By Turna Ray
In unanimously invalidating Prometheus Laboratories' patent clams on gauging metabolites to dose thiopurine drugs, the US Supreme Court this week indicated that merely using "well-understood, routine, conventional" methods to correlate naturally occurring biological processes to treatment decisions isn't patent eligible — a ruling that is likely to have a broad impact on diagnostics developers and the personalized medicine field.
Section 101 of the Patent Act restricts the patenting of "laws of nature, natural phenomena, and abstract ideas." In its decision in Mayo Collaborative Services v. Prometheus Laboratories, issued on Tuesday, the Supreme Court acknowledged that "an application of a law of nature … to a known structure or process may [deserve] patent protection," but emphasized that in order to transform a law of nature into something worthy of a patent, the applicant "must do more than simply state the law of nature while adding the words 'apply it.'"
The patent "must limit its reach to a particular, inventive application of the law," the court held.
It is not clear how this ruling will impact another ongoing lawsuit of interest to the personalized medicine community, Association for Molecular Pathology et al. vs. the United States Patent and Trademark Office et al., where the patentability of isolated gene sequences is at issue. The plaintiffs in that case, the American Civil Liberties Union and the Public Patent Foundation, have filed a writ of certiorari with the Supreme Court, challenging an August 2011 decision by the Court of Appeals for the Federal Circuit that such patents on BRCA 1 and BRCA 2 genes, held by Myriad Genetics, are valid (PGx Reporter 8/3/2011).
The Supreme Court has not yet decided whether it will hear this case. Still, following news of the court's decision in Mayo v. Prometheus, Myriad's stock fell 5 percent from the previous day's close to $24.31.
While the two cases appear to have much in common, there are differences between the patents at the heart of the suits that make it difficult to predict the court's next steps with regard to AMP v. USPTO.
For example, the Prometheus claims described a patented process or method, and ACLU/PUBPAT want to challenge at the Supreme Court level Myriad's patent claims describing the chemical composition of isolated gene fragments. The "isolation of blood" at issue in Prometheus's patents, and the "isolation of DNA" involved in Myriad's patents, "are different processes (albeit both are considered relatively simple scientifically)," analyst David Ferreiro of the investment firm Oppenheimer & Co. pointed out in a research note.
Following its decision in Mayo v. Prometheus, the Supreme Court can take several actions in AMP v. USPTO: it could grant ACLU/PUBPAT's writ of certiorari, reject it, or remand the case to the federal court of appeals to review its decision in light of Mayo v. Prometheus.
Regardless of its impact on gene patenting specifically, the decision in Mayo v. Prometheus certainly stands to impact diagnostics developers and the personalized medicine field at large.
"The decision regarding Prometheus sweeps away very broad patent claims. This is perhaps bad for the folks who hold those patents and wanted to seek rents on them," Robert Cook-Deegan, director of Duke University's Center for Genome Ethics, Law & Policy, told PGx Reporter via e-mail.
He added that the method claims described in the Prometheus patents "are much more apt to block diagnostics use, harder to work around, and probably more common than DNA molecule claims. So these [types of patent claims] being invalidated frees up a bunch of space for developing new tests."
Moreover, Quest subsidiary Athena Diagnostics may be harder hit than Myriad by the decision in Mayo v. Prometheus. PUBPAT Executive Director Daniel Ravicher has said that the ACLU and PUBPAT initially considered challenging Athena's method patents and composition-of-matter claims, because the company has also aggressively exercised its exclusive licenses on genetic tests to block research and test access, but decided to take on Myriad instead.
The Supreme Court's conclusions regarding the Prometheus method claims could "sweep away some of Athena's patents, including all three ApoE Alzheimer's patents from Duke University (pure method-association patents) and some of their other broad method claims," Cook-Deegan reflected. "I would hope it will start a rash of re-examinations or challenges … Everybody is talking about Myriad, but it's Athena whose business model is most threatened."
Invalidating the Conventional
The Supreme Court granted writ of certiorari to Mayo last year after the company challenged a federal appeals court decision that upheld two method patents – US Patent Nos. 6,355,623 and 6,680,302 – to which Prometheus held exclusive licenses.
Prometheus first sued Mayo in 2006 when the lab said it would stop using Prometheus's tests for determining doses of thiopurine drugs because it had developed its own tests. In its defense, Mayo held that the Prometheus patents — describing methods of "administering" and "determining" whether metabolite levels in the body are indicative of harmful levels of thiopurine drugs to treat stomach disorders — claim a natural phenomenon and are therefore patent ineligible under the Patent Act.
A district court agreed with Mayo, deeming Prometheus's claims not patentable, but that decision was overturned by the Court of Appeals for the Federal Circuit. Even after Mayo appealed to the Supreme Court and the higher court sent the case back to the federal circuit court for a second look, the appeals court upheld its earlier decision.
With its second petition to the Supreme Court, Mayo's position is finally upheld. According to the Supreme Court justices, Prometheus' claimed patents do not sufficiently transform a naturally occurring phenomenon into patentable subject matter.
"Because the laws of nature recited by Prometheus’ patent claims — the relationships between concentrations of certain metabolites in the blood and the likelihood that a thiopurine drug dosage will prove ineffective or cause harm — are not themselves patentable, the claimed processes are not patentable unless they have additional features that provide practical assurance that the processes are genuine applications of those laws rather than drafting efforts designed to monopolize the correlations," wrote Justice Stephen Breyer in issuing the decision of the court.
Specifically, the court rejected Prometheus's claims instructing a doctor to "administer" the drug to a patient; telling the doctor to "determine" or measure the metabolite level in the patient after the drug is given; and discussing the metabolite concentrations at which the patient might experience drug-related harms or might not derive any benefit.
"Doctors had been using these drugs for this purpose long before these patents existed," the Supreme Court determined. "Because methods for making such determinations were well known in the art, this step simply tells doctors to engage in well-understood, routine, conventional activity previously engaged in by scientists in the field."
As such, "we conclude that the patent claims at issue here effectively claim the underlying laws of nature themselves," Breyer wrote. "[Prometheus'] claims are consequently invalid. And the Federal Circuit’s judgment is reversed."
Drug and diagnostic industry stakeholders have been closely following Mayo v. Prometheus because of its potential to shape the intellectual property landscape around personalized medicine products, which usually involve methods of measuring naturally occurring molecules in the body to make treatment decisions.
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The Supreme Court decision "may not come as a surprise to those who have been following this case," but the court's decision that Prometheus' claims are invalid because they claim laws of nature "upsets the status quo of patent-eligibility that was upheld twice by the Federal Circuit and supported by the Patent Office," Courtenay Brinckerhoff, a partner at the law firm Foley & Lardner, told PGx Reporter via e-mail.
In Brinckerhoff's view, the justices didn't provide any concrete direction about how a patentee might apply a law of nature in a way so that the method would be patent eligible.
"While the court parsed each method step and found each to be conventional, it stopped short of advising that claims with 'less conventional' features would have satisfied Section 101, thus providing little concrete guidance for applying this decision to other cases in the personalized medicine field," she noted. "On the other hand, the court was careful to distinguish patents directed to 'a new drug or a new way of using an existing drug.'"
In a statement, Prometheus warned that the Supreme Court's decision will spur development of "me too" healthcare products at the expense of true innovation. "Without the availability of patent protection, future healthcare will suffer as companies may opt out of new research and development," it said. "This decision will, in our view, encourage imitation, not innovation."
The potential impact of the decision on Myriad's patents is also driving speculation in the industry.
Analysts on Wall Street this week sought to manage investor reactions to the Supreme Court's decision in Mayo v. Prometheus by downplaying its potential impact on the gene patents at issue in AMP v. USPTO. Some industry observers opined that if the Supreme Court were to remand AMP v. USPTO to the federal appeals court, asking it to revisit its prior decision in light of Mayo v. Prometheus, then the appeals court will likely uphold its invalidation of Myriad's methods claims and still maintain that the composition-of-matter claims on genes are valid.
"The Supreme Court's decision to invalidate Prometheus' patents … should have limited implications for the relevance of [Myriad's] composition-of-matter patents, in our view, which are more critical to the strength of Myriad's IP estate," analyst Jon Wood of Jefferies & Company wrote in a note. "Our perspective is that the Mayo v. Prometheus decision … is most akin to the Court of Appeals for the Federal Circuit's decision on the relevance of [Myriad's] methods claims, which, as mentioned, have largely already been invalidated."
Restricting Future Innovation
Since the Supreme Court's decision in Mayo v. Prometheus is focused on the patentability of methods claims embodying natural phenomena, it offers limited insight into the justices' thinking about composition-of-matter claims on gene fragments.
In their certiorari petition, the ACLU and PUBPAT are specifically challenging the federal circuit court's decision that gene patents are patentable subject matter. Whether the case is taken up by the Supreme Court or goes back to the federal appeals court, the judges will be tasked with determining whether isolated DNA sequences as described in Myriad's patents are substantially different from DNA naturally occurring inside the body.
Myriad's composition-of-matter claims "define the genes according to how [they] function in the body," ACLU and PUBPAT said in their petition to the Supreme Court.
Furthermore, the plaintiffs assert that the gene patent claims are too broad to be patentable. "The referenced sequences identify the lengthy nucleotide sequences found in a [normal] BRCA1 gene and the amino acid sequence found in a protein created by a wild-type BRCA1 gene," ACLU and PUBPAT state in their petition. "Other claims cover all variations and mutations in the BRCA1 and BRCA2 genes, both known and unknown."
Myriad, meanwhile, has argued that the process of isolating gene fragments from the surrounding genetic material differentiates them from how they function as DNA inside a person. In this regard, the federal court of appeals sided with Myriad, ruling that "the claimed isolated DNA molecules are distinct from their natural existence as portions of larger entities, and their informational content is irrelevant to that fact."
Meanwhile, the ACLU and PUBPAT have hinged their argument on the assertion that Myriad's patents on isolated BRCA sequences should be thrown out because they quash future innovations in cancer diagnosis and treatment by restricting the flow of information about naturally occurring processes in the body. The plaintiffs have reasoned that naturally occurring DNA contains the same information as DNA fragments isolated from the body, and as such, patents on isolated gene fragments restrict other groups from using that information to develop new, better diagnostics, and bar patients from getting a second opinion from another lab.
Based on Justice Breyer's discussion in Mayo v. Prometheus, it seems that the Supreme Court is wary of broad patent claims the embody laws of nature because such patents threaten to proscribe entire fields of innovation. This may be of some help to ACLU and PUBPAT's arguments that Myriad's overly broad claims on isolated DNA could have a chilling effect on the burgeoning personalized medicine field.
"This court has repeatedly emphasized a concern that patent law not inhibit future discovery by improperly tying up the use of laws of nature and the like," Breyer wrote. "Rewarding with patents those who discover laws of nature might encourage their discovery. But because those laws and principles are 'the basic tools of scientific and technological work,' there is a danger that granting patents that tie up their use will inhibit future innovation," particularly when a patented process "forecloses more future invention than the underlying discovery could reasonably justify."
At last year's federal circuit court hearing for AMP v. USPTO, the judges probed the extent to which Myriad's patent claims could impact researchers' and doctors' ability to look at BRCA mutations within the context of a person’s whole genome (PGx Reporter 4/6/2011).
The discussion at the time yielded no clear answers. Myriad's lawyer, reluctant to take a position on the issue, eventually told judges that whole-genome sequencing procedures that did not involve an isolating procedure directed at gauging BRCA mutations would not infringe Myriad’s patents. Genomics experts have questioned what the company's lawyer could have meant by "isolating" in this instance, since most whole-genome sequencing technologies involve a purification step.
Although industry observers have largely dismissed the possibility that the US courts will broadly invalidate gene patents, ACLU and PUBPAT are apparently not chasing a hopeless cause.
The federal appeals court's decision in AMP v. USPTO was a two-to-one decision, in which federal circuit court Judge William Bryson disagreed with Judges Alan Lourie and Kimberly Moore that Myriad's claims on BRCA gene fragments are patent ineligible. In his dissenting view, Bryson harkened back to the point that some of Myriad's "composition claims effectively preempt any attempt to sequence the BRCA genes, including whole-genome sequencing."
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