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Federal Circuit Upholds Personalized Medicine Claims

Posted by Courtenay Brinckerhoff on Posted in 101; Federal Circuit Decisions; Myriad; Personalized Medicine; Prometheus

The Federal Circuit decided for the second time that the personalized medicine claims at issue in Prometheus Laboratories, Inc. v. Mayo Collaborative Services satisfy the requirements for patent-eligibility set forth in 35 U.S.C. § 101, even under the Supreme Court’s decision in Bilski v. Kappos. In so doing, the court followed a two-part analysis that provides a framework for analyzing other method claims that may raise similar issues.

Prometheus’s Claims

Prometheus’s claims relate to personalized methods of optimizing the dosing of specific drugs used to treat gastrointestinal autoimmune diseases. Representative claims from the Prometheus’s patents are set forth below.

1. A method of optimizing therapeutic efficacy for treatment of an immune-mediated 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 immune-mediated gastrointestinal disorder,
wherein the level of 6-thioguanine less than about 230 pmol per 8×108 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 8×108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

46. A method of optimizing therapeutic efficacy and reducing toxicity associated with treatment of an immune-mediated gastrointestinal disorder, comprising:
(a) determining the level of 6-thioguanine or 6-methylmercaptopurine in a subject administered a drug selected from the group consisting of 6-mercaptopurine, azathiop[u]rine, 6-thioguanine, and 6-methyl-mercaptoriboside, said subject having said immune-mediated gastrointestinal disorder,
wherein the level of 6-thioguanine less than about 230 pmol per 8×108 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 8×108 red blood cells or a level of 6-methylmercaptopurine greater than about 7000 pmol per 8×108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.

Thus, while many claims recite both an “administering” step and a “determining” step, some claims recite only a “determining” step.

The Road to the Supreme Court – The District Court & The Metabolite Dissent

The district court had invalidated Prometheus’s claims under 35 U.S.C. § 101, applying the rationale from Supreme Court Justice Breyer’s 2006 dissent to the dismissal of certiorari in Laboratory Corp. of American Holdings v. Metabolite Labs., Inc.

The claims at issue in Metabolite recited:

A method for detecting a deficiency of cobalamin or folate in warm-blooded animals comprising the steps of:
assaying a body fluid for an elevated level of total homocysteine; and
correlating an elevated level of total homocysteine in said body fluid with a deficiency of cobalamin or folate.

Justice Breyer summed up the claimed methods as involving only

  1. obtaining test results and
  2. thinking about them.

He opined that the claims “embody only the correlation between homocysteine and vitamin deficiency that the researchers uncovered. In my view, that correlation is an unpatentable ‘natural phenomenon.’”

The Road to the Supreme Court – The Federal Circuit’s 2009 Decision

Prometheus appealed to the Federal Circuit, who reversed the district court in a decision issued in 2009. The Federal Circuit found that the claims satisfied § 101 under its machine-or-transformation test, because the methods “transform a particular article into a different state or thing.”

The “administering” claims do so because they “are in effect claims to methods of treatment, which are always transformative.”

The “determining” claims do so, because the level of 6-thioguanine or 6-methylmercaptopurine “cannot be determined by mere inspection,” but requires transformative chemical analysis, such as high-performance liquid chromatography (HPLC).

The Federal Circuit rejected arguments that the administering and determining steps were “insignificant post-solution activities” or merely “data gathering,” but found instead that they were “central to the claims,” “part of a treatment protocol” and “transformative.” The Federal Circuit also stated that the “mental steps” embodied in the “wherein” clauses were not fatal to patentability when the claims were considered as a whole.

The Supreme Court GVR Order

Mayo petitioned the Supreme Court for certiorari, which the Court granted, but only to vacate the Federal Circuit decision and remand to the Federal Circuit in view of its decision in Bilski v. Kappos.  (This is referred to as a “GVR order” for “grant,” “vacate,” and “remand.)

Back at the Federal Circuit

On remand, the Federal Circuit requested new briefs from the parties, and accepted seven amicus briefs. Prometheus argued that its claims should be found to be patent-eligible because the Supreme Court did not invalidate the machine-or-transformation test, while Mayo argued that the claims do not satisfy § 101 because they preempt all practical uses of a natural phenomenon.

The Federal Circuit began its analysis by noting that the Supreme Court has consistently construed § 101 broadly, in accord with Congressional intent, as reflected in the “expansive terms” used in the statute. The Federal Circuit nevertheless acknowledged that § 101 is not unlimited, because Supreme Court precedent provides three specific exceptions to § 101’s broad patent-eligibility principles:

laws of nature, physical phenomena, and abstract ideas.

On this point, the Federal Circuit noted that Supreme Court precedent also holds that “an application of a law of nature or mathematical formula to a known structure or process may well be deserving of patent protection.”

Turning to case before it, the Federal Circuit characterized the issue on remand as “whether Prometheus’s asserted claims are drawn to a natural phenomenon, the patenting of which would entirely preempt its use . . . or . . . only to a particular application of that phenomenon,” which would be patent-eligible.

The Federal Circuit’s Two-Part Analysis

The Federal Circuit rejected Mayo’s argument (which has been echoed in speculation from the patent bar) that the Supreme Court’s Bilksi decision or its remand of this case required a “wholly different analysis or a different result.” To the contrary, the Federal Circuit stated that the Supreme Court’s Bilksi decision “did not undermine our preemption analysis” and “did not disavow the machine-or-transformation test.”

The Federal Circuit reconsidered Prometheus’s claims under a two-part analysis:

1.   The court explained that the claimed methods “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.”

In reaching this conclusion, the court noted:

[T]he 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.

2.   The court confirmed that the claimed methods satisfy the machine-or-transformation test.

Again, the court expressed its belief that “administering a drug” always involves a transformation, because “[t]he drugs do not pass through the body untouched without affecting it” or without being metabolized.

The court emphasized that the fact that the method “relies on natural processes does not disqualify the administering step from the realm of patentability.” The court agreed with Prometheus that “every transformation of physical matter can be described as occurring according to natural processes and natural law.” But, the court said, ”[t]he transformation here . . . 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.” 

With regard to the “determining” claims that do not include an “administering” step, the court noted that “[s]ome form of manipulation, such as the high pressure liquid chromatography method specified in several of the asserted dependent claims . . . is necessary to extract the metabolites from a bodily sample and determine their concentration.” Thus, these claims satisfy the test as inherently involving a transformation. 

This two-part analysis is similar to the USPTO’s Interim Bilski Guidance (promulgated July 27, 2010), which advises examiners to evaluate patent-eligibility of method claims by (1) considering whether the claimed method is directed to an abstract idea and (2) determining if it satisfies the machine-or-transformation test.

Other Exclusions Ruled Out

The Federal Circuit (again) rejected arguments that the “administering” and “determining” steps were mere “data gathering” steps or “insignificant extra-solution activity.” To the contrary, the court found that the steps were “central to the purpose of the claims, which the court found to be “optimizing efficacy and reducing toxicity of treatment regimes.” 

The Federal Circuit also (again) made clear that the presence of the “mental steps” in the “wherein” clauses did not defeat patent-eligibility, because the claims must be evaluated as a whole:

A subsequent mental step does not, by itself, negate the transformative nature of prior steps.

Because “[n]o claim in the Prometheus patents claims only mental steps” the prohibition against patenting mental steps per se did not impact Prometheus’s claims. 

The Bottom Line

The Federal Circuit wrapped up its opinion with this query:

[W]hen 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.

By emphasizing these characteristics in this case, the court may be leaving itself room to reach different results in different cases, including Classen Immunotherapies, Inc. v. Biogen Idec (PDF) and Association for Molecular Pathology v. USPTO (the ACLU/Myriad BRCA1 case).

While much of this Prometheus decision reiterates the analysis from the 2009 Federal Circuit decision, the fact that there is “nothing new here” is news. The Supreme Court’s GVR order had cast a shadow of uncertainty over the patent-eligibility of personalized medicine methods, even as health care innovators and practitioners are promoting personalized medicine as offering the promise of more effective—and more cost-effective—treatments. Now the Federal Circuit has provided some guidance on the types of claims that can be found to satisfy § 101 post-Bilski, and has hinted at the types of claims that may be found to go too far.

Solving Utility Problems

Posted by Courtenay Brinckerhoff on Posted in Federal Circuit Decisions

The Federal Circuit decisions in Cancer Research Technology Ltd. v. Barr Labs., Inc. (Nov. 2010) and In Re ’318 Patent Infringement Litigation ("Janssen") (Sep. 2009) present an interesting contrast in utility issues. In Cancer Research, the USPTO raised utility rejections that the applicant eventually overcame and the patent was found to be enforceable, while in Janssen, the USPTO never raised the issue but both the district court and the Federal Circuit found the patent invalid for lack of utility. The Federal Circuit may address a similar situation again this week, when it hears oral arguments in Eli Lilly & Co. v. Actavis on Thursday.

The Janssen Case

The Janssen Patent & Prosecution History

The patent at issue in Janssen (U.S. 4,663,318) was directed to:

A method of treating Alzheimer’s disease and related dementias which comprises administering to a patient suffering from such a disease a therapeutically effective amount of galanthamine or a pharmaceutically-acceptable acid addition salt thereof.  

As characterized by the Federal Circuit:

The specification of the ’318 patent was just over one page in length, and, according to the courts, provided almost no basis for its stated conclusion that it was possible to administer "an effective Alzheimer’s disease cognitively-enhancing amount of galanthamine."

The specification cited prior art publications reporting the administration of galanthamine to humans or animals for other purposes with other effects, such as increasing plasma cortisol levels in humans, increasing short-term memory in dogs, and antagonizing scopolamine-induced amnesia in rats. But, the specification did not explain how these results supported the use of galanthamine to treat Alzheimer’s disease.

The USPTO rejected the claims for obviousness, but withdrew the rejection when the applicant explained that the subjects in the prior art studies were "normal," and so the "circumstances [of the prior art studies] [had] no relevance to Alzheimer’s disease." The applicant also stated:

[E]xperiments [are] underway using animal models which are expected to show that treatment with galanthamine does result in an improvement in the condition of those suffering from Alzheimer’s disease.

The USPTO granted the ’318 patent without asking for that data and, indeed, before the data were available.

The ’318 Patent Litigation

Janssen’s product received FDA approval in 2001. In 2005, a number of generic drug manufacturers filed Abbreviated New Drug Applications (ANDAs) with "Paragraph IV" certifications alleging that the ’318 patent was invalid.

The district court found that the patent was invalid for lack of enablement under 35 USC § 112 for failing to demonstrate a utility under 35 USC § 101. On appeal, the Federal Circuit summarized several principles of the utility requirement in the context of therapeutic methods:

  • patents claiming new methods of treatment typically are supported by test results
  • testing need not be conducted by the inventor
  • human trials are not required for a therapeutic invention to be patentable
  • results from animal tests or in vitro experiments can be sufficient

Because the ’318 patent had no data whatsoever "involving the use of galanthamine to treat Alzheimer’s-like conditions," the Federal Circuit affirmed the finding of invalidity.

The Brana Footnote

In In re Brana (Fed. Cir. 1995), the court held that data submitted during prosecution

can be used to substantiate any doubts as to the asserted utility [in the specification] since this pertains to the accuracy of a statement already in the specification. . . .  It does not render an insufficient disclosure enabling, but instead goes to prove that the disclosure was in fact enabling when filed (i.e., demonstrated utility).

 In a footnote that I find troubling, the Federal Circuit in Janssen distinguished Brana on two grounds:

(1) the finding in Brana did not depend on the post-filing date test results and
(2) in Brana the testing was submitted to the USPTO during prosecution.

But, in Brana the court did say that

Even if one skilled in the art would have reasonably questioned the asserted utility, i.e., even if the PTO met its initial burden thereby shifting the burden to the applicants to offer rebuttal evidence, applicants proffered sufficient evidence to convince one of skill in the art of the asserted utility. . . . Such evidence alone should have been sufficient to satisfy applicants’ burden.

Moreover, the Janssen opinion offers no rationale for drawing a line between data submitted to the USPTO during prosecution and data submitted to a court during litigation.

The Cancer Research Case 

The Cancer Research Patent & Prosecution History

The patent at issue in Cancer Research (U.S. 5,260,291) was directed to a class of tetrazine derivatives and therapeutic methods using them, including methods of treating cancer. The teachings relating to anti-cancer use are found in this paragraph:

The new tetrazine derivatives of general formula I possess valuable antineoplastic activity, for example against carcinomas, melanomas, sarcomas, lymphomas and leukaemias. They possess useful activity against glioma and mycosis fungoides. They have proved particularly active in mice at daily doses between 0.5 and 16 mg/kg animal body weight, administered intraperitoneally, against TLX5 (S) lymphomas according to the procedure of Gescher et al, Biochem. Pharmacol. (1981), 30, 89, and ADJ/PC6A and M5076 (reticulum cell sarcoma). Against leukaemia L1210, grafted intraperitoneally, intracerebrally and intravenously, and P388, according to the procedure described in "Methods of Development of New Anticancer Drugs" (NCI Monograph 45, March 1977, pages 147-149, National Cancer Institute, Bethesda, United States), the compounds were active both intraperitoneally and orally at doses of between 2.5 and 10 mg/kg animal body weight. Inhibition of both primary tumour and metastasis was obtained against the Lewis lung carcinoma by similar dosage regimes. Against the B16 melanoma and C38 tumour in mice (NCI Monograph 45, op cit.) the compounds were active intraperitoneally at doses of between 6.25 and 25 mg/kg animal body weight.

The examples relate to the synthesis of the compounds and pharmaceutical compositions.

The USPTO rejected the cancer treatment claims for lack of utility. (Indeed, back in those days—1983—the treatment of cancer was viewed as "per se" in-credible by the USPTO—you might as well have been claiming a perpetual motion machine or cold fusion method). The USPTO examiner indicated that the rejection could be overcome with human clinical data.

Instead of responding to the Office Action, the applicant abandoned the application in favor of a continuation application. That application eventually was rejected for lack of utility. Again, the applicant simply abandoned the application in favor of a continuation application. This cycle continued for eight more times (a near impossibility now with the 20-year term), until the final continuation application was filed in 1991.

By 1991, the applicant had obtained some favorable human clinical data (and some less favorable data), but it was never submitted to the USPTO.  Rather, in the 1991 continuation application the applicant challenged the utility rejection, citing the animal data in the specification and favorable case law on point. Eventually, the USPTO was convinced, and the patent was granted in 1993.

The Cancer Research Litigation

The patentee obtained FDA approval for a product within the scope of the patent (Temodar®) in August 1999, and obtained a 1,006 day Patent Term Extension under 35 USC § 156. In 2007, Barr filed an ANDA with a Paragraph IV certification alleging that the patent was unenforceable for prosecution laches and inequitable conduct.

Although the district court agreed with Barr, the Federal Circuit reversed on both counts.

On the laches issue, the Federal Circuit found that Barr could not prevail because it did not allege any prejudice due to the prosecution delays. (The court also noted that the facts here are not likely to be repeated in view of the 20-year term.)

On the inequitable conduct issue, the Federal Circuit found that the district court had erred by relying "solely on its finding of materiality to infer intent." Moreover, the Federal Circuit stated that while the publication of the clinical trial data at issue "does not foreclose a finding of deceptive intent," it "is inconsistent with finding that intent to deceive is the single most reasonable inference to draw from the evidence."

 The Eli Lilly Case

The Eli Lilly case relates to Lilly’s Straterra® product for ADHD. The patent at issue is U.S. 5,658,590 which claims:

A method of treating attention-deficit/hyperactivity disorder comprising administering to a patient in need of such treatment an effective amount of tomoxetine.

In addition to making assertions of usefulness and disclosing appropriate therapeutic doses, the specification states the following regarding tomoxetine’s activity:

Tomoxetine is a well-known drug, the chemical name of which is (R)-(-)-N-methyl-3-(2-methylphenoxy)-3-phenylpropylamine. It is regularly used as a salt, and salts are included in the term tomoxetine as used here. See, for example, Gehlert, et al., Neuroscience Letters 157, 203-06 (1993), for a discussion of the mechanism of tomoxetine’s activity as a norepinephrine reuptake inhibitor. Tomoxetine is quite active in that function, and moreover is substantially free of other central nervous system activities at the concentrations or doses at which it effectively inhibits norepinephrine reuptake. Thus, it is quite free of side effects and is properly considered to be a selective drug.

In the pending ANDA litigation, the claims were challenged for lack of enablement. The district court followed Janssen by finding that Eli Lilly could not rely on post-filing date evidence to support utility because it had not been submitted to the USPTO, but noted that unlike Janssen, Eli Lilly had explained how the prior art discussed in the specification would have been understood to support utility.  Thus, the court denied the motion for summary judgment of invalidity.

As noted above, the Federal Circuit is scheduled to hear oral arguments in this case on Thursday, December 9, 2010.

Solving Utility Problems

I am troubled by the doctrine that seems to be sprouting from these cases:

An applicant can solve a utility problem—overcome a utility/enablement rejection—with post filing-date evidence as long as the problem is raised by the USPTO examiner, but a patentee cannot solve the same problem with the same evidence if its not raised until litigation.

Because this "doctrine" stems from a mere footnote in Janssen that provides no supporting rationale, I am at a loss as to where it comes from and why the court finds the need to draw this line.

Given the ever-evolving nature of patent law—where thresholds, standards and burdens can change with each Federal Circuit or Supreme Court decision—there is always a possibility that a patent that satisfied the law as it was understood, interpreted and applied at the time of prosecution may require additional evidence to establish that it satisfies a higher (or different) threshold, standard, or burden that may apply when it is challenged years later. Why should the patentee be limited to evidence made of record at the USPTO when the USPTO had no reason to require more evidence at the time and the applicant had no reason to believe that more was warranted? 

Maybe the Federal Circuit will take a closer look at this "doctrine" in the Eli Lilly case. If if doesn’t reconsider it or rein it in, I hope it will at least explain it.