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On Supreme Court Remand, Federal Again Upholds Validity of Patented Methods to Calibrate Drug for Treating Crohn’s Disease

December 17, 2010

The U.S. Court of Appeals for the Federal Circuit, in a case that was remanded in light of the U.S. Supreme Court’s in Bilski v. Kappos, again concluded Dec. 17 that methods of calibrating the proper dosage of a drug to treat Crohn’s disease fall within the realm of patentable subject matter under Section 101 of the Patent Act (Prometheus Laboratories v. Mayo Collaborative Services, Fed. Cir., No. 2008-1403, 12/17/10).

The appellate court said that the Supreme Court did not reject its machine-or-transformation test, which holds that a process is patentable under Section 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. Rather, the Bilski court stressed that the machine-or-transformation test is not the sole test for determining the patent eligibility of process claims, Judge Alan D. Lourie explained.

Under Bilski, patent eligibility in this case turns on whether Prometheus’s asserted claims are drawn to a natural phenomenon, the patenting of which would entirely preempt its use, or whether the claims are drawn only to a particular application of that phenomenon. “We conclude they are drawn to the latter,” Lourie wrote.

Reversal of Invalidity Ruling Is Vacated, Remanded in Light of Bilski.

Prometheus is the exclusive licensee of two patents (6,355,623 and 6,680,302) claiming methods for calibrating the proper dosage of thiopurine drugs, which are used for treat inflammatory bowel diseases (“IBD”) such as Crohn’s disease and ulcerative colitis.

After Prometheus sued Mayo Collaborative Services for patent infringement, Mayo moved for summary judgment of invalidity on the ground that the patents are invalid for claiming unpatentable subject matter under 35 U.S.C. § 101. To Mayo, the patents impermissibly claim natural phenomena—the correlations between, on the one hand, thiopurine drug metabolite levels and, on the other hand, efficacy and toxicity—and the claims wholly preempt use of the natural phenomena.

As reported in an earlier Intellirights story, the Federal Circuit in September 2009 reversed a district court’s ruling that these patents were invalid under Section 101 as drawn to non-statutory subject matter. Prometheus Laboratories, Inc. v. Mayo Collaborative Services, 581 F.3d 1336 (Fed. Cir. 2009). The district court identified three claimed process steps: (1) administering the drug to a subject; (2) determining metabolite levels; and (3) warning that an adjustment in dosage may be required. It said that the “administering” and “determining” steps are merely necessary data-gathering steps for any use of the correlations,” and that the final step—the “warning’ step”—is only a mental step. It went on to state that the warning step does not require any actual change in dosage and that natural phenomena is claimed because “it is the metabolite levels themselves that ‘warn’ the doctor that an adjustment in dosage may be required.”

In rejecting that analysis, the Federal Circuit drew from the U.S. Supreme Court’s ruling in Diamond v. Diehr, 450 U.S. 175 (1981) and its own decision in In re Bilski, 545 F.3d 943 (Fed. Cir. 2008) cert. granted, 129 S. Ct. 2735 (June 1, 2009), and concluded that the method steps were not invalid under Section 101 for merely reciting natural phenomena — correlations between certain thiopurine drug metabolite levels and therapeutic efficacy and toxicity. Beyond simply claiming natural correlations and data-gathering steps, these 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,” the appellate court wrote. It held that Prometheus’s asserted claims recite transformative “administering” and “determining” steps, and that Prometheus’s claims are drawn not to a law of nature, but to a particular application of naturally occurring correlations, and thus do not preempt all uses of the recited correlations between metabolite levels and drug efficacy or toxicity.

However, its decision was vacated and remanded in light of the Supreme Court’s ruling in Bilski v. Kappos, 130 S. Ct. 3218 (2010).

Even Under Bilski, Claims Still Drawn to Patentable Subject Matter.

On remand from the Supreme Court, the Federal Circuit said that “Bilski did not undermine our preemption analysis of Prometheus’s claims” but rejected the notion of the machine-or-transformation test as an “exclusive” test.

“In light of the Supreme Court’s decision in Bilski, patent eligibility in this case turns on whether Prometheus’s asserted claims are drawn to a natural phenomenon, the patenting of which would entirely preempt its use as in Benson [Gottschalk v. Benson, 409 U.S. 63 (1972)]or Flook [Parker v. Flook, 437 U.S. 584 (1978)], or whether the claims are drawn only to a particular application of that phenomenon as in Diehr,” Lourie stated. “We conclude they are drawn to the latter.”

Lourie wrote:

As before, we again hold that Prometheus’s asserted method claims recite a patent-eligible application of naturally occurring correlations between metabolite levels and efficacy or toxicity, and thus do not wholly preempt all uses of the recited correlations. As discussed below, the claims recite specific treatment steps, not just the correlations themselves. And the steps involve a particular application of the natural correlations: the treatment of a specific disease by administering specific drugs and measuring specific metabolites. As such, and contrary to Mayo’s assertions, the claims do not preempt all uses of the natural correlations; they utilize them in a series of specific steps. … The inventive nature of the claimed methods stems not from preemption of all use of these natural processes, but from the application of a natural phenomenon in a series of steps comprising particular methods of treatment. Other drugs might be administered to optimize the therapeutic efficacy of the claimed treatment.

We similarly reaffirm that the treatment methods claimed in Prometheus’s patents in suit satisfy the transformation prong of the machine-or-transformation test, as they “transform an article into a different state or thing,” and this transformation is “central to the purpose of the claimed process.” … The transformation is of the human body and of its components following the administration of a specific class of drugs and the various chemical and physical changes of the drugs’ metabolites that enable their concentrations to be determined. We thus have no need to separately determine whether the claims also satisfy the machine prong of the test.

Contrary to the district court and Mayo’s arguments on remand, 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 one of a defined group of drugs is administered to the body to ameliorate the effects of an undesired condition. More specifically, Prometheus here claimed methods for optimizing efficacy and reducing toxicity of treatment regimes for gastrointestinal and non-gastrointestinal autoimmune diseases that utilize drugs providing 6-TG by administering a drug to a subject. The invention’s purpose to treat the human body is made clear in the specification and the preambles of the asserted claims. …

When administering a drug such as AZA or 6-MP, the human body necessarily undergoes a transformation. The drugs do not pass through the body untouched without affecting it. In fact, the transformation that occurs, viz., the effect on the body after metabolizing the artificially administered drugs, is the entire purpose of administering these drugs: the drugs are administered to provide 6-TG, which is thought to be the drugs’ active metabolite in the treatment of disease, to a subject. … The fact that the change of the administered drug into its metabolites relies on natural processes does not disqualify the administering step from the realm of patentability. As Prometheus points out, quite literally every transformation of physical matter can be described as occurring according to natural processes and natural law. Transformations operate by natural principles. The transformation here, however, is the result of the physical administration of a drug to a subject to transform—i.e., treat—the subject, which is itself not a natural process. “It is virtually self-evident that a process for a chemical or physical transformation of physical objects or substances is patent-eligible subject matter.” Bilski, 545 F.3d at 962. The administering step, therefore, is not merely data-gathering but a significant transformative element of Prometheus’s claimed methods of treatment that is “sufficiently definite to confine the patent monopoly within rather definite bounds.”

Not all of the asserted claims, however, contain the administering step. That omission, which occurs in claims 46 and 53 of the ’623 patent, does not diminish the patentability of the claimed methods because we also hold that the determining step, which is present in each of the asserted claims, is transformative and central to the claimed methods. Determining the levels of 6-TG or 6-MMP in a subject necessarily involves a transformation. 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. As stated by Prometheus’s expert, “at the end of the process, the human blood sample is no longer human blood; human tissue is no longer human tissue.” … That is clearly a transformation. In fact, Mayo does not dispute that determining metabolite levels in the clinical samples taken from patients is transformative, but argues that this transformation is merely a necessary data-gathering step for use of the correlations. On the contrary, this transformation is central to the purpose of the claims, since the determining step is, like the administering step, a significant part of the claimed method. Measuring the levels of 6-TG and 6-MMP is what enables possible adjustments to thiopurine drug dosage to be detected for optimizing efficacy or reducing toxicity during a course of treatment. The determining step, by working a chemical and physical transformation on physical substances, likewise sufficiently confines the patent monopoly, as required by the machine-or-transformation test.

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.” Flook, 437 U.S. at 590. As made clear from the discussion above, the administering and determining steps are transformative and are central to the claims rather than 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. As explained above, the administering step provides thiopurine drugs for the purpose of treating disease, and the determining step measures the drugs’ metabolite levels for the purpose of assessing the drugs’ dosage during the course of treatment.

In re Grams Distinguished.

Further, the court distinguished this case from In re Grams, 888 F.2d 835 (Fed. Cir. 1989), saying that the administering and determining steps are not  “merely” data-gathering steps or “insignificant extra-solution activity,” but are part of treatment regimes for various diseases using thiopurine drugs.  While noting that the final “wherein” clauses of the claims involve mental steps that are “not patent-eligible per se,” it stressed that “the claims are not simply to the mental steps.” Here, Lourie pointed out that “[a] subsequent mental step does not, by itself, negate the transformative nature of prior steps.”

“Viewing the treatment methods as a whole,” Lourie said, “Prometheus has claimed therapeutic methods that determine the optimal dosage level for a course of treatment.” When asked, under Grams, “What did the applicant invent?,” he said, “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.”

The opinion was joined by Chief Judge Randall R. Rader and Judge William C. Bryson.

Prometheus was represented by Richard P. Bress of Latham & Watkins, Washington, D.C.

Jonathan E. Singer of Fish & Richardson, Minneapolis, represented Mayo.

Amicus curiae Christopher M. Holman Christopher M. Holman of the University of Missouri-Kansas City School of Law, represented himself.

Jennifer Gordon of Baker Botts, New York, represented amicus curiae Novartis Corp.

Jay Z. Zhang of Myriad Genetics Inc., Salt Lake City, represented amicus curiae Myriad Genetics.

Edward R. Reines of Weil Gotshal & Manges, Redwood Shores, Calif., represented amicus curiae American Intellectual Property Law Association.

Katherine J. Strandburg of DePaul University College of Law, Chicago, represented American College of Medical Genetics and other amici curiae.

Roy T. Englert Jr. of Robbins, Russell, Englert, Orseck, Untereiner & Sauber, Washington, D.C., represented Arup Laboratories Inc. and other for amici curiae.

Jeffrey P. Kushan of Sidley Austin, Washington, D.C. represented amicus curiae Biotechnology Industry Organization.

Read the Dec. 17 opinion in Prometheus Laboratories v. Mayo Collaborative Services.


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