Why the Gene Patenting Controversy Persists

Abstract

A puzzling aspect of the controversy over patenting genes has been its timing. Other controversies over patenting new subject matter—such as microorganisms, animals, software, and business methods—have typically erupted promptly upon the allowance of patents in these areas, and then diminished as people and institutions got used to it. By contrast, public controversy over patenting genes initially trailed patenting practice by a decade or more, yet it has remained remarkably robust ever since, despite many years of experience with gene patents. Throughout the 1980s, while Congress1 and commentators2 focused concerned attention on the patenting of living things, the practice of patenting genes was becoming well established beneath the radar of media attention. The first significant public controversy over patenting DNA sequences did not erupt until the early years of the Human Genome Project, when the National Institutes of Health (NIH) filed patent applications on the first few hundred expressed sequence tags (ESTs) identified in the laboratory of Dr. Craig Venter.3 But if critics of gene patenting were slow in launching public discussion of the issue, they have certainly been persistent in keeping the controversy alive. What accounts for this peculiar pattern of delayed, yet enduring, controversy? Although at a formal level patenting genes looks like an established practice, the interests that it implicates have shifted over time, bringing different stakeholders forward and raising different concerns and arguments that were not salient in the early days. In particular, in recent years the patenting of genes has raised evolving issues concerning (1) the patenting of DNA diagnostic products that are the object of mixed clinical and research use; (2) the patenting of “upstream” discoveries that are still some distance away from end-product development but are nonetheless of immediate scientific interest to researchers; and (3) the patenting of routine research results obtained through a mechanized process requiring no more than ordinary skill on the part of the inventors. Each of these issues has cast a new light upon the practice of patenting genes as science and technology move forward, bringing into focus questions that were neither raised nor resolved in the prior course of gene patenting. PATENTING GENES AS DRUGS Patenting genes began with little fanfare and little controversy in the early years of the biotechnology industry, with the patenting of newly cloned genes encoding therapeutic proteins.4 As a matter of legal doctrine, the courts and the Patent and Trademark Office (PTO) treated these inventions as chemicals,5 a characterization that provided an extensive body of precedent to consult in establishing the patent ground rules for this emerging field. Having long ago decided that chemicals isolated from nature through human intervention were eligible for patent protection,6 the courts and the PTO hardly blinked at allowing patents on newly isolated genes. In these early, low-controversy days, patenting genes looked more or less like patenting drugs. The case for patenting drugs, although disputed by some, is straightforward and plausible, given the high costs and risks of drug development7 and the avowed patent-sensitivity of the industry.8 The gene-patenting pioneers in the new biotechnology firms of the 1980s saw themselves as high-technology drug developers and, in their search for a viable business model for therapeutic protein development, emulated the patent strategies of the major pharmaceutical firms. Often the proteins that they sought to develop as drugs were familiar, but they were difficult and costly to isolate in significant quantities. By cloning the genes that encoded these proteins, biotechnology firms were able to produce the proteins in recombinant organisms in quantities sufficient to meet therapeutic needs. Patenting the genes and recombinant materials secured profitable exclusive franchises to manufacture these products. Although only a handful of these pioneering firms survived and prospered, gene patents undoubtedly played a critical role in attracting the necessary private investments to launch this industry. Patents on genes encoding therapeutic proteins have been the focus of numerous judicial opinions concerning the requirements for patent protection,9 priority of invention,10 and determinations of infringement.11 Judicial opinions resolving these disputes provide most of the existing legal precedent involving the patenting of DNA. Some firms continue to follow essentially the same business model as the biotechnology pioneers, searching for new therapeutic proteins and filing patent applications on the corresponding genes in order to secure profitable exclusive markets for these products. But as the underlying science has advanced, research strategies and business models have become more diverse, generating patents that play different roles in the economy of biomedical research and practice. PATENTING GENES AS DIAGNOSTIC PRODUCTS The research that yielded the first generation of gene patents used knowledge of therapeutically useful proteins to clone the corresponding genes. Later, the development of new tools and techniques for detecting genetic differences among individuals enabled researchers to bypass the stages of protein isolation and characterization and to identify directly the genes associated with diseases (or disease susceptibilities) through positional cloning.12 These genetic discoveries had immediate value as diagnostic products. They were also useful as research tools in the search for therapeutic products, but the relationship between gene and therapeutic product was typically less straightforward than it had been for the first generation of biotechnology products. Patents on these discoveries, although similar in form to patents on genes encoding therapeutic proteins, played a different and less familiar role in the biomedical community, setting the stage for conflict with people and institutions that had barely taken note of the first generation of gene patents. Professional societies of doctors and clinical geneticists have been particularly outspoken critics of both disease gene patents and exclusive licenses to perform DNA diagnostic tests.13 These groups advance many arguments against the patenting of genes, some of which would seem to apply with equal force to the patenting of drugs (e.g., that patents raise the costs of genetic tests and restrict patient access to a type of medical care) or of genes encoding therapeutic proteins. Setting these arguments aside, two additional arguments suggest why these groups have been more troubled by the patenting of disease genes than they were by the patenting of genes encoding thereapeutic proteins. First, they argue that giving patent owners the right to limit who may perform genetic tests interferes with the practice of medicine. Second, they argue that exclusive licenses to large commercial laboratories to perform genetic tests prevent other laboratories from identifying and validating new mutations and restrict the range of testing services that are offered. These arguments are particularly compelling to doctors and geneticists working in academic medical centers that are equipped to administer “home brew” genetic diagnostic tests themselves in pursuit of a mixed mission of treatment and research. That these arguments were not advanced when gene patents related primarily to the market for therapeutic products, but became salient when gene patents began to affect the market for diagnostic products, reveals interesting differences between these two markets. It is relatively easy for patents to confer effective monopolies in therapeutic products because patents are not the only constraint on competition in these markets. In order to bring a new drug (or a new biologic such as a therapeutic protein) to market, it is necessary to get approval from the Food and Drug Administration (FDA), a process that entails considerable costs for clinical testing and clearing administrative hurdles. Drug manufacturing requires specialized facilities and know-how that further limit entry into these markets. Doctors and non-commercial laboratories are not about to meet the therapeutic needs of their patients by making these products themselves, even after the relevant patents expire, and patents on these products therefore do not feel like a constraint on their activities, whatever impact they may have on the cost of medical care for their patients. On the other hand, many laboratories are equipped to perform DNA diagnostic tests, particularly in academic medical centers. Diagnostic products are far less extensively regulated than therapeutic products and are typically given to patients on a one-time basis, minimizing the non-patent obstacles to performing such tests. Even when a test is available at reasonable cost elsewhere, doctors in academic medical centers may prefer to use their own institutions' facilities for diagnostic testing rather than to ship samples off to a commercial laboratory in order to identify (or look for) new or rare mutations or to learn more about the underlying disease. They see restrictions on the provision of DNA diagnostic tests imposed by patent owners as an unaccustomed obstacle to their work as health care providers and researchers. Patents on disease genes also raise new challenges for patent owners seeking profitable strategies for deploying their patent rights. It is relatively simple to figure out how to deploy a patent on a drug that end users are not in a position to make safely and effectively for themselves. So long as the patent owner has a right to exclude competitors from making the patented product, it may secure a monopoly without having to sue end users. But if end users are capable of infringing the patent on their own without the intervention of a commercial competitor of the patent owner, it may become necessary to enforce the patent against them in order to maintain profitability. This adds to the costs of monitoring and enforcing patent rights, as well as creating bad public relations with potential customers. Indeed, this situation blurs the distinction between customers and competitors from the perspective of patent owners and places the interests of patent owners in conflict with those of health care providers, fueling opposition to gene patenting from groups that scarcely noticed the first generation of gene patents. The fact that DNA diagnostic products are routinely subject to incremental improvement as more is learned about the genetics of a disease further aggravates the problem of establishing and enforcing a lucrative patent position in these products. While the patented genes encoding therapeutic protein products typically are the same as the single most prevalent sequence carried by healthy individuals, DNA diagnostic products typically seek to identify aberrations in the sequence that are associated with disease. Practicing physicians with access to family pedigrees may discover many such aberrations over time. Limiting the number of laboratories permitted to do the testing could slow this incremental process of discovery. On the other hand, permitting multiple investigators to search for mutations in an uncoordinated fashion could fragment ownership of patent rights as each laboratory patents the mutations that it discovers, making it difficult to secure the necessary permissions to market a comprehensive diagnostic test.14 In this challenging strategic environment, it is not clear that the interests of owners of disease gene patents will converge with the social interest in promoting continuing technological progress. Arguments that gene patents interfere with the practice of medicine beg the question of why medical practitioners should be treated differently from any other providers of goods and services under the patent laws. Medical practitioners succeeded once before in persuading Congress to grant them special relief from enforcement of patents on medical and surgical techniques.15 Efforts to secure similar protection from enforcement of patents on DNA sequences would be likely to encounter more serious resistance from the genomics industry, which has invested substantial resources in R&D in reliance on the availability of effective patent rights in their discoveries. Arguments that gene patents interfere with incremental innovation in DNA diagnostics, although plausible, fly in the face of the strong presumption within the patent community that patents promote, rather than retard, progress.16 Notwithstanding the skepticism of medical practitioners and academic scientists, it is also plausible that eliminating or weakening patent incentives would retard the development of DNA diagnostic products, to the long-run detriment of medical practice. This is ultimately a complex empirical question with no clear answer. Different starting intuitions could lead different observers to sharply divergent interpretations of the available evidence. PATENTING GENES AS RESEARCH TOOLS The advent of high-throughput DNA sequencing facilitated the sequencing of DNA in advance of understanding the functions or disease relevance of particular sequences, raising the possibility of obtaining patents on “upstream” genetic discoveries that were still far removed from product development. Patent applications filed by the NIH on the first ESTs identified by Craig Venter set off alarm bells in the scientific community,17 although research scientists had previously expressed little concern about the patenting of genes encoding therapeutic proteins. If the DNA sequence discoveries that were claimed in the provocative NIH patent filings encoded therapeutic proteins, no one knew it at the time. The most obvious value of ESTs was not the speculative value of particular gene fragments for therapeutic or diagnostic uses, but the immediate value of growing collections of such sequences for use in gene discovery. With this shift, patenting genes started to look less like patenting end products and more like patenting scientific information. Scientists argued that the progress of biomedical research would be better served by making the human genome freely available than by permitting its balkanization through patent claims and restrictive licensing agreements.18 This opposition became more vehement as EST-sequencing moved from the NIH to the private sector, and as terms of access to privately held EST databases were set beyond reach of many academic institutions.19 The gene-patenting controversy arose during a period of rapid and uneasy change in the culture of academic biomedical research from a tradition of open science to a more restrictive, proprietary enterprise. Although by this point many academic scientists had begun patenting their own inventions and licensing them to private firms, they still enjoyed relatively free access to scientific information and methods for use in their own research. The first patent filings on results of large-scale DNA sequencing coincided with a broader trend in the biomedical research community to claim intellectual property rights in research and to these rights against academic The availability of patent protection for research tools has undoubtedly private investments in and many research to the of researchers in the public and private the case for patenting research tools is far more than the more familiar case for patenting end products. 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It is difficult to which research will profitable products, and it may years before the value of research biomedical researchers have resources to make for access to research some providers to terms in the form of on product or licenses to inventions through use of their These terms have the of making tools available at cost for use in non-commercial while still permitting the owner to the if the research a commercial But many users at to As such terms become more in research the imposed by different providers may into or that incentives for product development. it may be difficult on to a particular or product to the prior use of a research and to that the product is subject to the These the costs of over terms of access to proprietary research their and research. That patents are less to the of genetic research tools for use in R&D than they are to the of therapeutic end products is by the fact that gene-patenting in the scientific community have enjoyed from the pharmaceutical Although to a legal that they see as critical to their own pharmaceutical firms have their the for a genome by such as the Genome and the to make DNA sequence information freely available in the public academic scientists, pharmaceutical firms see DNA sequence information primarily as a for and feel by patents that interfere with (or raise the cost access to this that patents an to R&D is to those who administer the patent and is to be to A more is that the patent in innovation by allowing to the value of their inventions from users. to this if a patent and in of this potential users may use of the and make do with them no off then they would have been without the patent therefore that of research like of therapeutic proteins, would from and therefore the patents that other firms to develop new products for their But this on an for gene patents in the of high-throughput DNA the patent is making to the technology that would not be freely PATENTING GENES AS about the impact of gene patents on the use of information in research not the level of expressed by of gene patenting in the scientific is by the among scientists that patents on the results of high-throughput DNA sequencing discoveries and a corresponding on the more challenging and work that to be in order to the functions of genes. 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