A landmark judgment of the U.S. Supreme Court ends Myriad Genetics Inc.’s exclusive rights over the DNA sequences of two genes, detection of whose mutations through diagnostic tests can reveal the risk of cancer in women. The court holds that merely isolating genes that are found in nature does not make them patentable. By R. RAMACHANDRAN

ON June 13, in a unanimous, landmark judgment, a nine-member bench of the United States Supreme Court overturned patents held by the Utah-based Myriad Genetics Inc. on two naturally occurring genes, BRCA1 and BRCA2. Certain mutations of these genes are known to have a role in a woman’s predisposition to hereditary breast and ovarian cancer because these compromise the genes’ ability to suppress cancerous growth. Detection of these mutations through genetic diagnostic tests can reveal if a woman is at increased risk of cancer. A woman with a BRCA mutation faces a 36 to 85 per cent chance of contracting breast cancer and a 16 to 60 per cent chance of contracting ovarian cancer.

The patents on the genes amount to claiming rights over every naturally occurring version of these genes on the grounds that Myriad invented something that is patent eligible just by isolating the genes from the body. That is, until now Myriad had exclusive rights over the deoxyribonucleic acid sequences of the two genes, their usage, mutations and genetic manipulations in them, diagnostic tests based on them and methods to screen for drugs based on their DNA sequences. Any use of these patented genes, either for commercial or for research purposes, amounted to patent infringement inviting a lawsuit.

The verdict pertains to Association for Molecular Pathology (AMP) and others vs Myriad Genetics and others. The case challenged the basis on which patents relating to BRCA1/2 had been granted to Myriad by the U.S. Patent and Trademark Office (USPTO). The AMP, founded in 1995, represents geneticists, pathologists and laboratory professionals, as well as individual researchers, breast cancer and women’s health groups, genetic counsellors and individual women, including those accused of infringing on Myriad’s patents on the BRAC genes. The American Civil Liberties Union (ACLU) and the U.S. Public Patent Foundation (PUBPAT) filed the lawsuit on behalf of the AMP on May 12, 2009.

Though the company had many patents based on its discovery and isolation (separation from the surrounding cellular material and the genetic material in the human genome) of the BRCA genes, the claims that were challenged included only three: the two granted for the isolated BRCA1/2 genes and the third for the associated construct of the complementary DNA (cDNA), which is a synthetic product that mirrors the protein-coding sequences of the genes and omits the non-coding sections. Since isolation of the genes is necessary for preparing “primers” (DNA fragments having short DNA sequences from the genes) for use in polymerase chain reaction-based genetic testing, for example, the patents covered the primers used in the diagnosis of breast/ovarian cancers as well.

According to the U.S. law 35 USC 101, “any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof” is patent eligible. This has been consistently interpreted by the U.S. courts to imply that laws of nature, abstract ideas and natural phenomena cannot be patented.

“A naturally occurring DNA segment,” the court ruled with regard to the patents in question, “is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patentable because it is not naturally occurring.” The court held that merely isolating genes that are found in nature did not make them patentable. “These discoveries do not involve the creation of a new and useful… composition of matter.”

“The decision helps to lay the foundation for continued research and application of diagnosis and treatment of diseases at the molecular level,” said the AMP in a press release. “We believe the court… removed a significant barrier to innovation in molecular pathology testing and we look forward to future advancements in clinical diagnostics and therapeutics that will accrue to the benefit of our patients and our field,” it added.

But BRCA1/2 are not the only human genes that have been granted patent protection and monopoly control over their chemical composition, all the information contained in them, and their usage. The USPTO has granted thousands of patents on isolated DNA sequences as a new and useful “composition of matter”, which are patent eligible under U.S. law. In fact, according to a 2005 study published in the journal Science, of the 23,688 human genes in the U.S. National Centre for Biotechnology Information’s gene database, 4,382 have claims of intellectual property on them. This means that about 20 per cent of our genes are patented.

The ACLU suit actually went beyond the specific case of BRCA genes. The petition’s arguments challenged the USPTO’s interpretation of the U.S. law in granting patents on human genes in general. The ACLU spokesperson, Briana Ryan, clarified in an email message that the patents that had already been issued on isolated DNA were no longer enforceable after the court’s ruling on BRCA1/2. Further legal proceedings would be necessary only to the extent that a patent holder tried to enforce them.

Thus, while the verdict will definitely have an impact on the validity of patents granted to all these other naturally occurring genes under U.S. law, it is also likely to have an influence on the nature of the broader discourse and practice with regard to gene patenting—a widely debated issue—in accordance with patent laws around the world, in particular those of the European Union/European Patent Office and Australia. The U.S. court’s judgment has already been referenced in the appeal in the Australian apex court against the patent granted to Myriad for the BRCA1 gene by a lower Australian court in February. The Indian Patents Act, 1970 (as amended in 2002 and 2005), already precludes patenting of naturally occurring genes; see sections 3(c) and 3(j) of the Act.

The judgment on Myriad’s patents comes after a four-year run of the litigation, and it is instructive to dwell a bit on its history. In 1990, a team of scientists led by Marie-Claire King from the University of California, Berkeley, discovered the BRCA1 gene through analysis of gene correlations with increased risk of breast cancer. They also localised it to the long arm of chromosome 17. Myriad Genetics was founded in 1994 as a start-up company by scientists from the University of Utah who were involved in research on BRCA genes.

In August 1994, researchers from Utah, along with their colleagues at Myriad, the U.S. National Institutes of Health (NIH) and McGill University, published the sequence of BRCA1 they had isolated. In the same year, a patent for BRCA1 was filed by Myriad, the University of Utah (through the Bayh-Dole Act) and the National Institute of Environmental Health (NIEH). In 1995, Myriad and Utah researchers isolated and sequenced BRCA2, and the first BRCA2 patent was filed in the U.S. by the University of Utah and other institutions. In 1996, Myriad launched its BRAC Analysis product, which detects mutations in BRCA1/2 genes which were regarded to put women at high risk of getting breast and ovarian cancer.

Like patenting oxygen

The case was originally heard in the Southern District Court of New York, which ruled in March 2010 that the claims of Myriad that had been challenged by the AMP were indeed not patent eligible. Myriad claimed that the isolated and modified genes were patent eligible because they did not occur in nature and isolation rendered them different in character from their form in the human genome. The company argued that since USPTO issued patents for genes as “isolated sequences” in the same way it issued patents for any other chemical compound, the patents were valid. The AMP, on the other hand, held that Myriad only isolated, and did not modify, a gene already existing in nature and that this isolated gene performed a function that was no different from the gene in natural form.

Myriad’s argument is akin to claiming a patent for separating oxygen from air or water, and not at all like creating a new chemical compound in the laboratory. Indeed, the district court had noted in its judgment how an earlier patent claim for purified tungsten had been turned down by the Supreme Court as it was not any new composition of matter. The other related patent granted to Myriad was for using the DNA sequences of BRCA1/2 for diagnostics by “comparing” and “analysing” the sequences for mutations. The district court’s verdict stated: “DNA’s existence in an ‘isolated’ form alters neither this fundamental quality of DNA as it exists in the body nor the information it encodes. Therefore, the patents at issue directed to ‘isolated DNA’ containing sequences found in nature are unsustainable as a matter of law and are deemed unpatentable under 35 USC 101.”

The court also declared that comparisons of DNA sequences were abstract mental processes and hence not patent eligible, and that the drug screening claims merely involved a basic scientific principle and were, therefore, unpatentable.

Myriad then appealed to the Federal Circuit Appeals Court. In spite of the fact that the Department of Justice had provided a unilateral opinion on the case that supported the plaintiffs’ argument, on July 29, 2011, the federal court overturned the district court’s decision in part and concurred with its verdict only with regard to the ineligibility of comparing DNA sequences for a patent. Relying on a misplaced comparison with a 1980 case, Diamond vs [Ananda] Chakrabarty, where a genetically modified organism had been granted a patent on the grounds that it was “markedly different” from those found in nature, the ruling concluded that since Myriad’s patents described DNA sequences that did not exist alone in nature, they were patent eligible. It also reversed the decision with regard to finding drugs for cancer using the DNA sequences by ruling that assays used to screen drugs were patentable.

Following this ruling, the AMP petitioned the Supreme Court asking for a review of the judgment. The apex court granted the writ and on March 26, 2012, revoked the original federal court decision and asked it to hear the case all over again. This was prompted in the wake of a Supreme Court judgment less than a week earlier in Mayo vs Prometheus Laboratories Inc., which held that certain medical diagnostics patents, which included natural phenomena (measurement of metabolites of that drug that decided the dosage of the drug), were not patentable. In this case, the Supreme Court had ruled that the correlation between the naturally produced metabolites and therapeutic efficacy and toxicity was an unpatentable “natural law”. The patent claims, the ruling said, were “efforts designed to monopolise the correlations.” The Supreme Court wanted the lower court to take cognisance of this ruling in Mayo vs Prometheus.

Following the rehearing of the case, in its ruling on August 16, 2012, the federal court only reiterated its earlier decision of awarding the patents on isolated BRCA1/2 sequences to Myriad. The 2:1 decision was identical to the earlier one. And, now reinforced by the verdict on Mayo vs Prometheus, it also reiterated, in concurrence with the district court’s ruling, that patent claim on “comparing” or “analysing” DNA sequences cannot be sustained as they involved no transformative or inventive steps and were merely abstract mental steps.

However, there was a note of dissent by one of the judges, which aptly puts the issue with regard to granting gene patents in the correct perspective. He wrote: “Just as a patent involving a law of nature must have an ‘inventive concept’ that does ‘significantly more than simply describe…natural relations’,… a patent involving a product of nature should have an inventive concept that involves more than merely incidental changes to the naturally occurring product. In cases such as this one, in which the applicant claims a composition of matter that is nearly identical to a product of nature, it is appropriate to ask whether the applicant has done ‘enough’ to distinguish his alleged invention from the similar product of nature. Has the applicant made an ‘inventive’ contribution to the product of nature? Does the claimed composition involve more than ‘well-understood, routine, conventional’ elements? Here, the answer to those questions is no. Neither isolation of the naturally occurring material nor the resulting breaking of covalent bonds makes the claimed molecules patentable…. The functional portion of the composition—the nucleotide sequence—remains identical to that of the naturally occurring gene.”

Following the federal court’s verdict, which was a return to the status quo, the ACLU and the PUBPAT filed another petition for a review of the second federal court ruling. In November 2012, the Supreme Court admitted the appeal for the review. The hearing took place on April 15 and the judgment, which will have a significant bearing on the ongoing world-wide debate on whether naturally occurring genes when isolated from the body become patentable, was delivered on June 13.

Watson's observations

James Watson, who, along with Francis Crick, discovered the double helical structure of the DNA (for which they won the Nobel Prize in Medicine in 1962), submitted a brief to the courts, which is significant for its observations. Finding fault with the federal court’s reasoning, Watson said that it had focussed on trivial chemical differences that result once DNA is removed from the cell and disregarded how isolated DNA encodes for the same proteins as DNA in one’s body. “The myopic viewpoint thinks of a human gene as merely another chemical compound, composed of various bases and sugars…. A human gene, which is a product of nature, is useful because it conveys vital information,” he said.

Another critical issue with regard to gene patents is whether they impede scientific research and foreclose innovation. Watson stated, “To this day, we continue to learn how human genes function. We estimate that humans have approximately 22,000 genes. We have yet to fully understand the functions of all human genes, but this lack of understanding is further reason that scientists should be permitted to experiment on human genes free from any threat of patent infringement.”

As the ACLU has said, “Gene patents—unlike patents on drugs or tests —cannot be ‘invented around’ because they claim DNA itself. While another company can create a new drug to treat the same condition as another patented drug, patents on DNA block access to people’s genetic information. They stop other labs from testing the patented genes—regardless of the testing method that is used or whose sample is tested—and chill research, impeding the progress of science. As a result, patients face barriers to obtaining the most comprehensive testing, second opinions and low-cost testing.”

Indeed, the Supreme Court did dwell on such instances. “Myriad,” the judgment said, “was not the only entity to offer BRCA testing after it discovered the genes. The University of Pennsylvania’s Genetic Diagnostic Laboratory [GDL] and others provided genetic testing services to women. Petitioner Dr Harry Ostrer, then a researcher at New York University School of Medicine, routinely sent his patients’ DNA samples to GDL for testing. After learning of GDL’s testing and Ostrer’s activities, Myriad sent letters to them asserting that the genetic testing infringed Myriad’s patents. In response, GDL agreed to stop testing and informed Ostrer that it would no longer accept patient samples. Myriad also filed patent infringement suits against other entities that performed BRCA testing....”

In an article on May 14 in The New York Times, which was perhaps coincidentally timed with the ongoing litigation with regard to BRCA1/2 patents to Myriad, American actress and celebrity Angelina Jolie noted in the context of her decision to undergo double mastectomy to reduce the risk of breast cancer: “It has got to be a priority to ensure that more women can access gene testing and life-saving preventive treatment, whatever their means and background, wherever they live. The cost of testing for BRCA1 and BRCA2, at more than $3,000 in the U.S., remains an obstacle for many women.” What she either perhaps did not realise was that this was a direct consequence of Myriad’s complete control over the genes and their usage in diagnosis. But her article has indeed resulted in an increased number of women queuing up for BRCA1/2 testing worldwide, including in India.

In a statement, the ACLU said, “While genetic testing technologies have advanced to the point where all 23,000 human genes can be sequenced for $1,000, Myriad has raised its price for BRCA genetic testing to over $4,000 in the last few years and still does not capture all known BRCA mutations [emphasis added]. Other laboratories cannot provide second opinions, and they cannot include the BRCA genes when offering testing of the multiple genes that are now associated with breast and ovarian cancer risk.... And by virtue of its patents, Myriad controls most of the data about the BRCA genes and has refused to share that information with the scientific community.”

Indeed, in a recent interview following the Supreme Court verdict, Marie-Claire King said: “What was different about Myriad was its insistence that it was the only entity that could do the test and its aggressive efforts to shut down anyone else…. Developing multi-gene panels—one-stop shops for testing for susceptibility to breast and ovarian cancers on many genes—has been a very high priority. The multi-gene test we developed, called BROCA, has been used for months, but until today we had to mask BRCA1 and BRCA2. The Supreme Court ruling removes the illogical situation of being able to test all genes but having to mask some.”

It may be noted here that the Myriad’s patents on BRCA1/2 and associated testing technique will, in any case, expire after the mandatory 20 years, which is 2014-15. One could, therefore, argue that the true impact of the Supreme Court’s decision may not be all that substantive.

“The Myriad decision is important… [as] already, a number of additional laboratories are offering BRCA1 and BRCA2 testing, and costs have fallen substantially,” the AMP’s spokesperson Roger Kline said in an e-mail message. “The impact of the case is far broader… as it removes intellectual property barriers to genetic testing for many other patented genes. Therefore, our members are likely to begin testing for other genes previously covered by valid patents. We expect the increased competition this engenders to lower costs, increase patient access, and accelerate innovation in both clinical testing and research,” he added.