[Federal Register Volume 67, Number 213 (Monday, November 4, 2002)]
[Notices]
[Pages 67201-67203]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 02-27901]


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

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.

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

[[Page 67202]]

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.

Identification of a Novel BHD Gene

    Laura S. Schmidt (NCI), DHHS Reference Nos. E-190-02/0 filed 31 May 
2002 and E-190-02/1 filed 20 Jun 2002, Licensing Contact: George Pipia; 
301/435-5560; [email protected].
    Birt-Hogg-Dube (BHD) syndrome is an inherited autosomal dominant 
neoplasia syndrome characterized by benign hair follicle tumors and is 
associated with a higher risk for developing renal cancer, spontaneous 
pneumothorax and /or lung cysts.
    The present invention describes identification of the BHD syndrome 
associated germline mutations in a novel human gene, herein called BHD 
gene. This gene encodes for the protein, folliculin, functions of which 
remain currently unknown.
    This discovery makes possible the development of a diagnostic 
method for BHD syndrome using a simple blood test. The test is 
particularly useful in detecting BHD mutations in asymptomatic carriers 
within BHD families.
    Patients with kidney tumors can be evaluated for BHD gene mutations 
using a similar genetic diagnostic test, which will allow for a more 
accurate diagnosis of a kidney cancer and improved patient prognosis. 
The BHD encoding sequence is the third gene found to be responsible for 
inherited kidney cancer, and mutation testing allows for a correct 
diagnosis and initiation of the proper treatment, which is different 
for each of the types of kidney cancer caused by the three genes.
    Methods of using BHD encoding sequence also allows for a 
differential genetic diagnosis of spontaneous pneumothorax, or 
collapsed lung. Since collapsed lung can be caused by several factors, 
a BHD diagnostic test allows a physician to determine predisposition 
and recurrence of additional spontaneous pneumothoraces due to 
mutation(s) in the BHD gene.
    The discovery should also lead to the development of novel 
pharmaceutical products and methods for treating BHD skin lesions using 
creams containing the BHD gene product, folliculin. Such products and 
methods of treatment are expected to reduce the size and appearance of 
the benign hair follicle tumors.
    The disclosed technology will provide new and exciting 
methodologies to correctly diagnose BHD syndrome and should lead to the 
development of novel pharmaceutical reagents for treatment of BHD skin 
lesions as well as other skin diseases.

Novel Anti-CD30 Antibodies and Recombinant Immunotoxins Containing 
Disulfide-Stabilized Fv Fragments

    Ira H. Pastan et al. (NCI), DHHS Reference No. E-135-02/0 filed 07 
Jun 2002, Licensing Contact: Jonathan Dixon; 301/435-5559; 
[email protected].
    The present invention discloses the creation of new anti-CD30 stalk 
antibodies and anti-CD30 dsFv-immunotoxins, which have shown good 
cytotoxic activity.
    CD30 is a member of the tumor necrosis factor receptor super 
family. It is an excellent target due to its high expression in 
malignant Reed Sternberg cells of Hodgkin's Lymphoma (HL) and in 
anaplastic large cell lymphomas (ALCL), and due to its expression in 
only a small subset of normal lymphocytes. Previous attempts to target 
CD30 include the scFv immunotoxin Ki-4 that has shown specific binding 
to CD30-positive lymphoma cell lines and killed target cells.
    The immunotoxins of the present invention are more stable and have 
higher affinity for CD30 then their predecessors. Research thus far has 
shown that the dsFv-immunotoxins are able to kill a variety of CD30-
positive lymphoma cell lines in vitro as well as CD30-transfected A431 
cells via specific binding to CD30.
    As claimed in this patent application, the antibodies are able to 
bind to the stalk or to a cleavage site that is destroyed when sCD30 is 
cleaved away. This enhancement further increases the ability of 
immunotoxins to target and treat lymphomas expressing CD30.
    The researchers are also interested in seeking a partner(s) under a 
Cooperative Research and Development Agreement (CRADA). For information 
on this CRADA opportunity, please contact Dr. Patrick Twomey of the NCI 
Technology Transfer Branch at [email protected].

Cytotoxic Agents Delivered Into Tumor Cells Through Specific Cell 
Surface Receptors and Conjugates of Ligand, Linker and Cytotoxic Agent 
and Related Compositions and Methods of Use

    DHHS Reference No. E-057-02/0 filed 27 Feb 2002 and DHHS Reference 
No. E-057-02/1 filed 05 Apr 2002, Nadya Tarasova, Christophe A. 
Michejda, Marcin Dyba, Carolyn Cohran (NCI), Licensing Contact: George 
Pipia; 301/435-5560; [email protected].
    Systemic toxicity of drugs is one of the most serious problems in 
cancer chemotherapy and frequently is dose limiting. Specific delivery 
of cytotoxic drugs to cancer cells remains among the most intractable 
problems of cancer therapy. Targeted delivery of anti-proliferation 
drugs through the cell surface receptors that are over expressed on 
cancer cells can reduce systemic toxicity and increase effectiveness of 
a treatment.
    The present invention describes cytotoxic compounds with an 
intracellular target that can selectively enter tumor cells through 
specific receptors on the cell surface. The invention also describes a 
conjugate comprising a cytotoxic agent, a linker arm and a ligand 
capable of delivering a cytotoxic agent in a cell specific manner. Such 
conjugates of a cytotoxic agent and a ligand (delivery moiety) have 
increased selectivity for tumor cells. The toxic moiety and the ligand 
are joined by a linker arm that is stable in circulation, but is easily 
cleaved in lysosomes upon internalization of the conjugate. A panel of 
compounds comprised of a variety of cytotoxic warheads, against various 
intracellular targets linked to an assortment of ligands, has been 
developed and tested in a model system. Ligand moieties of these 
conjugates are capable of specific delivery of cytotoxic agents to 
receptors that are frequently over expressed in gastric, colon, lung, 
breast, ovarian and pancreatic tumors. These compounds have the 
potential to be highly effective anti-tumor agents with considerably 
little negative effect. This disclosed technology could provide new and 
exciting methodologies to treat cancer.

Novel Form of MRP9 in Breast Cancer

    I. Pastan, T. Bera, and B. Lee (NCI), U.S. Provisional Patent 
Application 60/350,053 filed 17 Jan 2002, Licensing Contact: Brenda 
Hefti; 301/435-4632; [email protected].

[[Page 67203]]

    MRP9 is a member of the ATP binding cassette (ABC) transporter 
super family. This gene has at least two splice variants, one of which 
is membrane-associated and expressed in normal breast, breast cancer 
and testis, and the other of which is expressed in several other 
tissues. Anti-peptide antibodies designed to react with the amino 
terminus of the protein detect only the variant found in breast and 
testis. This protein should be a useful target for immunotherapy in 
breast cancer.
    The patent application has claims directed towards use of MRP9 in 
detecting various cancers, including breast, testicular and pancreatic 
cancers. The application also contains claims directed toward 
immunotherapeutic agents, which could be useful to treat said cancers.

Use of a Histone Deacetylase Inhibitor To Increase the Entry of an 
Adenoviral Agent into a Cell

    Tito A. Fojo et al. (NCI), DHHS Reference No. E-198-01/0 filed 24 
Aug 2001, Licensing Contact: Matthew Kiser; 301/435-5236; 
[email protected].

    This technology is directed to the use of any histone deacetylase 
inhibitor, including but not limited to FR901228 (depsipeptide, FK228), 
to increase the expression of Coxsackie-Adenovirus Receptor (CAR) and/
or ``-'' integrins on the surface of a cell, such as a normal or 
cancerous cell, so as to increase the entry into the cell of a 
subsequently administered adenovirus-based therapeutic agent.
    This disclosed method comprises exposing a cell to a histone 
deacetylase inhibitor in an amount sufficient to increase the 
expression of CAR and/or ``-'' integrin on the surface of the cell and, 
simultaneously with or subsequently to, exposing the cell to an 
adenoviral agent, whereupon the uptake of the adenoviral agent by the 
cell is increased relative to an otherwise identical cell that has not 
been exposed to a histone deacetylase inhibitor.

PEGylation of Linkers Improves Antitumor Activity and Reduces Toxicity 
of Immunoconjugates

    I. Pastan, Y. Tsutsumi, M. Onda, S. Nagata and B. Lee (NCI), DHHS 
Reference No. E-216-00/2 filed 08 Jun 2001 (PCT Application PCT/US01/
18503), Licensing Contact: Jonathan Dixon; 301/435-5559; 
[email protected].

    The present invention relates to site-directed PEGylation of 
immunoconjugates. In particular, it provides a new approach for 
modifying with polyethylene glycol (PEG) a connector molecule that 
attaches the toxin moiety to the targeting moiety of an immunotoxin. 
The PEGylated immunotoxin has comparable in vitro specific toxicity 
against tumor cells, but other properties including stability, plasma 
half-life, antitumor activity, immunogenicity and non-specific toxicity 
are greatly improved.
    The application contains composition of matter claims towards 
PEGylated connector molecules and method claims for using said 
PEGylated connector molecules.

Inhibitor of DNA Methylation

    Victor E. Marquez (NCI), Erik Selker, Cindy Matson, Sheldon Greer, 
Peter Jones, PCT filing claiming priority to 60/309,242 filed on July 
31, 2001, Licensing Contact: Brenda Hefti; 301/435-4632; 
[email protected].
    DNA methyltransferases (also referred to as DNA methylases) 
transfer methyl groups from the universal methyl donor S-adenosyl 
methionine to specific sites on a DNA molecule. When gene sequences 
contain many methylated cytosines, they are less likely to be 
expressed. Several such 'silenced' genes are now known to be an 
important contributing factor in many cancers where expression of tumor 
suppressor genes has been suppressed. Preventing DNA methyltransferase 
production, or inhibiting the enzyme, may allow tumor suppressor genes 
that have been silenced by hypermethylation to be re-activated. Re-
activation of tumor suppressor genes is intended to stop or slow tumor 
growth by restoring growth control mechanisms. Thus, there exists a 
need for an effective, stable, and low-toxicity inhibitor of DNA 
methylation.
    The inventors have discovered a potent inhibitor of DNA methylation 
that can specifically reactivate silenced tumor suppressor genes. This 
agent can be used to inhibit methylation and thereby combat certain 
cancers that have been linked to hypermethylation. This agent has also 
been shown in initial animal testing to be active orally and is more 
stable than some other agents in this same area of therapy and is a 
suitable candidate for further pre-clinical and clinical development as 
an anti-cancer agent to be used as monotherapy and/or as an adjunct to 
existing anti-cancer therapeutics.

    Dated: October 24, 2002.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 02-27901 Filed 11-1-02; 8:45 am]
BILLING CODE 4140-01-P