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Government-Owned Inventions; Availability for Licensing

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National Institutes of Health, Public Health Service, DHHS.




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.


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.

Minimally Immunogenic Germline Sequence Variants of COL-1 Antibody and Their Use

Syed Kashmiri (NCI), Eduardo Padlan (NIDDK), and Jeffrey Schlom (NCI)

U.S. Provisional Application No. 60/562,781 filed 15 Apr 2004 (DHHS Reference No. E-105-2004/0-US-01) and U.S. Provisional Application No. Start Printed Page 1510860/580,839 filed 16 Jun 2004 (DHHS Reference No. E-105-2004/1-US-01)

Licensing Contact: Jeffrey Walenta; 301/435-4633;

This invention relates to humanized monoclonal antibodies that bind to the tumor antigen carcinoembryonic antigen (CEA). More specifically, the present technology relates to humanized COL-1 antibodies that have minimal immunogenicity and retain antigen-binding affinity for CEA. CEA is over expressed in 95% of gastrointestinal and pancreatic tumors. Because CEA is over expressed consistently, it is anticipated that CEA would be an excellent target for an antibody-based therapeutics.

The invention also discloses a novel method for humanizing monoclonal antibodies. This humanization method encompasses grafting xenogenic Specificity Determining Regions (SDRs) onto Complementarity Determining Regions (CDR) templates derived from several different human germline sequences. The use of several different human germline sequences greatly reduces the potential for immunogenicity and greatly minimizes the number of SDRs required for equivalent or better antigen binding of the antibody.

This humanization method is applicable to development of antibodies to any immunogenic epitopes.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Modulating p38 Kinase Activity

Jonathan D. Ashwell et al. (NCI)

PCT Application filed 04 Feb 2005 (DHHS Reference No. E-010-2004/2-PCT-01)

Licensing Contact: Marlene Shinn-Astor; 301/435-4426;

Protein kinases are involved in various cellular responses to extracellular signals. The protein kinase termed p38 is also known as cytokine suppressive anti-inflammatory drug binding protein (CSBP) and RK. It is believed that p38 has a role in mediating cellular response to inflammatory stimuli, such as leukocyte accumulation, macrophage/monocyte activation, tissue resorption, fever, acute phase responses and neutrophilia. In addition, p38 has been implicated in cancer, thrombin-induced platelet aggregation, immunodeficiency disorders, autoimmune diseases, cell death, allergies, osteoporosis and neurodegenerative disorders.

This invention includes compositions and methods for controlling the activity of p38 specifically in T cells through an alternate activation pathway. By controlling p38 activity through interference with this alternate pathway, the T cells themselves can be controlled which in turn can be a treatment for conditions or diseases characterized by T cell activation such as autoimmune diseases, transplant rejection, graft-versus-host disease, systemic lupus erythematosus, and viral infections such as HIV infections. One major benefit for this invention is the development of small molecular inhibitors of the alternative p38 activation pathway (i.e. Gadd45a-mimetics). The inventors have found that Gadd45a specifically inhibits the activity of p38 phosphorylated on Tyr-323. p38 activated by MKK6 (which phosphorylates Thr-180/Tyr-182) is found not to be inhibited by Gadd45a. This emphasizes the specific nature of the activating modification and its regulation by Gadd45a, including its suitability as a tissue-specific molecular target.

References: JM Salvador et al., “The autoimmune suppressor Gadd45alpha inhibits the T cell alternative p38 activation pathway,” Nat. Immunol. advance online publication, 27 Feb 2005 (doi:10.1038/ni1176); JM Salvador et al., “Alternative p38 activation pathway medicated by T cell receptor-proximal tyrosine kinases,” Nat. Immunol. advance online publication, 27 Feb 2005 (doi:10.1038/ni1177).

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Mu Opiate Receptor Knockout Mouse

George R. Uhl (NIDA)

DHHS Reference No. E-034-2003/0—Research Material

Licensing Contact: Norbert Pontzer; 301/435-5502;

The researchers produced heterozygous and homozygous mu opiate receptor knockout mice that displayed 54% and 0% of wild-type levels of mu opiate receptor expression, respectively. These knockout mice were generated by injecting 15-20 homologous, recombinant ES cells into blastocysts harvested from C57BL/6J mice and by implanting the blastocysts into the uteri of pseudopregnant CD-1 mice.

Morphine acts on opiate receptors found on spinal and supraspinal neurons in the central nervous system. There are three main subtypes of these receptors, mu, kappa, delta. Morphine produces an analgesic effect by acting through these receptors, especially the mu receptor. However, the roles played by each of these receptors in pain processing in either drug-free or morphine-treated states are not clear. A mu opiate receptor knockout mouse model can be used to elucidate mechanistic and behavioral roles of this receptor subtype.

Reference: I. Sora et al., “Opiate receptor knockout mice define mu receptor roles in endogenous mociceptive responses and morphine-induced analgesia,” Proc. Natl. Acad. Sci. USA 18 Feb 1997 94(4):1544-1549.

In addition to licensing, the technology is available for further development through collaborative research opportunities with the inventors.

Tryptophan as a Functional Replacement for ADP-ribose-arginine in Recombinant Proteins

Joel Moss et al. (NHLBI)

U.S. Patent Application No. 10/517,565 filed 07 Dec 2004 (DHHS Ref. No. E-160-2002/0-US-03), claiming priority to 28 Jun 2002; Foreign rights available

Licensing Contact: Marlene Shinn-Astor; 301/435-4426;

Bacterial toxins such as cholera toxin and diphtheria toxin catalyze the ADP-ribosylation of important cellular target proteins in their human hosts, thereby, as in the case of cholera toxin, irreversibly activating adenylyl cyclase. In this reaction, the toxin transfers the ADP-ribose moiety of Nicotinamide Adenine Dinucleotide (NAD) to an acceptor amino acid in a protein or peptide. ADP-ribosylation leads to a peptide/protein with altered biochemical or pharmacological properties. Mammalians proteins catalyze reactions similar to the bacterial toxins. The ADP-ribosylated proteins represent useful pharmacological agents, however, their use is limited by the inherent instability of the ADP-ribose-protein linkage.

The NIH announces a new technology wherein recombinant proteins are created that substitute tryptophan for an arginine, thereby making the protein more stable, and better suited as agents for therapeutic purposes. The modification creates an effect similar to ADP-ribosylation of the arginine. An example of a protein that can be modified is the defensin molecule, which is a broad-spectrum antimicrobial that acts against infectious agents and plays an important role in the innate immune defense in vertebrates.

In addition to licensing, the technology is available for further development through collaborative Start Printed Page 15109research opportunities with the inventors.

Cannula for Pressure Mediated Drug Delivery

Stephen Wiener, Robert Hoyt, John Deleonardis, Randal Clevenger, Robert Lutz, Brian Safer (NHLBI)

PCT Application No. PCT/US99/11277 filed 21 May 1999, which published as WO 99/59666 on 25 Nov 1999 (DHHS Reference No. E-196-1998/2-PCT-01); U.S., Australian, Japanese, and European rights pending

Licensing Contact: Michael Shmilovich; 301/435-5019;

Available for licensing are methods and devices for selective delivery of therapeutic substances to specific histologic or microanatomic areas of organs (introduction of the therapeutic substance into a hollow organ space (such as an hepatobiliary duct or the gallbladder lumen) at a controlled pressure, volume or rate allows the substance to reach a predetermined cellular layer (such as the epithelium or sub-epithelial space). The volume or flow rate of the substance can be controlled so that the intralumenal pressure reaches a predetermined threshold level beyond which subsequent subepithehal delivery of the substance occurs. Alternatively, a lower pressure is selected that does not exceed the threshold level, so that delivery occurs substantially only to the epithelial layer. Such site-specific delivery of therapeutic agents permits localized delivery of substances (for example to the interstitial tissue of an organ) in concentrations that may otherwise produce systemic toxicity. Occlusion of venous or lymphatic drainage from the organ can also help prevent systemic administration of therapeutic substances, and increases selective delivery to superficial epithelial cellular layers. Delivery of genetic vectors can also be better targeted to cells where gene expression is desired. The access device comprises a cannula with a wall piercing tracar within the lumen. Two axially spaced inflatable balloons engage the wall securing the cannula and sealing the puncture site. A catheter equipped with an occlusion balloon is guided through the cannula to the location where the therapeutic substance is to be delivered.

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Dated: March 17, 2005.

Steven M. Ferguson,

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

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[FR Doc. 05-5875 Filed 3-23-05; 8:45 am]