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Government-Owned Inventions; Availability for Licensing

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AGENCY:

National Institutes of Health, Public Health Service, DHHS.

ACTION:

Notice.

SUMMARY:

The inventions listed below are owned by agencies 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.

Mouse Strain Deficient for the Protein MT1-MMP (MMP14)

Kenn Holmbeck et al. (NIDCR)

DHHS Reference No. E-191-00/0

Licensing Contact: Marlene Shinn; 301/496-7056 ext. 285; e-mail:shinnm@od.nih.gov

Matrix metalloproteinases (MMPs) constitute a family of zinc endopeptidases that are capable of degrading most of the structural components of the extracellular matrix. The NIH announces a new mouse model deficient in MT1-MMP activity. This mouse model demonstrates the necessity of MT1-MMP for normal development of cranial bones, long bones and general housekeeping of connective tissues throughout the body. Since studies in the pharmaceutical industry are currently aiming at inhibiting the MMP family at large for purposes of cancer and arthritis treatment, this mouse model provides a valuable demonstration of the possible side effects that such treatment may lead to. As such this mouse model may also provide a test bed for the substances that can alleviate the unwanted side effects of MMP inhibitor treatments.

HIV Protease Inhibitors, Ritonavir and Saquinavir Are Potent Inhibitors of Calcium Activated Neutral Peptidases, Calpains

Paolo DePetrillo, Wenshuai Wan (NIAAA)

DHHS Reference Number E-041-00/0 filed 04 May 2000

Licensing Contact: John Rambosek, Ph.D.; 301/496-7056 ext. 270; e-mail: rambosej@od.nih.gov

This invention discloses a novel use for compounds that are inhibitors of the HIV Protease: specifically, the invention shows that HIV protease inhibitors are also potent inhibitors of Calcium Activated Neutral Proteases (Calpain). Activation of calpain plays a central role in tissue destructive processes following tissue trauma caused by, for example, stroke, heart attack, brain trauma, and spinal cord injury. Thus specific inhibition of calpain is an important therapeutic target in these disease processes. The estimated total market for these classes of therapeutic agents is on the order $500 million to 1 billion annually. The inventor has specifically demonstrated that in vitro the HIV protease inhibitors ritonavir and saquinavir are also potent inhibitors of calpain. This technology has a variety of practical applications: (1) Existing HIV Start Printed Page 48723proteases may be used as calpain inhibitors; (2) Existing HIV protease inhibitors which are FDA approved drugs will require less studies to develop as therapeutics; (3) HIV proteases inhibitors are small molecules with oral availability; (4) Other lead compounds developed as HIV protease inhibitors, but not commercialized, may be reevaluated as calpain inhibitors; (5) HIV protease inhibitors used as calpain inhibitors will not require chronic administration; and (6) calpain inhibitors may address therapeutic areas where there are not current effective therapies.

A Provisional Patent Application Serial Number 60/202,378 has been filed for this technology. It is available for licensing through a DHHS Patent license.

Synthesis of Soluble Magnetodendrimer

Jeff W. Bulte (CC), Trevor Douglas

Serial No. 60/193,360 filed 31 Mar 2000

Licensing Contact: Norbert Pontzer; 301/496-7735, ext. 284; e-mail: pontzern@od.nih.gov

The invention provides a soluble composite material comprising an organic polymer and nanoparticles of a magnetic iron oxide. Poly(amidoamine) (PAMAM)dendrimers aggregate with magnetic particles in an oligocrystalline structure which makes them extremely magnetic and soluble in solution. These superparamagnetic nanoparticles are readily taken up by cells. Because the preparation is superparamagnetic rather than ferromagnetic there is a very large relaxation effect and hysteresis is not shown. The combination of solubility, cellular uptake and strong paramagnetic properties give these novel magnetodendrimers a number of potential uses.

Magnetodendrimers have a high non-specific affinity for cellular membranes and will label cells by simple in vitro incubation regardless of the cells origin or surface proteins. After uptake of magnetodendrimer, cells can be readily separated by simple permanent magnets within seconds. When used as a magnetic resonance imaging (MRI) contrast agent, the magnetically labeled cells allow non-invasive monitoring of the temporal spatial dynamics of a wide variety of cell transplants. After incubation with magnetodendrimer, cellular relaxation enhancement is 3-5 times higher than earlier approaches. For example, the magnetically labeled cells can be injected into a patient undergoing stem cell therapy to follow the migration, distribution and integration of new tissue. Magnetic dendrimers could also be injected into tumors and other areas to directly label cells and tissues in vivo. Such uses include cancer hyperthermia therapy, ultrasound imaging-microwave radiation, and nuclear isotope imaging using59 Fe preparations. The magnetodendrimer could be attached to therapeutic compounds or other clinically relevant molecules for research, diagnostic or therapeutic purposes.

Fluorescent Magnesium Indicators

Robert London, Pieter Otten, Louis A. Levy (NIEHS)

DHHS Reference Number E-067-00/0 filed 24 March 2000

Licensing Contact: John Rambosek; 301/496-7056 ext. 270; e-mail: rambosej@od.nih.gov

Links between magnesium status and diseases such as ischaemic heart disease, hypertension, atherosclerosis, osteoporosis, migraine headaches, and other chronic diseases have been reported. These correlations have been difficult to confirm, however, mainly because of poor methods for determining free magnesium levels. This invention discloses new compounds that are fluorescent indicators for free (ionized) magnesium—the physiologically important form of magnesium. These compounds are analogs of fluoroquinolone antibiotics. Unlike other methods and indicators, they show a particularly high degree of specificity for Mg2+ versus Ca2+. They represent an exciting improvement over other methods and indicators used to measure Mg2+ because they significantly increase the ability to accurately measure intra and extracellular Mg2+ levels in a wide variety of cells, tissues, and fluids under conditions where calcium is elevated. These compounds will be important research reagents, and have the potential to be very useful as diagnostic reagents in a variety of therapeutic areas.

Methods for Wound Treatment

Sharon M. Wahl et al. (NIDCR)

DHHS Reference No. E-131-99/0 filed 01 Mar 2000

Licensing Contact: Marlene Shinn; 301/496-7056 ext. 285; e-mail: shinnm@od.nih.gov

Impaired wound healing states in the elderly have lead to major problems in terms of morbidity and mortality, affecting over four million U.S. citizens per annum and costing over 9 billion dollars. NIH investigators have recently found that Secretory Leukocyte Protease Inhibitor (SLPI) plays an important and specific role in cutaneous wound healing. SLPI is an inhibitor of serine proteases, and evidence demonstrates a requirement for SLPI as an anti-proteolytic defense against elastase and possibly additional tissue degradative enzymes and is consistent with excess elastolytic activity in pathologic, nonhealing wounds and venous ulcers. Our researchers have found that the absence of SLPI causes delayed or aberrant wound healing, an increased and prolonged inflammatory response, enhanced elastase activity, and delayed matrix accumulation in mice.

This new technology provides an improved method for treating diseases or disorders involving tissue destruction. The use of SLPI in such treatment provides a combination of advantages, including improved anti-bacterial, anti-viral, anti-fungal, and anti-inflammatory functions. SLPI also provides a number of relevant functions that accelerate the wound healing process of a variety of tissues, including skin, mucosal surfaces, and joints. Additionally, our investigators have developed a SLPI gene knock out mouse which is a useful animal model to study the functions of SLPI in the host innate immune response.

Inhibition of Cell-Mediated Immunity by Inhibition of fMLP Receptor Function by Bile Acids

Joost J. Oppenheim et al. (NCI)

DHHS Reference No. E-044-00/0 filed 03 Dec 1999

Licensing Contact: Marlene Shinn; 301/496-7056 ext. 285; e-mail: shinnm@od.nih.gov

It is well known that patients with bilary cholestatic diseases are susceptible to complications of systemic infection and endotoxemia, which may be attributable to impaired host immunity. Extensive studies in the past have shown that some bile acids, particularly chenodeoxycholic acid (CDCA), one of two major human primary bile acids, possessed immunosuppressive properties including inhibiting the production of Interleukin 1 (IL-1), IL-6 and tumor necrosis factor-α (TNF-α) by monocytes. The precise mechanistic basis for the immune suppression was unclear.

The NIH announces the discovery that deoxycholic acid and many of its naturally occurring variants block the function of formyl peptide receptors by reversibly blocking the ligand-binding site on the receptors. The formyl peptide receptors are responsible for inducing many cell types to migrate to sites of inflammation and infection and have been shown to participate in host defense against microbial agents, the formation of atherosclerosis plaques, Start Printed Page 48724granulomas, autoimmune disease and possibly Alzheimer's disease. In particular, our researchers have shown that co-incubation of the bacterially derived N-formyl peptide (fMLP) with major components of human bile, namely dexocholic acid or chenodeoxycholic acid, inhibited chemotaxis and binding by monocytes that act as phagocytic leukocytes in cell-mediated immunity. Deoxycholic acid and its variants therefore have potential usefulness as anti-inflammatory agents with a broad range of potential applications.

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Dated: July 31, 2000.

Jack Spiegel,

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

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[FR Doc. 00-20037 Filed 8-8-00; 8:45 am]

BILLING CODE 4140-01-P