[Federal Register Volume 70, Number 148 (Wednesday, August 3, 2005)]
[Notices]
[Pages 44665-44667]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-15347]


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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, HHS.

ACTION: Notice.

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SUMMARY: 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.

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.

A Method With Increased Yield for Production of Polysaccharide-Protein 
Conjugate Vaccines Using Hydrazide Chemistry

Che-Hung Robert Lee and Carl Frasch (FDA).
U.S. Provisional Application No. 60/493,389 filed 06 Aug 2003 (HHS 
Reference No. E-301-2003/0-US-01);
PCT Application No. PCT/US04/25477 filed 06 Aug 2004 (HHS Reference No. 
E-301-2003/0-PCT-02);
PCT Application No. PCT/US04/26431 filed 06 Aug 2004 (HHS Reference No. 
E-301-2003/1-PCT-01).
Licensing Contact: Peter Soukas; 301/435-4646; [email protected].

    Current methods for synthesis and manufacturing of polysaccharide-
protein conjugate vaccines employ conjugation reactions with low 
efficiency (about twenty percent). This means that up to eighty percent 
of the added activated polysaccharide (PS) is lost. In addition, 
inclusion of a chromatographic process for purification of the 
conjugates from unconjugated PS is required.
    The present invention utilizes the characteristic chemical property 
of hydrazide groups on one reactant to react with aldehyde groups or 
cyanate esters on the other reactant with an improved conjugate yield 
of at least sixty percent. With this conjugation efficiency the 
leftover unconjugated protein and polysaccharide would not need to be 
removed and thus the purification process of the conjugate product can 
be limited to diafiltration to

[[Page 44666]]

remove the by-products of small molecules. The new conjugation reaction 
can be carried out within one or two days with reactant concentrations 
between 1 and 25 mg/mL at PS/protein ratios from 1:2 to 3:1, at 
temperatures between 4 and 40 degrees Centigrade, and in a pH range of 
5.5 to 7.4, optimal conditions varying from PS to PS.
    Therefore, this invention can reduce the cost of conjugate vaccine 
manufacture.

Modulators of Nuclear Hormone Receptor Activity: Novel Compounds, 
Diverse Applications for Infectious Diseases, Including Anthrax (B. 
anthracis)

E.M. Sternberg (NIMH), J.I. Webster (NIMH), L. H. Tonelli (NIMH), S. H. 
Leppla (NIAID), and M. Maoyeri (NIAID).
U.S. Provisional Application No. 60/416,222 filed 04 Oct 2002 (HHS 
Reference No. E-247-2002/0-US-01);
U.S. Provisional Application No. 60/419,454 filed 18 Oct 2002 (HHS 
Reference No. E-348-2003/0-US-01);
PCT Application No. PCT/US03/31406 filed 03 Oct 2003 (HHS Reference No. 
E-247-2002/1-PCT-01);
U.S. Patent Application No. 10/530,254 filed 04 Apr 2005 (HHS Reference 
No. E-247-2002/1-US-02).
Licensing Contact: Peter Soukas; 301/435-4646; [email protected].

    Technology summary and benefits: Nuclear hormones such as 
glucocorticoids dampen inflammatory responses, and thus provide 
protection to mammals against inflammatory disease and septic shock. 
The Anthrax lethal factor represses nuclear hormone receptor activity, 
and thus may contribute to the infectious agent causing even more 
damage to the host. This observation can be exploited to find new means 
of studying and interfering with the normal function of nuclear hormone 
receptors. Scientists at NIH have shown that under the appropriate 
conditions, these molecules can be used to modulate the activity of 
various nuclear hormone receptors. Identifying useful agents that 
modify these important receptors can provide relief in several human 
disorders such as inflammation, autoimmune disorders, arthritis, 
malignancies, shock and hypertension.
    Long-term potential applications: This invention provides novel 
agents that can interfere with the action of nuclear hormone receptors. 
It is well known that malfunction or overdrive of these receptors can 
lead to a number of diseases such as enhanced inflammation; worse 
sequelae of infection including shock; diabetes; hypertension and 
steroid resistance. Hence a means of controlling or fine-tuning the 
activity of these receptors can be of great benefit. Current means of 
affecting steroid receptor activity are accompanied by undesirable 
side-effects. Since the conditions for which these treatments are 
sought tend to be chronic, there is a critical need for safer drugs 
that will have manageable side-effects.
    Uniqueness or innovativeness of technology: The observation that 
the lethal factor from Anthrax has a striking effect on the activity of 
nuclear hormone receptors opens up new routes to controlling their 
activity. The means of action of this repressor is sufficiently 
different from known modulators of hormone receptors (i.e. the 
classical antagonists). For instance, the repression of receptor 
activity is non-competitive, and does not affect hormone binding or DNA 
binding. Also, the efficacy of nuclear hormone receptor repression by 
Anthrax lethal factor is sufficiently high that the pharmacological 
effect of this molecule is seen at vanishingly small concentrations. 
Taken together, these attributes may satisfy some of the golden rules 
of drug development such as the uniqueness or novelty of the agent's 
structure, a low threshold for activity, high level of sophistication 
and knowledge in the field of enquiry, and the leeway to further refine 
the molecule by rational means.
    Stage of Development: In vitro studies have been completed, and a 
limited number of animal studies have been carried out.

Methods and Compositions for Production and Purification of Recombinant 
Staphylococcal Enterotoxin B (rSEB)

Daniel Coffman, Steven Giardina, Jianwei Zhu (NCI).
U.S. Provisional Application No. 60/328,017 filed 09 Oct 2001 (HHS 
Reference No. E-075-2001/0-US-01);
PCT Application No. PCT/US02/31114 filed 27 Sep 2002 (HHS Reference No. 
E-075-2001/0-PCT-01);
U.S. Patent Application No. 10/492,105 filed 08 Apr 2004 (HHS Reference 
No. E-075-2001/0-US-02).
Licensing Contact: Peter Soukas; 301/435-4646; [email protected].

    This invention claims processes and compositions for fermentation, 
recovery, and purification of recombinant bacterial superantigens 
(rSAgs), exemplified by a recombinant staphylococcal enterotoxin B SEB 
(rSEB) protein mutated for use in administration to a mammalian 
recipient. This process generates an economically viable quantity of 
rSEB vaccine protein meeting FDA parenteral drug specifications. The 
purification methods generally involve multiple steps including 
hydrophobic interaction chromatography (HIC), buffer exchange 
(desalting), and cation exchange. The final product of the purification 
is a highly purified rSAg composition satisfying clinical safety 
criteria and is immunogenic and protective against lethal aerosol 
challenge in a murine model. The methods and compositions claimed in 
the patent application provide possible therapeutics and prophylactics 
for diseases caused by bacterial SAgs, such as food poisoning, 
bacterial arthritis and other autoimmune disorders, toxic shock 
syndrome, and the potential use of SAg biowarfare agents.

Method for Determining Sensitivity to a Bacteriophage

Carl R. Merril (NIMH), Sankar Adhya (NCI), Dean M. Scholl (NIMH).
U.S. Provisional Application No. 60/351,458 filed 23 Jan 2002 (HHS 
Reference No. E-318-2000/0-US-01);
PCT Application No. PCT/US03/02179 filed 23 Jan 2003 (HHS Reference No. 
E-318-2000/0-PCT-02);
U.S. Patent Application No. 10/498,428 filed 10 Jun 2004 (HHS Reference 
No. E-318-2000/0-US-03).
Licensing Contact: Peter Soukas; 301/435-4646; [email protected].

    Traditionally, chemical antibiotics have been used to treat a 
variety of bacterial infections. However, bacterial resistance to 
current antibiotics is an increasingly serious problem in human and 
veterinary health as well as agriculture. Many experts believe that 
strains of disease-causing bacteria resistant to all common antibiotics 
will arise in the next ten to twenty years. Bacteriophages offer a 
promising therapeutic alternative to antibiotics for these antibiotic 
resistant bacteria. There are also situations in which bacteriophage 
may be more suitable than antibiotics to treat infections caused by 
against antibiotic-sensitive bacteria. Bacteriophages are highly host-
specific, thus determining whether a phage would be therapeutically 
useful against a particular bacterium or strain of bacteria is very 
important but can be a time-consuming and labor-intensive process.
    The current invention claims a method for selecting a therapeutic 
bacteriophage that would be effective against a particular disease-
causing bacteria, comprising a number of bacteriophages containing 
reporter nucleic acids capable of being expressed

[[Page 44667]]

when the bacteriophage infects a bacterial cell. These bacteriophages 
are separately contacted with a sample contaminated by a bacterium. 
Expression of the reporter is then detected, indicating which 
bacteriophage has infected a bacterial cell and is thus a potential 
therapeutic phage against the particular bacteria. Also claimed in the 
application are kits allowing for the rapid identification of 
potentially therapeutic bacteriophages.

Bacteriophage Having Multiple Host Range

Carl Merril (NIMH), Sankar Adhya (NCI), Dean Scholl (NIMH).
U.S. Provisional Application No. 60/220,987 filed 25 Jul 2000 (HHS 
Reference No. E-257-2000/0-US-01);
PCT Application No. PCT/US01/22390 filed 25 Jul 2001 (HHS Reference No. 
E-257-2000/0-PCT-02);
U.S. Patent Application No. 10/350,256 filed 21 Jan 2003 (HHS Reference 
No. E-257-2000/0-US-03).
Licensing Contact: Peter Soukas; 301/435-4646; [email protected].

    Recently, there has been a renewed interest in the use of phages to 
treat bacterial infections. The inventors have discovered FK1-5, a 
highly lytic, non-lysogenic, stable bacteriophage with the ability to 
kill bacteria rapidly, making it a good candidate for phage therapy. 
The designation FK1-5 denotes the phage's ability to infect E. coli 
strains that contain the K1 polysaccharide in their outer capsule as 
well as E. coli strains that contain the K5 polysaccharide in their 
outer capsule. Sequence analysis of the tail proteins of phage FK1-5 by 
the inventors has shown that they are arranged in a cassette structure, 
suggesting that the host range of phages can be broadened to other K 
antigens, and even possibly other species of bacteria by recombinant 
techniques. FK1-5 has a particular advantage because it recognizes and 
attaches to the structures that confer virulence to bacteria. The 
inventors' demonstration that a phage can contain multiple tail 
proteins that expand its host range is useful for generating phage with 
broad-spectrum antibacterial properties for the treatment of infectious 
diseases. The inventors have completed in vitro studies on this phage. 
Furthermore, because of the possibility of engineering the expression 
of recombinant tail proteins, gene transfer to organisms that are not 
normally infected by phages is also contemplated by the invention.

CC Chemokine Receptor 5 DNA, New Animal Models and Therapeutic Agents 
for HIV Infection

C. Combadiere, Y. Feng, E.A. Berger, G. Alkahatib, P.M. Murphy, C.C. 
Broder, P.E. Kennedy (NIAID).
U.S. Provisional Application No. 60/018,508 filed 28 May 1996 (HHS 
Reference No. E-090-1996/0-US-01);
U.S. Patent Application No. 08/864,458 filed 28 May 1997 (HHS Reference 
No. E-090-1996/0-US-04);
U.S. Patent Application No. 10/439,845 filed 15 May 2003 (HHS Reference 
No. E-090-1996/0-US-05);
U.S. Patent Application No. 10/700,313 filed 31 Oct 2003 (HHS Reference 
No. E-090-1996/0-US-06);
U.S. Patent Application No. 10/846,185 filed 14 May 2004 (HHS Reference 
No. E-090-1996/0-US-07);
PCT Application No. PCT/US97/09586 filed 28 May 1997 (HHS Reference No. 
E-090-1996/0-PCT-02);
European Patent Application No. 97929777.7 filed 28 May 1997 (HHS 
Reference No. E-090-1996/0-EP-03).
Licensing Contact: Peter Soukas; 301/435-4646; [email protected].

    Chemokine receptors are expressed by many cells, including lymphoid 
cells, and function to mediate cell trafficking and localization. CC 
chemokine receptor 5 (CCR5) is a seven-transmembrane, G protein-coupled 
receptor (GPCR) which regulates trafficking and effector functions of 
memory/effector T-lymphocytes, macrophages, and immature dendritic 
cells. Chemokine binding to CCR5 leads to cellular activation through 
pertussis toxin-sensitive heterotrimeric G proteins as well as G 
protein-independent signalling pathways. Like many other GPCR, CCR5 is 
regulated by agonist-dependent processes which involve G protein 
coupled receptor kinase (GRK)-dependent phosphorylation, beta-arrestin-
mediated desensitization and internalization.
    Human CCR5 also functions as the main coreceptor for the fusion and 
entry of many strains of human immunodeficiency virus (HIV-1, HIV-2). 
HIV-1 transmission almost invariably involves such CCR5-specific 
variants (designated R5); individuals lacking functional CCR5 (by 
virtue of homozygosity for a defective CCR5 allele) are almost 
completely resistant to HIV-1 infection. Specific blocking of CCR5 
(e.g. with chemokine ligands, anti-CCR5 antibodies, CCR5-blocking low 
MW inhibitors, etc.) inhibits entry/infection of target cells by R5 HIV 
strains. Cells expressing CCR5 and CD4 are useful for screening for 
agents that inhibit HIV by binding to CCR5. Such agents represent 
potential new approaches to block HIV transmission and to treat 
infected people. A small animal expressing both human CCR5 along with 
human CD4 supports entry of HIV into target cells, a necessary hurdle 
that must be overcome for development of a small animal model (e.g. 
transgenic mouse, rat, rabbit, mink) to study HIV infection and its 
inhibition.
    The invention embodies the CCR5 genetic sequence, cell lines and 
transgenic mice, the cells of which coexpress human CD4 and CCR5, and 
which may represent valuable tools for the study of HIV infection and 
for screening anti-HIV agents. The invention also embodies anti-CCR5 
agents that block HIV env-mediated membrane fusion associated with HIV 
entry into human CD4-positive target cells or between HIV-infected 
cells and uninfected human CD4-positive target cells.
    This technology was reported in Alkhatib et al., ``CC CKR5: a 
RANTES, MIP-1alpha, MIP-1beta receptor as a fusion cofactor for 
macrophage-tropic HIV-1,'' Science 272:1955-1958 (1996). The technology 
is available for exclusive or nonexclusive licensing.

    Dated: July 19, 2005.
Steven M. Ferguson,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
[FR Doc. 05-15347 Filed 8-2-05; 8:45 am]
BILLING CODE 4140-01-P