Quick Company Notes

• Zidovudine/AZT/Retrovir Glaxo won a messy patent lawsuit and owns the key use patent for AZT, but the government clearly played a major role. The Michigan Cancer Foundation initially synthesized AZT on a grant from the National Cancer Institute (NCI).

• Lamivudine/3TC/Epivir. Invented by BioChem Pharma and licensed to Glaxo for 14 percent royalty. Yale and Emory have also important 3TC patents. US government has sponsored more than 40 clinical trials invovlving 3TC.

• Abacavir/Ziagen. Glaxo was sued for patent infringement by University of Minnesota, where Abacavir was apparently invented, with support from NIH. Glaxo will pay U of Minn royaltyies of 5 to 10 percent, depending upon sales.

• Amprenavir/Agenerase. Glaxo's protease inhibitor was licensed from Vertex Phamaceuticals.

• Didanosine/ddI/Videx. The US government invented ddI and licensed the drug to BMS on an exclusive basis. The NIH license to BMS has a reasonable pricing clause, but US governemnt refuses to enforce the agreement.

• Stavudine/d4T/Zerit. The Michigan Cancer Foundation initially synthesized d4T on a grant from the National Cancer Institute (NCI). Yale University holds the key use patent for d4T.

Specific AIDS Drugs (approved by FDA)

The following is a list of products approved by the Food and Drug Administration. Included in the table is information about how government research was involved in the development. The information is not complete at all, and additional information on the subject would be appreciated. This project was started by Shivan Mehta, a student at Yale. Now Thiru Balasubramaniam has been asked to work on this, so sent comments to him at thiru@cptech.org.

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)

Intellectual Property Status

AZT was initially synthesized under an NCI grant by Dr. Jerome Horowitz of the Michigan Cancer Foundation (Karmanos Cancer Institute) in 1964. Burroughs Wellcome applied for and received a patent for the idea of using AZT to treat AIDS in 1988 ( Patent #4,724,232). Several patent suits have challenged the patent rights, as NIH scientists claim they were the first to identify anti-HIV activity and clinical efficacy of AZT. For a discussion of the relative roles of NIH and Burroughs Wellcome in developing AZT, see September 28, 1989 letter to the NY Times.

Federal Involvement in Development

Discovery of Agent: AZT initially synthesized under NCI grant; also involved in idea of treatment for HIV/AIDS
Preclinical Research: Yes
Clinical Research:

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 ( Patent #4,861,759), which lists the inventors as Hiroaki Mitsuya and Samuel Broder of the National Cancer Institute (NCI).

Patent Information

According to UNAIDS, the United States of America has been granted patent rights in Austria, Belgium, Canada, France, Germancy, 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

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 be used right now 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 NDA was filed on March 29, 1991 and approved in less than seven months, on October 9, 1991.

Federal Involvement in Development

Discovery of Agent: Yes
Preclinical Research: Yes
Clinical Research: Yes

Intellectual Property Status

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.

Federal Involvement in Development

Discovery of agent: Yes
Preclinical research: Yes
Clinical research: Yes.


The National Cancer Institute (NCI) conducted the first clinical trial of ddC in 1987.

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. Incidentally, some researchers apparently use this date to estimate the length on time it takes a company to develop an HIV/AIDS drug, even though this research was publicly funded, and not done by a drug company.

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.

It is possible that other firms may be sought to obtain patents on d4T in other countries, particularly in countries that have a "first to file" system. Other persons may also hold other patents on d4T, such as formulation, dose or treatment regime patents. We have not looked at this yet. But the US "orange" book only lists the Yale patent.

License to BMS

The Yale patent was filed in the US on December 17, 1986, and approved on December 18, 1990. But 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.

During this period, the FDA annouced that d4T would be made available for expanded Investigational use" as the first drug available under the agency's "parallel track" policy. See the Centers for Disease Control press release.

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.

Federal Involvement in Development

Discovery of agent: Yes
Preclinical research: Yes
Clinical research: Yes

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. However, Emory 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 (see August 5, 1996 Emory Report article). A dispute in United States courts is currently pending between Emory University and BioChem Pharma over the rights to 3TC. Emory is requesting a portion of the royalties from drug sales.

Federal Involvement in Development

biomedical research projects conducted at universities, hospitals, and other research institutions through federal funding.

Discovery of agent: No
Preclinical research: the research done by Emory on the process of synthesizing 3TC was supported by NIH grant no. 5-21935
Clinical research: Yes.

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

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).

In late March, 2001, students at the University of Minnesota asked the administration to state publicly that it is unconditionally opposed to the application of legal pressure on any government or generic company wishing to make HIV/AIDS treatments accessible at affordable prices, urge GlaxoSmithKline to withdraw its lawsuit against the South African government, and join with GlaxoSmithKline to permit generic versions of abacavir to be produced, imported, and distributed in poor countries. See the CPT page on Abacavir and the University of Minnesota.

Federal Involvement in Development

Discovery of agent: No
Preclinical research: Yes, NIH-sponsored grants were used in the development of compounds used to manufacture Abacavir.
Clinical research: Yes

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.

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).

Federal Involvement in Development

Discovery of agent: Yes, NIH research was pivotal to the discovery of protease inhibitors as an effective treatment for HIV/AIDS
Preclinical research:
Clinical research: Yes (ACTG 229)

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

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).

Federal Involvement in Development

Discovery of agent: Yes
Preclinical research:
Clinical research: Yes

Intellectual Property Status

A patent was issued to Merck for the use of indinavir in the treatment of AIDS ( Patent #5,413,999).

Federal Involvement in Development

Discovery of agent: Yes, as with the other protease inhibitors, NIH research was involved in linking them to the treatment of AIDS
Preclinical research:
Clinical research: Yes

Intellectual Property Status

Nelfinavir was developed by Agouron with the pharmaceutical division of Japan Tobacco, and it was issued the patent (Patent #5,484,926).

Federal Involvement in Development

Discovery of agent: Yes, preliminary research into protease inhibitors
Preclinical research:
Clinical research: Yes

Intellectual Property Status

There are no unexpired patents for the oral capusle, but 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.

Federal Involvement in Development

Discovery of agent: Yes, preliminary research into protease inhibitors
Preclinical research:
Clinical research: Yes, ACTG involved in phase II monotherapy study (see Vertex Corporate information article)

Non-Nucleoside Reverse Transcriptase Inhibitors (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).

Federal Involvement in Development

Discovery of agent:
Preclinical research:
Clinical research: Yes

Intellectual Property Status

The Upjohn Company was issued the patent for delavirdine ( Patent #5,484,926).

Federal Involvement in Development

Discovery of agent:
Preclinical research:
Clinical research: Yes.

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

Discovery of agent:
Preclinical research:
Clinical research: Yes. NDA approval of efavirenz was based on data from three pivotal clinical trials. NIAID sponsored one of these trials, ACTG 364.