domingo, 14 de julio de 2013

Gene Patenting — The Supreme Court Finally Speaks — NEJM

Gene Patenting — The Supreme Court Finally Speaks — NEJM

Gene Patenting — The Supreme Court Finally Speaks

Aaron S. Kesselheim, M.D., J.D., Robert M. Cook-Deegan, M.D., David E. Winickoff, J.D., and Michelle M. Mello, J.D., Ph.D.
July 10, 2013DOI: 10.1056/NEJMhle1308199
Are human genes patentable? On June 13, the Supreme Court gave its long-awaited answer — a unanimous “no.” The case, Association for Molecular Pathology v. Myriad Genetics, 1 has generated enormous interest among medical institutions, industry organizations, patient advocacy groups, and scientists. “ Life's instructions,” James Watson asserted in one of 49 amicus curiae briefs, “ought not be controlled by legal monopolies created at the whim of Congress or the courts.” For some, the gene patents were symbols of a shrinking public domain and an overreaching patent system that traded too much monopolistic power for too little innovation. For others, the challenge to the patented genes amounted to an attack on the intellectual-property protections that fuel private investment in biomedical discovery. Although ethical and policy arguments were a major feature of the debate surrounding the case, the decision focused squarely on the definitions of two codes: the genetic code and the patent code. All nine Justices of the Court agreed that the segments of DNA that make up human genes are not patentable subject matter under section 101 of the Patent Act2 because they are products of nature. However, the Court held, molecules that are reverse-transcribed from messenger RNA (mRNA) to eliminate intron sequences — so-called complementary DNA (cDNA) — are eligible for patents. The decisive sentence of Justice Clarence Thomas's ruling crisply stated that, “a naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but that cDNA is patent eligible because it is not naturally occurring.” The decision joins a suite of recent Supreme Court cases that are reshaping patent law, with important implications for innovation in the life sciences. Here we review the Myriad Genetics case and the reasoning of the Court and discuss the implications for health care and the biotechnology industry. Patient advocates and industry groups alike can find something to celebrate in this Supreme Court decision: although it will open up competition in the genetic testing arena and drive down prices, it leaves undisturbed most of the intellectual-property rights on which the biotechnology industry depends.

The Battle over Patenting Breast-Cancer Genes

The human genes at issue in the Myriad Genetics case are BRCA1 and BRCA2. In federally funded research dating back to the 1980s, Mary-Claire King and others identified a region of chromosome 17 that must contain a gene mutated in families with many cases of breast cancer. That gene became known as BRCA1, and it turned out to also predispose women to ovarian cancer. King's 1990 report of genetic linkage for a “breast-cancer gene”3 set off an intense race to clone and sequence it. A team led by Mark Skolnick of the University of Utah won that race4; Skolnick was also a cofounder of Myriad Genetics. In 1994, Michael Stratton and others mapped another locus in chromosome 13,5 which precipitated another furious race to identify and clone what became known as BRCA2. That race ended in a near tie,6 with the Stratton group publishing in Nature 7 just a day after Myriad filed a patent application,8-10 having gotten wind of the Stratton work.11 Myriad sought patent protection for methods of detecting and comparing DNA sequence variations and for the isolated DNA molecules. The claims on DNA molecules included cDNA and genomic DNA, sometimes both in the same claim. The Supreme Court parsed these elements in its decision (Table 1Table 1Types of Patents Issued to Myriad Genetics Relating to BRCA.). Applications by Myriad for BRCA1 and BRCA2 were broken into separate patents, covering different aspects of the work. These patents undergirded the commercialization of its BRACAnalysis test for predisposition to breast cancer, which Myriad first made available in 1996. Myriad filed subsequent patents and acquired rights to other BRCA patents by out-of-court settlements and now states that it has 24 patents containing over 500 claims relating to this field.12 The American Civil Liberties Union (ACLU) and the Public Patent Foundation, representing more than 20 plaintiffs, filed suit against Myriad in May 2009 in federal court for the southern district of New York. The litigation arose in large part because, in the intervening decade, a steady drumbeat of criticism had grown against the business practices of Myriad and against patents on genes in general. Objections raised by public health advocates included the restriction set by Myriad on certain uses of its genes in the context of research, its refusal to allow independent confirmatory testing of ambiguous initial results,13 and the high price of its genetic test (up to $4,000).14 Advances in sequencing technology had made it possible for patients to have dozens of genes sequenced for less than what Myriad charged for BRCA1 and BRCA2 testing.15 Fueling advocates' arguments were surveys showing that gene patents reduced access to testing16,17 and research showing that legal restrictions on gene sequences reduced product development by up to 20 to 30%, as compared with diagnostic products arising from freely available sequences.18 Inventors must satisfy several statutory criteria in the Patent Act to obtain patent protection, but the Myriad case focused on just one: whether the claimed inventions met the basic definition of patentable subject matter. That is, did they constitute inventions at all? The Patent Act defines the scope of patentable subject matter as “any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof.”2 The Supreme Court has previously established that “Anything under the sun that is made by man” is eligible for a patent19 but has read into the patent statute an important implicit caveat that laws of nature, natural phenomena, and abstract ideas belong in the public domain. In March 2010, Judge Robert Sweet of the southern district of New York issued a summary judgment order in the Myriad case, invoking long-standing Supreme Court doctrines to conclude that this caveat excluded DNA from patentability.20 He invalidated all 15 claims challenged in seven of the Myriad patents. The next year, a divided panel of the Court of Appeals for the Federal Circuit tempered the district court holding. The three-judge panel unanimously affirmed Judge Sweet's determination that Myriad could not patent its method of testing for cancer risk by comparing a patient's isolated BRCA1 and BRCA2 sequences to the reference sequences. By contrast, the panel upheld the method claim for the use of BRCA1 and BRCA2 in screening potential therapeutic agents against cancer and held that cDNA could be patented. Most controversially, the Federal Circuit split 2 to 1 on whether DNA molecules corresponding to sequences found in cells were patentable because they were described in the patent claim as “isolated.”21 The two judges in the majority reached their conclusion that isolated DNA is eligible for patents in different ways. Judge Alan Lourie reasoned that the act of severing covalent bonds in the process of isolating the DNA created a new molecule, and Judge Kimberly Moore argued that not only fragmentation but also the demonstrable utility of isolated DNA sequences, as compared with native DNA, was the basis for patent eligibility.22 Judge William Bryson wrote a vigorous dissent arguing that isolated molecules were not eligible for patents because they were not different enough from their natural counterparts. The Supreme Court reviewed the decision of the Federal Circuit court in 2011 but sent the case back for reconsideration in light of a newly issued Supreme Court decision invalidating a patent on a method of diagnostic testing.23 The Federal Circuit court judges did not substantively change their opinions in 2012, reiterating the same logic and coming to the same 2-to-1 split.24 On November 30, 2012, the Supreme Court agreed to hear arguments on one question only: Are human genes patentable?

Supreme Court Decision

To answer this question, the Supreme Court returned to the opaque and oft-contested boundary line between human inventions and discoveries of naturally occurring phenomena. Writing for a unanimous Court, Justice Thomas cited the long history of the Court of drawing a distinction between compositions of matter that are made by humans and those that are naturally occurring (Table 2Table 2Major Supreme Court Decisions Defining the Boundary between Inventions and Products of Nature.). The relevant doctrine, however, has been “vague and malleable,” in the words of Justice Felix Frankfurter in a seminal 1948 case.25 Cases have lacked clarity and consistency during the past hundred years, with the criterion that inventions must involve the application of human ingenuity seemingly established in different ways. In considering patents on DNA sequences, Justice Thomas struck a balance between the long-standing principle that discoveries of natural phenomena are not patentable and the competing notion that “all inventions at some level . . . apply laws of nature, natural phenomena, or abstract ideas” by drawing a line between genomic DNA and cDNA. The isolated DNA sequences were not the proper subject of patents, he wrote, because they were not markedly different from the sequences found in nature. Indeed, they derived their diagnostic usefulness from having the identical sequence. Justice Thomas distinguished between the claims of Myriad and those at issue in the landmark 1980 case of Diamond v. Chakrabarty, which ushered in the modern explosion in biotechnology patents. In that case, a bacterium was genetically engineered to contain four naturally occurring plasmids, each of which was useful in breaking down oil. The inventor inserted the plasmids into the DNA of the microbe, giving rise to an organism not found in nature. No similar transformation of a product of nature was present in the claims of Myriad covering the isolated DNA sequences. The cDNA claims, the Court held, were another matter. Because cDNA is reverse-engineered by scientists from mRNA to include only the protein-coding exons, it is different from any naturally occurring genetic material. It thus falls on the invention side of the line between discovery and invention. To then earn a patent, a sequence of cDNA would have to meet the remainder of the criteria required in the Patent Act of all inventions, including novelty, utility, and nonobviousness, although these considerations were not at issue in the Myriad case. The parties challenging the cDNA patent claims argued that cDNA is a product of nature because it represents the naturally determined stretch of nucleotides that codes for the mRNA. Its information is what matters, they asserted, and that is the same as naturally occurring DNA. However, the Court focused on the human ingenuity involved in reverse-transcribing the sequence as a separate nucleotide array. The fact that some DNA sequences mimicking cDNA may occur by chance in nature was deemed insufficient to undercut its patentability. Myriad represents the third in a series of decisions since 2010 in which the Supreme Court has redefined the boundaries of its three main exclusions from patentability — laws of nature, natural phenomena, and abstract ideas. In each of these categories, the Supreme Court has ultimately shown a more restrictive stance on patent eligibility than the Patent and Trademark Office. The first case, Bilski v. Kappos, involved an abstract idea. In striking down a patent on an investment strategy, the Court announced that it supported a “high enough bar” on patenting abstract ideas that would not “put a chill on creative endeavor and dynamic change.”26 The patent was invalidated because it “would preempt use of this approach in all fields,” over a vigorous dissent from Justice John Paul Stevens, who agreed with the outcome but wanted to set down an even more formal rule excluding business methods from patent eligibility. Next in 2012 came Mayo v. Prometheus, in which the Court unanimously invalidated patent claims on a method of adjusting the dose of thiopurine antiinflammatory drugs on the basis of metabolite levels.23 In that decision, the Court expressed concern “that patent law not inhibit further discovery by improperly tying up the future use of laws of nature,” which in that case was the correlation between doses of a drug and its physiological effects.27 Myriad extends this judicial anxiety to the context of DNA molecule claims. In concluding that “[g]roundbreaking, innovative, or even brilliant” discoveries of such natural phenomena are not patentable, the Court stressed the social cost: it “would `tie up' the use of such tools and thereby `inhibit future innovation premised upon them.'”

Implications for Health Care and Innovation

Advocacy groups have heralded the Myriad decision as a huge win for patients. “VICTORY!,” the ACLU declared, “Our genes belong to us!”28 The invalidation of genomic DNA claims — and the earlier refusal by the appellate court to allow patents on methods of detecting BRCA1 and BRCA 2 mutations — permits other companies to market their own genetic tests. Indeed, within days of the Myriad ruling, at least five competitors had announced that they would enter the market.29,30 Myriad has responded to this new competition with further infringement litigation.31 Patent claims by Myriad covering other methods and other “synthetic” DNA sequences such as primers and probes have not been challenged, and the Supreme Court specifically noted that they might indeed cover patentable subject matter. With the prospects for such infringement claims uncertain, however, Myriad may also seek to capitalize on its proprietary library of BRCA mutations, which provides a competitive advantage in interpreting rare mutations. The last deposit of data on BRCA variations by Myriad into the federal Breast Cancer Information Core database occurred in 2004, and a group of coauthors, including some from Myriad, published a manuscript listing 118 additional mutations in 2006.32 Since then, Myriad has not made public other BRCA variations that it received while holding its monopoly on testing. Recently, a physician-led grassroots effort has been organized to obtain data on rare variants directly from patients and their providers and publicly disseminate it, which could undermine this competitive advantage.33,34 Ultimately, the end of the Myriad monopoly should improve access to genetic testing and rapid turnaround of results by driving down the price — DNA Traits, for example, will charge less than $1,000 — and expanding capacity for analyzing samples. When the case was brought, one crucial concern was whether the claims in question blocked analysis by means of whole-genome sequencing. Myriad argued that its patents on isolated DNA involved sequestering BRCA sequences from others in the genome and that whole-genome sequencing would not infringe such patents. The ACLU pointed out, however, that the plain meaning of the claims would indeed cover molecules created during whole-genome sequencing. Given the outcome of the case (and in light of the oral arguments presented by Myriad before the Court), institutions offering whole-genome sequencing should no longer fear lawsuits from parties holding patents on isolated DNA.35 Although the Myriad decision places in jeopardy thousands of patent claims, its effects on biotechnology companies and innovation will probably be modest. A recent analysis estimated that as many as 3535 unexpired patents on naturally occurring, human gene sequences may be affected,36 although the applicability of the decision will depend on the specifics of each individual patent claim. Furthermore, because nothing about the reasoning of the Supreme Court would prevent its holding from being applied to nonhuman genes, several thousand patent claims relating to other organisms may also be affected, with implications for a range of applications outside human medicine. However, the same study showed that patent claims on merely isolated DNA were already on the decline. Since 2005, companies have sought to patent naturally occurring gene sequences much less frequently than they did in the past, perhaps because the Patent and Trademark Office raised the bar for meeting another requirement for patenting an invention — showing that it has practical utility. Some companies also found it more difficult than expected to profit from these DNA sequences and abandoned their patents.35,37,38 As a result, after Myriad, we expect that companies developing DNA-based therapeutic agents will need to more clearly distinguish their inventions from the genome itself and specify the claimed uses so as to avoid questions about covering the naturally occurring sequences. Claims on DNA that has been engineered, in contrast, have been on the rise — in both frequency and scientific importance36 — and will continue to enjoy protection after Myriad.35 Patents on synthetic DNA include those on vectors and engineered molecules that could be useful as therapeutic agents themselves (e.g., in gene transfer) or in the process of making therapeutic proteins for so-called biologic drugs. Since these technologies remain squarely within the bounds of patentability outlined by the Supreme Court, the effects on innovation emerging from these areas should be minimal. The impact of the Myriad decision on innovation will also be muted by the fact that the holding itself was clearly limited by Justice Thomas to isolated DNA corresponding to sequences found in nature. However, it may affect patent applications on DNA-based therapeutic agents, such as (still experimental) DNA vaccines, which will now have to clarify how the active sequence is not merely isolated but has been transformed and has a specific utility. It could also spill over into other areas of medical research, such as the development of diagnostic testing for microbes, which have genomes lacking introns altogether. Finally, Myriad is important as an expression of strident judicial opposition to patents on methods of making medical diagnoses. The method claims for detecting genetic sequence alterations were struck down unanimously by the Federal Circuit court, and the Supreme Court declined to take up the question on appeal. It will therefore be impossible for companies to mimic a business model of identifying a gene sequence and attempting to control the production of diagnostic tests from it. The combination of the Myriad and Mayo decisions greatly diminishes the prospects of Myriad or any other company claiming monopolies on genetic diagnostic tests alone, without a direct linkage to therapeutic agents or other molecular transformations. For example, companies seeking to develop multigene diagnostic or prognostic tests will have to try to claim some combination of methods of diagnosis and modification of the DNA molecules, rather than relying simply on patents covering the underlying isolated DNA. Whether this will reduce private investment in genetic diagnostic testing and necessitate supplemental public research funding remains to be seen.


The Myriad decision will be an important symbol for those who seek to foster scientific discovery by protecting and expanding the public domain. It also has symbolic resonance with the ideal that our common humanity cannot be owned. The Universal Declaration on the Human Genome and Human Rights declares the human genome to be “the heritage of humanity” and that “the human genome in its natural state shall not give rise to financial gains.”39 The Supreme Court quietly came to a similar conclusion, though with attention to preserving the incentives important for biomedical innovation. It is interesting that although the Supreme Court decision concerns human genes, humanness had no bearing on the decision. Nor does the law allow courts to consider whether patenting human genes — or anything else — should be disallowed on grounds of morality. There is a disconnect, then, between the reasons the Supreme Court articulated for its decision and the rich set of ethical and policy concerns that have animated much of the public interest in the case. Those powerful ideas may or may not have swayed the Court as it considered a vague and open-ended legal doctrine. If the questions raised during oral argument are any indication, however, the justices were primarily interested in innovation — both in preserving patent incentives for investing in research and in the blocking effects that patent rights can have on upstream discovery. Viewed in this light, the decision represents a careful balancing act.
Disclosure forms provided by the authors are available with the full text of this article at This article was published on July 10, 2013, at

Source Information

From the Division of Pharmacoepidemiology and Pharmacoeconomics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (A.S.K.), and the Department of Health Policy and Management, Harvard School of Public Health (M.M.M.) — all in Boston; the Institute for Genome Sciences and Policy and Sanford School of Public Policy, Duke University, Durham, NC (R.M.C.-D.); and the Department of Environmental Science, Policy, and Management, University of California, Berkeley, Berkeley (D.E.W.).

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