Prometheus bound, but myriad loose ends

Within hours of a Supreme Court decision in June 2013 that seemed to clear the way for wider testing of the BRCA1 and BRCA2 genes, 2 companies jumped into a lucrative market that had been monopolized by Salt Lake City-based Myriad Genetics. That is when things got interesting, with a new round of patent infringement lawsuits, an antitrust countersuit, and a growing sense of how little has been resolved in the attempt to distinguish between a natural, nonpatentable process and a synthetic, patentable one. “Perhaps the biggest upshot of the decision is that it's going to be providing employment to patent litigation attorneys for the foreseeable future,” says Jacob Sherkow, JD, a fellow at Stanford Law School Center for Law and the Biosciences in Stanford, California. The high-stakes wrangling over the largest-volume genetic analysis in the world, which has quantified breast and ovarian cancer risk for more than 1 million women, is also turning on issues of accessibility and accuracy. More broadly, experts say the case illustrates how a contentious legal battle that could wend its way through the courts for years may yet be superseded by technological advances. Although the patentability of biological material has been litigated for decades, a landmark case in 2012 set the stage for the BRCA ruling. In Mayo Collaborative Services v. Prometheus Laboratories Inc, the US Supreme Court unanimously struck down 2 testing patents held by San Diego-based Prometheus Laboratories. The test in question had been designed to check metabolite levels in patients' blood to establish the proper dosage of thiopurines. The court invalidated what it ruled was an attempt to patent a natural process that amounted to reciting a law of nature and then instructing physicians to apply that law. “Einstein could not patent his celebrated law that E=mc2, nor could Newton have patented the law of gravity,” wrote Justice Stephen Breyer in his decision. That finding prompted a judicial review of Myriad's patent claims, and in another unanimous decision, the court ruled that merely discovering “products of nature” such as genes and genetic markers does not make them patentable. The court did, however, uphold the notion of patentable cDNA, or synthetic DNA, a move that court watchers attributed to its desire to preserve therapeutic protein patents. A long list of plaintiffs, including multiple public interest groups, cheered the apparent end of the BRCA testing monopoly. However, when Ambry Genetics of Aliso Viejo, California, and Houston-based Gene by Gene Ltd began selling their own test versions within hours of the court's decision, Myriad and 4 patent co-owners filed new lawsuits. Myriad contends that its BRCA-related probes, primers, and other specifically designed DNA segments are still valid and enforceable intellectual properties, even if the actual genes and mutations are not. With an investment of $500 million, the company has signaled that it intends to fight to the end. Legal experts say the cases are likely to hinge on 2 overriding questions: whether Myriad's previously untested claims remain valid, and whether Ambry and Gene by Gene's sequencing methods infringe on those claims. The first question may provoke the biggest battle, whereas the second may require a deep slog through technical molecular biology terrain. Ardy Arianpour, Ambry's senior vice president of business development, maintains that his company's next-generation sequencing methods do not involve cDNA analysis and therefore do not infringe on existing claims. “Our methodology analyzes isolated genomic DNA,” he stresses. And that, he says, “is fair game.” Ambry also filed an antitrust countersuit that contends Myriad is “using overreaching practices to wrongfully monopolize the diagnostic testing” of the BRCA genes. “It's about freedom of your genes,” says Arianpour. “The BRCA patent owners are confident in our case, and we believe that Ambry's counterclaims are without merit,” replies Myriad spokesman Ronald Rogers. Robert Cook-Deegan, MD, a research professor at the Institute for Genome Sciences and Policy and the Sanford School of Public Policy at Duke University in Durham, North Carolina, sees strengths and weaknesses on both sides. “I don't think either one of them has a slam-dunk case,” he says. Ambry's counterclaim also alleges that Myriad employees have wrongfully inflated Ambry's BRCA variant of unknown significance (VUS) rate to between 10% and 30%. The rate refers to genetic variations that lack a known consequence, meaning they cannot be functionally classified or clearly linked to cancer risk. In fact, Arianpour says, his company's rate is closer to 5%. Myriad itself claims a VUS rate of less than 3%, but critics contend that without sharing any of its data publicly, its assertion of superiority has been impossible to vet. “Who in the world knows whether that's true or not, other than Myriad?” Dr. Cook-Deegan says. “And the answer is, no one. There's no way to independently verify that.” Furthermore, he says, other laboratories would be hard-pressed to ever match Myriad's VUS rate without outside access to its huge and proprietary database. The legal case received an unexpected burst of public attention in mid-May. In an op-ed piece in The New York Times, actress Angelina Jolie announced her decision to undergo a double mastectomy based on Myriad test results suggesting that her BRCA1 mutation gave her an 87% chance of developing breast cancer and a 50% chance of being diagnosed with ovarian cancer. In the first few weeks after her announcement, calls for new appointments at the GenRISK Adult Genetics Program at Cedars-Sinai Medical Center in Los Angeles tripled in number, according to program director Ora Karp Gordon, MD, MS. Through the normally slow summer months, the program saw a sustained doubling of its initial rate. News accounts have suggested a similar uptick elsewhere. “It's been incredible, in terms of both a change in awareness and a huge influx in interest and demand for risk assessment and evaluation,” Dr. Gordon says. “That impact I never would have ever anticipated.” The unprecedented demand has sharpened the focus on both accessibility and cost. Whereas Myriad had been charging roughly $4000 for its comprehensive BRCA test, Ambry and Gene by Gene set their prices at $2200 and $995, respectively. “We've had an overwhelming response from our clients,” says Arianpour. Dr. Gordon credits Myriad with transforming what was once an inefficient and largely academic BRCA test into a highly efficient and user-friendly commercial product with a turnaround time of fewer than 2 weeks and nearly universal coverage by major insurers (in Europe and Canada, by contrast, the turnaround time is generally measured in months). However, she faults the company for aggressively protecting a monopoly that has kept out not only other commercial interests, but also academic researchers seeking data. “It's time to let it go,” she says. Regardless of how the Myriad lawsuits play out, observers note that the outcome may have limited ramifications for other genetic tests. The majority of other genetic testing patent holders have licensed their technology to outside laboratories and made their variant data publicly available, for example, potentially curbing any spillover effect. In addition, the first of Myriad's BRCA-related patents will begin expiring in 2016, meaning that the company's monopoly may soon end anyway. Once the patents expire, Sherkow says, “the road is open.” As he points out, US patents are enforceable only within the United States, which also means foreign companies could offer BRCA testing to patients who mail in saliva samples. Even if the remaining legal issues are not definitively resolved by the courts anytime soon, rapidly advancing sequencing technology may render many of those issues moot. With the rise of next-generation sequencing making multigene testing increasingly attractive to insurers and providers due to more comprehensive and cost-effective risk information, the days of single-gene tests may be numbered. In September 2013, Myriad followed the lead of other testing companies and launched myRISK, a 25-gene panel that covers 6 cancers. Multigene panels based on whole-genome sequencing, several experts say, will not only become the new standard of diagnostic care but also be less vulnerable to patent infringements based on cDNA, primers, and probes. “Ten years from now, nobody—and I repeat, nobody—is going to be offering patented, single-gene sequencing tests with clinical data in a monopolistic fashion,” Sherkow says. “I think the technology is going to outstrip the need to resolve any of these difficult questions.”

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