Table 12
Notes on government role in the development of HIV/AIDS drugs
Version 1.6
Nucleoside Analogue Reverse Transcriptase Inhibitors (RT)
Generic name: Zidovudine (AZT, ZDU)
Brand name: Retrovir
Marketing Firm: Glaxo Wellcome
FDA Approval date: March 19, 1987
Class: nucleoside analogue reverse transcriptase inhibitor (RT)
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:
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 administrative 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).
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
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 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 3.1:
"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."
Paragraph 3.2:
"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."
Clinical trials used in NDA
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.
The FDA NDA was filed on March 29, 1991 and approved in less than seven months, on October 9, 1991.
Generic name: Zalcitabine (ddC)
Brand name: Hivid
Marketing Firm: Hoffman-La Roche
FDA Approval date: June 19, 1992
Class: nucleoside analogue reverse transcriptase inhibitor (RT)
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)
Brand name: Zerit
Marketing Firm: Bristol-Myers Squibb
FDA Approval date: June 24, 1994
Class: nucleoside analogue reverse transcriptase inhibitor (RT)
Intellectual Property Status
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.
Discovery that d4T would treat HIV/AIDS
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.
License to BMS
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.
NIAID and BMS Phase I/II trials
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).
BMS trial used in NDA
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.
NDA approval
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.
There was subsequent testing of d4T, and expanded marketing approvals for use in combination therapy.
Generic name: Lamivudine (3TC)
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.
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
Generic name: Abacavir
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 MinnesotaFactsheet 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).
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
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).
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
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).
Generic name: Amprenavir
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)
Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTI)
Generic name: Nevirapine
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).
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
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).
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: 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.
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