Supreme Court’s opinion in Mayo Collaborative Services v. Prometheus Laboratories1 (March 20, 2012) expanded the traditional doctrine that “laws of nature” are not patentable subject matter under 35 U.S.C. § 101. The decision, which addressed the patentability of methods for optimizing the efficacy of a certain type of drug through measurement of the drug’s metabolites in a patient’s blood, is of most immediate interest to the medical diagnostics industry. Prometheus might affect more than diagnostics, however. For example, in a case of great importance to the biotechnology industry, Association for Molecular Pathology v. U.S. Patent and Trademark Office and Myriad Genetics,2 the Supreme Court has vacated the Federal Circuit’s 2011 ruling that isolated genes and shorter DNA sequences are patent eligible and remanded for reconsideration of that issue in light of Prometheus. This article examines Prometheus and explores its possible effects on the patentability of medical diagnostic methods and the isolated genes at issue in the Myriad Genetics remand.
The claims at issue in Prometheus were directed to methods of optimizing the efficacy of thiopurine drugs for the treatment of immune-mediated gastrointestinal disorders, such as Crohn’s disease and ulcerative colitis. The efficacy of these drugs had long been known to depend on the concentrations of certain metabolites of the thiopurine drug in the patient’s blood after the drug’s administration. Moreover, it was known that metabolite production varied significantly among patients: the same dose administered to two patients of the same weight, age, and overall health could result in significantly different blood levels of the key metabolites. Physicians knew, therefore, that it was more useful to focus on the metabolite levels in a patient’s blood than the dose of thiopurine drug administered.3 This is analogous to blood alcohol testing, which is based on the fact that the level of alcohol in someone’s blood is a better indicator of his or her condition than the number of drinks consumed.
The inventors of the patents at issue in Prometheus claimed to have identified the metabolite levels that correlate with the drug being either harmful or ineffective: concentrations above a certain level were likely to be toxic; concentrations below another level were likely to be ineffective.4 This was the inventors’ contribution to the art: “the precise correlations between metabolite levels and likely harm or ineffectiveness. The patent claims at issue here set forth processes embodying researchers’ findings that identified those correlations with some precision.”5 A representative claim from one of the patents was as follows:
A method of optimizing therapeutic efficacy for treatment of an immunemediated gastrointestinal disorder, comprising:
(a) administering a drug providing 6- thioguanine to a subject having said immune-mediated gastrointestinal disorder; and
(b) determining the level of 6-thioguanine in said subject having said immunemediated gastrointestinal disorder, wherein the level of 6-thioguanine less than about 230 pmol per 8x108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and
wherein the level of 6-thioguanine greater than about 400 pmol per 8x108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.
In simpler terms, the claimed invention involved two steps: (1) “administering” the drug to a patient; and (2) “determining” the level of active metabolite in the patient, wherein a level less than about X “indicates a need to increase” the dosage, and a level greater than about Y “indicates a need to decrease” the dosage.
The Federal Circuit held the claims patentable under the “machine or transformation” test of Bilski v. Kappos,6 which looks to whether an invention is tied to a specific machine, or involves the transformation of matter into a different state or thing, as an “important and useful clue”7 to patenteligibility under 35 U.S.C. § 101. It held that the Prometheus claims were “transformative” and therefore patent-eligible because the administration of the drug to the patient (the “administering” step) transforms the human body, and the “determining” step transforms the blood sample. Those transformations, moreover, were central to the purpose of the claimed process.8
Supreme Court: Applicant Cannot Patent “Law of Nature” Combined Only with “Well- Understood, Routine, Conventional Activity, Previously Engaged in by Those in the Field”
The Supreme Court unanimously reversed the Federal Circuit, holding the claims unpatentable under the “law of nature” exclusion. The Court began by noting that the relationships between the concentrations of certain metabolites and the likelihood that a dosage of a thiopurine drug will be toxic or effective are laws of nature. “While it takes a human action (the administration of a thiopurine drug) to trigger a manifestation of this relation in a particular person, the relation itself exists in principle apart from any human action. The relation is a consequence of the ways in which thiopurine compounds are metabolized by the body—entirely natural processes.”9 “[A] patent that simply describes that relation,” the Court concluded, “sets forth a natural law.”10 While a law of nature cannot be patented, “an application of a law of nature . . . to a known structure or process may well be deserving of patent protection.”11 Accordingly, the Court turned next to the question of whether the claims added enough to the natural correlation between metabolite levels and toxicity or efficacy to constitute patent-eligible processes that apply natural laws. It determined that they did not.
The “administering” step, according to the Court, simply identifies the “audience” who will be interested in the natural law, namely doctors who treat patients with thiopurine drugs. Moreover, physicians had been administering thiopurine drugs to treat immune-mediated disorders long before the claimed invention was made.12 The “determining” step tells the doctor to measure the blood levels of the relevant metabolites without specifying any particular process for doing so. This too was a routine activity that doctors had been carrying on for years before Prometheus’s alleged invention. And the “wherein” clauses “simply tell a doctor about the relevant natural laws, at most adding a suggestion that he should take those laws into account when treating his patient.”13 Considering the three parts of the claim as an “ordered combination” did not help: “Anyone who wants to make use of these laws must first administer a thiopurine drug and measure the resulting metabolite concentrations, and so the combination amounts to nothing significantly more than an instruction to doctors to apply the applicable laws when treating their patients.”14
The critical deficiency the Court found in Prometheus’s claims was that, beyond the unpatentable law of nature (the correlation between the specified metabolite concentrations and toxicity or efficacy), the claims recited nothing but “wellunderstood, routine, conventional activity already engaged in by the scientific community.”15 The Court summarized the deficiency as follows:
Beyond picking out the relevant audience, namely those who administer doses of thiopurine drugs, the claim simply tells doctors to: (1) measure (somehow) the current level of the relevant metabolite, (2) use particular (unpatentable) laws of nature (which the claim sets forth) to calculate the current toxicity/inefficacy limits, and (3) reconsider the drug dosage in light of the law. These instructions add nothing specific to the laws of nature other than what is well-understood, routine, conventional activity, previously engaged in by those in the field.16
The Court reiterated this principle when it warned that “simply appending conventional steps, specified at a high level of generality, to laws of nature, natural phenomena, and abstract ideas cannot make those laws, phenomena, and ideas patentable.”17
Finally, the Court criticized the Federal Circuit’s application of the “machine or transformation” test. The Court appeared to accept the notion that the “administering” step transforms the human body, but called that transformation “irrelevant” because the step “simply helps to pick out the group of individuals who are likely interested in applying the law of nature.”18 And the Court disagreed with the Federal Circuit’s conclusion that the “determining” step was transformative, reasoning that “the second step could be satisfied without transforming the blood, should science develop a totally different system for determining metabolite levels that did not involve such a transformation.”19 Even if the “machine or transformation” test was satisfied, moreover, the Court warned that it is only an “important and useful clue” to patentability that does not trump the “law of nature” exclusion.20
Implications for Industry
Prometheus has the potential to fundamentally change the analysis of what constitutes patenteligible subject matter under § 101. For example, in evaluating claims that recite a law or product of nature, it could be argued that courts and the PTO should now have to engage in an analysis similar to that for novelty under § 102 and obviousness under § 103 to assess whether additional elements of the claimed invention are “well-understood,” “routine,” or “conventional.” If so, it would imply that the same claimed invention may constitute patenteligible subject matter on one date but not at a later date. It remains to be seen whether the PTO or the lower courts will adopt such an analysis. In its only guidance on Prometheus to date, the PTO instructed its examiners to continue relying on its “Interim Bilski Guidance” issued July 27, 2010 (which does not involve evaluations of novelty or obviousness), with the added proviso that a claim that includes a law of nature, natural phenomenon, or abstract idea must also recite other elements “such that . . . the claimed product or process amounts to significantly more than a law of nature, a natural phenomenon, or an abstract idea with conventional steps specified at a high level of generality appended thereto.”21
Prometheus may have especially profound effects in the fields of diagnostics and “personalized medicine,” i.e., the use of information concerning a given patient’s genes, proteins, or other characteristics to select treatment options for that patient. For example, a typical claim to a diagnostic method reads something like this:
A method for diagnosing disease X in a patient comprising detecting in a sample taken from such patient the presence of sequence Y in gene Z, wherein the presence of sequence Y in gene Z indicates the likelihood of developing disease X.
Depending on the particular facts of each individual case, it is conceivable that some defendants may challenge such claims under the theory that they simply advise a physician of a natural law (the correlation between sequence Y and disease X), and recite the conventional step of “detecting” the sequence Y in the patient’s sample. Given the large number of issued patents in this and similar forms, however, and the Supreme Court’s earlier admonition that “courts must be cautious before adopting changes that disrupt the settled expectations of the inventing community,”22 it is not clear whether district courts and the Federal Circuit will be receptive to such arguments. In any event, at least with respect to pending applications and applications filed in the future, patent drafters might try to avoid the law of nature problem by reciting additional limitations such as use of a new, unconventional technique to determine whether the relevant DNA sequence is present, or perhaps even conventional techniques as long as they are not “specified at a high level of generality.”23
Prometheus may also have profound effects on the biotechnology industry, which until now has relied heavily on patents claiming isolated genes and shorter DNA sequences. In Association for Molecular Pathology v. U.S. Patent and Trademark Office and Myriad Genetics24 (the “Myriad Genetics” case), the Federal Circuit rejected contentions that isolated genomic DNA sequences (i.e., sequences that are identical to naturallyoccurring gene sequences) are unpatentable products of nature. In the now-vacated majority opinion in that case, the court ruled that such an isolated gene is not a product of nature because it is a “distinct chemical entity” that is “markedly different” from the gene as it exists in nature.25 The court based this ruling on the facts that, even though the nucleotide sequences of the native and the isolated genes are the same, the isolated gene was only one thousandth the size of the chromosome in which it exists in nature, and the covalent bonds between the gene and the rest of the chromosome had been severed.26
The Supreme Court has vacated the Federal Circuit’s Myriad Genetics ruling and remanded the case for reconsideration in light of Prometheus.27 Supplemental briefs on the effect of Prometheus were filed on June 15, 2012; oral argument is scheduled for July 20, 2012. If the Federal Circuit maintains its position that an isolated gene is a “distinct chemical entity” from the gene as it exists in nature, claims to such isolated genes should remain patent-eligible. Under the “distinct chemical entity” theory, claims reciting an isolated gene do not recite a product of nature and there is therefore no need for the claim to include additional, novel limitations. That was the principal argument of the patentee (Myriad) in its supplemental brief filed on June 15, 2012.28 Myraid’s supplemental brief also argued that Prometheus does not affect composition-of-matter claims. Rather, it argued that the proper test for composition claims is the test that the Federal Circuit applied in its now-vacated opinion, namely, the “distinctive name, character and use” test of Diamond v. Chakrabarty.29
The plaintiffs, on the other hand, focus on whether claims to isolated genes “improperly t[ie] up the future use” of a product of nature, a concern which the Supreme Court “has repeatedly emphasized.”30 The principal point of the plaintiffs’ June 15, 2012, supplemental brief on the effect of Prometheus was that Myriad’s isolated DNA claims had exactly this effect. The plaintiffs argued that these claims preempt both a law of nature and a product of nature. According to the plaintiffs, the natural law covered by the claims “is the correlation between the patented DNA and the BRCA protein it encodes, which in turn correspond to traits such as risk for breast and ovarian cancers. The product is the DNA itself.”31 It is impossible to “invent around” these claims, the plaintiffs asserted: “In [Prometheus], the Court suggested that a claim on a new drug would not raise the concern that invalidated [the patents at issue there] because another company could develop another drug treating the same condition without infringing. . . In contrast, the ‘isolated’ DNA claims . . . do preempt future use of laws and products of nature because another entity cannot invent a DNA molecule that encodes for the same protein and embodies a person’s BRCA1 and BRCA2 genetic information.”32
Unsurprisingly, the plaintiffs also argue that Myriad’s isolated DNA claims do not “add enough” to the natural gene to render the claims patentable. They assert that “[i]solation of DNA was a wellknown technique at the time these patents were sought, and continues to be a routine, conventional preparatory step for using human genes in research and clinical practice. The only addition of the ‘isolated’ DNA claims to the progress of science is disclosure of the natural law itself - the fact that this DNA encodes for the BRCA protein and embodies the information needed to understand a person’s heredity and disease susceptibility.”33
A second set of claims at issue in the Myriad Genetics remand is directed to methods of screening potential anti-cancer drugs. These claims, containing three steps and a “wherein” clause, can be summarized as follows:
Growing cells that have been transformed with a cancer-causing BRCA1 gene in presence of the drug candidate;
Growing the transformed cells in the absence of the drug candidate; and
Determining cells’ growth rate with and without the drug candidate;
Wherein slower growth rate in presence of drug candidate is indicative of therapeutic activity.34
The Federal Circuit’s now-vacated opinion held these claims patentable under the “machine or transformation” test because they are transformative. The “determining” step, for example, “necessarily involves physical manipulation of the cells.”35 Prometheus may lead to a different result on remand. For example, the Federal Circuit could rule that the claims apply the natural correlation between certain mutations in the BRCA1 gene and the likelihood of cancer, and add nothing to that natural correlation but routine, wellunderstood actions: growing the cells with and without the drug candidate, and comparing the cells’ growth rates. To paraphrase Prometheus, it could be argued that the claims simply advise researchers of the natural correlation between a BRCA1 mutation and cancer, and instruct them to apply it to the screening of drug candidates. This was the position that the plaintiffs adopted in their June 15, 2012, supplemental brief.36 Myriad, on the other hand, argued that none of the method claims was a subject of the petition for certiorari, and that the Federal Circuit’s previous decision upholding those claims was undisturbed by the Supreme Court’s “grant, vacate, and remand” order.37
The foregoing observations show that Prometheus may have fundamentally changed the law under 35 U.S.C. § 101, with potentially important consequences for the medical diagnostics and biotechnology industries. Its full effects may take years for lower courts and the PTO to work out, but the decision may make it more difficult to obtain and enforce patent claims that include a law of nature, a product of nature, or a natural phenomenon among their limitations.