[Federal Register Volume 76, Number 64 (Monday, April 4, 2011)]
[Notices]
[Pages 18561-18564]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2011-7925]


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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, HHS.

ACTION: Notice.

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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.

New Molecules for HIV Therapeutics: Fab, scFv, and Related Binding 
Molecules Specific for HIV-1 Rev

    Description of Invention: The invention offered for licensing and 
commercial development is in the field of HIV therapeutics. More 
specifically, the invention relates to methods and compositions for 
treating and/or inhibiting HIV infection or any other lentivirus. The 
invention describes the identification, though phage display, of a 
chimeric rabbit/human anti-Rev Fab (SJS-R1) that can inhibit 
polymerization of the HIV Rev protein and thus inhibit its normal 
function in virus replication. The Fab binds with very high affinity to 
a conformational epitope in the N-terminal half of HIV-1 Rev. The 
corresponding single chain antibody (scFv) was also prepared and 
characterized. Methods of making and using SJS-R1 Fab and SJS-R1 scFv, 
and antibodies and antibody fragments that share at least one CDR with 
SJS-R1 Fab, are provided. Specific described methods include methods of 
preventing or reversing polymerization of HIV Rev, methods of reducing 
infectivity of replication of a lentivirus, inhibiting Rev function in 
a cell infected with a lentivirus, and methods of treating a

[[Page 18562]]

disease or symptom associated with Rev expression in an animal.
    Applications: HIV therapeutics.

Advantages

     The invention utilizes a novel target and thus can be 
effective in conjunction with other HIV drugs.
     The chimeric structure of the Fab makes it possible to 
produce it in rabbit in high yields while being readily applicable for 
human treatment.
    Development Status: The therapeutic molecules have been produced 
and their strong affinity to Rev and its inhibitory effect on HIV 
proliferation was demonstrated.
    Inventors: Stephen J. Stahl (NIAMS) et al.
    Patent Status: U.S. Provisional Application No. 61/439,307 filed 
February 3, 2011 (HHS Reference No. E-064-2011/0-US-01), entitled 
``Generation and Use of Fab, scFv, and Related Binding Molecules 
Specific for HIV-1 Rev.''

Related Publications

    1. Stahl SJ, Watts NR, Rader C, DiMattia MA, Mage RG, Palmer I, 
Kaufman JD, Grimes JM, Stuart DI, Steven AC, Wingfield PT. Generation 
and characterization of a chimeric rabbit/human Fab for co-
crystallization of HIV-1 Rev. J Mol Biol. 2010 Apr 2;397(3):697-708. 
[PubMed: 20138059]
    2. DiMattia MA, Watts NR, Stahl SJ, Rader C, Wingfield PT, Stuart 
DI, Steven AC, Grimes JM. Implications of the HIV-1 Rev dimer structure 
at 3.2 A resolution for binding to the Rev response element. Proc Natl 
Acad Sci U S A. 2010 Mar 30;107(13):5810-5814. [PubMed: 20231488]
    Licensing Status: Available for licensing and commercial 
development.

Licensing Contacts

     Uri Reichman, PhD, MBA; 301-435-4616; [email protected].
     John Stansberry, PhD; 301-435-5236; [email protected].
    Collaborative Research Opportunity: The National Institute of 
Arthritis and Musculoskeletal and Skin Diseases, Protein Expression 
Laboratory is seeking statements of capability or interest from parties 
interested in collaborative research to further develop, evaluate, or 
commercialize the technology. Please contact Cecilia Pazman, PhD at 
301-402-5579 for more information.

Modulation of Leucine-Rich Repeats and Calponin Homology Domain-
Containing Protein 4 (Lrch4) Activity for Therapeutic Applications

    Description of Invention: NIH Inventors have recently discovered a 
novel Leucine-rich repeat and calponin homology domain-containing 
protein 4 (Lrch4) in a proteomic screen of the plasma membrane of 
lipopolysaccharide (LPS)-exposed macrophages. Expression data by RT-PCR 
revealed that all Lrch family members (1-4) are expressed in 
macrophages, but only Lrch4 was recruited into lipid rafts (signaling 
microdomains of the plasma membrane) by LPS. Lrch4 is the most highly 
expressed Lrch family member in mouse tissues. It is a predicted 
single-spanning transmembrane protein that is encoded by the Lrch4 gene 
in humans. The Lrch4 ectodomain is predicted to have a series of 
leucine-rich repeats, the motifs by which Toll like Receptors (TLR) are 
thought to bind microbial ligands. The human form of Lrch4 is 83% 
identical to murine Lrch4 and is predicted to have 680 amino acids and 
a molecular weight of 73 kDa.
    NIH inventors have shown that Lrch4 is expressed on the plasma 
membrane of macrophages. They have determined that Lrch4 regulates pro-
inflammatory signals (NF-[kappa]B activation, cytokine induction) 
emanating from all TLRs tested, and also regulates ligand-independent 
signals from MyD88. Further, LPS-induced p38, JNK, and NF[kappa]B 
activation are attenuated following Lrch4 knockdown, indicating that 
Lrch4 regulates upstream LPS signaling events. LPS-induced expression 
of the NF-[kappa]B-dependent cytokine TNF[alpha] was attenuated 
following Lrch4 knockdown at the level of both transcript and protein. 
Based on these and other findings, the inventors of this technology 
propose that Lrch4 may be a novel component of TLR receptor complexes 
and that modulation of Lrch4 activity might open up new opportunities 
for developing novel therapeutics for inflammatory diseases.
    Applications: Identification and development of modulators of Lrch4 
activity to treat inflammatory disorders, cancer, and sepsis.
    Development Status: Early-stage.
    Inventors: Michael B. Fessler, et al. (NIEHS).
    Related Publication: Dhungana S et al. Quantitative proteomics 
analysis of macrophage rafts reveals compartmentalized activation of 
the proteasome and of proteasome-mediated ERK activation in response to 
lipopolysaccharide. Mol Cell Proteomics 2009 Jan; 8(1):201-213. 
[PubMed: 18815123]
    Patent Status: U.S. Provisional Application No. 61/433,491 filed 17 
January 2011 (HHS Reference No. E-012-2011/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contact: Suryanarayana Vepa, PhD, J.D.; 301-435-5020; 
[email protected].
    Collaborative Research Opportunity: The National Institute of 
Environmental Health Sciences (NIEHS) Laboratory of Respiratory Biology 
is seeking statements of capability or interest from parties interested 
in collaborative research to further develop, evaluate, or 
commercialize Lrch4. Please contact Dr. Elizabeth M. Denholm at 
[email protected] for more information.

Superparamagnetic Nanocomplexes and Their Use as Contrast Agents in MRI

    Description of Invention: The invention offered for licensing and 
commercial development relates to the fields of cell therapy and 
tracking of such therapy by magnetic resonance imaging. More 
specifically the technology describes novel superparamagnetic magnetic 
resonance contrast agents, methods of making the agents, and methods of 
labeling cells with the contrast agents and imaging the labeled cells 
using magnetic resonance.
    The self assembled agents are composed of three (3) components: 
Superparamagnetic iron oxide nanoparticle (e.g. F3O4), associated with 
a carbohydrate coating (e.g., a polycation (e.g., Protamine Sulfate); 
and a polycation (e.g., glycosaminoglycan:Heparin). Self-assembling 
superparamagnetic nanocomplexes made from simple commercially available 
chemicals such as Heparin sulfate (H), Protamine sulfate (P), and 
Ferumoxytol nanocomplexes (HPF nanocomplexes) can effectively label 
stem cells, immune cells, tumor cells, or any other therapeutically 
engineered cells for cellular MRI. Biological cells can be labeled with 
the nanocomplexes by contacting cells under conditions sufficient to 
produce the nanocomplexes, or by contacting the cells with pre-
assembled nanocomplexes. The labeled biological cells can be 
transplanted into an individual, imaged by MRI and the migration 
pattern and/or cellular distribution pattern of the labeled biological 
cells in the subject can then be detected. This technique will readily 
facilitate the tracking of the therapeutic cells, and thus render cell-
based therapy and/or tissue repair more precise, accurate and 
effective.

Applications

    Clinical--
     Cell-based therapy (e.g. stem cells, or immune cells 
therapy, genetic engineered cells); monitoring and

[[Page 18563]]

detecting cell trafficking and distribution.
     Diagnostics.
    Research--
     Cell-based therapy.
     Tissue regeneration.

Advantages

     Avoid radioactive labeling.
     More efficient cell incorporation than the use of 
noncomplexed paramagnetic or superparamagnetic particles.
     Non toxic.
     Easily prepared from three (3) commercially available FDA 
approved drugs off label. No synthesis is required (self assembled).
     No FDA approved MRI contrast agent containing paramagnetic 
or superparamagnetic iron oxide nanoparticles.

Development Status

     The labeling complex has been repeatedly prepared. May 
require some further optimization for specific cell products and scale 
up.
     Incorporation into mammal cells has been demonstrated.
    Market: The total U.S. market for imaging reagents was $2.8 billion 
in 2003 and is expected to grow to $4.5 billion by 2010 at an average 
annual growth rate of 6.9%. Sales of MRI reagents for cardiovascular 
applications were $770 million in 2003 and are expected to rise at an 
average annual growth rate of 7.0%. Reagents used in oncology and 
gastrointestinal tract are rising at average annual growth rates of 
7.0% and 5.1%, respectively. The subject technology maybe readily 
applied in both diagnostics and therapeutic fields. A commercial 
development of the subject technology may therefore be attractive for 
commercial organizations.
    Inventors: Joseph A. Frank et al. (CC).
    Patent Status: U.S. Provisional Application No. 61/439,106 filed 
February 3, 2011 (HHS Reference No. E-285-2010/0-US-01), entitled 
``Superparamagnetic Nanocomplexes, Articles, and Methods of Use 
Thereof''.

Relevant Publications

    1. Frank JA, Anderson SA, Kalsih H, Lewis BK, Yocum GT, Arbab AS. 
Methods for magnetically labeling stem and other cells for detection by 
in vivo magnetic resonance imaging. Cytotherapy. 2004; 6(6):621-625. 
[PubMed: 15773025]
    2. Arbab AS, Liu W, Frank JA. Cellular magnetic resonance imaging: 
current status and future prospects. Expert Rev Med Devices. 2006 
Jul;3(4):427-439. [PubMed: 16866640]
    Licensing Status: Available for licensing and commercial 
development.

Licensing Contacts

     Uri Reichman, PhD, MBA; 301-435-4616; [email protected].
     John Stansberry, PhD; 301-435-5236; [email protected].
    Collaborative Research Opportunity: The Clinical Center, Frank 
Laboratory, Radiology and Imaging Sciences, is seeking statements of 
capability or interest from parties interested in collaborative 
research to further develop, evaluate, or commercialize this 
technology. Please contact Joseph A. Frank MS MD at 301-402-4314 or 
[email protected] for more information.

Methods of Treating Age-Related Macular Degeneration

    Description of Invention: Available for licensing is a novel method 
of treating age related macular degeneration (AMD). AMD is the leading 
cause of irreversible blindness in elderly populations worldwide. 
Inflammation, among other factors, has been suggested to play an 
important role in AMD pathogenesis. Recent studies have demonstrated a 
link between the complement system, inflammation, and AMD pathogenesis. 
Notably, researchers at NEI have shown that certain members of the C5a 
pathway are increased in AMD patients, and in vitro experiments 
demonstrated that those same pathway members cause a decrease in 
retinal pigment epithelium (RPE) viability, a hallmark of AMD. Blocking 
the C5a pathway presents a promising approach to prevent and treat AMD.
    Application: Prevention and/or treatment of Age-related Macular 
Degeneration.
    Development Status: In vivo mouse studies are in progress to test 
the effectiveness of the treatment.
    Market: Age-related macular degeneration is a leading cause of 
severe, irreversible vision impairment in developed countries (http://geteyesmart.org/eyesmart/diseases/amd.cfm). It is estimated that 1.8 
million Americans 40 years and older are affected by AMD and an 
additional 7.3 million with large drusen (yellow or white deposits 
under the retina) are at substantial risk of developing AMD. The number 
of people with AMD is estimated to reach 2.95 million in 2020. AMD is 
the leading cause of permanent impairment of reading and fine or close-
up vision among people aged 65 years and older (http://www.cdc.gov/visionhealth/basic_information/eye_disorders.htm).
    Inventors: Robert B. Nussenblatt et al. (NEI).
    Patent Status: U.S. Provisional Application No. 61/429,580 filed 04 
Jan 2011 (HHS Reference No. E-099-2010/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contact: Jaime M. Greene, M.S.; 301-435-5559; 
[email protected].

Methods for Inhibiting Proinflammatory Cytokine Expression Using 
Ghrelin

    Description of Invention: Ghrelin, an endogenous ligand for growth 
hormone secretagogue receptors (GHS-R), is primarily produced by the 
stomach but also by many other organs systems in the body (including 
the immune system) serves as a potent circulating orexigen controlling 
energy expenditure, adiposity and GH secretion. We have discovered that 
ghrelin exerts anti-inflammatory effects via inhibiting the secretion 
of both acute and chronic cytokines including IL-1, IL-6, TNF-alpha, 
IFN-gamma, IL-12 p40, Il-17, various chemokines and CSFs in vitro in 
human and murine cells as well as in vivo in murine models of sepsis, 
inflammation and aging. We also found that ghrelin directly controls 
human growth hormone and insulin growth factor expression by human 
immune cells.
    Applications: This invention is useful for treatment of various 
inflammatory disorders including inflammatory bowel disease, Crohn's 
disease, rheumatoid arthritis, multiple sclerosis, atherosclerosis, 
endotoxemia and graft-versus-host disease.
    Inventors: Vishwa D. Dixit and Dennis D. Taub (NIA).

Relevant Publications

    1. Dixit VD, Schaffer EM, Pyle RS, Collins GD, Sakthivel SK, 
Palaniappan R, Lillard JW Jr, Taub DD. Ghrelin inhibits leptin- and 
activation-induced proinflammatory cytokine expression by human 
monocytes and T cells. J Clin Invest. 2004 Jul; 114(1):57-66. [PubMed: 
15232612] Note: Article highlighted in this issue of JCI. This was also 
the subject of a Science SAGE KE News Focus article--M Leslie. 
Opposites Detract. Sci Aging Knowl Environ. 2004 Jul 14; 28:nf65 [doi: 
10.1126/sageke.2004.28.nf65].
    2. Dixit VD, Weeraratna AT, Yang H, Bertak D, Cooper-Jenkins A, 
Riggins GJ, Eberhart CG, Taub DD. Ghrelin and the growth hormone 
secretagogue receptor constitute a novel autocrine pathway in 
astrocytoma motility. J Biol Chem. 2006

[[Page 18564]]

Jun 16; 281(24):16681-16690. [PubMed: 16527811]
    3. Dixit VD, Yang H, Sun Y, Weeraratna AT, Smith RG, Taub DD. 
Ghrelin promotes thymopoiesis during aging. J Clin Invest. 2007 Oct; 
117(10):2778-2790. [PubMed: 17823656] Note: Article highlighted in this 
issue of JCI.
    4. Yang H, Dixit VD, Patel K, Vandanmagsar B, Collins G, Sun Y, 
Smith RG, Taub DD. Reduction in hypophyseal growth hormone and 
prolactin expression due to deficiency in ghrelin receptor signaling is 
associated with Pit-1 suppression: relevance to the immune system. 
Blood Behav Immun. 2008 Nov; 22(8):1138-1145. [PubMed: 18602461]
    5. Dixit VD, Yang H, Cooper-Jenkins A, Giri BB, Patel K, Taub DD. 
Reduction of T cell-derived ghrelin enhances proinflammatory cytokine 
expression: implications for age-associated increases in inflammation. 
Blood. 2009 May 21; 113(21):5202-5205. [PubMed: 19324904]

Relevant Reviews

    6. Dixit V and Taub DD. Ghrelin and immunity: a young player in an 
old field. Exp. Gerontol. 2005 Nov; 40(11):900-910. [PubMed: 16233968]
    7. Taub DD. Novel connections between the neuroendocrine and immune 
systems: the ghrelin immunoregulatory network. Vitam Horm. 2008; 
77:325-346. [PubMed: 17983863]
    8. Taub DD. Neuroendocrine interactions in the immune system. Cell 
Immunol. 2008 Mar-Apr; 252(1-2):1-6. [PubMed: 18619587] Note: Image 
from article used on the cover of this issue.
    9. Redelman D, Welniak LA, Taub D, Murphy WJ. Neuroendocrine 
hormones such as growth hormone (GH) and prolactin (PRL) are integral 
members of the immunological cytokine network. Cell Immunol. 2008 Mar-
Apr; 252(1-2):111-121. [PubMed: 18313040]
    10. Patel K and Taub DD. Role of neuropeptides, hormones, and 
growth factors in regulating thymopoiesis in middle to old age. F1000 
Biol Rep. 2009 May 28; 1. pii: 42. [PubMed: 20948643]
    11. Taub DD, Murphy WJ, Longo DL. Rejuvenation of the aging thymus: 
growth hormone-mediated and ghrelin-mediated signaling pathways. Curr 
Opin Pharmacol. 2010 Aug; 10(4):408-424. [PubMed: 20595009]
    Patent Status: U.S. Patent Application No. 11/596,310 filed 06 Jun 
2008 (HHS Reference No. E-016-2004/0-US-07) and related international 
applications.
    Licensing Status: Available for licensing.
    Licensing Contact: Sally H. Hu, PhD, M.B.A.; 301-435-5606; 
[email protected].
    Collaborative Research Opportunity: The National Institute on Aging 
is seeking statements of capability or interest from parties interested 
in collaborative research to further develop, evaluate, or 
commercialize Methods of Inhibiting Proinflammatory Cytokine Expression 
Using Ghrelin. Please contact Nikki Guyton at 301-435-3101 or 
[email protected] for more information.

    Dated: March 29, 2011.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 2011-7925 Filed 4-1-11; 8:45 am]
BILLING CODE 4140-01-P