By Turna Ray
In revisiting its decision in Prometheus v. Mayo — a case in which Mayo Collaborative Services is challenging Prometheus Labs' patent claims on "methods for determining the optimal dosage of thiopurine drugs" — a federal appeals court last week upheld its earlier decision that the contested patents passed muster under the law.
Diagnostic developers and legal experts have been keeping a close watch on Prometheus since the Federal Circuit Court of Appeals' handling of diagnostic method patents in that case may impact another lawsuit, Association for Molecular Pathology et al. vs. the United States Patent and Trademark Office et al, which is pending review by the same court.
In AMP v. USPTO, Myriad and the University of Utah are appealing a district court's invalidation of several patent claims for BRACAnalysis, a genetic test marketed by Myriad that gauges mutations in the BRCA 1 and BRCA 2 genes to determine whether a woman is at higher risk for hereditary breast and ovarian cancer.
In this case, patients, healthcare providers, and researchers represented by the American Civil Liberties Union and the Public Patent Foundation are challenging Myriad's patent claims on methods of comparing cDNA and naturally occurring DNA, as well as claims on the composition of cDNA. Specifically, the lawsuit alleges that the BRCA gene patents held by the University of Utah Research Foundation and exclusively licensed to Myriad "stifle research that could lead to cures and limit women's options regarding their medical care" (PGx Reporter 05/13/09).
The federal appeals court's recent decision in Prometheus could speak to the method claims at issue in AMP v. USPTO, insofar as they meet the so-called machine-or-transformation test. A term that originated during the Industrial Age, the machine-or-transformation test is a way of determining patentable subject matter based on whether it is tied to a particular apparatus or transforms an article into a different state. This test has been applied in many patent cases to determine patent eligibility, including Prometheus and AMP v. USPTO.
Following the Federal Circuit Court's recent finding in Prometheus, some legal experts believe that the appeals court could similarly apply the machine-or-transformation test and rule favorably with regard to Myriad's method claims. Others feel that the federal appeals court's decision on Prometheus' patents is not that meaningful for Myriad's patents since the machine-or-transformation test will not be the sole determinant of patent validity in AMP.
In Light of Bilski
The method claims at issue in Prometheus v. Mayo — and to an extent the method claims challenged in AMP v. USPTO — are impacted by the Supreme Court's discussion of the machine-or-transformation test in its recent decision in Bilski v. Kappos.
In June, the Supreme Court held in Bilski that method patent claims for hedging risk in commodities trading were invalid because they were abstract ideas, but not because they failed the machine-or-transformation test. In the majority opinion, Justice Anthony Kennedy wrote that while the machine-or-transformation test is useful for determining patentability, it may be too restrictive as a sole determinant of patentability for inventions in the Information Age (PGx Reporter 06/30/10). This narrow ruling left open the possibility for certain innovations not tied to a physical instrument, such as software, data-driven processes, and medical diagnostics, to still remain patent eligible.
At the time, in Prometheus v. Mayo, Mayo had filed for a writ of certiorari, requesting the Supreme Court to consider the Federal Circuit Court's finding in favor of Prometheus' patents.
Two patents are at issue in Prometheus v. Mayo — US Patent Nos. 6,355,623 and 6,680,302 — for which Prometheus holds exclusive licenses. The patents claim methods of measuring a patient's metabolite level to calibrate doses of a thiopurine drug to treat stomach disorders. The litigation started in 2004, when Mayo announced its intent to sell its own tests that measured the same metabolites as Prometheus' test, prompting Prometheus to sue Mayo for infringement.
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A federal district court in 2008 found Prometheus' method claims were not patentable subject matter under 35 USC 101. Prometheus appealed the district court's decision to the Federal Circuit Court, which last year reversed the lower court's decision and found in favor of Prometheus that its method claims for determining metabolite levels for drug dosing met the machine-or-transformation test, and were therefore patentable.
"We conclude that the methods of treatment claimed in the patents in suit squarely fall within the realm of patentable subject matter because they 'transform an article into a different state or thing,'" and this transformation is "central to the purpose of the claimed process," the Federal Circuit wrote in its decision at the time.
However, the Supreme Court in June granted Mayo certiorari by vacating the appeals court's earlier decision, and instructed the lower court to revisit its decision in light of Bilski (PGx Reporter 06/30/10).
In reassessing its earlier decision, the federal appeals court maintained that Prometheus' patents are valid because they meet the "transformation" part of the machine-or-transformation test. "When asked the critical question, 'What did the applicant invent?,' the answer is a series of transformative steps that optimizes efficacy and reduces toxicity of a method of treatment for particular diseases using particular drugs," wrote Circuit Judge Alan Lourie in the decision regarding Prometheus.
Additionally, the circuit judges also held that the Prometheus' method claims "satisfy the preemption test" in that they do not try to patent a natural phenomena, which is one of three exceptions to patent eligibility under 35 USC 101. The appeals court concluded that Prometheus' method claims on "administering" and "determining" naturally occurring metabolite levels for the purposes of adjusting drug doses are "drawn only to a particular application of a natural phenomena," which is patentable.
This may be meaningful when it comes time for Myriad to argue that the federal district court Judge Robert Sweet erred in his application of the machine-or-transformation test regarding its BRCA method claims.
Defining 'Transformation'
When Sweet deemed Myriad's patents invalid in March of this year, the Supreme Court had not yet decided Bilski, and Prometheus had not be reassessed by the Federal Circuit Court. As such, in applying the "machine-or-transformation" test as set forth in the Federal Circuit's initial decision in Bilski, Sweet deemed Myriad's method claims of "analyzing" and "comparing" gene sequences as mental processes not meeting the transformation test.
Now, in appealing the decision on its BRCA patents, Myriad will likely cite the Federal Circuit Court's discussion of what constitutes a patent-worthy transformative step in Prometheus.
"Determining the levels of 6-TG or 6-MMP in a subject necessarily involves a transformation," the Federal Circuit Court said. "Some form of manipulation, such as the high pressure liquid chromatography method specified in several of the asserted dependent claims or some other modification of the substances to be measured, is necessary to extract the metabolites from a bodily sample and determine their concentration."
So far, the plaintiffs in AMP v. USPTO have "scrupulously avoided the wet chemistry aspects, focusing on the letters on a page" instead, observed Kevin Noonan, a patent lawyer for McDonnell Boehnen Hulbert & Berghoff. Noonan, who was previously a molecular biologist, said that "these letters are mere representations of chemical molecules that exist in nature and need to be analyzed to be understood. So, I would think that would be how [Myriad's] arguments would go."
If the amicus briefs filed with the Federal Circuit Court in AMP v. USPTO are any signal, the use of the machine-or-transformation test in the district court ruling will likely be called into question. Even stakeholders who submitted briefs in support of neither party have argued that Sweet misapplied the machine-or-transformation test.
For example, in October, the American Intellectual Property Law Association submitted a brief in support of a reversal of the district court's decision, but not on the side of either party, arguing that Myriad's claims do not preempt an abstract idea. Citing the appellate court's first decision in Prometheus v. Mayo, AIPLA argues that Myriad's diagnostic method claims "do not preempt natural processes; [but instead] utilize them in a series of specific steps."
In invalidating Myriad's patents, Sweet determined that isolated DNA containing BRCA1/2 gene sequences, as described in Myriad's patents, is not markedly different from gene sequences naturally occurring in the body in function or in the information they contain, and so are not patentable.
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But AIPLA's rejoinder to Sweet's determination, which has been voiced by others who support a reversal of the district court's decision, is that "even if the claimed methods invoke scientific principles, such as the correlation between certain DNA sequences and susceptibility to disease, Myriad's methods apply such principles in a series of transformative acts that rely upon novel diagnostic or screening tools, i.e., the claimed purified, isolated BRCA DNA molecules."
Similarly, in upholding Prometheus' patent claims in last week's decision, the appeals court reasoned that the "administering and "determining" steps claimed in the patents are "not merely insignificant extra-solution activity" performed for the purposes of data gathering. "Instead, the administering and determining steps are part of a treatment protocol, and they are transformative," the Federal Circuit Court wrote.
According to Jennifer Gordon of the law firm Baker Botts, Myriad's method claims can most readily benefit from the appeals court's reasoning with regard to claim 46 of US Patent No. 6,355,623, which covers a "determining" step for gauging 6-TG levels to "optimize therapeutic efficacy and reduce toxicity."
Noting that Myriad's patents claims use terms like "analyzing" and "comparing" instead of "determining" as in Prometheus, Gordon believes that the Federal Circuit Court might weigh in on such claim interpretation. "That 'determining' is transformative [in Prometheus] is very important," said Gordon, who was part of a team of lawyers at Baker Botts who crafted an amicus brief on behalf of the Biotechnology Industry Organization in support of Myriad's opposition to the ACLU's motion for summary judgment.
"If the Federal Circuit Court is of the view that a person skilled in the art would interpret 'analyzing' … to mean performing transformative steps (like extraction, sequencing, etc.), then … the reasoning in Prometheus applies and the Myriad claims pass muster under Section 101," Gordon added.
The AIPLA brief maintains that there are several "transformative" steps required to practice the methods described in Myriad's contested patents, including "drawing blood or removing a tissue sample from a subject, extracting BRCA DNA or RNA from the biological sample, and detecting alterations in the subject's BRCA nucleotide sequence in order to analyze the BRCA DNA, RNA or cDNA made from an mRNA of the sample."
In AIPLA's view, "the extraction process" is transformative because it "radically alters the structure and function of the native DNA, creating a new chemical compound that does not exist in nature." In the same way, comparing cDNA to naturally occurring genes in the body also meets the test in AIPLA's opinion, since "such comparisons cannot be made by the naked eye but instead require sophisticated biotechnological methods of sequencing nucleic acids and/or detecting alterations that involve chemical or physical transformation."
What constitutes a transformative step in AMP v. USPTO will likely get even more complex and highly specific, as some have taken the stance that the process of isolating DNA does not significantly alter the material from the naturally occurring substance to warrant a patent.
The US Department of Justice issued an amicus brief in the case attempting to find a middle ground regarding the composition of matter claims on cDNA. While the DoJ held that the district court erred in invalidating the composition claims directed at cDNA, it also asserted that "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." (PGx Reporter 11/01/10). Essentially, the DoJ appears to be asserting that the process of isolation and purification may not be patentable, while methods of manufacturing protein in cells would be.
Uncertain Times
As AMP v. USPTO gets reviewed by the Federal Circuit Court, the recent decision on Prometheus is unlikely to be the last word in how the machine-or-transformation test gets applied with regard to Myriad's patents. Mayo can file another writ of certiorari to the Supreme Court, and the case might continue. As such, the residual impact of Prometheus on gene patenting is uncertain.
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Although the Federal Circuit Court did not apply any other test than the machine-or-transformation criteria in Prometheus following the Supreme Court's Bilski decision, it is important to remember that in Bilski, the Supreme Court did assert that machine-or-transformation may not be a definitive test for patentability, especially in the area of medical diagnostics testing.
While the Supreme Court "made clear they think the [machine-or-transformation] test is good evidence of patentability … they were worried it might be incomplete (i.e., some things that flunk the test should nonetheless be patentable...)," said Robert Cook-Deegan, director of Duke University's Center for Genome Ethics, Law & Policy, in an e-mail.
When the Federal Circuit Court hears AMP v. USPTO, they "may or may not agree with Judge Sweet's conclusions regarding the machine-or-transformation test," Cook-Deegan noted. "Even if they do agree, they will have to decide if the BRCA test is one of those things that might be patentable even if it does flunk the test."
Additionally, Myriad's 15 claims at issue in AMP v. USPTO also include composition-of-matter claims on cDNA. The latter are not addressed by the Federal Circuit Court's determinations in Prometheus.
In the end, "I don't think we've learned much" from the recent Prometheus decision," Cook-Deegan said. And the appeals court "did not use this as the opportunity to clarify their criteria" for patentability.
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