in part to the ability of free deoxygenated hemoglobin (deoxyHb) to 
scavenge for nitric oxide (NO) thus rendering it unavailable for 
vasodilating blood vessels.
    This technology is a method of using nitrites to reduce the 
deleterious effects associated with HBOC use as blood substitutes. Free 
nitrites or nitrite-methemoglobin when added to stroma-free HBOCs are 
converted to NO and N2O3 which escapes the scavenging activity of 
deoxyHb and thus is free to vasodilate blood vessels. This maintains 
oxygen release and NO delivery enabling improved clinical outcomes. 
Recent studies, using this technology as a blood substitute, have led 
to a reversal of vasoconstriction, hypertension and hemorrhagic shock 
in animal models. This new approach also reduces the toxicity 
associated with the use of HBOCs as a blood substitute and may allow 
the widespread use of HBOCs as an alternative to cell based sources. In 
combination with this technology, HBOC blood substitutes may now be 
used to efficiently deliver therapeutic agents and maintain organ 
perfusion during trauma and surgery.
    Advantages: Reduced toxicity of cell free hemoglobin blood 
substitutes; Increased blood perfusion in patients; Decreased 
dependence on blood donations.
    Development Status: Pre-clinical.
    Inventors: Mark T. Gladwin (NHLBI) et al.
    Publication: S Basu, R Grubina, J Huang, J Conradie, Z Huang, A 
Jeffers, A Jiang, X He, I Azarov, R Seibert, A Mehta, R Patel, SB King, 
N Hogg, A Ghosh, MT Gladwin, DB Kim-Shapiro. Catalytic generation of 
N2O3 by the concerted nitrite reductase and anhydrase activity of 
hemoglobin. Nat Chem Biol. 2007 Dec;3(12):785-794.
    Patent Status: U.S. Provisional Application No. 60/996,530 filed 31 
Aug 2007 (HHS Reference No. E-259-2007/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contact: Fatima Sayyid, M.H.P.M.; 301-435-4521; 
Fatima.Sayyid@nih.hhs.gov.

    Dated: April 8, 2008.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
 [FR Doc. E8-8218 Filed 4-16-08; 8:45 am]

BILLING CODE 4140-01-P