“According to a 2016 report, about 66% of clinical decisions are based on guidance provided by in vitro diagnostic tests. Disincentives to the development of new diagnostic tests are therefore not in the public interest.”

In each of the recent Federal Circuit decisions on medical diagnostics inventions, Athena Diagnostics v. Mayo Collaborative Services, 2017-2508, (Fed. Cir. Feb. 6, 2019) (“Athena”) and Cleveland Clinic Found. v. True Health Diagnostics LLC, 2018-1218 (Fed. Cir. April 1, 2019; non-precedential) (“Cleveland Clinic II”), the court affirmed a district court ruling that found a medical diagnostic or a related patent invalid for being directed to ineligible subject matter. Athena and Cleveland Clinic II follow the hard stance taken by the Federal Circuit against medical diagnostics inventions, first in Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1376 (Fed. Cir. 2015) (“Ariosa”) and next in Cleveland Clinic Found. v. True Health Diagnostics LLC, 859 F.3d 1352, 1361 (Fed. Cir. 2017) (“Cleveland Clinic I”).

In Athena, the patent covered a method for diagnosing a disease in a subpopulation of affected individuals based on the discovery of a correlation between the disease and certain autoantibodies found only in that subpopulation. In Cleveland Clinic I, the patent claims were directed to diagnosing the risk of atherosclerotic cardiovascular disease (CVD) based on the correlation between elevated levels of a protein found in the blood and occurrence of atherosclerotic CVD. In Cleveland Clinic II, the claims were directed to methods of identifying elevated levels of the protein but did not include any recitation of the correlation.

Notably, despite confirming the invalidity of the patent, the panel majority in Athena affirmed that “providing patent protection to novel and non-obvious diagnostic methods would promote the progress of science and useful arts”—the constitutional purpose patents serve. Athena, Majority opinion at 15. Also, the majority agreed with the dissent that “the public interest is poorly served by adding disincentive to the development of new diagnostic methods.” Id. Nonetheless, the majority felt that its hands were tied by Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012) (“Mayo”). Id. (stating, “[b]ut, whether or not we as individual judges might agree or not that these claims only recite a natural law…the Supreme Court has effectively told us in Mayo that correlations between the presence of a biological material and a disease are laws of nature, see 566 U.S. at 77, and “[p]urely ‘conventional or obvious’ ‘[pre]-solution activity’ is normally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law.” (citation omitted).

In Mayo, the U.S. Supreme Court held that a patent directed to a method was invalid as a natural law if the method, in addition to the natural law, involved only well-understood, routine, conventional steps previously engaged in by scientists in the field. The court formulated a two-step test for examining patent eligibility under which step one requires determining whether a claim is directed to a judicial exception, (i.e., a law of nature, a natural phenomenon, or an abstract idea). If so, then step two requires determining whether any element or combination of elements in the claim is sufficient to ensure that the claim amounts to something significantly more than the judicial exception.

The Mayo test, expanded in Alice Corp. v. CLS Bank International, 573 U.S. 208 (2014), for abstract ideas, and now commonly referred to as the Alice/Mayo test, leads to the dissection of a claim to first extract the judicial exception. The remainder is analyzed for an inventive concept to determine whether the additional elements “transform the nature of the claim” into a patent-eligible application. A claim failing the second step is held patent-ineligible as being directed to the judicial exception. Many medical diagnostics patent claims detect correlations using commonly known techniques and thus are likely to suffer the same fate as the claims in Ariosa and Athena, for example. This problem became widely recognized in the wake of Ariosa where the Federal Circuit, applying the Alice/Mayo analysis, struck down Sequenom’s important innovation for prenatal diagnosis of fetal abnormalities. The court first determined that the claim was directed to a patent ineligible concept and then proceeded to the next step, explaining, “[W]e next consider the elements of each claim both individually and ‘as an ordered combination’ to determine whether additional elements ‘transform the nature of the claim’ into a patent-eligible application.” Ariosa at 1375 (emphasis added).

This compartmentalized approach was criticized by the dissent in Athena, which cited four Supreme Court precedents supporting the proposition that a claim must be analyzed as a whole. These include Mercoid Corp. v. Minneapolis-Honeywell Regulator Co., 320 U.S. 680, 684 (1944), stating, “a patent on a combination is a patent on the assembled or functioning whole, not on the separate parts;” and Aro Mfg. Co. v. Convertible Top Replacement Co., 365 U.S. 336, 344 (1961), stating, “if anything is settled in the patent law, it is that the combination patent covers only the totality of the elements in the claim and that no element, separately viewed, is within the grant.” Athena, Dissenting opinion at 4-5.

In this regard, the U.S. Patent and Trademark Office’s 2019 Revised Patent Subject Matter Eligibility Guidance does require considering the claim as a whole in the first step, the “directed to” inquiry step, of the Alice/Mayo test. The guidance addresses eligibility of patent claims that recite an abstract idea. According to the guidance, a claim is not “directed to” a judicial exception, and thus is patent eligible, if the claim as a whole integrates the recited judicial exception into a practical application of that exception. The guidance explains integration as follows: “[a] claim that integrates a judicial exception into a practical application will apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception, such that the claim is more than a drafting effort designed to monopolize the judicial exception.” The guidance seems to require mainly that the claim impose a meaningful limit on the judicial exception. However, the guidance does not have the force of law, and there is no certainty that the Federal Circuit will endorse the guidance.

Further, it is worth noting that the court has required more than a meaningful limit on the judicial exception to avoid full eligibility analysis. For example, in Enfish, LLC v. Microsoft Corp., 822 F.3d 1327, (Fed. Cir. 2016) (“Enfish”), the court, in determining that the claims at issue were not directed to an abstract idea within the meaning of Alice, stated that rather, they were “directed to a specific improvement to the way computers operate…” Enfish at 1336. Also, in McRO, Inc. v. Bandai Namco Games Am. Inc., 837 F.3d 1299, (Fed. Cir. 2016) (“McRO”), the court stated that when looked at as a whole, the claim at issue was “directed to a patentable, technological improvement over the existing, manual 3-D animation techniques.” McRO at 1316.

The requirement for an improvement to the technology involved in carrying out the claimed method is a steep hurdle for the eligibility of most medical diagnosis inventions, since the essence of such inventions is applying a newly discovered correlation to deliver a practical benefit—not improving the technology used to provide the diagnosis. In this regard, medical diagnostic inventions are unique. This point was highlighted by the Athena dissent through reference to the amici curiae Five Life Sciences Patent Practitioners’ brief, which stated, “[medical] diagnostic methods . . . are so tightly bound to underlying natural laws and phenomen[a], they are especially susceptible to undue expansion of the eligibility standards…” Athena Dissenting opinion at 13.

Since all patent eligibility determinations have to satisfy the requirements set forth in Mayo, the broad question is whether Mayo can be read with prior Supreme Court patent eligibility cases in a way that medical diagnostics claims can be found eligible. Before exploring answers to this question, however, several post-Mayo Federal Circuit decisions related to patent eligibility of medical diagnostics patents are outlined below.

Ariosa v. Sequanom

In Ariosa, the claims were directed to a method for detecting paternally inherited cell-free fetal DNA (cffDNA) in maternal plasma or serum to determine fetal characteristics such as gender. The method was based on the discovery that cffDNA could be found in maternal plasma/serum. The method required amplifying the cffDNA present in the plasma/serum and detecting the paternally inherited cffDNA using known laboratory techniques. Prior art prenatal diagnoses methods were invasive and risky to the mother and to the pregnancy.

The panel majority in Ariosa found that the claimed method started with maternal cffDNA and ended with paternally inherited cffDNA. It reasoned that since the existence of each was a natural phenomenon, the method began and ended with a natural phenomenon and therefore was directed to naturally occurring matter. Because techniques like polymerase chain reaction (PCR) to amplify and detect cffDNA were well-understood, routine, and conventional, the only subject matter new and useful, the majority observed, was the discovery of the presence of cffDNA in maternal plasma/serum.

Cleveland Clinic I

In Cleveland Clinic I, the patent at issue claimed methods for characterizing the risk of cardiovascular disease in an individual by determining the level of the enzyme myeloperoxidase (MPO) in a bodily sample taken from the individual and comparing that level with the MPO levels in persons not having cardiovascular disease. MPO is released when an artery is damaged or inflamed. Detection of MPO could be performed with known methods. In step one of the Alice/Mayo analysis, the Federal Circuit determined that the claims were directed to multistep methods for observing a law of nature, namely, that MPO correlates with cardiovascular disease. The Court observed that, as in Ariosa, the claimed method started and ended with naturally occurring phenomena with no meaningful non-routine steps in between.

Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc.

In Rapid Litig. 827 F.3d 1042 (Fed. Cir. 2016), the asserted claims were directed to a method of producing a preparation of hepatocytes that could be frozen and thawed at least two times. Because cryopreservation can damage cells, it was believed that hepatocytes could be frozen only once without losing viability. As such, upon thawing they had to be either used or discarded, which was a significant limitation. The inventors discovered that some fraction of hepatocytes was capable of surviving multiple freeze-thaw cycles. Based on this discovery, they developed an improved process of preserving hepatocytes, which they patented. The district court found the claims ineligible as directed to a law of nature, the law being that hepatocytes are capable of surviving multiple freeze-thaw cycles. The Federal Circuit reversed, determining that the claims were directed to a new and useful laboratory technique for preserving hepatocytes. Unlike Ariosa, the end result was not simply an observation or detection of the ability of hepatocytes to survive multiple freeze-thaw cycles, but a new and useful method of preserving hepatocytes, the court explained.

Athena v. Mayo

In Athena, the patent at issue claimed methods of diagnosing neurological disorders such as Myasthenia gravis (MG) by detecting autoantibodies that bind to an epitope of a membrane protein called MuSK. Autoantibody detection could be performed using techniques known in the art. About 80% of patients with MG produce acetylcholine receptor autoantibodies, but the other 20% do not, even though they experience the same MG symptoms. The inventors discovered that many of the 20% of MG patients without acetylcholine receptor autoantibodies instead generate autoantibodies to a protein called MuSK. No disease had previously been associated with MuSK.

Mayo argued that the claims were directed to a natural law—the correlation between naturally-occurring MuSK autoantibodies and MuSK-related neurological diseases like MG. Athena argued the opposite and pointed out that the claims recited innovative, specific, and concrete steps that do not preempt a natural law. The panel majority determined that as in Cleveland Clinic I and Ariosa, the claims were directed to a natural law because the claimed advance was only in the discovery of a natural law, and that the additional recited steps only applied conventional techniques to detect that natural law.

The majority acknowledged that the step one “directed to” inquiry focuses on the claim as a whole but added that the court had frequently considered whether the claimed advance improved upon a technological process or merely an ineligible concept, citing Ariosa, Rapid Litig., and McRO among others. The majority also distinguished the claims in Athena from those in Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117, 1133–36 (Fed. Cir. 2018) on the ground that the latter claimed a new treatment based a natural law, not the natural law.

Cleveland Clinic II

In Cleveland Clinic II, the claims were directed to methods of identifying elevated levels of MPO in blood. Unlike Cleveland Clinic I, the claims recited neither diagnosing the risk for atherosclerotic CVD nor the correlation between elevated levels of MPO and CVD risk. Cleveland Clinic argued in part that the claims were not directed to a natural law because they did not recite or describe any ineligible concept. The argument was based on the USPTO guidance published May 4, 2016 (Example 29) that if a claim does not recite or describe any ineligible concept, it is not directed to natural law. The Federal Circuit rejected this argument, noting that the guidance does not have the force of law.

Turning back to Supreme Court precedents on patent eligibility, despite strongly disagreeing with the majority, the Athena dissent did not view the Mayo decision as generally barring the typical medical diagnostics invention. For example, it stated, “[a]pplying the Mayo/Alice protocol of two-step claim analysis, claims 7–9 of the ’820 patent are patent-eligible under Step 1, for this method of diagnosing Myasthenia Gravis is not a law of nature, but a man-made chemical-biomedical procedure.” Athena Dissenting opinion at 11. Rather, in its view, the panel majority misapplied precedent and misinterpreted 35 U.S.C. 101. Id. at 14. Beyond underscoring that a claim must be considered as a whole (see above), it pointed to statements in Mayo and Alice cautioning against wielding the two-step subject matter eligibility test too heavily: “too broad an interpretation of this exclusionary principle could eviscerate patent law. For all inventions at some level embody, use, reflect, rest upon, or apply laws of nature, natural phenomena, or abstract ideas,” (Mayo, 566 U.S. at 71); and “[a]t the same time, we tread carefully in construing this exclusionary principle lest it swallow all of patent law.” (Alice, 573 U.S. at 217). Id. at 9.

A contrary position is that Mayo leaves no room for finding medical diagnostics claims patent eligible. As noted above, this appears to be the view of the Athena majority. Such was the view also of the concurrence in Ariosa, which indicated that the problem lay in the manner in which the Mayo court had applied the second part of the patent eligibility test. The concurrence observed that the Mayo court, referring to Diamond v. Diehr 450 U.S. 175 (1981) (Diehr), explained that in Diehr the overall process was patent eligible because of the way the additional steps of the process integrated the equation (the judicial exception) into the process as a whole, yet it discounted the conventional activities recited in the claim in Mayo. Ariosa at 1380.

While disregarding conventional activities might have been warranted in Mayo because there the conventional activities were steps that doctors were already performing (administering the thiopurine drug, measuring metabolite levels, and adjusting dosing based on the metabolite levels), the Supreme Court did not limit its ruling to those particular facts and circumstances, the concurrence observed. Id at 1381. As a result, a conventional activity (e.g., PCR) that had never been carried out for detecting the natural correlation at issue (e.g., detection of cffDNA in Ariosa) but had been been performed in other contexts, could be disregarded without testing if it integrated the natural correlation into the method. This is contrary to Diehr.

Only Time Will Tell

Medical diagnostics inventions continue to face strong challenges on the ground of subject matter ineligibility. These inventions are unique in that the practical benefits they provide do not necessarily depend on improvements to the techniques used for detecting the natural correlations on which the inventions are based. According to a 2016 report, about 66% of clinical decisions are based on guidance provided by in vitro diagnostic tests. Ulrich-Peter Rohr, et al., (2016) The Value of In Vitro Diagnostic Testing in Medical Practice: A Status Report, 11 PLoS One 11(3): e0149856. Disincentives to the development of new diagnostic tests are therefore not in the public interest. Many strongly believe that resolving the current eligibility impasse would require congressional action. In May of 2018, two major IP groups, Intellectual Property Owners Association (IPO) and American Intellectual Property Law Association (AIPLA) jointly proposed a legislative solution to amend 35 U.S.C. § 101 to clarify the patent eligibility standard and restore the scope of eligibility limited by the Supreme Court’s recent decisions. Currently, lawmakers in both the House and the Senate are engaged in efforts to redefine patent eligibility to bring certainty to what is patentable, especially in the areas of medical diagnostics and computer software. In this regard, they have been collecting stakeholders’ responses to the central question of how narrow or broad section 101 should be in order for it to serve a gatekeeping function. Not everybody is in favor of a narrow reading of this function, however. A broad reading helps defeat patent infringement lawsuits based on subject matter ineligibility and is favored by certain sections of certain industries. Only time will tell if there will be a change to section 101 and how far that change will go.