Mayo at Five: Eligibility of Diagnostic Method Claims

Just over five years ago, the Supreme Court began reshaping the concept of patent-eligible subject matter in the life sciences with its decision in Mayo v Prometheus.^[i]  Decisions following Mayo — from the Supreme Court to the district courts to the USPTO — have further changed the paradigm for determining what inventions in the life sciences field are eligible for patent protection in the United States.

The evolving jurisprudence regarding patent eligibility under 35 U.S.C. § 101 has raised questions for many in the patent bar and in the life sciences industry. At least one biopharmaceutical organization (PhRMA) has highlighted the importance of this developing area of law explaining, "[p]atents are critical for biopharmaceutical innovation given the research-intensive nature of this sector and the substantial upfront investment needed to discover and develop products that meet FDA approval requirements."[ii] This organization, among others in the industry, has voiced concerns that the present direction of § 101 jurisprudence "has made it harder for companies to consistently rely on the U.S. patent system to protect their innovations," putting the United States at a disadvantage in global markets.[iii]

In our linked full-length article, we evaluate the eligibility landscape for different types of life sciences patent claims five years post-Mayo, including by examining key Federal Circuit and district court decisions, and discussing relevant USPTO examples and practice. In this first of a series of blog posts, we discuss how courts have treated diagnostic method claims in the post-Mayo world. A more detailed analysis and discussion of the relevant cases is in our full-length article.

Bilski, Mayo, Myriad, and Alice, in Brief

In the late 1970s and early 1980s, the Supreme Court's decisions in § 101 cases such as Diamond v. Diehr[iv] and Diamond v. Chakrabarty[v] began a period of over three decades where courts took a broad view of patent-eligible subject matter for life science-related patents. The breadth of § 101 law during this period prompted some to posture that § 101 was no longer a meaningful limitation and essentially a "dead letter."[vi]

In 2010, the Supreme Court began reshaping patent-eligibility jurisprudence when it rejected the prevailing "machine-or-transformation" test as the sole test for patent eligibility in Bilski v. Kappos.[vii]

In 2012, the Supreme Court's decision in Mayo v Prometheus[viii] established a new two-step test for patent eligibility in the context of Prometheus' patent claims directed to diagnostic methods used to determine the appropriate dose of thiopurine drugs in different patients. Under the new framework, courts must first determine whether claims are directed to a patent ineligible concept, i.e., a law of nature, natural phenomena, or an abstract idea.[ix] If so, courts must then search for an "inventive concept" by determining whether additional elements "transform the nature of the claim" into a patent-eligible application.[x]

Using this new analysis, the Mayo Court found Prometheus' patent claims ineligible. Under the first step, the Court found "Prometheus' patents were directed to laws of nature — namely, relationships between concentrations of certain metabolites in the blood and the likelihood that a particular dose of a thiopurine drug will prove ineffective or cause harm."[xi] Regarding the second step, the Court found that the claimed "administering," "determining," and "wherein" steps were not "sufficient to transform the nature of the claim."[xii]

The year after Mayo, the Supreme Court revisited § 101 in Association for Molecular Pathology v. Myriad Genetics, this time in the context of composition claims.[xiii] The Court found claims to isolated DNA from a gene discovered by the inventors not patent eligible because "Myriad did not create or alter any of the genetic information encoded in the BRCA1 and BRCA2 genes. The location and order of the nucleotides existed in nature before Myriad found them."[xiv] In contrast, the Court found cDNA containing only the exons of that gene patent eligible because the exon-only sequence, without introns, does not exist in nature and thus is "not naturally occurring."[xv]

The Supreme Court last addressed patent eligible subject matter in 2014 in Alice Corp. v CLS Bank.[xvi] The Alice court reaffirmed the Mayo two-­step framework in determining that patent claims directed towards a scheme for using a third party to mitigate settlement risk were drawn to a patent-ineligible abstract idea.[xvii]

The Impact of Mayo and Myriad on Diagnostic Method Claims

Patents with claims directed towards diagnostic methods have frequently been the focus of patent eligibility challenges within the life sciences industry since the Supreme Court's decision in Mayo.

In 2014, the Federal Circuit addressed the eligibility of additional Myriad Genetics patent claims related to the BRCA1 and BRCA2 genes in In re BRCA1- and BRCA2- Hereditary Cancer Test Patent Litigation.^[xviii] The two method claims at issue recited methods of identifying a mutation in a patient's BRCA1 gene by comparing the patient's BRCA sequences with wild-type BRCA sequences.[xix]

The Federal Circuit found the claims ineligible as directed to an abstract idea under the Mayo/Alice test. On the first Mayo/Alice step, the Court found that the method claims were "directed to the patent-ineligible abstract idea of comparing BRCA sequences and determining the existence of alterations," which "require[s] merely comparing the patient's gene with the wild-type [sequences] and identifying any differences that arise."[xx] As to the second Mayo/Alice step, the court found that the elements describing the way in which the sequences are compared (via probe or via amplification and sequencing) "set forth well-understood, routine and conventional activity engaged in by scientists at the time of Myriad's patent applications."[xxi] The court held that these elements did not add "enough" to make the claims patent eligible because "[n]othing is added by identifying the techniques to be used in making the comparison because those comparison techniques were . . . techniques that a scientist would have thought of when instructed to compare the two sequences."[xxii]

The Federal Circuit again found diagnostic claims ineligible under § 101 in Ariosa Diagnostics, Inc. v. Sequenom, Inc.[xxiii] The inventors in Ariosa discovered that maternal blood plasma harbored a small amount of non-cellular DNA that the fetus inherited from its father ("cffDNA"). Based on this discovery, Sequenom developed a prenatal diagnostic test that used the maternal blood plasma, previously discarded as medical waste, to a determine a fetus's gender and identify genetic defects, thereby avoiding the risks of previous techniques that obtained samples directly from the fetus or placenta.

The Federal Circuit found Sequenom's claims related to this diagnostic method ineligible. On the first step, the court found that the "existence of cffDNA in maternal blood is a natural phenomenon" and that the claimed methods started with cffDNA taken from maternal plasma and ended with paternally inherited cffDNA, "which is also a natural phenomenon."[xxiv] On the second step, the court held that the additional elements of the claimed methods did not amount to "an inventive concept that transform[ed] the natural phenomenon of cffDNA into a patentable invention."[xxv] The court found the additional steps of preparing, amplifying, and detecting paternally-derived cffDNA, including polymerase chain reaction (PCR) techniques, to be "well-understood, conventional and routine" steps, appended to a natural phenomenon, even though no one had previously applied those techniques to cffDNA.[xxvi] Notably, Judges Linn, Dyk, and Lourie all indicated that they did not agree that the Sequenom claims should be patent ineligible but felt bound to reach that decision based on Mayo.[xxvii] As Judge Lurie explained, he felt that claims "should not be patent-ineligible on the ground that they set forth natural laws or abstractions" because "it is unsound to have a rule that takes inventions of this nature out of the realm of patent-eligibility on grounds that they only claim a natural phenomenon plus conventional steps."[xxviii]

Last year, in Genetic Techs. Ltd. v. Merial L.L.C., the Federal Circuit found patent claims to a method for analyzing correlations between different regions of DNA ineligible under § 101.[xxix] The inventor there discovered that coding regions of a gene may be linked to non-coding regions located either within that gene or elsewhere in the genome. As a result, the inventor realized that the alleles of a particular gene could be detected by looking at the non-coding regions known to be linked with the gene, instead of looking directly at the coding regions.

The Federal Circuit found claims to methods of using the non-coding DNA to identify of the coding region of interest ineligible under the Supreme Court's two-step Mayo/Alice test. First, the Federal Circuit found that the claims were directed to a "law of nature": the linkage between non-coding and coding sequences and "the tendency of such non-coding DNA sequences to be representative of the linked coding sequences."[xxx] Second, the court found that the steps of amplifying DNA and analyzing the amplified sequence were well known in the art at the time of filing and did not constitute an "inventive concept."[xxxi] In so holding, the Federal Circuit rejected Genetic Techs.' argument that, even if detecting alleles by the amplification process was well known, no one had ever amplified "non-coding regions" to detect "coding regions."[xxxii]

The Federal Circuit most recently found diagnostic method claims ineligible under § 101 in The Cleveland Clinic Foundation v. True Health Diagnostics.[xxxiii] The inventors in Cleveland Clinic developed a way to correlate the amount of myeloperoxidase (MPO) in a body fluid sample with the subject's risk of developing cardiovascular disease.

The Federal Circuit found claims to methods for characterizing a subject's risk for cardiovascular disease by measuring the level of MPO in a bodily fluid sample did not pass the Mayo/Alice test. On step one, the Federal Circuit noted that the patents' specifications indicate that the inventions are "based on the discovery that patients with cardiovascular disease have significantly greater levels of leukocyte and MPO."[xxxiv] Analogizing to Ariosa, the court noted that the patent discussed "detection of MPO and other MPO-related products, which are naturally occurring," and did not purport to alter MPO levels in any way.^[xxxv] Applying step two, the Federal Circuit found that "[t]he claims, whether considered limitation-by-limitation or as a whole, do not sufficiently transform the natural existence of MPO in a bodily sample and its correlation to cardiovascular risk into a patentable invention. The process steps here merely tell those interested in the subject about the correlations that the researchers discovered."[xxxvi] The court specifically reasoned that the inventors did not claim to have invented any of the recited methods for detecting MPO in bodily samples, nor to have derived any new statistical methods to arrive at the control levels of MPO used to assess a subject's disease risk.[xxxvii] In short, the claims failed step two because they did not recite the use of any new detection or analytical techniques.[xxxviii]

Diagnostic methods have also fared poorly in district court decisions post-Mayo. In a notable recent case, the District of Massachusetts joined the Federal Circuit in rejecting diagnostic method claims in Athena Diagnostics, Inc. v. Mayo Collaborative Services.[xxxix] The inventors there purported to discover that, in a certain percentage of patients, Myasthenia Gravis is caused by IgG antibodies attacking the muscle specific tyrosine kinase ("MuSK"). The patents claimed a method for diagnosing Myasthenia Gravis by screening for MuSK antibodies in a patient's body fluid through use of a radio-labeled complex.[xl]

Applying the now familiar two-part Mayo/Alice framework, the court found that step one was satisfied because the claims were directed to a patent ineligible law of nature, namely that some patients with Myasthenia Gravis have MuSK antibodies in their body fluid.[xli]  On step two, on Mayo's original motion, the court found that discovery was needed to determine whether Athena's method "uses standard techniques in the art, or whether it is sufficiently inventive to be patentable under the second step of Mayo."[xlii] But, after some discovery, the court considered a renewed motion and found that the iodination and immunoprecipitation techniques disclosed in the patent were standard in the art.[xliii] Importantly, the court found that the claim's inclusion of a man-made molecule, the radiolabeled MuSK, did not make the claims patent eligible because the claims themselves were directed to "a process for detecting autoantibodies, not a process for creating the [radiolabeled] MuSK."[xliv]

In addition to court decisions, the USPTO has provided Subject Matter Eligibility Guidance on the eligibility of diagnostic claims post-Mayo, which may have raised more questions than it answered for diagnostic method claims. In Example 29 of its § 101 guidance, the USPTO analyzed several example claims directed to methods for detecting and diagnosing a hypothetical disease called "julitis."[xlv] Claim 1 recited a method for detecting a julitis antibody called "JUL-1" in a patient by screening for the antibody in a sample of the patient's plasma.[xlvi] Claim 2 added a step of "diagnosing the patient with julitis when the presence of JUL-1 in the plasma sample is detected."[xlvii] Otherwise, claim 2 contained the exact same language as claim 1, with the exception of reciting a method of "diagnosing julitis" in the preamble, instead of "detecting JUL-1."[xlviii]

Despite the similarities between claim 1 and claim 2, the USPTO came to different conclusions on the eligibility of the claims. According to the USPTO, claim 1 would be patent-eligible, but claim 2 would not be, even though it adds an additional limitation.[xlix] According to the USPTO, claim 1 was not directed to a law of nature and was thus patentable pursuant to Step 1 of the Mayo/Alice test.[l] On the other hand, the addition of a diagnosis step in claim 2 introduced reliance on a natural law — the "correlation or relationship between the presence of JUL-1 in a patient's plasma and the presence of julitis in the patient."[li] Thus, claim 2 was not patentable because it fell under the judicial exception for claims directed to natural laws, and the claim's "additional elements fail[ed] to transform the exception into a patent-eligible application of that exception."[lii] Public comments have been critical of this example.[liii]

Conclusion

Four Supreme Court decisions in the last decade, Bilski, Mayo, Myriad, and Alice, have dramatically shifted the landscape of patent eligibility jurisprudence. In the wake of those cases, the courts and USPTO have struggled to apply the Supreme Court's new eligibility framework fairly and consistently across different types of claims within the life sciences.

Following Mayo, courts have routinely found diagnostic method claims patent ineligible, with the Federal Circuit going 4 for 4 invalidating these types of claims. This has left some to question to what extent patent claims to diagnostic methods remain patentable. While diagnostic method claims have fared poorly in the post-Mayo world, most of the claims found ineligible have also been broad, and it remains an open question whether a narrowly-tailored diagnostic method claim could survive the two-part Mayo/Alice test or whether the Federal Circuit or Supreme Court will pare back the reach of Mayo in the diagnostic area.

[i] Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66 (2012).

[ii] https://www.uspto.gov/sites/default/files/documents/comments_PHRMA_Jan182017.pdf at 2.

[iii] Id. at 9; see also https://www.law360.com/ip/articles/939165/tech-pharma-divided-over-section-101-challenges-post-alice?nl_pk=7f45793d-94ac-4cab-82b6-68c62c2735c9&utm_source=newsletter&utm_medium=email&utm_campaign=ip; http://www.corpcounsel.com/id=1202774015808/At-Stanford-Patent-Experts-Sound-Off-on-Section-101?mcode=0&curindex=0&curpage=ALL&slreturn=20170610202429.

Outside of the life sciences field, the American Intellectual Property Association has also stated its "concern[s] that recent section 101 jurisprudence has put the United States at risk of falling behind the patent system of other developed countries." https://www.uspto.gov/sites/default/files/documents/comments_aipla_jan182017.pdf at 3.

[iv] Diamond v. Diehr, 450 U.S. 175 (1981).

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

[vi] See Peter M. Brody and Jennifer Kwon, Social Media and Patent Eligibility, Social Media Law & Policy Report, Bloomberg BNA (March 24, 2015).

[vii] Bilski v. Kappos, 561 U.S. 593, 603-04 (2010).

[viii] Mayo, 566 U.S. 66.

[ix] Id. at 70-71.

[x] Id. at 72-73.

[xi] Id. at 77.

[xii] Id. at 78-79.

[xiii] Ass'n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107 (2013).

[xiv] Id. at 2116.

[xv] Id. at 2119.

[xvi] Alice Corp. Pty. v. CLS Bank Int'l, 134 S. Ct. 2347 (2014).

[xvii] Id. at 2355, 2357.

[xviii] In re BRCA1- and BRCA2- Hereditary Cancer Test Patent Litig., 774 F.3d 755 (Fed. Cir. 2014).

[xix] Id. at 761.

[xx] Id. at 763.

[xxi] Id. at 764.

[xxii] Id.

[xxiii] Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371 (Fed. Cir. 2015).

[xxiv] Id. at 1376.

[xxv] Id.

[xxvi] Id. at 1377-78.

[xxvii] Id. at 1380; Ariosa Diagnostics, Inc. v. Sequenom, Inc., 809 F.3d 1282 (Fed. Cir. 2015).

[xxviii] Ariosa, 809 F.3d at 1285, 1287.

[xxix] Genetic Techs. Ltd. v. Merial L.L.C., 818 F.3d 1369 (Fed. Cir. 2016).

[xxx] Id. at 1374-76.

[xxxi] Id. at 1376-77.

[xxxii] Id. at 1377-78.

[xxxiii] The Cleveland Clinic Found. v. True Health Diagnostics, LLC, 859 F.3d 1352 (Fed. Cir. 2017).

[xxxiv] Id. at 1360-61.

[xxxv] Id. at 1361-62.

[xxxvi] Id. at 1362.

[xxxvii] Id.

[xxxviii] Id.

[xxxix] Athena Diagnostics, Inc. v. Mayo Collaborative Servs., Civil Action No. 15-cv-40075-IT, 2016 WL 4491832 (D. Mass. Aug. 25, 2016).

[xl] Id. at *3.

[xli] See id. at *4.

[xlii] Id. at *5.

[xliii] Athena Diagnostics, Inc. v. Mayo Collaborative Servs., Civil Action No. 15-cv-400075-IT, 2017 WL 3336275, *5 (D. Mass. Aug. 4, 2017).

[xliv] Id. at *3-5.

[xlv] https://www.uspto.gov/sites/default/files/documents/ieg-may-2016-ex.pdf at 9-11.

[xlvi] Id. at 10.

[xlvii] Id.

[xlviii] Id.

[xlix] Id. at 11-12.

[l] Id. at 11.

[li] Id. at 11-12.

[lii] Id. at 12.

[liii] See, e.g., https://www.uspto.gov/sites/default/files/documents/comments_PHRMA_Jan182017.pdf at 4 ("Examples such as this one, where one claim is patentable but another almost identical claim is not, re-enforces the arbitrary nature of the Mayo two-step test.").

Authors: Geoffrey D. Biegler, Megan A. Chacon, Dalia Kothari