The Prometheus  v. Mayo case, what Hal Wegner calls “Metabolite déjà vu II,” has represented perhaps the most troubling development for medical treatment patents in recent times.  The case concerns a patent for a means to measure the level of 6-thioguinine (6-TG) and 6-methylmercaptopurine (6-MMP), which indicates that an adjustment in drug dosage may be required at certain metabolite levels.

The patent includes only two active steps, “administering” the drug and then “determining” metabolite levels.  The claim really just explains the correlation between metabolite levels and therapeutic efficacy and “what the inventors claim to have discovered is that particular concentrations of 6-TG and 6-MMP correlate with therapeutic efficacy and toxicity in patients taking AZA drugs.”  The district court decided as a matter of law that the asserted claims were drawn to non-statutory subject matter and as such, unpatentable.

Thankfully, cooler heads appear to have prevailed and the US Court of Appeals for the Federal Circuit has held that methods of treatment claims fall squarely within the realm of patentable subject matter. Prometheus Laboratories, Inc. v. Mayo Collaborative Services (08-1403).

Prometheus is the sole and exclusive licensee of U.S. Patents 6,355,623 and 6,680,302, which claim methods for calibrating the proper dosage of thiopurine drugs and are used for treating both gastrointestinal and non-gastrointestinal autoimmune diseases.

These drugs include 6-mercaptopurine (6-MP) and azathiopurine (AZA), a pro-drug that upon administration to a patient converts to 6- MP, which are used to treat inflammatory bowel diseases such as Crohn’s disease and ulcerative colitis. 6-MP is broken down by the body into various 6-MP metabolites, including 6-methyl-mercaptopurine (6-MM P) and 6-thioguanine (6-TG) and their nucleotides. The patents involve measurements of these two metabolites. Drugs that deliver 6-TG are widely used for their cytotoxic and immunosuppressive properties.

Although drugs such as 6-MP and AZA have been used for years to treat autoimmune diseases, non-responsiveness and drug toxicity may complicate treatment in some patients. So, these patents claim methods to optimize therapeutic efficacy while minimizing toxic side effects.

As written, the methods typically include two separately lettered steps: (a) administering a drug that provides 6-TG to a subject and (b) determining the levels of the drug’s metabolites, 6-TG and/or 6-MMP, in the subject. The measured metabolite levels are then compared to pre-determined metabolite levels, wherein the measured metabolite levels indicate a need to increase or decrease the level of drug to be administered so as to minimize toxicity and maximize efficacy of treatment.

Prometheus marketed a PROMETHEUS Thiopurine Metabolites test (formerly known as the PRO-PredictRx® Metabolites test) that used the technology covered by the patents in suit. Mayo Collaborative Services and Mayo Clinic Rochester formerly purchased and used Prometheus’s test, but in 2004, Mayo announced that it intended to begin using internally at its clinics and selling to other hospitals its own test. Mayo’s test measured the same metabolites as Prometheus’s test, but Mayo’s test used different levels to determine toxicity of 6-TG and 6-MMP.

The district court held that Mayo’s test literally infringed claim 7 of the ’623 patent, construing “indicates a need” to mean “a warning that an adjustment in dosage may be required.” This construction did not require doctors to adjust drug dosage if the metabolite level reached the specified levels; rather, the court found the wherein phrases to mean “that when the identified metabolites reach the specified level, the doctor is warned or notified that a dosage adjustment may be required, if the doctor believes that is the proper procedure.”

Mayo argued that the patents claim natural phenomena — the correlations between, on the one hand, thiopurine drug metabolite levels and, on the other hand, efficacy and toxicity — and that the claims wholly preempt use of the natural phenomena.

The district court  noted that the warning step does not require any actual change in dosage and that “it is the metabolite levels themselves that ‘warn’ the doctor that an adjustment in dosage may be required.” With this understanding of the claims, the court concluded that the claims recited the correlations between particular concentrations of 6-TG and 6-MMP and therapeutic efficacy or toxicity in patients taking AZA drugs.

So, the district court found that those correlations were natural phenomena and not patentable inventions because the correlations resulted from a natural body process. The court stated that the inventors did not “invent” the claimed correlation; rather, “6-TG and 6-MMP are products of the natural metabolizing of thiopurine drugs, and the inventors merely observed the relationship between these naturally produced metabolites and therapeutic efficacy and toxicity.”

Section 101 provides that:

Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent thereof, subject to the conditions and requirements of this title. 35 U.S.C. § 101.

The Supreme Court has construed § 101 broadly, noting that Congress intended statutory subject matter to “include anything under the sun that is made by man.” Diamond v. Chakrabarty. But, the Court has held that a claim to a process is not patent-eligible if it claims “laws of nature, natural phenomena, and abstract ideas.” Diamond v. Diehr.

At the same time, it has also been established that “while a claim drawn to a fundamental principle”—i.e., a law of nature, natural phenomenon, or abstract idea—“is unpatentable, ‘an application of a law of nature or mathematical formula to a known structure or process may well be deserving of patent protection.’” Bilski quoting Diehr.

The key issue for patentability, then, at least on the present facts, is whether a claim is drawn to a fundamental principle or an application of a fundamental principle. Although this inquiry is hardly straightforward, following the Supreme Court, we articulated in Bilski a “definitive test” for determining whether a process is patent-eligible under § 101: “A claimed process is surely patent- eligible under § 101 if: (1) it is tied to a particular machine or apparatus, or (2) it transforms a particular article into a different state or thing.” Id. The machine-or-transformation test is a “two-branched inquiry,” i.e., the patentee “may show that a process claim satisfies § 101 either by showing that his claim is tied to a particular machine, or by showing that his claim transforms an article.” Id. at 961.

The machine-or-transformation test has two further aspects: “the use of a specific machine or transformation of an article must impose meaningful limits on the claim’s scope to impart patent-eligibility,” and “the involvement of the machine or transformation in the claimed process must not merely be insignificant extra-solution activity.” Bilski, 545 F.3d at 961-62 (citations omitted).

Prometheus argued that the claimed processes satisfy § 101 because they meet both prongs of the machine-or-transformation test articulated in Bilski. That is, that the patents inextricably rely on numerous machines to process the bodily sample, determine the metabolite levels, and thereby calibrate the proper dose.

Prometheus contended that the district court was wrong to not look at the dependent claims, some of which specify measurement through high pressure liquid chromatography, which clearly requires the use of machines. In addition, Prometheus argued that the synthetic drugs used in its treatment methods are compositions of matter, and the claims’ central reliance on those drugs is enough to meet the machine-or-transformation test.

Prometheus points to three “transformations” within its claimed process: (1) the first step of administering a synthetic drug transforms the biochemical makeup of the patient’s body for the purpose of treating disease; (2) the second step requires the transformation of a bodily sample to determine the created metabolites’ concentration levels; and (3) the metabolite levels are transformed into a warning for a doctor to alter the dosage. Prometheus felt that physical transformations, such as the human body’s metabolic reaction to drugs, initiated by human actions and artificial chemical compounds, such as the administration of a thiopurine drug into the body, cannot be unpatentable under Bilski simply because they proceed according to natural laws or occur within the human body because everything proceeds according to natural laws.

Prometheus also argued that all of the methods available to determine the metabolite levels in a bodily sample require a physical transformation of blood or human tissue in order to extract the metabolite and determine its concentration. And, the processes transform the patient’s treatment regime while avoiding deadly side effects by transforming the metabolite levels into a warning regarding dosage.

The Federal Circuit decided that more was involved here than just mere natural phenomenon:

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.” See Bilski, 545 F.3d at 962. The transformation is of the human body following administration of a drug and the various chemical and physical changes of the drug’s metabolites that enable their concentrations to be determined. Because the claimed methods meet the transformation prong under Bilski, we do not consider whether they also meet the machine prong.

Contrary to the district court, we do not view the disputed claims as merely claiming natural correlations and data-gathering steps. The asserted claims are in effect claims to methods of treatment, which are always transformative when a defined group of drugs is administered to the body to ameliorate the effects of an undesired condition.

A further requirement for patent-eligibility is ensuring that the involvement of the transformation in Prometheus’s claimed process is not merely insignificant extra- solution activity.

The crucial error the district court made in reaching the opposite conclusion was failing to recognize that the first two steps of the asserted claims are not merely data- gathering steps…. While it is true that the administering and determining steps gather useful data, it is also clear that the presence of those two steps in the claimed processes is not “merely” for the purpose of gathering data. Instead, the administering and determining steps are part of a treatment protocol, and they are transformative.

The presence of a mental step does not detract from patentability:

A subsequent mental step does not, by itself, negate the transformative nature of prior steps. Thus, when viewed in the proper context, the final step of providing a warning based on the results of the prior steps does not detract from the patentability of Prometheus’s claimed methods as a whole. The data that the administering and determining steps provide for use in the mental steps is obtained by steps well within the realm of patentable subject matter. The addition of the mental steps to the claimed methods thus does not remove the prior two steps from that realm.

Thus, the claimed methods satisfy all of the requirements under Bilski’s transformation prong for patent-eligible subject matter under § 101.