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biolink Legal Column - August 2014

Thursday, August 21, 2014   (0 Comments)
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"Laws of Nature" and Current Controversies in Patenting Biomarker Technology

James F. Kamp, Partner, Honigman Miller Schwartz and Cohn LLP

 

 James F. Kamp

Section 101 of the U.S. Patent Act, 35 U.S.C. §101, governs “Inventions Patentable:”
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 therefor, subject to the conditions and requirements of this title. 

In Diamond v. Chakrabarty (1980)1, the U.S. Supreme Court described the realm of patentable subject matter as “anything under the sun that is made by man.”  In the same decision, the Supreme Court also stated that “laws of nature, physical phenomena, and abstract ideas” were not patentable subject matter because “such discoveries are ‘manifestations of …nature, free to all men and reserved exclusively to none.’” Thirty-four years after Chakrabarty, and in the wake of the Supreme Court’s 2012 decision in Mayo Collaborative Services v. Prometheus Labs., Inc., the boundary between unpatentable “laws of nature” and patentable subject matter remains as controversial as ever, especially in medical arts concerning biomarker technology. The continuing controversy mandates a comprehensive, strategic approach to patenting in this field.
   
Medical research and practice have become increasingly molecular as new research and diagnostic tools have come online, and knowledge of the human body’s development and manifestation of pathological states, and reaction to therapeutic interventions, has increased. Much effort has been focused on the detection and use of clinically significant “biomarkers.” The National Institutes of Health Biomarkers Definitions Working Group once defined a biomarker as “a characteristic that is objectively measured and evaluated as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention.”  The World Health Organization has defined “biomarkers” at least as broadly to include “almost any measurement reflecting an interaction between a biological system and a potential hazard, which may be chemical, physical, or biological. The measured response may be functional and physiological, biochemical at the cellular level, or a molecular interaction.”2 A “Holy Grail” in the biomarker field is to discover the correlation between a clinically significant biomarker and the presence or absence of a disease state, or as an indicator of therapeutic efficacy.3

Such a biomarker was central to the Supreme Court’s 2012 decision in Mayo Collaborative Services v. Prometheus Laboratories, Inc. (respectively, “Mayo” and “Prometheus”).4 Prometheus was the exclusive licensee of two patents concerning the use of thiopurine drugs to treat immune-mediated gastrointestinal diseases such as Crohn’s disease and ulcerative colitis. It was known that patients metabolized thiopurine drugs at different rates and therefore the same dose of the thiopurine drug could have a different effect among patients, leading to uncertainty in determining a safe and effective dose for the patient. The licensed patents encompassed methods related to the inventors’ identification of correlations between thiopurine metabolite levels and the likelihood that a particular dosage of a thiopurine drug could cause harm or prove ineffective. Thus, the patents at issue claimed methods for “optimizing therapeutic efficacy” in the disease treatment by administering the drug, determining metabolite level, and adjusting the patient’s dosage, for example: 

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 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.5 


Mayo had licensed the technology but after developing its own test, indicated that it would stop licensing from Prometheus. After Prometheus sued Mayo for patent infringement, the federal district court ruled that, although at least one patent claim was infringed, the patents were invalid because they claimed natural laws or natural phenomena. In two rounds of appeals, the Federal Circuit Court of Appeals, the intermediate appellate court, reversed the trial court, finding that the patents were valid because at least two steps of the claim, the “administering” step and the “determining” step, were “transformative” under existing precedent. 

In a unanimous decision, the Supreme Court reversed the Federal Circuit and held that the patents were indeed invalid. The Court first considered whether the method at issue recited a natural law or natural phenomenon, finding that:

Prometheus’ patents set forth laws of nature - namely, relationships between concentrations of certain metabolites in the blood and the likelihood that a dosage of a thiopurine drug will prove ineffective or cause harm.”... The relation is a consequence of the ways in which thiopurine compounds are metabolized by the body—entirely natural processes. And so a patent that simply describes that relation sets forth a natural law. [Emphasis added.]


The Court then considered whether “the patent claims add enough to their statements of the correlations to allow the processes they describe to qualify as patent-eligible processes that apply natural laws.” [Emphasis in original.]  The Court found that “the answer to this question is no,” further holding that:

If a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself. [Emphasis added.]

Specifically, the Court found that the additional steps in the claims added nothing that was patently significant:

The upshot is that the three steps simply tell doctors to gather data from which they may draw an inference in light of the correlations. To put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately.

The Court characterized its decision as consistent with a longstanding concern that “patent law not inhibit further discovery by improperly tying up the future use of laws of nature.” Addressing Prometheus’ argument that “denying patent coverage here will interfere significantly with the ability of medical researchers to make valuable discoveries, particularly in the area of diagnostic research,” the Court noted competing policy considerations espoused by the American Medical Association and others. With a nod toward the U.S. Congress’ role in addressing the balancing of competing interests, the Court declined to “depart[-] from established general legal rules lest a new protective rule that seems to suit the needs of one field produce unforeseen results in another.”

The Supreme Court’s decision in Mayo v. Prometheus established no “bright line” rule for patenting “process” claims for technologies that involve “natural laws” and biomarkers. Nonetheless, on July 3, 2012, in the wake of the Mayo decision, the U.S. Patent and Trademark Office (“USPTO”) issued an “Interim Procedure for Subject Matter Eligibility Analysis of Process Claims Involving Laws of Nature” (the “2012 Interim Procedure”) for use by USPTO personnel in determining subject matter eligibility of process claims post-Mayo. The 2012 Interim Procedure set out three “essential inquiries” to determine whether a patent claim as a whole is drawn to patent-eligible subject matter, the third inquiry representing the USPTO’s apparent assessment of Mayo’s takeaways: 

Does the claim include additional elements/steps or a combination of elements/steps that integrate the natural principle into the claimed invention such that the natural principle is practically applied, and are sufficient to ensure that the claim amounts to significantly more than the natural principle itself?  (Is it more than a law of nature + the general instruction to simply “apply it”?) If no, the claim is not patent-eligible and will be rejected. If yes, the claim is patent-eligible. [Emphasis added.]

The 2012 Interim Procedure further stated that “there must be at least one additional element or step that applies, relies on or uses the natural principle so that the claim amounts to significantly more than the natural principle itself.” [Emphasis added.]

It was widely thought that the 2012 Interim Procedure, with its “additional element or step” criterion, would lead to increased Section 101 rejections. Nonetheless, on June 13, 2013, while the 2012 Interim Procedure was still being digested by the USPTO and the patenting community, the Supreme Court decided American Association for Molecular Pathology v. Myriad Genetics, Inc. (the “Myriad” case)6. In Myriad, the Court held that naturally occurring DNA segments, specifically, segments of BRCA1 and BRCA2 genes, were “products of nature” and were not patent - eligible merely because they had been isolated. Like Mayo v. Prometheus, the Myriad case represents a significant pronouncement by the Supreme Court concerning the scope of patent eligibility under Section 101 of the Patent Act. 

On March 4, 2014, the USPTO issued a “Guidance For Determining Subject Matter Eligibility of Claims Reciting Or Involving Laws of Nature, Natural Phenomena and Natural Products” (the “Guidance”). The Guidance announced the USPTO’s intention to implement new examination procedures to address “changes in the law relating to subject matter eligibility” in view of Mayo v. Prometheus and the Myriad case. The Guidance proposed a unitary approach to addressing all claims, whether machine, composition, manufacture or process claims, that recited or involved laws of nature or natural principles, natural phenomena, or natural products. The Guidance set out another three-step process of determining subject matter eligibility: 

  1. Is the claim directed to one of the four statutory categories, i.e., process, machine, manufacture, or composition of matter?  If yes:
  2. Does the claim recite or involve a judicial exception (for example, abstract ideas, laws of nature/natural principles, natural phenomena, or natural products)?  If yes:
  3. Does the claim as a whole recite something “significantly different” than the judicial exception? [Emphasis added.]  If no, the claim will be rejected as drawn to patent ineligible subject matter. 

The USPTO’s Guidance, including its “significantly different” criterion, was met by an immediate firestorm of criticism. In partial response, on May 9, 2014, the USPTO hosted a day-long forum to receive public feedback on the Guidance and to allow concerned persons and entities to present their interpretation of the impact of Supreme Court precedent on subject matter eligibility analyses. During the May 9th forum, the USPTO stated that it would be updating the Guidance, and invited the public to submit any written comments they wished to be considered for the update.7 

The period for public comment on the Guidance closed on July 31, 2014. Although some commenters voiced support for aspects of the 2014 Guidance, many comments voiced serious concerns about its propriety, scope, and implications for future patenting activities. For example, in their joint comments, the Association for University Technology Managers (“AUTM”) and other university-related entities wrote in part:

“[We] are deeply concerned about the USPTO Guidance Memorandum and its unwarranted, as well as its legally inconsistent broad changes in examination practice…The Guidance adversely and unnecessarily impacts our ability not only to license and commercialize future discoveries and inventions, but also the validity of many existing patents for products, particularly in life science areas which make up the majority of university patents…”;

[The Guidance’s position on patenting diagnostic assays] “comes from a strained and overreaching interpretation of Mayo v. Prometheus which is not required by the Supreme Court’s holding in that case…”; and

“By drafting and releasing this Guidance, the PTO is assuming a judicial authority that is not properly PTO’s to assume by erroneously re-interpreting Supreme Court case law, with no opportunity for public comment.”

In similar fashion, the American Intellectual Property Law Association (“AIPLA”) wrote in part that: 

“[T]he [USPTO’s] Guidance on applying the Myriad decision is a unilateral expansion of the rules that reads all of the limiting language out of the opinion ..;” 

and

“The Guidance sets forth a single approach on “How to Analyze ‘Significantly Different’” for both product and process claims. This approach deviates from Supreme Court precedent by combining considerations that are only applicable to product claims with considerations only applicable to process claims. Such an approach is not supported by precedent; the Supreme Court decisions maintain an analytically separate approach for process and product claims.”  

The USPTO has not announced a timetable for considering comments and updating the 2014 Guidance.8

Despite the shifting nature of this controversy and the applicable criteria for patentability, there is some indication of recent successes in obtaining patents for biomarker-related technologies in the face of Section 101 rejections. For example, on August 5, 2014, the USPTO issued U.S. Patent No. 8,795,963, titled “Genetic markers for risk management of atrial fibrillation and stroke” (the “ ‘963 Patent”). According to its Abstract, “[t]he invention relates to procedures and methods of determining a susceptibility to cardiac arrhythmia, including Atrial Fibrillation, Atrial Flutter and Stroke, by assessing the presence or absence of alleles at polymorphic markers found to be associated with risk of these conditions.” Claim 1 of the ‘963 Patent reads as follows:

A method for determining a susceptibility to a condition selected from the group consisting of: cardiac arrhythmia selected from Atrial Fibrillation and Atrial Flutter, and Stroke, in a human individual, the method comprising: 

analyzing nucleic acid from a biological sample from the human individual for a T allele of a polymorphic marker rs7193343; 

detecting a T allele of rs7193343 in the nucleic acid; 

determining that the individual has an increased genetic susceptibility to a condition selected from the group consisting of: cardiac arrhythmia selected from Atrial Fibrillation and Atrial Flutter, and Stroke from the detection of the T allele of rs7193343 in the nucleic acid; and 

performing an electrocardiogram or initiating anticoagulant therapy on the individual determined to have the increased susceptibility to the condition.

The USPTO Examiner rejected the claim as originally written under Section 101 and Mayo v. Prometheus, asserting that the claim as a whole was directed to a law of nature/natural principle, namely, a relationship between allelic content and a risk of developing a clinical phenotype. In overcoming the Examiner’s Section 101 rejection, the applicants argued inter alia that none of the Supreme Court’s judicially- created exceptions to patentability applied because: (1) although the claimed invention was based in part on the inventors’ observation that certain specific genetic markers appeared more frequently in the patient population of interest, the claimed invention was not based on these observations or measurements thereof per se but rather “to practical application thereof” (emphasis in original); and (2) the claims were not directed to a “natural law,” but rather to a practical application thereof, in view of the fact that “the claims do not preempt all uses of the so-called law.” After additional interviews with the Examiner and resulting amendments, the claim was allowed. Although the USPTO record is not clear on the point, it appears that the addition of a step beyond the correlation, namely, an additional diagnostic or treatment step, might have helped distinguish the claim from the “law of nature.”9 Thus, the applicants were successful in a patenting approach that addressed the Supreme Court’s judicially-created exceptions to patentability as well as the Court’s policy concern over “inhibit[ing] further discovery by improperly tying up the future use of laws of nature.”

In summary, Mayo v. Prometheus stands as an example of the proposition that not all discoveries, regardless of their significance, are patentable inventions. More specifically, the mere discovery of the correlation between a clinically significant biomarker and a disease state, or an indicator of therapeutic efficacy, is unlikely by itself to support patent-eligible subject matter. Patent applicants wishing to pursue method claims for biomarker applications should anticipate, well in advance, the need to argue that, in important respects, the claimed method is not conventional in the art and will not hinder others from studying the correlation between the biomarker and any clinically or therapeutically significant indicia. Moreover, other claim types beyond or in addition to method claims may need to be considered in order to characterize the sought-after invention as outside the judicially- created exceptions to patentability. For example, depending on the circumstances, combining a novel product or test with the correlation may help contribute to a finding of patent-eligible subject matter.

Whether the discovery of a clinically significant correlation can be leveraged successfully into a patentable invention will require strategic thinking during the development of the idea, the data, and the written description supporting the claimed invention. It will also require careful thought in the characterization of the invention in patent claim terms, while addressing the public policy concerns over technologies that relate to or involve laws of nature and natural principles. Those who pursue this process creatively and persistently are more likely to enjoy the fruits of success from their innovations. 

Jim Kamp is a partner and registered patent attorney with Honigman Miller Schwartz and Cohn LLP, where he practices IP litigation and patent prosecution in biotechnology/life sciences and other areas. Along with others in Honigman’s IP Group, Jim has been recognized as a “2014 IP Star” by “Managing Intellectual Property” magazine. Jim can be reached at (248) 566-8408 or JKamp@honigman.com.


1 Diamond v. Chakrabarty, 447 U.S. 303 (1980).

2 See generally, Strimbu et al., “What are Biomarkers?”, Curr Opin HIV AIDS 5(6): 463-466 (November 2010), available at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3078627.

3 Indeed, market interest in the use of biomarkers remains very high. See for example, “Report: Biomarkers market to grow 18.5% by 2018” (October 2, 2013) at http://www.fiercediagnostics.com/story/report-biomarkers-market-grow-185-2018/2013-10-02

4 Mayo Collaborative Services v. Prometheus Labs., Inc., 566 U.S. __, 132 S. Ct. 1289 (2012).

5 See for example, Claim 1 of U.S. Patent No. 6,355,623, titled “Method of treating IBD/Crohn's disease and related conditions wherein drug metabolite levels in host blood cells determine subsequent dosage.”

6 569 U.S. __, 133 S.Ct. 2107 (2013).

7 See generally http://www.uspto.gov/patents/announce/myriad-mayo.jsp.

8 Public comments can be viewed at http://www.uspto.gov/patents/law/comments/myriad-mayo_guidance_comments.jsp.

9 In view of the evolving standards for patentability, only time will tell whether the allowance was anomalous and the approach would not be followed by other Examiners, and whether the claim would withstand the crucible of litigation should the patentee have to enforce it. 


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