Federal Tech Transfer Opportunities

During the past week, the following agencies have listed inventions available for licensing.

• NASA (3 inventions)
• Department of Health & Human Services (14 inventions)

NASA

The inventions listed below are assigned to the National Aeronautics and Space Administration, have been filed in the United States Patent and Trademark Office, and are available for licensing.

FOR FURTHER INFORMATION CONTACT: John Kusmiss, Patent Counsel, NASA Management Office_JPL, 4800 Oak Grove Drive, Mail Stop 180_801, Pasadena, CA 91109; Tel. (818) 354_7770.

• NASA Case No. NPO 19289_1: On_Chip Learning in VLSI Environment;
• NASA Case No. NPO_20403_1: Inrush Current Control Circuit;
• NASA Case No. DRC 099_006: Algorithm and Test Technique for a Frequency Excitation Using an Optimized Multiple Frequency Sweep Waveform (Sweepstack).

Department of Health & Human Services – National Institutes of Health

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.

1. Use of Cumulative Distribution Functions To Determine Protein Purity and Homogeneity
Alfred L. Yergey, Paul S. Blank, Christin M. Sjomeling (NICHD)
DHHS Reference No. E_163_00/0 filed 28 Apr 2000
Licensing Contact: Vasant Gandhi; 301/496_7056 ext. 224; e_mail:gandhiv@od.nih.gov

Successful solutions to numerous problems in the biochemical sciences depend on the ability to produce ``pure'' proteins and recognize the degree to which proteins might be modified. Current methods used for assessing purity are relatively nonspecific and insensitive to small differences in molecular weight. The inventors have developed a computer_implemented method and system for nonparametric statistical analysis of matrix_assisted laser desorption ionization (MALDI) protein spectra but is equally applicable to deconvoluted electrospray ionization (ESI) spectra. The invention facilitates assessing protein heterogeneity and detection of otherwise indistinguishable differences in the distribution of molecular weight. A principal advantage is that no additional instrumentation is required beyond that typically included in a mass spectrometry analysis system.

2. Hsp70_Like ATPase Peptide Binds Chap1/Dsk2
Frederic J. Kaye (NCI)
DHHS Reference No. E_282_99/0 filed 15 Sep 1999
Licensing Contact: Elaine White; 301/496_7056 ext. 282; e_mail: gesee@od.nih.gov

The current invention embodies the identification of a novel gene and protein, Chap1/Dsk2, a ubiquitin_linked protein which appears to play a vital role in regulating mitosis. Identified also is the conserved 20 amino acid region within the ATPase domain of the protein chaperone STCH, an Hsp70_like protein, which is the binding site for Chap1/Dsk2 and other ubiquitin_linked proteins.

Protein chaperones are essential for cell viability, regulating various cell cycle events including the biosynthesis, folding and unfolding, transport, multiunit assembly, and degradation of cell proteins. Overexpression of protein chaperones, such as STCH, can serve to suppress tumorigenesis and apoptosis. It therefore is believed that the peptide identified as the binding domain of STCH may have potential for use as a therapeutic agent against cancer or various infectious diseases, via modulation of tumorigenesis, apoptosis, or the multiunit assembly of viral particles such as HIV.

3. Polypeptides Comprising IL_6 Ligand Binding Receptor Domains and Related Nucleic Acids, Antibodies, Compositions and Methods
W. Carl Saxinger (NCI)
DHHS Reference No. E_061_99/0 filed 27 Aug 1999
Licensing Contact: Richard Rodriguez; 301/496_7056 ext. 287; e_mail: rodrigur@od.nih.gov

The biological activities of IL_6 include the stimulation of B and T cell growth and differentiation, production of acute_phase proteins by hepatocytes, multilineage hematopoiesis, osteoblast formation, maturation of megakaryocytes and platelet production. An abnormal expression of IL_6 may be involved in the pathogenesis of a variety of diseases, among which are multiple myeloma, rheumatoid arthritis, postmenopausal osteoporosis, chronic autoimmune diseases, Castleman's disease and AIDS. Methods of abrogating the effects of abnormal expression of IL_6 can be made at its site of production or at its target. The inventors of this technology have focused on the latter technique. Using a unique, newly patented, automated peptide array system, the inventors have studied specific sequences potentially involved in protein_protein interactions at the molecular level. This system was used to identify and isolate potential target peptide sequences within the IL_6 receptor molecule. Candidate peptide sequences were identified by direct binding to the IL_6 ligand by optimally displayed IL_6 receptor peptide segments in solid phase form. The specific binding properties of the peptide sequences were verified by using IL_6 heteroantisera, and the peptides have been shown to mitigate or reverse the effects of the above referenced properties of IL_6 in tissue culture.

4. Receptor_Mediated Uptake of an Extracellular Bcl_XL Fusion Protein Inhibits Apoptosis
Richard J. Youle, Xiuhuai Liu, JoAnn Castelli (NINDS)
DHHS Reference No. E_073_99/0 filed 16 Aug 1999
Licensing Contact: Richard Rodriguez; 301/496_7056 ext. 287; e_mail: rodrigur@od.nih.gov

The present invention relates to the field of apoptosis, in particular, it relates to apoptosis_modifying fusion proteins with at least two domains, one of which targets the fusion proteins to a target cell, and another of which modifies an apoptotic response of the target cell. For example, fusing various cell_binding domains to Bcl_XL and Bad allows targeting to specific subsets of cells in vivo, permitting treatment and/or prevention of cell_death related consequences of various diseases and injuries. This technology could be used to minimize or prevent apoptotic damage that can be caused by neurodegenerative disorders, e.g., Alzheimer's disease, Huntington's disease or spinal_muscular atrophy, stroke episodes or transient ischemic neuronal injury, e.g., spinal cord injuries. Additionally, apoptotic_enhancing fusion proteins of the current invention could be used to inhibit cell growth, e.g., uncontrolled cellular proliferation.

5. DNA Binding Protein and Sequence as Insulators Having Specific Enhancer Blocking Activity for Regulation of Gene Expression
Adam C. Bell, Adam G. West, Gary Felsenfeld (NIDDK)
DHHS Reference Nos. E_220_98/0 filed 30 Jun 1999 and E_220_98/1 filed 19 Apr 2000
Licensing Contact: Girish Barua; 301/496_7735 ext. 263; e_mail: gb18t@nih.gov

This patent application has two components. The first is the identification of a functional 50bp fragment of a previously known chicken chromatin insulator protein. The second component is the

identification of the REBL (Required for Enhancer Blocking) CTCF protein (CCCTC_binding factor) which binds to the 50bp fragment. [The relationship between these two can be analogized as a receptor (50 bp fragment) and its ligand (the REBL CTCF protein).] These two elements can be used separately or together to regulate gene expression.

An insulator is a DNA sequence which is capable of acting as a barrier to neighboring cis_acting elements, preventing gene activation when juxtaposed between an enhancer and a promoter (i.e., when the insulator is placed between the enhancer and the promoter gene activation is blocked). An insulator will also act to protect a stably integrated reporter gene from position effects. This 50 bp fragment represents a functionally active domain of the chicken insulator protein which is both necessary and sufficient for enhancer blocking activity in human cells. The previously described chicken chromatin insulator is a 1.2 kb fragment which, where overall size of the vector to be delivered is a concern, for example, in gene therapy, may be too large for some applications. The identification of this active 50 bp fragment may therefore be a preferred alternative.

The identification of the REBL CTCF protein as an agent which binds to the 50 bp insulator fragment and whose binding activity is necessary for blocking of enhancer activity provides an additional element which may be used to more specifically control gene regulation. As most gene expression is dependent on the activity of multiple components the identification of a specific binding factor which functions as a blocking enhancer activity may permit more precise control of gene expression. The human REBL protein has regions which share homology with previously disclosed partial human cDNAs. It has a molecular weight of 135 kDa. A chicken homolog has also been identified. CTCF was originally identified as a repressor of the chicken c_myc gene.

ADDRESSES: Licensing information and copies of the U.S. patent applications listed below may be obtained by contacting Marlene Shinn, J.D., at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852_3804; telephone: 301/496_7056 ext. 285; fax: 301/402_0220; e_mail: shinnm@od.nih.gov. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

6. Inhibition of Smad3 To Prevent Fibrosis and Improve Wound Healing
Anita B. Roberts et al. (NCI)
DHHS Reference No. E_070_00/0 filed 19 May 2000; PCT/US00/13725

Millions of dollars are spent each year to heal chronic non_healing wounds and in the treatment of severe burn patients. The NIH announces a new technology that may lead to improved approaches to treatment of burn patients and the reduction of scarring and more rapid closure of both acute (surgical) and chronic wounds (e.g., diabetic, decubitus, and venus statis ulcers).

Smad2 and Smad3 are highly homologous cytoplasmic proteins which function to transduce signals from Transforming Growth Factor_beta (TGF_) and activin receptors to promoters of target genes found in the nucleus. This new technology indicates that interference with specific signaling pathways downstream of TGF_ may be more selective and have a better outcome than approaches aimed at blocking all effects of this pleiotropic cytokine. Specifically, it is proposed that elimination or inhibition of Smad3 may interfere with fibrogenic mechanisms and reduce the accumulation of scar tissue associated with high dose radiation and wound healing, while increasing the rate of re_epithelialization of wounds.

Although this technology is still in an early stage, our researchers have obtained solid evidence of the involvement of Smad3 in these processes by use of a Smad3 null mouse model which they have developed. Based on these results, it is believed that antisense Smad3 or small molecule inhibitors of Smad3 will have clinical applications in wound healing, in improving growth and reducing unwanted fibrosis of autologous skin grafts for treatment of burn patients, and in treatment of radiation fibrosis and other fibrotic diseases associated with chronic inflammation. In addition, the discovery of inhibitors to Smad3 signaling may lead to radiation dose escalation and accelerated tumor cell death while reducing the side effects associated with radiation therapy.

7. Anti-H2A Antibody and Method for Detecting DNA Double_Stranded Breaks
William M. Bonner, Efthimia P. Rogakou (NCI)
Serial No. 09/351,721 filed 12 Jul 1999

There presently exist assays for determining DNA breakage due to stresses such as radiation and toxins. These include the TUNEL assay and single cell gel electrophoresis, among others. The difficulty in using these and other assays arises in that a great number of DNA breaks are necessary for adequate detection of the breakage. Since only 40 double_stranded breaks in the DNA leads to cell death, it is evident that there is a need for an assay with greater specificity.

The NIH announces a new technology which relates to such an improvement over current DNA detection assays, with the ability to be sensitive enough to detect a single DNA double_stranded break in a cell's nucleus. This method for detection uses antibodies directed against a synthetic phosphorylated peptide containing the mammalian_H2AX C_terminal sequence for deletion of DNA double_stranded breaks. It centers on the activity of the H2A histone. In response to a DNA break, H2A can become phosphorylated in great numbers and provide protection for the break site to assist in repair. The antibody and method available show specificity for this occurrence and thus allow detection at levels much lower than are presently needed by other detection techniques. Use of such technology could be widespread, both as a diagnostic tool and with specific DNA breakage_related disease and syndrome research.

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.

8. A High Yield Pertussis Vaccine Production Strain and Method for Making Same
Tod J. Merkel, Jerry M. Keith and Xiaoming Yang (NIDCR)
DHHS Reference No. E_159_99/0 filed 26 Jun 2000
Licensing Contact: Uri Reichman; 301/496_7736 ext. 240; e_mail: reichmau@od.nih.gov

Pertussis Toxin (PT) in its chemically detoxified forms has emerged as the most promising acellular vaccine against Bordetella pertussis (B. pertussis), the organism responsible for whooping cough. Genetically detoxified forms of PT have recently been demonstrated as potential vaccine candidates against this organism, and may offer the advantages of enhanced stability and ease of manufacturing. The need for production of large quantities of PT and its genetically detoxified forms keeps growing, but the current methods of production of the toxin from B. pertussis have proven to be rather cumbersome and inefficient, resulting in poor yields and impure form of the desired protein. The present invention provides for a new way to circumvent these difficulties and renders the process more amenable to industrial needs. The present invention describes the development of a new genetically engineered strain of Bordetella bronchiseptica, named BBPT, which grows at a high rate relative to B. pertussis, and is capable of producing wild type or genetically detoxified form of PT in pure form, with high yields and in a cost effective fashion. The high degree of purity of the product is achieved due to the knockout of the filamentous hemagglutinin (FHA) gene in this new strain. The presence of the FHA protein, which is inherent in the conventional methods of production, requires extra purification steps, thus resulting in poor and inconsistent yields of the toxin. The BBPT strain of the present invention may play a major role in the acceleration of programs dedicated to the development of improved and efficacious vaccines against B. pertussis.

9. Activation of Antigen Presenting Cells to Respond To a Selected Antigen
Polly Matzinger, Stefania Gallucci, Martijn Lolkema (NIAID)
DHHS Reference No. E_018_00/0 filed 25 Oct 1999
Licensing Contact: Peter Soukas; 301/496_7056 ext. 268; e_mail: soukasp@od.nih.gov

The inventors have found that alpha interferon and the supernatant of necrotic cells can act as adjuvants when co_injected along with a protein, such as OVA, to initiate a primary in vivo immune response in mice. The compositions of the present invention can induce dendritic cells to activate and become good Antigen Presenting Cells (APCs) and consequently initiate an immune response. The advantage of these adjuvants is that they are more physiological and they allow for repeated vaccination, which current adjuvant technology makes difficult due to the side effects of the adjuvants. The invention also provides uses and applications for the adjuvants, including, but not limited to, transplant rejection, spontaneous tumor rejection, some forms of spontaneous abortion, and some forms of autoimmunity. The invention is further described in Nature Medicine 1999 Nov; 5(11):1249_55.

ADDRESSES: Licensing information and copies of the U.S. patent applications listed below may be obtained by Uri Reichman, Ph.D., at the Office of Technology Transfer, National Institutes of Health, 6011 Executive Boulevard, Suite 325, Rockville, Maryland 20852_3804; telephone: 301/496_7736 ext. 240; fax: 301/402_0220; e_mail: reichmau@od.nih.gov. A signed Confidential Disclosure Agreement will be required to receive copies of the patent applications.

10. Use of Recombinant Parainfluenza Viruses (PIVs) as Vectors To Protect Against Infection and Disease Caused by PIV and Other Human Pathogens
B. Murphy, P. Collins, A. Durbin, M. Skiadopoulos and T. Tao (NIAID)
DHHS Reference No. E_099_99/0 filed 10 Dec 1999

The invention relates to the design and creation of recombinant chimeric parainfluenza viruses, novel vaccine candidates against PIV and non_PIV pathogens. The chimeric viruses utilize the PIV genome as a carrier/vector for heterologous PIV or non_PIV genes that code for the protective antigens of the pathogens. For example, the glycoproteins genes of PIV1 and PIV2 can be incorporated into PIV3 genome, either substituting for or in addition to the vector's glycoprotein genes. The latter design can serve as a single vaccine against the three types of PIV pathogens. Furthermore, PIV can serve as a carrier for the ``protective'' genes of non_PIV pathogens such as measles, RSV, mumps, herpes, influenza and more. In this design, again, the ``donor'' genes can substitute for or be added to the vector's protecting genes. The latter design can serve as a single vaccine against plurality of pathogens. In particular, the invention describes the potential benefit of developing new vaccine candidates against the measles virus.

The live attenuated measles virus currently in commercial use must be administered by intramuscular injection, and cannot be given until 12 months of age due to neutralization by maternal antibodies present in young infants. There is a strong need to develop a vaccine which will be effective in the first year of life. A chimeric PIV3_measles vaccine described in this invention has shown to confer protection against the two pathogens. Initial studies indicate that this vaccine candidate will be able to circumvent the difficulties encountered by the currently licensed vaccine, i.e., it will be possible to administer the vaccine by intranasal route so that it will be effective in the presence of maternal antibodies. This vaccine will make it possible, for the first time, to immunize young infants against the deadly measles virus.

11. Attenuated Human_Bovine Chimeric Parainfluenza Virus (PIV) Vaccines
M. Skiadopoulos, P. Collins, B. Murphy and A. Schmidt (NIAID)
DHHS Reference No. E_201_00/0 filed 05 Jul 2000

The invention relates to the engineering and creation of recombinant chimeric human_bovine parainfluenza viruses (PIVs) and novel vaccine candidates against PIV. The chimera of the invention include a partial or complete ``background'' PIV genome or antigenome derived from or patterned after a bovine PIV virus, combined with one or more heterologous gene(s) or genome segment(s) of a human PIV virus to form a human_bovine chimeric PIV genome or antigenome. The inverted design is also possible, where the chimeric PIV incorporates a partial or complete human PIV ``background'' genome or antigenome, combined with one or more heterologous gene(s) or genome segment(s) from bovine PIV, whereby the resultant chimeric virus is attenuated by virtue of the host_range restriction specified by the bovine genes. In particular, the invention describes the creation of chimera where the human PIV HN and F ``protective'' genes are incorporated into a bovine ``background'' genome, and another one where bovine PIV3 P and M open reading frames replace that of human in a human PIV3 ``background'' genome. The vaccine candidates created by this recombinant technique can be further attenuated by incorporating specific point mutations and nucleotide modifications into the genome to yield desired phenotypic and structural effects.

12. Respiratory Syncytial Virus Vaccines Expressing Protective Antigens From Promoter_Proximal Genes
C. Krempl, P. Collins, B. Murphy, U. Buchholz and S. Whitehead (NIAID)
DHHS Reference No. E_225_00/0 filed 23 Jun 2000

The invention relates to the engineering and creation of novel live_attenuated RSV vaccine candidates. The viruses of this invention have been modified by shifting the position of one or more of various viral genes relative to the viral promoter. The gene_shifted RSVs are constructed by insertion, deletion and rearrangement of genes or genome segments within the recombinant genome or antigenome. Shifting the position of the gene(s) in this manner provides for a selective increase or decrease in expression of the gene(s), depending on the nature and degree of the positional shift. Genes of interest for manipulation to create gene position_shifted RSV include any of the NS1, NS2, N, P, M, SH, M2(ORF1), M2(ORF2), L, F or G genes or genome segment.

One modification of particular interest is to place the G and F protective antigen genes in a promoter_proximal position for increased expression. The gene position_shifted RSV can be further manipulated by the addition of specific nucleotide and amino acid point mutations or host range restriction determinants to yield desired phenotypic and structural effects. This technique offers the possibility of producing a vaccine that is ``better than nature'' by increasing the relative expression of particular genes.

13. Multiple Hybridization System for the Identification of Pathogenic Mycobacterium Species and Method of Use
Steven Fischer, Gary Fahle, Patti Conville and Jang Rampall (CC)
DHHS Reference No. E_278_99/0 filed 03 March 2000

The invention relates to a multiplex system that allows simultaneous detection and identification of any one of six different species of mycobacteria, M. gordonae, M. intracellulare, M. avium, M. tuberculosis, M. marinum, or M. kansasii. The Mycobacterium species included in this detection system, collectively, constitute about 90% of the patient isolates detected in many clinical mycobacteriology lab sections. The system includes primers and amplification reagents that, when applied to the clinical specimen can generate detection oligonucleotide for the Mycobacterium species, in one step and in a single tube. The system also includes a plastic device comprising an array of the corresponding capture oligonucleotides of known sequences. Upon generating the amplified detection probes, the detection mixture is applied to the plastic device for hybridization to take place. Following a wash step, the hybridized locations on the array are detected by fluorescence or chemiluminescence to determine which of the six possible Mycobacterium species are present in the sample. The system is simple to operate and permits the identification of these six mycobacteria in patient samples in a single day.

14. Method of Diagnosing Multidrug Resistant Tuberculosis
Clifton E. Barry, III, Andrea E. DeBarber, Khisimuzi Mdluli and Linda_Gail Bekker (NIAID)
DHHS Reference No. E_093_00/0 filed 26 Jun 2000

The invention relates to the discovery that a putative gene of Mycobacterium tuberculosis (MTb) with no previously identified function is responsible for the ability of the bacteria to activate a class of second line thioamide drugs used for MTb infections. The gene, termed ``etaA'', codes for the synthesis of a monooxigenase, the enzyme responsible for the oxidative activation of the drugs. Mutation in the etaA gene leads to the expression of mutated, inactivated enzyme, thus resulting in thioamide drug_resistant bacteria. The significance of this discovery is that now, resistance to the class of thioamide drugs in clinical isolates can be identified in a relatively short time, eliminating the need to perform lengthy culturing procedures. The invention claims test methods for determining resistance to thioamide drugs by detecting gene mutation. These include (a) amplifying the etaA gene or a portion of it containing the mutation, with a set of primers which provide amplified product, and sequencing the amplified product to compare the sequence with a known sequence of the wild_type etaA. A difference in sequence patterns indicate mutation, (b) subjecting the amplified gene product to digestion by restriction enzymes and comparing the cleaved DNA gel pattern to the one obtained from digestion of the wild type etaA gene. A difference indicates mutation in etaA, and (c) detecting the mutations by probe hybridization techniques, where the amplified product hybridizes to a nucleic acid of known sequence under stringent conditions, and the hybridized product is detected. In addition to the above, the invention proposes other detection methods such as commonly used for SNPs. Other methods claimed in the invention are immunoassay (i.e. ELISA) for the etaA gene product or mutated versions of it, or immunoassay and chemical analysis of the drug metabolites, whereby the absence of the metabolites indicates gene mutation and impaired activating ability.

State Science & Technology Institute
5015 Pine Creek Drive
Westerville, OH 43081
Phone: (614) 901-1690
Fax: (614) 901-1696
Email: ssti@ssti.org

  © 2002 State Science and Technology Institute. All rights reserved.