[Federal Register Volume 74, Number 60 (Tuesday, March 31, 2009)]
[Notices]
[Pages 14565-14568]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E9-7207]


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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.

Cell Based Immunotherapy

    Description of Technology: The invention hereby offered for 
licensing is in the field of Immunotherapy and more specifically in 
therapy of autoimmune diseases such as Type I diabetes, multiple 
sclerosis, rheumatoid arthritis and systemic lupus erythematosis and 
immune mediated allergies such as asthma as well as in transplantation-
related disorders, such as graft acceptance and graft-versus-host-
disease (GVHD).
    While the role of FOXP3\+\ regulatory T cells (Tregs) in the 
maintenance of self-tolerance and immune homeostasis has been 
established and thus their use in adoptive immunotherapy has been 
contemplated, there is still no good way to purify and expand these 
cells in an efficient and reproducible manner ex vivo for use in human 
therapy. The subject invention provides a method that allows such 
purification for use in expansion cultures to generate sufficient 
numbers of cells and purity for cell-based immunotherapy. The method is 
based on the finding that Tregs selectively express Latency Associated 
Peptide (LAP) and CD121b (IL-1 Receptor Type 2) and on the ability to 
selectively separate these cells from other immune cells that are 
potentially hazardous, through the use of magnetic particles which 
specifically bind to either one of these two surface molecules and 
selectively separate those cells from the non-Tregs.
    Applications:
    Immunotherapy, primarily for autoimmune diseases such as Type I 
diabetes, hematologic disorders such as aplastic anemia, 
transplantation-related disorders, such as graft acceptance and graft-
versus-host-disease (GVHD) and allergic diseases such as asthma.
    Facilitating detailed studies and analysis of human Treg function 
in health and disease.

[[Page 14566]]

    Assay to differentiate thymic-derived versus peripheral-derived 
FOXP3\+\ Tregs.
    Potential assay to monitor disease status, progression and 
prognosis such as early detection or response to therapy of GVHD after 
transplantation, solid organ graft rejection post-transplantation or a 
flare-up of systemic lupus erythematosus.
    Advantages: The method of purification of FOXP3\+\ Tregs for human 
treatment may be superior in efficiency and practicality than currently 
existing techniques. After the magnetic separation, the final product 
contains more than 90% fully functional FOXP3\+\ Tregs. This novel 
protocol should facilitate the purification of Tregs for both cell-
based therapy as well as for detailed studies of human Treg function in 
health and disease. It is important to note that most of the treatments 
for specific autoimmune diseases (i.e. hormone replacement therapy, 
enzyme replacement therapy, corticosteroids, NSAIDs, plasmaphereses, 
immunosuppressants and intravenous immunoglobulins) do not constitute 
cure for the specific diseases. Immunotherapy with Tregs has a 
potential to provide cure or prolonged remission for many of these 
diseases.
    Development Status: The purification protocol has been proven 
simple and efficient in a laboratory setting.
    Market: As indicated above the technology may be applied to 
allergies and many human diseases that are characterized by diminished 
frequency or dysfunction of Tregs, including systemic lupus 
erythematosus (SLE), type 1 diabetes, multiple sclerosis, aplastic 
anemia, idiopathic thrombocytopenic purpura, graft-versus-host disease 
(GVHD) and transplant rejection etc. As noted above treatment with 
Tregs may have a potential to provide cure to many of these diseases, 
thus collectively, the commercial market opportunities for the 
technology are wide-ranging and the contribution to public health may 
be highly significant.
    The following information provides further detail concerning the 
potential market size for therapeutic use of Tregs:
     As a group, autoimmune diseases afflict millions of 
Americans. While individually not very common, with the exception of 
thyroid disease, diabetes and systemic lupus erythematosus (SLE), taken 
as a whole, autoimmune diseases represent the fourth largest cause of 
disability among women in the United States. According to the National 
Women's Health Centre, 75% of cases of autoimmune diseases occur in 
American women.
     Similarly, Type 1 Diabetes is the second most common 
chronic disease in children after asthma. About 13,000 new cases are 
diagnosed in the U.S. alone each year. Patients with Type 1 Diabetes 
make up about 5% to 10% of all cases of diabetes. It most commonly 
appears in girls and boys when they are fourteen years old.
     Multiple sclerosis is a chronic disease that starts early 
in life and as many as 400,000 patients are afflicted with this disease 
which lasts for decades.
     More than 19,000 transplants are performed in the United 
States each year. That equates to 1,583 per month, 365 per week, 52 per 
day, and 2 per hour for a rate of approximately 1 in 14,315 or 0.01% of 
the U.S population.
    Inventors: Dat Q. Tran and Ethan M. Shevach (NIAID).
    Publications:
    1. J Andersson, DQ Tran, M Pesu, TS Davidson, H Ramsey, J O'Shea, 
EM Shevach. CD4+Foxp3+ regulatory T cells confer infectious tolerance 
in a TGF[beta]-dependent manner. J Exp Med. 2008 Sep 1;205(9):1975-
1981.
    2. EM Shevach, DQ Tran, TS Davidson, J Andersson. The critical 
contribution of TGF-beta to the induction of Foxp3 expression and 
regulatory T cell function. Eur J Immunol. 2008 Apr;38(4):915-917.
    3. DQ Tran, R Ramsey, EM Shevach. Induction of FOXP3 expression in 
na[iuml]ve human CD4+FOXP3- T cells by T cell receptor stimulation is 
TGF[beta]-dependent but does not confer a regulatory phenotype. Blood. 
2007 Oct 15;110(8):2983-2990.
    Patent Status: U.S. Provisional Application No. 61/090,788 filed 21 
Aug 2008 (HHS Reference No. E-312-2008/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contacts: Uri Reichman, Ph.D., MBA; 301-435-4616; 
[email protected]; John Stansberry, Ph.D.; 301-435-5236; 
[email protected].
    Collaborative Research Opportunity: The NIAID/NIH Laboratory of 
Immunology is seeking statements of capability or interest from parties 
interested in collaborative research to further develop, evaluate, or 
commercialize the use of CD121b or LAP to produce a Treg product for 
cell-based immunotherapy. Please contact Nicole Mahoney at 301-435-9017 
for more information.

Compositions and Methods for Inhibiting and Treating Herpes Simplex 
Virus (HSV) Infection and HSV-1 Containing a UL3 Deletion

    Description of Technology: The invention offered hereby for 
licensing is in the fields of viral and cancer therapeutics and in 
particular related to Herpes Simplex Virus. It is based on the finding 
that Protein Disulfide Isomerase (PDI) family members bind in vitro to 
the herpes simplex protein UL3 and that HSV entry to the host cell is 
mediated through HSV's interaction with the host cell's surface 
protein(s) belonging to PDI family members. Inhibition of virus entry 
can therefore be accomplished by inhibitors of the PDI protein family 
members. The inventors demonstrated the following:
     A small molecule such as 5,5'-Dithiobis(2-nitro-benzoic 
acid) (DTNB) can block HSV infection by blocking PDI-like activity.
     Anti-PDI antibodies can block HSV infection.
     Disulfide Isomerase family members bind in vitro to the 
herpes simplex protein UL3.
    Accordingly, the inventors further suggest that a UL3-like peptide 
or its analogues and derivatives can be effective as inhibitors of HSV 
infection.
    The invention further provides for methods and kits to screen for 
new inhibitors, based on the entry mechanism mentioned above.
    In another aspect of the invention, it is proposed that such PDI 
inhibitors or binding proteins can potentially serve as antitumor 
agents based on the finding that cancer cells express increased levels 
of PDI compared to healthy cells.
    With respect to cancer therapeutics, the invention further claims a 
recombinant mutant herpes simplex virus devoid of the capability to 
express UL3 or expressing a mutant HSV UL3 protein. Such a virus can 
serve as an oncolytic virus for treatment of cancer.
    Applications:
     Antiviral therapeutics.
     Anticancer therapeutics.
     Screening for new antiviral and anticancer agents.
     Developing of Oncolytic Viruses for cancer therapy.
    Advantages: Herpes Simplex Viruses are responsible for a wide range 
of human diseases. Herpes simplex virus is the causative agent of oral 
and genital herpes, and is associated with sexual transmission. 
Infections with herpes simplex can be acute, or latent with recurring 
periodic outbreaks. An infection by herpes simplex is marked by watery 
blisters in the skin or mucous membranes of the mouth, lips or

[[Page 14567]]

genitals that can be painful and thus can severely affect the quality 
of life of an infected individual. The virus can lead to potentially 
fatal infections in babies whose mothers are infected, and to permanent 
neurological damage in adults with herpes encephalitis. The virus may 
also play a role in the spread of HIV as it can make people more 
susceptible to HIV infection.
    In spite of the severity of diseases caused by HSV and in spite of 
the many years of efforts to develop effective anti-HSV medications and 
vaccines, there is still no effective cure for herpes in existence. The 
existing antiviral medications such as Acyclovir, Valacyclovir and 
Famciclovir that work by inhibiting the virus' DNA synthesis (targeting 
the enzyme DNA Polymerase) cannot eradicate the virus from the body, 
but merely reduce the extent of the symptoms and the frequency of 
breakouts. Other small molecules in development also aiming at DNA 
synthesis are targeting another virus enzyme (Helicase-primase 
complex). The therapeutic strategy described in the subject technology 
provides a completely different mechanism, i.e. inhibition of the virus 
entry. Thus it may provide advantages compared to the existing drugs 
with respect to toxicity and efficacy.
    With respect to cancer therapy, the subject invention may offer a 
new class of drugs which act by an alternate mechanism in comparison to 
conventional cancer drugs. The technology may thus prove to be 
advantageous with respect to toxicity and efficacy. In addition, drugs 
developed by this technology may be given to patients in combination 
with existing drugs.
    Development Status:
     The inhibition of HSV infection by DTNB and antibodies 
against the PDI surface protein have been demonstrated in vitro.
     Pre-clinical or clinical data is not yet available.
     Further development to identify PDI inhibitors applicable 
for viral therapy and cancer therapy is currently ongoing.
     Further development and optimization of recombinant HSV to 
be utilized as an oncolytic virus is ongoing. Only in vitro data is 
available at present.
    Market: The market for anti-herpes drugs is huge. Results of a 
nationally representative study show that genital herpes is common in 
the United States. Nationwide, at least 50 million people ages 12 and 
older, or one of five adolescents and adults, have had a latent or 
acute genital HSV infection. There are up to 1 million new cases every 
year and according to some estimates genital herpes is now more common 
than diseases like diabetes and asthma. At the same time there is still 
no effective drug against this virus available, thus the commercial 
potential in developing a new effective drug is enormous.
    With respect to the market for cancer therapeutics the 
opportunities are also vast. This market has been growing in the last 
several years by an estimate of 18% a year due to the introduction of 
many new and innovative drugs, and some reports forecast a market size 
of close to $90 billion by 2011.
    Inventors: Nancy S. Markovitz and Stephen Daniell (FDA).
    Publications:
    1. NS Markovitz. The herpes simplex virus type 1 UL3 transcript 
starts within the UL3 open reading frame and encodes a 224-amino-acid 
protein. J Virol. 2007 Oct;81(19):10524-10531.
    2. E Bar, T Kimura, M Kikuchi, NS Markovitz. Protein disulfide 
isomerase (PDI) family members interact with the UL3 protein of herpes 
simplex virus-1. 31st International Herpesvirus Workshop, Abstract 
8.51, Seattle WA, July 22-28, 2006.
    3. KD Nguyen, EE Bar, MJ Dambach, NS Markovitz. Yeast Two Hybrid 
Identification of the Herpes Simplex Virus-1 UL3 protein domains that 
interact with cellular target proteins. NIH Research Festival, Abstract 
CB-19, Bethesda MD, October 2006.
    4. MJ Dambach, J Trecki, N Martin, NS Markovitz. Oncolytic viruses 
derived from the [gamma]34.5-deleted herpes simplex virus recombinant 
R3616 encode a truncated UL3 protein. Mol Ther. 2006 May;13(5):891-898.
    Patent Status: U.S. Provisional Application No. 61/134,566 filed 11 
Jul 2008 (HHS Reference No. E-236-2008/0-US-01).
    Licensing Status: Available for licensing.
    Licensing Contacts: Uri Reichman, PhD, MBA; 301-435-4616; 
[email protected]; John Stansberry, Ph.D.; 301-435-5236; 
[email protected].

Identification of Adaptive Mutations That Increase Infectivity of 
Hepatitis C Virus JFH1 Strain in Cell Culture

    Description of Technology: The technology offered for licensing is 
in the field of hepatitis C. More specifically the invention discloses 
an efficient way to grow the virus, a way that may facilitate advanced 
research in the field of hepatitis C (HCV) and its pathogenesis, as 
well as provide for convenient and effective ways to screen for new 
hepatitis C drugs. It also lends itself to the development of vaccines 
against hepatitis C.
    The invention is based on the finding that certain mutations in the 
JFH1 strain of HCV, as well as certain chimera of the mutated strain, 
can lead to an increase in production of infectious virus particles in 
cell cultures (i.e., Huh-7.5) between 100- to 1000-fold as compared to 
the wild type virus. Such mutations are introduced to a viral RNA that 
codes for hepatitis C and the latter is introduced to an appropriate 
cell to produce a high yield of highly infective virus.
    Progress in research in the field of HCV, as well as the 
development of drugs and vaccines to combat hepatitis C infections, has 
been hampered for years due to the lack of robust in vivo cell culture 
systems for the study of this virus. Several breakthroughs in the area 
that occurred in 2005 and thereafter (i.e., the isolation of HCV 
genotype 2a sequence (JFH1) and the generation of the unique cell line 
Huh-7.5) contributed significantly to progress in the field, but 
further optimization and improvements in the culture system have still 
been needed. The subject invention offers such improvements and thus 
may lead to enhanced progress in HCV research and in the development of 
the much needed drugs and vaccines against the virus.
    Applications:
     Research in the field of HCV and its pathogenesis.
     Screening and discovery of drugs that inhibit HCV 
infections.
     Development of vaccines for HCV.
    Advantages: 100- to 1000-fold more efficient method to grow virus 
particles.
    Development Status: The invention is fully developed and requires 
no additional work.
    Market: It is estimated that 170 million people worldwide suffer 
from HCV infection, with 3 to 4 million new cases each year. The 
primary causes of new HCV infections worldwide are unscreened blood 
transfusions and the reuse of syringes, without sterilization (WHO). It 
is estimated that nearly 4.1 million people in the U.S. are infected 
with HCV with 3.2 million of the 4.1 million people chronically 
infected. Approximately 70% of those chronically infected suffer from 
chronic liver disease (CDC). There has been a major decline in the 
number of new HCV infections per year in the U.S. from the 1980s 
(240,000) to 2004 (26,000) (CDC). In the U.S., the primary cause of new 
infections is needle-sharing by intravenous drug users. Despite the 
significant decrease in new HCV infections, the number of patients 
requiring treatment for chronic HCV is

[[Page 14568]]

expected to rise as patients with HCV infection age and progress to 
more serious liver diseases (McHutchison HG, et al. Chronic Hepatitis 
C: An Age Wave of Disease Burden 2005. American Journal of Managed 
Care. 11: S286-S295). From 2010-2019, it is estimated that direct 
medical expenditures for HCV will be $10.7 billion; the costs of 
decompensated HCV infection (cirrhosis and hepatocellular carcinoma) 
are estimated to be $21.3 billion; and indirect costs associated with 
the loss of life under age 65 are estimated to be $54.2 billion 
(McHutchison HG, et al. 2005).
    Chronic hepatitis C is a serious disease that can result in long-
term health problems, including liver damage, liver failure, liver 
cancer, or even death. It is the leading cause of cirrhosis and liver 
cancer and the most common reason for liver transplantation in the 
United States. Approximately 8,000-10,000 people die every year from 
hepatitis C related liver disease.
    Of every 100 people infected with the hepatitis C virus, about 75-
85 people will develop chronic hepatitis C virus infection; of those,
     60-70 people will go on to develop chronic liver disease.
     5-20 people will go on to develop cirrhosis over a period 
of 20-30 years.
     1-5 people will die from cirrhosis or liver cancer.
    In spite of the urgent public health need for effective drugs and 
vaccines against HCV as discussed above, and in spite of the huge 
market potential for such medical remedies, there are no effective 
drugs or vaccines in existence as of yet due to technical difficulties, 
one of them, as mentioned at the outset, is the difficulties in growing 
and culturing the virus. The only drugs available to treat HCV at the 
present time are Ribavirin and Interferon but none constitute a real 
cure for the disease. They also can present severe side effects that 
make the use of them prohibitive in many cases. The subject technology 
may therefore present an opportunity for drug and vaccine companies to 
accelerate their research and development in this area.
    Inventors: Rodney Russell, Jens Bukh, Robert H. Purcell, and 
Suzanne U. Emerson (NIAID).
    Publication: RS Russell, JC Meunier, S Takikawa, K Faulk, RE Engle, 
J Bukh, RH Purcell, SU Emerson. Advantages of a single-cycle production 
assay to study cell culture-adaptive mutations of hepatitis C virus. 
Proc Natl Acad Sci USA. 2008 Mar 18;105(11):4370-4375.
    Patent Status:
     U.S. Provisional Application No. 60/931,259 filed 21 May 
2007 (HHS Reference No. E-171-2007/0-US-01).
     U.S. Provisional Application No. 61/066,773 filed 22 Feb 
2008 (HHS Reference No. E-171-2007/1-US-01).
     PCT Application No. PCT/US2008/063982 filed 16 May 2008, 
which published as WO 2008/147735 on 04 Dec 2008 (HHS Reference No. E-
171-2007/2-PCT-01).
    Licensing Status: Available for licensing.
    Licensing Contacts: Uri Reichman, PhD, MBA; 301-435-4616; 
[email protected]; Rung C. Tang, JD, LLM; 301-435-5031; [email protected].

    Dated: March 24, 2009.
Richard U. Rodriguez,
Director, Division of Technology Development and Transfer, Office of 
Technology Transfer, National Institutes of Health.
 [FR Doc. E9-7207 Filed 3-30-09; 8:45 am]
BILLING CODE 4140-01-P