[Federal Register Volume 75, Number 51 (Wednesday, March 17, 2010)]
[Notices]
[Pages 12761-12764]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2010-5764]


-----------------------------------------------------------------------

DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institutes of Health


Government-Owned Inventions; Availability for Licensing

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

[[Page 12762]]

be required to receive copies of the patent applications.

Caspase Inhibitors Useful for the Study of Autoimmune or Inflammatory 
Diseases

    Description of Invention: Novel and potent caspase 1 inhibitors are 
available for licensing. In particular, this technology discloses 
potent and selective caspase 1 inhibitors that target the active site 
of the enzyme. Caspase 1 is known to play a pro-inflammatory role in 
numerous autoimmune and inflammatory diseases and therefore represents 
an excellent target for treatment of a broad range of diseases, 
including but not limited to Huntington's, amyotrophic lateral 
sclerosis, ischemia, rheumatoid arthritis, osteoarthritis, inflammatory 
bowel disease, and sepsis. Not surprisingly this enormous potential has 
resulted in at least three caspase 1 inhibitors entering clinical 
trials (VX-740, IDN-6556, and VX-765) in recent years.

Applications

     Potential therapeutic for a broad range of autoimmune 
diseases.
     Potential therapeutic for a broad range of inflammatory 
diseases.
    Development Status: Early stage.
    Market: The market size is potentially very large. For instance, 
rheumatoid arthritis alone affects 1% of the population, or about 2.5-3 
million Americans. Further, it is estimated that osteoarthritis affects 
at least 16 million people in America.
    Inventors: Craig J. Thomas and Matthew B. Boxer (NHGRI).
    Publication: Boxer MB, Quinn AM, Shen M, Jadhav A, Leister W, 
Simeonov A, Auld DS, Thomas CJ. A highly potent and selective caspase 1 
inhibitor that utilizes a key 3-cyanopropanoic acid moiety. Chem Med 
Chem., accepted.
    Patent Status: U.S. Provisional Application No. 61/299,790 filed 29 
Jan 2010 (HHS Reference No. E-308-2009/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contact: Steve Standley, PhD; 301-435-4074; 
[email protected].
    Collaborative Research Opportunity: The NIH Chemical Genomics 
Center is seeking statements of capability or interest from parties 
interested in collaborative research to further develop, evaluate, or 
commercialize appropriate lead compounds described in U.S. Provisional 
Application No. 61/299,790. Please contact Dr. Craig J. Thomas via e-
mail ([email protected]) for more information.

Defensin-Based Therapeutics for the Treatment of Pulmonary Disease

    Description of Invention: Investigators at the National Heart, Lung 
and Blood Institute have developed modified defensins that are 
resistant to degradation, have improved characteristics compared to 
unmodified defensins, and are promising candidates for pulmonary 
disease therapeutics.
    Defensins are small cationic peptides that defend the lung against 
pathogenic microorganisms and play an important role in innate 
immunity. However, during lung inflammation, defensin concentrations 
can reach levels that are cytotoxic for airway epithelial cells. 
Therefore, the development of methods to produce modified defensins 
that exhibit reduced cytotoxicity, while retaining the ability to 
stimulate the innate immune response, would be of potential therapeutic 
benefit for pulmonary diseases.
    The inventors have previously shown that a defensin, human 
neutrophil peptide 1 (HNP-1), is elevated in samples from the lungs of 
patients with inflammatory lung disease, and that the HNP-1 in these 
samples is ADP-ribosylated at one or both of two arginine residues 
within the protein. In vitro studies by the inventors show that ADP-
ribosyl-HNP-1 has reduced cytotoxic activity compared to HNP-1, while 
retaining its T cell chemotactic properties and ability to promote 
neutrophil recruitment, and thus ADP-ribosyl-HNP-1 may play an 
important role as a regulator of the inflammatory response. These 
properties would also be useful for treatment of pulmonary inflammation 
and lung diseases. However, ADP-ribosylated HNP-1 and other defensins 
are degraded rapidly in vivo due to the susceptibility of the ADP-
ribose moiety to attack by hydrolases and pyrophosphatases, which 
limits their therapeutic potential.
    The inventors have recently discovered that the ADP-ribosylated 
arginine residues in HNP-1 can be converted to ornithine through a non-
enzymatic process that results in a peptide with an altered 
pharmacological profile. The investigators have also successfully 
generated ornithine-substituted ADP-ribosyl HNP-1 and ornithine-HNP-1 
in vitro, which are currently being characterized. Thus, ornithine-
substituted ADP-ribosyl HNP-1 and ornithine-HNP-1 may be promising 
candidates for the development of therapeutics to treat pulmonary 
disease, and the strategy of replacing ADP-ribosylated residues with 
ornithine to enhance stability and therapeutic efficacy may also be 
extended to other defensins
    Through an earlier, related invention, the inventors have also 
demonstrated that recombinant proteins wherein tryptophan or 
phenylalanine residues substitute for ADP-ribosylarginine have a 
similar stabilizing impact on polypeptides, making them more suitable 
as therapeutic agents.
    The inventors also hypothesize that it would be possible to develop 
a treatment that increases levels of an ADP-ribosylated therapeutic 
protein, such as HNP-1, in the lung via inhalation administration of 
the therapeutic protein in conjunction with nicotinamide adenine 
dinucleotide (NAD), which is required for ADP-ribosylation. This could 
represent a unique therapeutic strategy for treating pulmonary disease.
    Applications: Development of defensin-based therapeutics that 
enhance the immune response in pulmonary disease patients, without 
damaging the epithelial cells lining the airway.

Advantages

    Modified defensins are less cytotoxic, while retaining ability to 
stimulate innate immunity.
    Ornithine-substituted defensins are resistant to enzymatic 
degradation, making them more promising as drug candidates.
    Development Status: In vitro studies, as well as analysis of 
patient samples, have been performed.
    Inventors: Joel Moss et al. (NHLBI).
    Relevant Publication: Stevens LA, Levine RL, Gochuico BR, Moss J. 
ADP-ribosylation of human defensin HNP-1 results in the replacement of 
the modified arginine with the noncoded amino acid ornithine. Proc Natl 
Acad Sci U S A. 2009 Nov 24;106(47):19796-19800. [PubMed: 19897717.]
    Patent Status: U.S. Provisional Application No. 61/241,311 filed 
September 10, 2009 (HHS Reference No. E-243-2009/0-US-01).

Related Technologies

     HHS Reference No. E-080-2002/0, ``Modified Defensins and 
Their Use.''
     HHS Reference No. E-160-2002/0, ``Tryptophan as a 
Functional Replacement for ADP-ribose-arginine in Recombinant 
Proteins.''
    Licensing Status: Available for licensing.
    Licensing Contact: Tara Kirby, PhD; 301-435-4426; 
[email protected].
    Collaborative Research Opportunity: The National Heart, Lung and 
Blood Institute Translational Medicine Branch is seeking statements of 
capability or

[[Page 12763]]

interest from parties interested in collaborative research to further 
develop, evaluate, or commercialize defensin-based therapeutic agents 
to treat pulmonary diseases. Please contact Brian W. Bailey, PhD at 
301-494-4094 or [email protected] for more information.

HTLV-II Vector and Methods of Use

    Description of Invention: The invention hereby offered for 
licensing is in the field of vaccines and vaccine vectors. More 
specifically the invention provides compositions and methods of use of 
HTLV-II viral vector. The vector comprises at least a portion of the 
HTLV-II genome encoding the gag, pro, and pol genes and lacking all or 
a portion of the pX region. A heterologous gene is inserted within the 
deletion of the pX region. The gene of interest may encode all or a 
portion of a protein that corresponds to a viral protein of a foreign 
virus. The viral vectors thus constructed are useful for inducing 
immune response to the viral protein from the foreign virus. In 
particular the invention claims vaccines against HIV and SIV.
    Applications: The technology can be used for DNA-based vaccines.

Advantages

     Vaccines based on HTLV-II vectors have exhibited the 
capability to eliciting T cell response effectively. In particular they 
induce specific CD4+ and CD8+ T cell response. Antibody response to the 
HTLV-II vector is almost undetectable. The vector is infectious, but 
highly attenuated, with respect to the wild type HTLV-II. Desirably, 
the HTLV-II viral vector induces antibodies that can participate in 
Antibody-Dependent-Cell-Mediated Cytotoxicity (ADCC), a mechanism that 
enhances its effectiveness.
     Most of the T-cell vaccines developed for HIV are based on 
microbial vectors that have limited replication capacity and do not 
persist in the host. Such vaccines do not protect macaques from SIV 
infection and their ability to protect against high virus load is 
merely transient (approximately six months). They are perceived to 
elicit too ``small T-cell responses'' that expand ``too late''. In 
addition, few of these vectors target mucosal sites, the first portal 
of HIV entry. In contrast, an HTLV II based vaccine is anticipated to 
infect macaques and replicate at very low level in lymphoid tissue and 
particularly in the gut which may enable them to maintain sufficient 
level of effectors CD8 memory cells to decrease early seeding of the 
virus, and sufficient level of central memory cells in lymph nodes that 
may limit the broadcasting of the virus at distal sites. These features 
make an HTLV-II based vaccine for HIV an excellent unique candidate to 
target mucosal tissues and provide long lasting mucosal immunity to 
HIV. In addition, the HTLV II infects dendritic cells both in vivo and 
in vitro, and the HTLV II infected dendritic cells have a mature 
phenotype, suggesting that HIV antigens expressed within dendritic 
cells could be effectively presented to the immune system.
     HTLV II is a human retrovirus with no clear disease 
associations neither in healthy nor in HIV infected individuals
     HTLV shares many biological and molecular characteristics 
of HIV, including routes of transmission, a T-cell tropism and gut 
tropism.
     Based on the above, it is believed that HIV vaccines based 
on HTLV II vector will exhibit superiority compared to other vaccines 
in development.
    Development Status: At the present only in vitro as well as animal 
(macaques) data that demonstrate the proof of concept are available. 
The data indicates that an HTLV II based vaccine could replicate in the 
appropriate body compartment and confer immunity in humans. The 
inventors continue to work on the development of this approach.
    Market: In spite of major global efforts of more than 25 years in 
developing a vaccine against HIV/AIDS, such a vaccine is still not in 
existence but yet very much needed for the fight against the global 
epidemic of HIV/AIDS. The market for HIV/AIDS drugs is currently at the 
level of approximately $6 billion a year and is expected to grow to $13 
billion by the year 2015. Should an effective vaccine be developed the 
market for such a vaccine may exceed this level. The instant technology 
may offer superiority to existence approaches in the area of HIV 
vaccines and thus a huge commercial opportunity for pharmaceutical/
vaccine enterprises as well as a major contribution for global public 
health.
    Inventors: Genoveffa Franchini et al. (NCI).
    Publications: Paper in preparation.
    Patent Status: PCT Application No. PCT/US2009/051138 filed 20 Jul 
2009, which published as WO 2010/009465 on 21 Jan 2010 (HHS Reference 
No. E-269-2008/1-PCT-01).
    Related Technologies: RhCMV SIV vaccine (Picker et al.)
    Licensing Status: Available for licensing.
    Licensing Contact: Susan Ano, PhD; 301-435-5515; [email protected].
    Collaborative Research Opportunity: The National Cancer Institute, 
Animal Models & Retroviral Vaccine Section, is seeking statements of 
capability or interest from parties interested in collaborative 
research to further develop, evaluate, or commercialize HTLV-II 
vectored HIV vaccines. Please contact John D. Hewes, PhD at 301-435-
3121 or [email protected] for more information.

Prevention and Treatment of Cancer With Kinase Inhibitors Targeting the 
PH Domain of AKT

    Description of Invention: Activation of the PI3K/Akt signaling 
pathway has been implicated in the development of cancer. Akt, a kinase 
that is central to this pathway, is found at elevated levels in many 
tumors and is associated with a poor disease prognosis. Further 
research has validated Akt as a therapeutic target for the development 
of anti-cancer drugs. Most efforts of drug development targeting Akt 
have focused on inhibitors of the ATP-binding domain which have the 
drawback that they interfere with other physiologically important 
kinases. This is reflected in that no Akt inhibitors have been 
clinically approved. However, investigators at the National Institutes 
of Health (NIH) and Georgetown University (GU) have developed an 
alternative strategy that improves Akt specificity by targeting the 
unique pleckstrin homology (PH) domain of Akt.
    Scientists at NIH and GU have discovered several lipid-based 
inhibitors of Akt called phosphatidylinositol ether lipid analogues 
(PIAs) that target the pleckstrin homology (PH) domain of Akt. These 
PIAs, which are analogues of the products of phosphatidylinositol 3-
kinase (PI3K), inhibit Akt within minutes and selectively kill cancer 
cells that contain high levels of Akt activation. The mechanism of 
action of these compounds has been intensively studied providing much 
insight into how PIAs inhibit the growth of cancer cells. In addition, 
several molecular targets have been identified that highly correlate 
with cancer cell sensitivity to PIA that potentially could serve as 
clinical biomarkers predictive of responsiveness to PIAs. U.S. and 
Australian patents issued for this invention have composition and 
method of use claims.

Applications

     Treating or preventing development of cancer or preventing 
progression of premalignant lesions to cancer.

[[Page 12764]]

     Used as single agents or in combination with other anti-
cancer treatments like chemotherapy, biological therapy, or radiation.
    Advantages: Targeting the PH domain improves specificity against 
Akt kinase in comparison to inhibitors of the ATP domain which 
typically are unspecific.
    Inventors: Phillip A. Dennis (NCI) et al.

Relevant Publications

    1. Memmott RM, Gills JJ, Hollingshead M, Powers MC, Chen Z, Kemp B, 
Kozikowski A, Dennis PA. Phosphatidylinositol ether lipid analogues 
induce AMP-activated protein kinase-dependent death in LKB1-mutant non 
small cell lung cancer cells. Cancer Res. 2008 Jan 15;68(2):580-588. 
[PubMed: 18199555.]
    2. Gills JJ, Castillo SS, Zhang C, Petukhov PA, Memmott RM, 
Hollingshead M, Warfel N, Han J, Kozikowski AP, Dennis PA. 
Phosphatidylinositol ether lipid analogues that inhibit AKT also 
independently activate the stress kinase, p38alpha, through MKK3/6-
independent and -dependent mechanisms. J Biol Chem. 2007 Sep 
14;282(37):27020-27029. [PubMed: 17631503.]
    3. Gills JJ, Holbeck S, Hollingshead M, Hewitt SM, Kozikowski AP, 
Dennis PA. Spectrum of activity and molecular correlates of response to 
phosphatidylinositol ether lipid analogues, novel lipid-based 
inhibitors of Akt. Mol Cancer Ther. 2006 Mar;5(3):713-722. [PubMed: 
16546986.]
    4. Car[oacute]n RW, Yacoub A, Li M, Zhu X, Mitchell C, Hong Y, 
Hawkins W, Sasazuki T, Shirasawa S, Kozikowski AP, Dennis PA, Hagan MP, 
Grant S, Dent P. Activated forms of H-RAS and K-RAS differentially 
regulate membrane association of PI3K, PDK-1, and AKT and the effect of 
therapeutic kinase inhibitors on cell survival. Mol Cancer Ther. 2005 
Feb;4(2):257-270. [PubMed: 15713897.]
    5. Castillo SS, Brognard J, Petukhov PA, Zhang C, Tsurutani J, 
Granville CA, Li M, Jung M, West KA, Gills JG, Kozikowski AP, Dennis 
PA. Preferential inhibition of Akt and killing of Akt-dependent cancer 
cells by rationally designed phosphatidylinositol ether lipid 
analogues. Cancer Res. 2004 Apr 15;64(8):2782-2792. [PubMed: 15087394.]
    6. Kozikowski AP, Sun H, Brognard J, Dennis PA. Novel PI analogues 
selectively block activation of the pro-survival serine/threonine 
kinase Akt. J Am Chem Soc. 2003 Feb 5;125(5):1144-1145. [PubMed: 
12553797.]
    Patent Status: U.S. Patent No. 7,378,403 issued 27 May 2008 (HHS 
Reference No. E-245-2002/0-US-03), and related international filings.
    Licensing Status: Available for licensing.
    Licensing Contact: Surekha Vathyam, PhD; 301-435-4076; 
[email protected].

    Dated: March 10, 2010.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 2010-5764 Filed 3-16-10; 8:45 am]
BILLING CODE 4140-01-P