[Federal Register Volume 64, Number 37 (Thursday, February 25, 1999)]
[Notices]
[Pages 9338-9339]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-4659]


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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, DHHS.

ACTION: Notice.

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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 contacting Richard U. 
Rodriguez, M.B.A., at the Office of Technology Transfer, National 
Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, 
Maryland 20852-3804; telephone: 301/496-7056 ext. 287; fax: 301/402-
0220; e-mail: [email protected]. A signed Confidential Disclosure 
Agreement will be required to receive copies of the patent 
applications.

Use Of Calreticulin And Calreticulin Fragments To Inhibit 
Endothelial Cell Growth And Angiogenesis, And Suppress Tumor Growth

G Tosato, SE Pike (FDA), DHHS Reference No. E-082-98/0 filed 06 Oct. 98

    Tumor growth and invasion into normal tissues is dependent upon an 
adequate blood supply, and agents that target tumor blood supply have 
been shown to prevent or delay tumor formation and to promote the 
regression or dormancy of established tumors in preclinical models. It 
has been shown that EBV-immortalized cell lines can promote regression 
of experimental Burkitt's lymphoma, colon carcinoma and other human 
malignancies established in athymic mice through a vascular-based 
process. The inventors analyzed the cultured-media from EBV-
immortalized cells and isolated a unique and potent factor which 
inhibits angiogenesis and tumor cell growth. This novel compound was 
named vasostatin. Vasostatin is an NH2-terminal fragment of 
human calreticulin, and it can inhibit endothelial cell proliferation 
in vitro, suppress neovascularization in vivo and prevent or reduce 
growth of experimental tumors while having minimal effect on other cell 
types. Vasostatin is the most conserved domain among calrecticulins so 
far cloned and has no homology to other protein sequences. Data 
suggests that the antitumor effects of vasostatin are related to 
inhibition of new vessel formation rather than to a toxic effect on 
established tumor vascular structures. Vasostatin has key differences 
from other inhibitors of angiogenesis. It is small and soluble, and it 
is stable for greater than 19 months in aqueous solution. It is easily 
produced and delivered. By comparison, angiostatin, endostatin and 
thrombospondin can be difficult to isolate, purify and deliver. 
Additionally, studies have shown that the effective dose of vasostatin 
is 4-10 fold lower than the effective doses of endostatin and 
angiostatin. Therefore, this new and potent anti-angiogenic molecule 
should prove highly useful for the prevention and treatment of human 
cancers.

Polynucleotide Inhibition Of RNA Destabilization And Sequestration

DJ Lipman (NLM)
DHHS Reference No. 3-130-97/1 filed 19 Aug 98; PCT/US98/17261

    A variety of mechanisms are available in eukaryotic cells for 
regulating gene expression such that each gene product is produced at 
appropriate times and in appropriate quantities. It is well established 
that a significant amount of control over gene expression can be 
exerted at the level of RNA processing and RNA stability. Evidence 
exists that suggests a role for antisense RNA transcripts 
(countertranscripts) in RNA destabilization and nuclear sequestration 
which promotes down-regulation of protein expression. 
Countertranscript-RNAs are encoded by the complementary-strand of a 
gene, and they are sometimes found in different tissues or 
developmental stages than their corresponding sense or transcript-RNAs, 
and these different expression patterns yield different gene-product 
expression patterns. Therefore, transcript-countertranscript complexes 
can play a critical role in the degradation and sequestration of RNAs 
and thus affect protein expression. The disclosed invention provides a 
means whereby defined polynucleotides can be introduced into a cell or 
tissue in order to prevent transcript-countertranscript interactions 
and thereby inhibit this degradation and nuclear sequestration of 
transcript RNA. This methodology could enhance the expression of a 
target gene-product encoded by a transcript-RNA by preventing 
transcript-countertranscript association. The polynucleotides 
themselves can be introduced or expression vectors can be created 
containing the polynucleotide sequence in order to express the defined 
polynucleotides in the cells or tissue of choice. These polynucleotides 
can also be used in in vivo and ex vivo regimens. As an example, these 
polynucleotides could be used to treat tumorigenic cells in such a way 
as to promote the expression of known apoptotic proteins whereby the 
tumorigenic cells are selectively killed. In summary, this technology 
could be used in any number of applications where the promotion of the 
expression of a particular gene-product is desirable.

Labeling DNA Plasmids With Triplex-Forming Oligonucleotides and 
Methods for Assaying Distribution of DNA Plasmids in Vivo

    IG Panyutin, RD Neumann, O Sedelnikova (CC), DHHS Reference No. E-
142-98/0 filed 26 May 98.
    Monitoring the intracellular distribution of circular plasmids that 
have been introduced into cells is problematic because labeling 
moieties are not readily attached to covalently closed circular DNA 
molecules. Monitoring the biodistribution of DNA vectors that are 
introduced into a host animal, e.g., to determine the efficiency of 
transfection of target tissues in developing a method for gene therapy,

[[Page 9339]]

is also problematic because commonly used assays based on detecting 
marker gene expression do not provide accurate biodistribution data due 
to failure to obtain a signal in those tissues in which the marker gene 
is not expressed. This invention obviates these deficiencies by 
disclosing the use of triplex-forming-oligonucleotides (TFO) which bind 
to their target sequences in circular plasmid DNA and thereby creating 
stable readily detectable triplex-complexes when introduced into living 
eukaryotic cells. These fluorescent or radio-labled polypurine TFOs can 
provide a noninvasive way to study the biodistribution of a plasmid of 
interest in vivo using tools developed for probe detection and 
radioimaging. In summary, this technology allows one to quantitatively 
monitor the whole-body distribution of labeled-vectors in living 
animals or patients.

Extension of a Protein-Protein Interaction Surface To Inactivate 
the Function of a Cellular Protein

    CR Vinson, D Krylov (NCI), DHHS Reference No. E-113-95/1 filed 29 
May 96, Related cases: Serial No. 08/690,111 filed 31 Jul 96; PCT/US96/
12590 filed 31 Jul 96.
    This invention uses sequence-specific DNA binding proteins as 
eukaryotic transcription factors, i.e., transcription regulatory 
proteins. Specifically, multimeric proteins having nucleic acid (DNA or 
RNA) binding domains in which the binding domain or protein interaction 
surface is engineered or modified to be acidic in nature. The acidic 
nature of the protein increases the stability of heteromultimeric or 
heterodimeric complexes that are formed. This type of nucleic acid 
binding protein should be capable of regulating the function of a 
target nucleic acid sequence or gene to which it is bound, thereby 
acting as a potent dominant-negative regulator of gene transcription, 
cell growth and cell proliferation. These proteins would be useful as 
drugs, inhibitory molecules or growth-controlling agents that can 
inhibit the expression,and thus the activity, of cellular proteins 
which have harmful, deleterious and even lethal effects on cell growth 
and survival. These proteins could also be used in gene therapy by 
using appropriate constructs to allow expression of a regulatory 
protein to treat suitable disease states. The constructs could also be 
used to create transgenic animals or plants in which the dominant-
negative protein interacts with the wild-type protein to provide viable 
phenotypes to evaluate and assess the in vivo effects of the protein. 
In summary, this technology provides for useful tools and therapeutics 
which are capable of regulating specific target gene expression and 
gene-product activity.

    Dated: February 16, 1999.
Jack Spiegel,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer.
[FR Doc. 99-4659 Filed 2-24-99; 8:45 am]
BILLING CODE 4140-01-M