Nucleoside Analogue Reverse Transcriptase Inhibitors (RT)
Generic name: Zidovudine (AZT, ZDU)
AZT was initially synthesized under an NCI grant by Dr. Jerome Horowitz of the
Michigan Cancer Foundation (Karmanos Cancer Institute) in 1964. In 1974
Wolfram Ostertag at the Max Planck Institute demonstrated an effect against
a mouse retroviruse. As described in a September 28, 1989 letter to the NY
Times by NIH and Duke University researchers, government or government supported
researchers developed the first application of the technology for determining
whether a drug like AZT could suppress live AIDS virus in human cells, at what
concentration this could be achieved in humans, were the first to administer
AZT to a human being with AIDS, performed the first clinical pharmacology
studies in patients, and performed the immunological and virological studies
necessary to infer that the drug might work, and was therefore worth pursuing
in further studies
Burroughs Wellcome worked with NIH and Duke researchers, and applied for and
received a US patent for using AZT to treat AIDS in 1988 (US Patent #4,724,232).
There was litigation over the patent rights, and indeed, fairly expensive
litigation, as described by the Judge in one proceeding:
According to UNAIDS, the United States of America has been granted patent
rights in Austria, Belgium, Canada, France, Germany, Ireland, Italy, Japan,
Liechtenstein, Luxembourg, the Netherlands, Sweden, Switzerland, the United
Kingdom, and USA (UNAIDS/WHO, Patent situation of HIV/AIDS related drugs in
80 countries). According to UNAIDS, the United States of America filed for
patent rights in Australia, Cyprus, Hong Kong, Israel, Mexico, New Zealand,
and Singapore (Ibid). The UNAIDS study also noted that the Wellcome Foundation
was granted patent rights for ddI in Canada, Austria Belgium, France, Germany,
Italy, Japan, Liechstenstein, Luxembourg, the Netherlands, South Africa, Sweden,
Switzerland, the United Kingdom, and the USA. The Wellcome Foundation filed for
patent rights in Australia, Denmark, Finland, Greece, Hungary New Zealand,
Portugal, and Spain (Ibid). Bristol-Myers Squibb has been granted foreign
patent rights in Australia, Austria, Belgium, France, Germany, Ireland, Israel,
Italy, Japan, Luxembourg, the Netherlands, New Zealand, Switzerland, Sweden,
and the United Kingdom.
License to BMS
Paragraph 3.1 gives the US government the right to use the patent or to grant
licenses to the World Health Organization or any foreign government. Paragraph
3.2 permits the government to issue additional licenses if BMS cannot
demonstrate, with evidence, that there is a reasonable relationship between the
pricing of ddI and the health and safety needs of the public. This provision
could, but has not, been used to speed the introduction of generic version of
ddI in the US market.
Paragraph 3.2:
The FDA NDA was filed on March 29, 1991 and approved in less than seven months,
on October 9, 1991.
Generic name: Zalcitabine (ddC)
DDC was initially synthesized under an NCI grant by Dr. Jerome Horowitz of the
Michigan Cancer Foundation (Karmanos Cancer Institute). in 1966. The United
Stated of America holds the key use patent. (Patent #4,879,277). It was then
exclusively licensed by Hoffman-La Roche for treatment of HIV/AIDS.
The National Cancer Institute (NCI) conducted the first clinical trial of ddC
in 1987. The US FDA approval for ddC cited three trials that were co-sponsored
by NIAID, a US government agency (ACTG 175: NIAID/ BMS/Glaxo Wellcome, CPCRA
002: BMS/NIAID/ Hoffmann-La Roche, ACTG 114: NIAID/ Hoffmann La Roche).
Generic name: Stavudine (d4T)
Intellectual Property Status
Discovery that d4T would treat HIV/AIDS
License to BMS
NIAID and BMS Phase I/II trials
BMS trial used in NDA
NDA approval
There was subsequent testing of d4T, and expanded marketing approvals for use
in combination therapy.
Generic name: Lamivudine (3TC)
Emory University filed and received a patent for the process of synthesizing
3TC, one of two components of BCH-189 (Patent #5,539,116). The individual
optical isomer patented by Emory is being marketed as Epivir. There has
been litigation in United States courts between Emory University and BioChem
Pharma over the rights to 3TC.
The research done by Emory on the process of synthesizing 3TC was supported by
NIH grant no. 5-21935
An Oct 11, 1999 search of the AIDS Clinical Trials Information Service (ACTIS)
database indicates there were at least 40 NIAID sponsored clinical trials
involving 3TC, one clinical trial co-sponsored by NIAID and two private firms
and two NCI sponsored clinical trials involving 3TC (out of a total of 90
clinical trials involving 3TC). For more information, see
http://www.cptech.org/ip/health/aids/3tc.html
Generic name: Abacavir
Protease Inhibitors
"The concept and feasibility of protease inhibitors grew in part out of
NIAID-supported basic research (Anthony S. Fauci, M.D., NIAID director)."
NIAID-supported basic research was instrumental to: "The discovery and
definition of the importance of the HIV protease enzyme. The definition of the
structure of the HIV protease enzyme. The development of assays to measure the
inhibition of the HIV protease enzyme. (Source: NIAID Factsheet: Two New
Protease Inhibitors Approved by FDA)
Generic name: Saquinavir
An Oct 11, 1999 search of the AIDS Clinical Trials Information Service (ACTIS)
database indicates there were at least 14 NIAID sponsored clinical trials
involving Saquinavir (out of a total of 33 clinical trials involving Saquinavir).
For more information see, ACTIS AIDSDRUG Library
Generic name: Ritonavir
Generic name: Amprenavir
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Generic name: Nevirapine
The US FDA marketing approval of Viramune was based upon evidence from the NIAID
co-sponsored ACTG 241, plus a trial sponsored by Boehringer Ingelheim.
Generic name: Delavirdine
The US FDA approval of the product cited three clinical trials: Studies 0017
0021 by Pharmacia & Upjohn, an NIAID's ACTG 261.
Generic name: Efavirenz
Brand name: Retrovir
Marketing Firm: Glaxo Wellcome
FDA Approval date: March 19, 1987
Class: nucleoside analogue reverse transcriptase inhibitor (RT)
In the twenty-five months transpiring between the filing of the initial
complaint in this consolidated patent infringement action on May 14, 1991,
and the commencement of the trial on June 28, 1993, approximately five hundred
forty-one pleadings have been filed and dozens of hearings on motions and
discovery matters have been conducted by the court. The court has entered
eighty-eight written orders and numerous bench rulings. Thus, the court is
intimately familiar with the facts of this case and the legal contentions of
the parties. To state that the case has been hotly contested would be an
understatement. The parties have amassed learned, experienced and sizable trial
teams who have represented their clients zealously and competently. The a
dministrative complexity [of] conducting a trial of this magnitude has been
enormous for the court and the parties. The sixty-year- old courtroom in New
Bern, North Carolina, has been converted into a contemporary high tech facility
utilizing real time court reporting and six computer-integrated video display
monitors. It is highly conceivable that the cost of this trial for the parties
exceeds $100,000 per day, in addition to the time and expense associated with
this court and the jury. As the case enters its fourth week of trial, the parties
estimate, somewhat conservatively the court suspects, that the trial will last
an additional six to eight weeks. Burroughs Wellcome Co. v. Barr Lab., 828
F. Supp. 1208, 1209 (E.D.N.C. 1993).
Generic name: Didanosine (ddI)
Brand name: Videx
Marketing Firm: Bristol-Myers Squibb
FDA Approval date: October 9, 1991
Class: nucleoside analogue reverse transcriptase inhibitor (RT)
Intellectual Property Status
Discovery of ddI
Didanosine (ddI) was originally synthesized by NIH scientists. United States of
America holds the key use patent for ddI ( US Patent #4,861,759), which lists
the inventors as Hiroaki Mitsuya and Samuel Broder of the National Cancer
Institute (NCI).
The US government patent for Didanosine (ddI) was exclusively licensed to
Bristol-Myers Squibb through the National Technical Information Service (NTIS),
a primary operating unit of the Department of Commerce. The licensing agreement,
effective February 1, 1988, between the National Technical Information Service
(NTIS) and Bristol-Myers Squibb states that the "NTIS desires, in the public
interest, that the subject invention be perfected, marketed and practiced so
that the benefits are readily available for the widest possible utilization in
the shortest time possible." BMS was granted ten years of exclusivity following
the first commercial sales of the drug.
Article VIII, section 8.4 states, "After bringing Licensed Product to the point
of practical application in the United States, LICENSEE agrees to keep Licensed
Product reasonably available to the United States public during the term of
this Agreement".
Paragraph 3.1:
Clinical trials used in NDA
"The licenses granted in Article II above are subject to the reservation by
NTIS of an irrevocable, nonexclusive, nontransferable, royalty-free license
for the practice of all inventions encompassed within the Licensed Patent(s)
throughout the world by and on behalf of the Government and on behalf of any
foreign government or international organization pursuant to any existing or
future treaty or agreement to which the United States is signatory, including
the right to engage in research on inventions including under the Licensed
Patent(s) either alone or with one or more third parties."
"LICENSEE acknowledges the concern of the Government that there be a reasonable
relationship between LICENSEE's pricing of Licensed Product and the health and
safety needs of the public and that this relationship be supported by evidence.
If, during the exclusive marketing term of this Agreement, as provided under
Paragraph 2.1 above, LICENSEE fails to provide such evidence upon reasonable
request of the Director, Division of Cancer Treatment, National Cancer
Institute, NTIS has the right to require LICENSEE to grant sublicenses under
Licensed Patent(s) to responsible applicants on reasonable terms when necessary
to fulfil health and safety need. It is agreed that such evidence will be
treated in a confidential manner. Any requirement to grant sublicenses shall be
deemed a modification of this agreement and shall be subject to the provisions
of Paragraphs 9.2 and 11.4."
The trials used by BMS for marketing approval were ACTG 116A and ACTG 116B/117
which looked at ddI in monotherapy. NIAID and BMS co-sponsored ACTG 116A, a
Phase II/III trial with 617 patients. NIAID and BMS co-sponsored ACTG 116B/117,
a Phase II/III trial with 913 patients.
Brand name: Hivid
Marketing Firm: Hoffman-La Roche
FDA Approval date: June 19, 1992
Class: nucleoside analogue reverse transcriptase inhibitor (RT)
Brand name: Zerit
Marketing Firm: Bristol-Myers Squibb
FDA Approval date: June 24, 1994
Class: nucleoside analogue reverse transcriptase inhibitor (RT)
Discovery of d4T
Stavudine (d4T) was initially synthesized under an NCI grant by Dr. Jerome
Horowitz of the Michigan Cancer Foundation (Karmanos Cancer Institute) in 1966.
Dr. Tai-Shun Lin (Yale) and Dr. William Prusoff (Yale) first discovered d4T's
capability to treat HIV/AIDS. Yale University holds the key use patent. The
patent number in the USA is 4,978,655 (Patent #4,978,655), which lists the
inventors as Tai-Shun Lin and William H. Prusoff. Yale licensed d4T to
Bristol-Myers Squibb for marketing and distribution. Yale used significant
government funding under Grant CA-28852 from the NIH. The patent is assigned to
Yale University. On the patent, it says:
This invention was made with United States government support under Grant
CA-28852 from the NIH. The United States Government has certain rights in this
invention.
Yale has been granted patent rights in Austria, Belgium, Canada,France, Germany,
Greece, Italy, Japan, Korea, Liechtenstein, Luxembourg, Netherlands,
Philippines, Spain, Sweden, Switzerland, United Kingdom, and the USA.
Yale filed for patent rights in Australia, Denmark, Egypt,Finland, Hong Kong,
Ireland, Israel, Mexico, New Zealand, Portugal, Romania, Singapore, South
Africa, and Taiwan.
The Yale patent was filed in the US on December 17, 1986, and approved on
December 18, 1990. Yale licensed its marketing and distribution rights to
Bristol-Myers Squibb on January 12, 1988.
On March 23, 1989, one year and two months after the Yale license to BMS, NIAID
and BMS began a Phase I/II trial for d4T. The projected accrual was 40 patients,
5 per treatment arm (10 week induction up to 104 weeks maintenance).
The trial used by BMS for Marketing approval was AI455-019, which looked at d4T
in monotherapy. It was conducted between May 19, 1992 and August 12, 1994. This
was a BMS sponsored Phase II/III trial with 822 patients. The median analysis
time was 6 months. The trial began one year and five months after the Yale
patent was approved.
The NDA was filed on December 28, 1993, and approved in less than six months,
on June 24, 1994. This was 2 years, one month and five days after the beginning
of the Ai455-019 trial.
Brand name: Epivir
Marketing Firm: Glaxo Wellcome
FDA Approval date: November 17, 1995
Class: nucleoside analogue reverse transcriptase inhibitor (RT)
Intellectual Property Status
BCH-189 was initially discovered and patented for the treatment of HIV/AIDS by
BioChem Pharma, a Canadian corporation (Patent #5,047,407). It then licensed
the rights to Glaxo Wellcome for marketing and sales in exchange for 14%
royalties on sales of 3TC. Glaxo Wellcome has the right to develop, manufacture,
and sell 3TC worldwide, except in Canada, where BioChem Pharma and Glaxo
Wellcome have formed a commercialized partnership.
Brand name: Ziagen
Marketing Firm: Glaxo Wellcome Inc.
FDA Approval date: December 17, 1998
Class: nucleoside analogue reverse transcriptase inhibitor (RT)
Intellectual Property Status
Burroughs Wellcome was issued the patents for abacavir as a therapeutic
nucleoside (Patents #5,034,394, #5,089,500). The University of Minnesota filed
a patent infringement suit against Glaxo-Wellcome in October 1998. Robert Vince,
a professor of medicinal chemistry at the University of Minnesota developed
"carbovir and several derivative compounds that resulted from work originally
sponsored by grants from the National Institutes of Health" (University of
Minnesota Press Service, October 5, 1999). The University of Minnesota began
applying for patents to the "Vince compounds" in 1988. These patents were
exclusively licensed to Burroughs Wellcome. The University of Minnesota claimed
that Ziagen was "within the series of compounds covered by the patents."
(University of Minnesota Factsheet on Ziagen settlement). Under the terms of
the settlement finalized on October 4, 1999 in the U.S. District Court in St.
Paul, Glaxo-Wellcome agreed to compensate the University of Minnesota on a
sliding fee scale in addition to a one-time fee of $7.25 million.
The university will receive five percent of the first $300 million in world
wide sales, seven percent of sales from $300 million to $700 million and 10
percent of sales over $700 million annually (University of Minnesota Press
Service, October 5, 1999).
Brand name: Invirase; Fortovase
Marketing Firm: Hoffman-La Roche
FDA Approval date: December 6, 1995; November 7, 1997
Class: protease inhibitor
Intellectual Property Status
Hoffman-La Roche holds the patent for saquinavir as an anti-viral treatment
(Patent #5,196,438). However, scientists at the NIH did much of the initial
research in determining the efficacy of protease inhibitors in the treatment of
AIDS.
Pivotal to the approval of saquinavir were data from an NIAIDsponsored clinical
trial known as AIDS Clinical Trials Group (ACTG) 229 (NIAID Factsheet: Two New
Protease Inhibitors Approved by FDA).
Brand name: Norvir
Marketing Firm: Abbott Laboratories
FDA Approval date: March 1, 1996
Class: protease inhibitor
Intellectual Property Status
The patent was issued to Abbott Laboratories, but it was invented with
significant government support from the NIAID under contract number AI27220
(Patent #5,541,206).
Brand name: Agenerase
Marketing Firm: Glaxo Wellcome Inc.
FDA Approval date: April 15, 1999
Class: protease inhibitor
Intellectual Property Status
Vertex Pharmaceuticals holds the patent for the oral solution as a sulfonamide
inhibitor of aspartyl protease (Patent #5,585,397). Amprenavir was discovered by
Vertex but licensed to Glaxo Wellcome for development.
ACTG was involved in phase II monotherapy study (see Vertex Corporate
information article)
Brand name: Viramune
Marketing Firm: Boehringer Ingelheim Pharmaceuticals, Inc.
FDA Approval date: June 21, 1996
Class: non-nucleoside reverse transcriptase inhibitor (NNRTI)
Intellectual Property Status
There are no unexpired patents for the oral suspension, but Boehringer Ingelheim
Pharmaceuticals was assigned the patent for the oral tablet (Patent #5,366,972).
Brand name: Rescriptor
Marketing Firm: Pharmacia and Upjohn
FDA Approval date: April 4, 1997
Class: non-nucleoside reverse transcriptase inhibitor (NNRTI)
Intellectual Property Status
The Upjohn Company was issued the patent for delavirdine (Patent #5,484,926).
Brand name: Sustiva
Marketing Firm: Dupont Pharmaceuticals
FDA Approval date: September 17, 1998
Class: non-nucleoside reverse transcriptase inhibitor (NNRTI)
Intellectual Property Status
Merck owns the patents for the use of benzoxazinones as inhibitors of HIV
reverse transcriptase (Patents #5,519,021, #5,663,169, #5,811,423). However,
the drug is marketed by both Dupont Pharmaceuticals and Merck.
Federal Involvement in Development
The FDA NDA approval of efavirenz was based on data from three pivotal clinical
trials. NIAID sponsored one of these trials, ACTG 364.