Originally published April 4.
This article has been updated with additional comments from Duke University's Robert Cook-Deegan.
By Turna Ray
Pressured by questioning from three federal circuit judges, Myriad’s legal counsel said in court this week that whole-genome sequencing that doesn’t involve an isolation step enabling specific investigation of BRCA mutations would not infringe the company's patents related to its flagship BRACAnalysis test.
The US Court of Appeals for the Federal Circuit on Monday heard Myriad’s appeal to overturn a New York Southern District Court’s decision last March that 15 claims in seven of its patents were invalid.
Last year, federal district court Judge Robert Sweet held that these patent claims on isolated DNA containing BRCA1/2 gene sequences, conferring susceptibility to the hereditary risk of breast and ovarian cancer, were not markedly different from naturally occurring gene sequences in the body, particularly in the information they contain. Sweet also asserted in his decision that comparisons of DNA sequences are abstract mental processes, which are also unpatentable under US patent law (PGx Reporter 03/31/10).
The appeal was heard by three circuit judges: Kimberly Moore, Alan Lourie, and William Bryson. Plaintiffs in the case, represented by the American Civil Liberties Union and the Public Patent Foundation, had filed a motion last year asking appeals court Chief Judge Randall Rader to recuse himself from the case due to statements he made that allegedly suggested a bias in favor of Myriad.
During the oral arguments, it was clear the circuit judges were well versed in the scientific complexities of the case. Given that the US Patent and Trademark Office has been granting patents on isolated gene sequences for more than 30 years, the judges openly acknowledged that the outcome of the case could have a great impact on the biotechnology and drug development industry.
The judges vigorously questioned both the defendants' and plaintiffs’ lawyers as to whether the case has standing as a result of an “immediate controversy” or a “definite or concrete dispute;” whether isolated gene sequences were sufficiently different from naturally occurring DNA; patentability of isolated gene sequences; and whether unspecified methods of “comparing” gene sequences are abstract mental processes.
However, throughout the hearing the discussion kept coming back to whether Myriad’s broad patents claims could potentially impact researchers and doctors looking at BRCA mutations within the context of a person’s whole genome. This exact question has been often pondered by academic researchers currently developing advanced whole-genome sequencing technologies and attempting to integrate these technologies more readily in healthcare.
According to experts PGx Reporter spoke to, Myriad's explanation in court regarding when whole-genome sequencing efforts might encroach on its BRCA patents was not very informative and raises even more questions.
The Question of Whole-Genome Sequencing
This was the first time Myriad has taken a public stance on the question of whether whole-genome sequencing techniques could potentially infringe its patents. Myriad’s BRACAnalysis test currently employs Sanger sequencing and PCR methods to gauge BRCA 1/2 mutations in women. The company has stated it is looking into next-generation sequencing techniques but has not introduced any tests that employ this method.
At the start of the hearing, when the circuit judges first raised the question of whether sequencing the whole genome of a person could infringe the company’s patents, Gregory Castanias, a Jones Day lawyer representing Myriad, didn’t give a straight answer. “I’m not sure my client has formed a view on that” issue, he said.
However, as the hearing proceeded, the judges kept returning to the topic, and by the end of the proceedings they were able to draw out from Castanias that Myriad has “made no claim to the entire genome.” Specifically, he noted that without an isolating procedure directed at gauging BRCA mutations, whole-genome sequencing would not infringe Myriad’s patents. Castanias, however, did not specify any particular method of “isolation.”
According to Robert Cook-Deegan, director of Duke University's Center for Genome Ethics, Law & Policy, Myriad's explanation doesn't provide whole-genome sequencing service providers and researchers much guidance given the vagueness of the term "isolation." Cook-Deegan has led several studies investigating the impact of gene patenting on patient access, test cost, and the genetic testing industry. He and Christopher Holman from the University of Missouri - Kansas City School of Law have submitted an amicus brief in AMP v. USPTO, in support of neither party.
"How do you do DNA sequencing without some purification step? Even nanopore or scanning-tunneling [electro machining] means isolating some piece of DNA," Cook-Deegan told PGx Reporter. "That's an 'isolated' molecule you're measuring. It's a meaningless distinction."
The general view among researchers has been that not only Myriad’s patents, but the whole US patent system, won’t be able to address gene patenting in the era of whole-genome sequencing.
At a gathering of genomics leaders in Cambridge, Mass., last year, Harvard University’s George Church observed that as the personalized medicine field makes greater use of whole-genome sequencing, "Myriad is losing the bigger battle." A leader of the Human Genome Project and a proponent of making individual genome sequences publicly available through the Personal Genome Project, Church suggested at the meeting that companies providing raw genome sequence data cannot be sued by Myriad.
"The entire industry will be reformatted" and gene association patents as they exist today "won't really matter," Church said at the time.
Since then, researchers have not only employed whole-genome sequencing techniques to try to improve methods for gauging BRCA mutations, but they have publicly discussed their findings.
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Mary-Claire King, a genetics pioneer who discovered the link between BRCA1 mutations and the hereditary risk for breast and ovarian cancers and who runs a sequencing laboratory at the University of Washington, published a proof-of-principle study in April 2010 in the Proceedings of the National Academy of Sciences, in which she and her UW colleagues demonstrated that they could specifically capture and sequence 21 breast and ovarian cancer-associated genes, including BRCA1 and BRCA2, for less than $1,500 per sample.
Whole genome sequencing companies don’t have an unified stance when reporting of BRCA mutations. Knome has said it does not report BRCA mutations in its whole-genome analysis service. However, one can learn of one’s BRCA mutation status through Illumina whole-genome sequencing service. Although Illumina’s service only reports the raw genome data, customers can choose have their genomic data analyzed through direct-to-consumer genomics firm 23andMe, which does provide information on BRCA mutation status.
What Was Said and Left Unsaid
Courtenay Brinckerhoff, vice chair of the law firm Foley & Lardner’s Chemical, Biotechnology & Pharmaceutical Practice, felt that Myriad’s stance on the intersection of its patents with whole-genome sequencing may be different from a court’s view on the subject, and hinges on the exact meaning of “isolated” in the claims.
“If ‘isolated’ means isolated from the rest of the genome, then Myriad is right,” Brinckerhoff told PGx Reporter in an e-mail. “If ‘isolated’ just means isolated from its natural surroundings, than maybe isolating the chromosome would be sufficient.”
During the hearing, ACLU attorney Christopher Hansen cited Church’s Personal Genome Project – through which a number of people have put their whole genome sequences online – to illustrate that anyone potentially seeking BRCA mutations in these published genomes could potentially be infringing Myriad’s patents. Although Myriad’s lawyer had earlier noted that the company is not claiming the entire human genome, Hansen wasn’t reassured.
He pointed out that the broadness of Myriad’s patents leaves open the possibility that the company may take action against doctors and researchers who are identifying their patients’ BRCA mutations via whole-genome sequencing techniques.
There are whole-genome sequencing techniques that wouldn’t require the use of probes and primers to which Myriad has patents to investigate BRCA 1 and BRCA 2 gene mutations. As such, Hansen noted that those whole-genome sequencing methods would not infringe Myriad’s patents.
Although Myriad’s claims on probes and primers used to generate cDNA related to the BRACAnalysis test are not challenged by the plaintiffs, much of the confusion surrounding the potential impact of Myriad’s patents on whole-genome sequencing arises from the fact that some of the company’s challenged claims cover large stretches of the BRCA gene and make no mention of specific probes or primers.
For example, Claim 1 of Myriad's US Patent No. 5,747,282 describes "an isolated DNA coding for a BRCA1 polypeptide, said polypeptide having the amino acid sequence set forth in SEQ ID NO:2."
As the US Department of Justice pointed out in it is amicus brief in the appeals case, “claim 1 of the '282 patent encompasses any isolated DNA molecule whose nucleotide sequence codes for the natural BRCA1 protein.
"This would include an ordinary BRCA gene isolated from a tissue sample taken from a woman in a hospital,” the DoJ wrote.
In its brief to the appeals court, the DoJ expressed the US government’s position on gene patenting for the first time, though the USPTO, a defendant in the case, did not sign the amicus brief. According to the brief, the government believes that the New York Southern District Court wrongly invalidated Myriad Genetics' composition claims "directed solely to cDNAs.” However, the government agrees with the lower court that genes as they occur in the body are not products of human invention worthy of a patent (PGx Reporter 11/03/2010).
"Crossing the threshold of [patentability under 35 USC] Section 101 … requires something more than identifying and isolating what has always existed in nature, no matter how difficult or useful that discovery may be," the DoJ stated.
Speaking at the appeals hearing this week, acting Solicitor General Neal Kumar Katyal reiterated the US DoJ’s position on gene patenting.
Although Judge Lourie had inquired throughout the hearing as to whether the breaking of covalent bonds when separating naturally occurring substances from their environment meets the requirements of patentability, Katyal disagreed. He cited the example of lithium, which is not patented and must be separated from other minerals occurring in nature by breaking covalent bonds.
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