Are Human Genes Patentable? Free

On 15 April 2013, the Supreme Court heard arguments to address the question, “Are human genes patentable?” and will deliver its ruling by the end of June. This will conclude a lawsuit that was filed on 12 May 2009, in the Federal District Court for Southern New York, Judge Robert Sweet presiding (1). The case centers on patents underlying genetic testing for inherited risk for breast and ovarian cancer attributable to 2 genes, BRCA1 and BRCA2. The patents enabled Myriad Genetics (Salt Lake City, Utah) to establish a service monopoly on such testing in the United States, with rights extending to clinical research and follow-up testing in cases of ambiguous results that Myriad does not authorize or perform itself. These patents have been highly controversial for more than 15 years (2).

The lawsuit is an unusual patent case in several respects. Most of these suits pit one company or inventor against another and center on who will get and enforce exclusive patent rights. This particular case is about changing the law by challenging whether patents on genes should be granted at all. The American Civil Liberties Union organized and litigated the case, with the Public Patent Foundation affiliated with Cardozo Law School in New York. It is the Union's first venture into patent law and the first public interest patent case in the United States.

The initial plaintiffs were individuals and organizations who objected to Myriad's patents on BRCA1 and BRCA2 genes. Plaintiffs included women who wanted testing done, physicians who wanted to test patients, and laboratory directors who wanted to offer BRCA testing. Other plaintiffs were organizations representing laboratory professionals, clinical geneticists, and breast cancer advocates. They sued Myriad and the U.S. Patent and Trademark Office (which was subsequently dropped from the suit).

In March 2010, Judge Sweet delivered a summary judgment that invalidated all 15 claims in 7 patents held by Myriad (3). Claims are the heart of a patent, defining its intellectual property. Myriad has another 17 patents and more than 500 claims pertaining to BRCA, but only 7 patents have been challenged in this case. A patent grants exclusive rights to make, use, sell, or import the claimed invention. Myriad's patents included 2 general categories of claims: methods for detecting “alterations” or mutations in the DNA sequence and isolated DNA molecules. The broadest method claims gave exclusive rights to any way of comparing the DNA sequence from a sample to the reference sequence of the BRCA1 and BRCA2 genes disclosed in Myriad's patents. These method claims were invalidated because they were based only on “comparing” or “detecting” variations. They neither entailed a transformation nor specified a machine. The isolated nucleic acid molecule claims covered sequences from the 2 BRCA genes. The patents did not claim DNA from a person's body, but claims were nonetheless broad and deliberately crafted to preclude others from making or using DNA molecules or detecting mutations. Judge Sweet argued that DNA is the embodiment of genetic information and claims on isolated DNA molecules in effect block access to that information. He ruled that the claimed molecules were not “markedly different” from corresponding, naturally occurring DNA molecules simply because they were isolated. He also ruled that the plaintiffs could sue.

However, following appeal to the Court of Appeals for the Federal Circuit (CAFC), a 3-judge panel ruled in July 2011 that only 1 of the plaintiffs had standing to sue, but that was sufficient (4). The CAFC affirmed Judge Sweet's invalidation of 5 broad method patents, arguably Myriad's broadest, and the hardest to work around. It also unanimously agreed that engineered DNA molecules, such as complementary DNA (cDNA), are eligible for patenting, thus reversing Judge Sweet's ruling that no DNA molecules are patent-eligible. The CAFC also unanimously upheld 1 method patent for using BRCA in screening drugs for cancer treatment.

The panel was split 2-to-1, however, on the matter that ultimately went to the Supreme Court—whether isolated DNA molecules corresponding to sequences in human genes are eligible to be patented. Judges Lourie and Moore said “yes,” although for somewhat different reasons, and Judge Bryson dissented, saying that the claimed DNA molecules were not markedly different in a way that should make them eligible to patent.

The Supreme Court returned the case to the CAFC in 2012 (5) after deciding another case, Mayo Collaborative Services v. Prometheus Laboratories, Inc., in which it unanimously invalidated patents over a laboratory test for a metabolite used to adjust doses for thiopurine drugs (6). In August 2012, the CAFC largely reiterated its prior ruling, with the same 2-to-1 split (7). In November 2012, the Supreme Court agreed to hear the case.

It is highly significant that the Solicitor General filed amicus briefs twice before the CAFC and once more before the Supreme Court (8, 9). The original decision to file a brief in October 2010 ended a contentious process within the executive branch. Officials from the National Institutes of Health and the U.S Patent and Trademark Office disagreed. The Solicitor General is the final arbiter of the government's position and argues cases before the higher courts. The final decision to weigh in was made at the White House. Solicitor General briefs are highly influential: In 10 of 12 patent cases in which the Solicitor General and the CAFC have disagreed, the Supreme Court has ruled with the Solicitor General (10). The Solicitor General's briefs tracked with Judge Bryson's dissenting argument that engineered DNAs, including cDNAs, are patent-eligible, but DNA molecules whose sequences are found in nature are not. The most recent brief also makes quite clear that the government's position was a deliberate step away from 3 decades of the U.S. Patent and Trademark Office's practice in granting claims on isolated DNA molecules whose sequences occur in nature.

The April 15 arguments demonstrated the justices' familiarity with the Solicitor General's brief. Their questions probed arguments against the Solicitor General's logic, but they heard only feeble counterarguments punctuated by technical gaffes. Two concerns were repeatedly aired. One was that Myriad's claims reached far upstream into research and innovation, precluding the study of BRCA genes. Many analogies centered on this basic concern, including ingredients in chocolate chip cookies, baseball bats, and anticancer sap from plants in the Amazon. Other questions signaled real concern about disrupting patent rights for biotechnology products. The justices sought assurance that barring patents on isolated DNA molecules with naturally occurring sequences could still preserve the claims on cDNA that undergird commercially valuable therapeutic proteins. If the questions predict an outcome, it is likely to be that isolated genomic DNA is not patentable, but engineered DNA molecules are.

Such a ruling would not threaten most patent claims that underlie therapeutic proteins (such as insulin, growth hormone, and erythropoietin) but would invalidate many claims on molecules and methods for DNA molecular diagnostics, weakening companies like Myriad Genetics and Athena Diagnostics. Other companies, such as those that offer multigene tests, exome sequencing, and whole-genome analysis, will breathe a sigh of relief as the shadow of infringement liability lifts.

The case might never have reached the highest court had Myriad Genetics adopted 2 policies it has long been urged to articulate: allowing research use and providing verification and follow-on biologic testing after initial BRCA testing. Myriad does not do expression analysis, knock-in or knock-out models, or other kinds of testing sometimes necessary to interpret ambiguous initial sequence-based testing. Most plaintiffs would no longer have had complaints, and the Supreme Court's concern about preempting science and innovation would be moot. By preserving its legal options to sue over research use and verification testing, Myriad may have killed its cash cow 2 years before its patents began to expire.

Myriad has recently reported its best financial quarter ever, projecting more than $500 million in revenue from its various BRCA tests in 2013. It runs an efficient laboratory and secures third-party payment. Moreover, all 3 CAFC judges agreed that Myriad could obtain patents on claims for primers, probes, and DNA constructs it made and disclosed. However, the Supreme Court seems to be poised to judge that Myriad's claims reached too far to secure exclusive rights on naturally occurring DNA sequences. If so, companies developing molecular diagnostics will have to comport with a new rule for U.S. patent jurisprudence: Yes, cDNA can be patented, but not genomic DNA.

This article was published at www.annals.org on 11 June 2013.