History of a gene patent: tracing the development and application of commercial BRCA testing.(Myriad Genetics)

Publication: Health Law Journal

Publication Date: 01-JAN-02

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COPYRIGHT 2002 Health Law Institute

1. Introduction

The patenting and commercialization of human genetic material raises a host of complex social, ethical, and policy issues, such as the potential for discrimination or stigmatization in access to health care services or employment, the exploitation of minority or indigenous communities in DNA prospecting, and the implications for ongoing biomedical research and access to health care services. But in order to conduct a comprehensive analysis of even one of these issues, it is crucial to first develop a detailed understanding of the particular history and context that have shaped the issue. The objective of this paper is to provide such a description of one particular case, namely the patenting by Myriad Genetics of the two genes (BRCA1 and BRCA2) associated with hereditary breast and ovarian cancer. Following a brief discussion of the aetiology of hereditary breast and ovarian cancer, the founding of Myriad Genetics and its transformation into a biopharmaceutical company is examined as part of the larger conte xt of the international race to discover and patent the BRCA genes. The paper then focuses on Myriad's development and control of public and commercial BRCA testing in the United States, their recent moves to enforce the patents and establish markets in Europe and Canada, and the mounting Canadian and international opposition to Myriad's commercialization and control of BRCA testing.

The Myriad case is a harbinger of an increasing number of instances where gene patents provide companies with monopolies on the development, marketing, and provision of genetic tests and therapeutics. Not surprisingly, this case has become a focal point in Canada and Europe for debates about the social and ethical implications of DNA patenting and the commercialization of genetic tests. There have been legal challenges of the BRCA patents in Europe, legislation to require compulsory licensing of diagnostic tests introduced in France, and in Canada an almost nationwide rejection of Myriad's monopoly rights to BRCA testing. There is clearly a need for sustained and comprehensive social, ethical, and policy analysis of the issues arising from this and similar cases. These issues will only touched on in this paper, as the primary task is to show how a rich description of a specific exemplar--the Myriad case--is essential groundwork for conducting a comprehensive social, ethical, and policy analysis of the commer cialization of new genetic technologies.

2. Biotechnology and Gene Patenting

By the early 1990s, enormous amounts of public and private funds were being invested in genetics research and biotechnology development. (1) The U.S. public expenditure on the Human Genome Project is estimated at greater than US$3 billion. The U.S. biotechnology industry invested US$11 billion in R&D in 1999 (2) and US$15.6 billion in 2001. (3) In Canada in 1998, federal biotechnology funding reached C$314 million, of which million was devoted to R&D; (4) Canadian industry invested C$341 million while not-for-profit institutes invested C$115 million. (5) With the creation of Genome Canada in February 2000, the federal government continued its support of biotechnology research by investing a further C$300 million specifically towards genomics R&D. (6) Similar funding initiatives have been launched in the United Kingdom (7) and other European and Asian nations.

While the potential health benefits to be derived from biotechnology were clearly a motivating factor for the substantial public investments, this goal was closely parallelled (if not exceeded) by the conviction that developing a strong biotechnology industry is essential for stimulating economic growth and building a 'knowledge-based economy.' (8) Public financial investments in biotechnology were thus also supported by government policies and regulations to facilitate technology transfer and commercialization. (9)

The 1980 U.S. Supreme Court case of Diamond v. Chakrabarly (10) was a landmark decision, and significantly influenced Canadian and international patent law. (11) This case, which overturned the U.S. Patent and Trademark Office's prior decision not to permit the patenting of a biological organism (a genetically modified bacteria for the bioremediation of oil spills), opened the door for patents on biological organisms and genes. (12) Following the U.S. decision, the 1982 Canadian case of Re Application of Abitibi Co. (13) forced the Canadian Intellectual Property Office to allow the patenting of biological organisms and genes. (14) The permissive nature of U.S. patent policy, as well as international trade and patent harmonization agreements such as the Agreement on Trade-Related Aspects of Intellectual Property Rights (TRIPS), the General Agreement on Trade and Tariffs (GAIT), and the North American Free Trade Agreement (NAFTA), have had a major impact on international gene patenting. (15) In developed and de veloping countries that are signatories to these agreements, genes (including those of human origin) are considered patentable material if they meet general patent criteria and are demonstrated to be new creations (e.g., artificial genes) or are isolated from nature and identified (i.e., cloned and sequenced), and shown to have a particular function and use.'6 In the late 1980s, genetically engineered plants and animals were patented in the U.S. (the Harvard 'Oncomouse' was patented in 1988) (17) and the number of gene and biological patents rapidly increased. (18) Between 1981 and 1995, more than 1,175 human gene patents were granted worldwide,19 with more than 25,000 DNA-based patents by 2000. (20)

Biotechnology start-up companies (whose main or only resources were often patents on potential 'disease genes') proliferated in the U.S., growing from 1,231 companies in 1992 to 1,457 in 2002. (21) Revenues more than doubled between 1993 and 1999 (US$8 billion to US$20 billion), and tripled (to US$27.6 billion) by 2001. The U.S. biotechnology industry, according to one estimate, (22) created (directly and indirectly) 437,400 U.S. jobs, generated US$47 billion in revenues, and provided US$10 billion in taxes for federal, state and local governments. In Canada, there are more than 500 biotechnology companies with industrial activities generating annual revenues of C$2 billion and exports of more than C$750 million. (23)

Despite the apparent economic success of this industry (and the government funding and legislation that has supported its development), there has also been a high turnover of biotechnology companies. Only a small percentage of companies remain solvent or independent a few years after start-up--most have either gone bankrupt or been absorbed by large biotechnology or pharmaceutical companies--and even fewer are able to show a profit. There has also been a convergence in markets and research technologies, such that biotechnology companies are consolidating around specific research areas (and not simply a particular gene or technology) and collaborating more closely with pharmaceutical companies to ensure long-term financing for R&D. (24)

One such biotechnology company is Utah-based Myriad Genetics, Inc. Myriad built its reputation and later established itself as a market leader in gene discovery and diagnostics--although they have also expanded into proteomics research--by helping to discover and patent the first genes (BRCA1 and BRCA2) to be associated with susceptibility for hereditary breast and ovarian cancer. (25)

3. Hereditary Breast Cancer

Breast cancer is one of the most common non-skin cancers affecting women and the second leading cause of death in this group after heart disease; less than 1% of breast cancers occur in men. In 2002, an estimated 20,500 new cases of breast cancer will be diagnosed in Canadian women (a cumulative lifetime risk of 1 in 9), and 5,540 women are predicted to die from the disease. (26) Breast cancer is a heterogeneous disease, but approximately 80% of breast cancers are infiltrating ductile carcinomas. Treatment and prevention of further cancers depends on the type and size of cancer involved, and whether it is encapsulated and restricted to one area or has spread to other parts of the breast and body. Treatment options include lumpectomy, partial or total mastectomy, radiation, chemotherapy, and drugs such as tamoxifen and raloxifene. (27)

Of those women who develop breast and ovarian cancers, current evidence suggests that only 5 to 10% are likely to have inherited a particular allele associated with increased risk of developing the disease. (28) To date, the genes BRCA1 and BRCA2 have been strongly associated with hereditary breast cancer. BRCA1 is a large gene on chromosome 17 with 22 exons made up of 5,592 base pairs, and codes for a protein of 1,863 amino acids. The protein is critical for DNA repair and transcription regulation; when the gene is inactivated through mutation and the protein altered, it leads to abnormal cellular gene expression. BRCA2 is located on chromosome 13 and is even larger, with 27 exons, 10,254 base pairs, and codes for a protein of 3,418 amino acids. The functions of the BRCA2 protein appear similar to that of BRCA1, although BRCA2 tumours have different cellular expression. (29)

Deleterious mutations in these two genes are caused by insertions or deletions of nucleotides (single or multiple), or by large scale deletions or rearrangements. Such mutations may shift the reading frame of triplet codons (the group of three DNA nucleotides that correspond to specific amino acids) during protein synthesis. This results in a premature stop instruction, abrupt termination of protein synthesis, and a truncated and non-functional protein. BRCA1 and BRCA2 are considered classic tumour-suppresser genes because the associated cancers are believed to result from a 'two-hit' process of gene/protein inactivation. The first hit is due to a mutated (non-functional) gene in the germ line (inherited from a parent), which leaves only one remaining functional copy (allele) of the gene in all cells of the body. A person with a deleterious BRCA mutation is predisposed to breast and ovarian cancer because the second allele may be knocked out (second hit) though random mutation. If this occurs, the tumour-sup presser function is inactivated with resulting loss of control over cellular growth.

Individuals with such mutations are estimated to have a cumulative lifetime risk of 40-85% for developing breast cancer, and 16-40% for developing ovarian cancer, depending on the mutation and family history. (30) Mutations in both BRCA genes confer risk in an autosomal dominant manner; in other words, only one such allele is needed for increased risk of developing cancer, although a person with a deleterious mutation may never develop breast or ovarian cancer. The children of BRCA mutation carriers have a 50% chance of inheriting the gene mutation. There is still much scientific uncertainty with respect to the BRCA1 and BRCA2 genes and the functions of the resulting proteins. And only about 20-25% of families meeting stringent entry criteria (e.g., extensive family history or early age of onset) for genetic testing at public cancer clinics will have an identifiable mutation in BRCA1 or BRCA2. (31) It is likely that there are other genes yet to be discovered that affect breast cancer risk in families negativ e for BRCA1 or BRCA2 mutations, some of which may be high penetrance genes that confer significantly increased risk such...

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