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###### Department of Health and Human Services

###### National Institutes of Health 

# 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                               ( print page 14590)                            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.                     

## Microarray for Detection and Subtyping of Human Influenza Viruses 

*Description of Technology:*                     Available for licensing and commercial development are a novel influenza virus microarray and methods for using the microarray for the identification of existing and new types and subtypes of human influenza viruses. There are three types of influenza viruses, type A, B and C. Influenza types A or B viruses cause epidemics of disease almost every winter, with type A causes major pandemic periodically. Influenza type A viruses are further divided into subtypes based on two proteins on the surface of the virus. These proteins are called hemagglutinin (H) and neuraminidase (N). There are 16 known HA subtypes and 9 known NA subtypes of influenza A viruses. Each subtype may have different combination of H and N proteins. Although there are only three known A subtypes of influenza viruses (H1N1, H1N2, and H3N2) currently circulating among humans, many other different strains are circulating among birds and other animals and these viruses do spread to humans occasionally. There is a requirement for sensitive and rapid diagnostic techniques in order to improve both the diagnosis of infections and the quality of surveillance systems. This microarray platform tiles the genomes of all types/subtypes of influenza viruses, and is capable of correctly identifying all 3 types/subtypes of influenza viruses from an influenza vaccine sample.                 

More specifically, the invention consists of: (1) Microarrays comprising a solid support with a plurality of n-mer influenza viral nucleotide segments of influenza Types A, B and C, including each respective subtypes, and (2) methods of detecting and identifying known and unknown influenza viral types and subtypes by: (a) Using hybridization microarrays to known influenza viral nucleotide sequences, (b) sequencing the nucleotides which hybridize to the microarrays and (c) analyzing the hybridized sequences using existing databases, thus identifying existing or new subtypes of influenza viruses. 

*Applications:*                     Detection and identification of human influenza viruses; Efficient discovery of new subtypes of influenza viruses; Diagnosis of influenza outbreaks.                 

*Development Status:*                     This microarray platform was capable of correctly identifying all 3 types/subtypes of influenza viruses from an influenza vaccine sample.                 

*Inventors:*                     Xiaolin Wu, Cassio S. Baptista, Elizabeth Shannon, and David J. Munroe (NCI).                 

*Patent Status:*                     U.S. Provisional Application No. 60/857,695 filed 07 Nov 2006 (HHS Reference No. E-208-2006/0-US-01).                 

*Licensing Status:*                     Available for non-exclusive or exclusive licensing.                 

*Licensing Contact:*                     Cristina Thalhammer-Reyero, PhD, MBA; 301/435-4507;                     *thalhamc@mail.nih.gov.*

## Improved Interleukin Expression for Immunogenic Compositions and Vaccine Adjuvant 

*Description of Technology:*                     The NIH is pleased to announce as available for licensing a technology that provides for optimized nucleic acids for improved expression of interleukin-15 (IL-15) and IL-15 receptor alpha (IL-15Ralpha) in mammalian cells. IL-15 is a cytokine important for both the innate and adaptive immune systems. Based on its many functions and relative safety in animal models, IL-15 finds use in vaccines, cancer immunotherapeutics, and autoimmune disease and as a vaccine adjuvant.                 

The present technology enhances the production and bioavailability of IL-15 through use of optimized nucleic acid sequences. Native IL-15 coding sequences do not express IL-15 optimally for several reasons, and the optimized sequences of the subject technology overcome these deficiencies. The nucleic acids can be part of expression vectors, which could be utilized either in vitro or in vivo. The expression vectors express IL-15 alone, IL-15Ralpha alone, or both molecules together from a single vector. Further enhanced expression of IL-15 and/or IL-15Ralpha can be achieved through the use of signal peptides or propeptides from heterologous proteins. These nucleic acids can be administered to enhance the immune response of an individual against one or more antigens. Primate studies have shown that co-administration of IL-15 and IL-15Ralpha increased antigen specific cells, cells expressing IL-2, and/or cells expressing IL-2 and IFN-gamma (i.e. multifunctional cells). The present compositions are useful for the increased bioavailability and therefore biological effects of IL-15 after its administration to humans or other mammals. 

*Applications:*                     Vaccines; Improved protein expression; Cancer immunotherapeutics; Autoimmune disease; Vaccine adjuvant.                 

*Inventors:*                     Barbara K. Felber and George N. Pavlakis (NCI).                 

*Related Publication:*                     MA Kutzler                     *et al.*                     Coimmunization with an optimized IL-15 plasmid results in enhanced function and longevity of CD8 T cells that are partially independent of CD4 T cell help. J Immunol. 2005 Jul 1;175(1):112-123.                 

*Patent Status:*                     U.S. Provisional Application No. 60/758,819 filed 13 Jan 2006 (HHS Reference No. E-254-2005/0-US-01); U.S. Provisional Application No. 60/812,566 filed 09 Jun 2006 (HHS Reference No. E-254-2005/1-US-01); PCT Application filed 13 Jan 2007 (HHS Reference No. E-254-2005/2-PCT-01).                 

*Licensing Status:*                     Available for non-exclusive or exclusive licensing.                 

*Licensing Contact:*                     Susan Ano, PhD; 301/435-5515;                     *anos@mail.nih.gov.*

## Potent Activation of Antigen Presenting Cells by the Hepatitis A Virus Cellular Receptor 1 and Its Role in the Regulation of Immune Responses 

*Description of Technology:*                     Available for licensing and commercial development are compositions and methods to regulate various immune responses through the hepatitis A virus cellular receptor 1 (HAVCR1). HAVCR1 (also known as TIM-1) is a member of the TIM family of receptors that is usurped by the hepatitis A virus (HAV) to infect cells. The gene encoding HAVCR1 has been shown to be an important asthma and allergy susceptibility gene. HAVCR1 plays a critical role in regulating T cell differentiation and the development of atopy. HAVCR1 is over-expressed in kidney ischemic cells and malignant renal tumors. The invention describes a ligand of HAVCR1 in antigen presenting cells (APCs) that is unrelated to murine Tim-4, a TIM family member reported as the ligand of murine Tim-1. The ligand was identified using an expression cloning strategy. The specific binding of HAVCR1 to this ligand on APCs causes activation and induces the expression of co-stimulatory receptors at the cell surface of the APCs and the secretion of cytokines such as IL-6, IL-10, and TNF-a. Furthermore, treatment of APCs with soluble forms of HAVCR1 induced T cell proliferation. The invention describes a novel mechanism by which HAVCR1 regulates immune responses, in which the activation of APCs is mediated by HAVCR1 binding to ligands on APCs. The association of HAVCR1 with the ligand identified in                           ( print page 14591)                        APCs also enhances the interaction of HAVCR1 with HAV.                 

                    Aspects of the technology are further described in Tami                     *et al.*, 2007. J. Virol., in press.                 

*Applications:*                     Therapies that target the interaction of HAVCR1 with the ligand on APCs, such as small molecules or monoclonal antibodies, can control immune responses, the development of asthma, allergies and other atopic diseases, hepatitis A, kidney regeneration, and cancer.                 

*Development Status:*                     The technology is in early stages of development.                 

*Inventors:*                     Gerardo Kaplan (CBER/FDA),                     *et al.*

*Patent Status:*                     U.S. Provisional Application No. 60/865,631 filed 13 Nov 2006 (HHS Reference No. E-035-2005/0-US-01).                 

*Licensing Status:*                     Available for non-exclusive or exclusive licensing.                 

*Licensing Contact:*                     Cristina Thalhammer-Reyero, PhD, M.B.A.; 301/435-4507;                     *thalhamc@mail.nih.gov.*

*Collaborative Research Opportunity:*                     The Food and Drug Administration, Center of Biologics Research and Evaluation, Laboratory of Hepatitis and Related Emerging Agents, is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize the hepatitis A virus cellular receptor as a potent activator of antigen presenting cells. Please contact Beatrice Droke, 301/872-7008 or                     *beatrice.droke@fda.hhs.gov,*                     for more information.                 

## Cyanovirins and Related Conjugates, Compositions, Nucleic Acids, Vectors, Host Cells, Methods of Production and Methods of Use for Microbicide Development 

*Description of Technology:*                     The development of an effective anti-HIV topical microbicide, especially a female-controlled, vaginal microbicide, has been deemed an urgent global priority by numerous international agencies, including the World Health Organization, the U.S. Department of Health and Human Services, the National Institute of Allergy and Infectious Diseases, and others. The present invention provides antiviral proteins (collectively referred to as cyanovirins), conjugates thereof, DNA sequences encoding such agents, host cells containing such DNA sequences, antibodies directed to such agents, compositions comprising such agents, and methods of obtaining and using such agents for the production of microbicides.                 

Cyanovirin-N (CV-N) potently and irreversibly inactivates diverse primary strains of HIV-1, including M-tropic forms involved in sexual transmission of HIV, as well as T-tropic and dual-tropic forms; CV-N also blocks cell-to-cell transmission of HIV infection. CV-N is directly virucidal, interacting in an unusual manner with the viral envelope, apparently binding with extremely high affinity to poorly immunogenic epitopes on gp120. Further, cyanovirin-N (CV-N) and homologous proteins and peptides potently inhibit diverse isolates of influenza viruses A and B, the two major types of influenza virus that infect humans. 

The described technology includes glycosylation-resistant mutants of CV-N, which code sequences to enable ultra large-scale recombinant production of functional cyanovirins in non-bacterial (yeast or insect) host cells or in transgenic animals or plants. Therefore, these glycosylation-resistant mutants may allow industry to produce CV-Ns on a large scale and make CV-Ns cheap enough for developing countries to benefit from this invention. 

CV-N was benign in vivo when tested in the rabbit vaginal toxicity/irritancy model, and was not cytotoxic in vitro against human immune cells and lactobacilli (unpublished). CV-N is readily soluble in aqueous media, is remarkably resistant to physicochemical degradation and is amenable to very large-scale production by a variety of genetic engineering approaches. 

*Applications:*                     Development of microbicides against HIV and influenza.                 

*Development Status:*                     Preclinical data is available at this time.                 

*Inventors:*                     Michael Boyd (NCI), Robert Shoemaker (NCI), Barry O'Keefe (NCI), Toshiyuki Mori (NCI), Angela Gronenborn (NIDDK).                 

*Related Publications:*

1. B Giomarelli, R Provvedi, F Meacci, T Maggi, D Medaglini, G Pozzi, T Mori, JB McMahon, R Gardella, MR Boyd. The microbicide cyanovirin-N expressed on the surface of commensal bacterium Streptococcus gordonii captures HIV-1. AIDS. 2002 Jul 5;16(10):1351-1356. 

2. CC Tsai, P Emau, Y Jiang, MB Agy, RJ Shattock, A Schmidt, WR Morton, KR Gustafson, MR Boyd. Cyanovirin-N inhibits AIDS virus infections in vaginal transmission models. AIDS Res Hum Retroviruses. 2004 Jan;20(1):11-18. 

*Patent Status:*

1. Patent Cooperation Treaty Serial No. PCT/US00/06247 filed 10 Mar 2000; National Stage Filing in United States, Japan, Australia, Europe, Germany, France, China, United Kingdom, and Belgium (HHS Reference No. E-074-1999/2).

2. Patent Cooperation Treaty Serial No. PCT/US99/18975 filed 19 Aug 1999; National Stage Filing in United States, Japan, Australia, Europe, Germany, France, China, United Kingdom, and Belgium (HHS Reference No. E-117-1995/3). 

*Licensing Status:*                     Available for licensing and commercial development.                 

*Licensing Contact:*                     Sally Hu, PhD; 301/435-5606;                     *HuS@mail.nih.gov.*

*Collaborative Research Opportunity:*                     The National Cancer Institute's Molecular Targets Development Program is seeking statements of capability or interest from parties interested in collaborative research to further develop, evaluate, or commercialize microbicides for HIV and influenza. Please contact John D. Hewes at (301) 435-3121 or                     *hewesj@mail.nih.gov*                     for more information.                 

Dated: March 16, 2007. 

Steven M. Ferguson, 

Director, Division of Technology Development and Transfer, Office of Technology Transfer, National Institutes of Health.

 [FR Doc. E7-5670 Filed 3-27-07; 8:45 am] 

BILLING CODE 4140-01-P