Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC

United States Court of Appeals for the Federal Circuit ______________________

ATHENA DIAGNOSTICS, INC., OXFORD UNIVERSITY INNOVATION LTD., MAX-PLANCK- GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN E.V., Plaintiffs-Appellants

v.

MAYO COLLABORATIVE SERVICES, LLC, DBA MAYO MEDICAL LABORATORIES, MAYO CLINIC, Defendants-Appellees ______________________

2017-2508 ______________________

Appeal from the United States District Court for the District of Massachusetts in No. 1:15-cv-40075-IT, Judge Indira Talwani. ______________________

Decided: February 6, 2019 ______________________

ADAM GAHTAN, Fenwick & West LLP, New York, NY, argued for plaintiffs-appellants. Also represented by ERIC M. MAJCHRZAK, VANESSA PARK-THOMPSON; ANDREW JOSEPH KABAT, EMMETT J. MCMAHON, Robins Kaplan LLP, Minneapolis, MN; DIMITRIOS T. DRIVAS, White & Case LLP, New York, NY.

JONATHAN ELLIOT SINGER, Fish & Richardson, PC, San 2 ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES

Diego, CA, argued for defendants-appellees. Also repre- sented by JOHN CAMERON ADKISSON, ELIZABETH M. FLANAGAN, PHILLIP GOTER, DEANNA JEAN REICHEL, Minne- apolis, MN.

AARON BARKOFF, McAndrews, Held & Malloy, Ltd., Chicago, IL, for amicus curiae The Chartered Institute of Patent Attorneys.

KEVIN EDWARD NOONAN, McDonnell, Boehnen, Hulbert & Berghoff, LLP, Chicago, IL, for amicus curiae Five Life Sciences Patent Practitioners. Also represented by JOHN DOMINIC CRAVERO, AARON VINCENT GIN, MICHAEL S. GREENFIELD, ANDREA KAY ORTH.

MELISSA A. BRAND, Biotechnology Innovation Organi- zation, Washington, DC, for amicus curiae Biotechnology Innovation Organization. Also represented by HANSJORG SAUER; BRIAN PAUL BARRETT, Eli Lilly and Company, Indi- anapolis, IN.

MATTHEW JAMES DOWD, Dowd Scheffel PLLC, Wash- ington, DC, for amici curiae Dan L. Burk, Richard A. Ep- stein, Christopher Michael Holman, Gus Hurwitz, Adam Mossoff, Kristen J. Osenga, Michael Risch, Mark F. Schultz, Ted M. Sichelman, Brenda M. Simon.

KATHLEEN M. SULLIVAN, Quinn Emanuel Urquhart & Sullivan, LLP, New York, NY, for amicus curiae ARUP La- boratories, Inc. Also represented by BRIAN C. CANNON, Redwood Shores, CA. ______________________

Before NEWMAN, LOURIE, and STOLL, Circuit Judges. Opinion for the court filed by Circuit Judge LOURIE. Dissenting opinion filed by Circuit Judge NEWMAN.

ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES 3

LOURIE, Circuit Judge. Athena Diagnostics, Inc., Oxford University Innova- tion Ltd., and the Max-Planck-Gesellschaft zur Forderung der Wissenschaften E.V. (collectively, “Athena”) appeal from the order of the United States District Court for the District of Massachusetts holding that claims 6–9 of U.S. Patent 7,267,820 (the “’820 patent”) are invalid under 35 U.S.C. § 101 and dismissing Athena’s complaint under Rule 12(b)(6). Athena Diagnostics, Inc. v. Mayo Collabora- tive Servs., LLC, 275 F. Supp. 3d 306 (D. Mass. 2017) (“De- cision”). Because the district court correctly concluded that the claims at issue are directed to a natural law and lack an inventive concept, we affirm. I. BACKGROUND Athena Diagnostics is the exclusive licensee of the ’820 patent, covering methods for diagnosing neurological dis- orders by detecting antibodies to a protein called muscle- specific tyrosine kinase (“MuSK”). ’820 patent Abstract. Athena also markets a test called FMUSK that functions by evaluating those antibodies. After Mayo Collaborative Services, LLC (“Mayo”) developed two competing tests that allegedly practice each step of one or more claims of the ’820 patent, Athena accused Mayo of infringing its patent. Mayo moved to dismiss under Rule 12(b)(6), arguing that the asserted claims of the ’820 patent were invalid under 35 U.S.C. § 101. The district court granted Mayo’s motion, concluding that the claims were invalid under § 101 for claiming ineligible subject matter. This appeal solely con- cerns whether claims 6–9 are patent eligible under § 101. A. Myasthenia gravis (“MG”) is a neurological disorder where patients experience muscle weakness and symptoms including drooping eyelids, double vision, and slurred speech. ’820 patent col. 1 ll. 13–23. It was previously dis- covered that MG is an autoimmune disease caused by a

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patient generating antibodies against her own acetylcho- line receptors. Id. col. 1 ll. 24–26. Antibodies which recog- nize a person’s own proteins as foreign antigens are known as autoantibodies. Id. col. 1 ll. 42–45. About 80% of patients with MG produce acetylcholine receptor autoantibodies. Id. col. 1 ll. 34–36. The other 20% do not, but they do experience the same MG symptoms. Id. col. 1 ll. 36–38. The named inventors of the ’820 patent discovered that many of the 20% of MG patients without acetylcholine receptor autoantibodies instead generate au- toantibodies to a membrane protein called MuSK. Id. col. 1 ll. 54–61. Prior to their discovery, no disease had been associated with MuSK. Id. col. 2 ll. 35–37. Having discovered the association between MuSK au- toantibodies and MG, the inventors of the ’820 patent dis- closed and claimed methods of diagnosing neurological disorders such as MG by detecting autoantibodies that bind to a MuSK epitope. 1 Id. col. 2 ll. 61–65. Claim 1, not at issue in this appeal, is the only independent claim and reads as follows: 1. A method for diagnosing neurotransmission or developmental disorders related to [MuSK] in a mammal comprising the step of detecting in a bod- ily fluid of said mammal autoantibodies to an epitope of [MuSK]. Id. col. 12 ll. 31–35. Claim 7 is at issue and depends from claim 1. It recites:

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7. A method according to claim 1, comprising contacting MuSK or an epitope or antigenic deter- minant thereof having a suitable label thereon, with said bodily fluid, immunoprecipitating any antibody/MuSK complex or antibody/MuSK epitope or antigenic determi- nant complex from said bodily fluid and monitoring for said label on any of said anti- body/MuSK complex or antibody/MuSK epitope or antigen determinant complex, wherein the presence of said label is indicative of said mammal is suffering from said neurotransmis- sion or developmental disorder related to [MuSK]. Id. col. 12 l. 62–col. 13 l. 5 (spacing added). Claim 8 de- pends from claim 7 and recites that the label is a radioac- tive label. Id. col. 13 ll. 6–7. Claim 9 depends from claim 8 and further recites that the radioactive label is 125I, a radioactive isotope of iodine. Id. col. 13 ll. 8–9. We focus on claim 9, the most specific one at issue, which requires: (1) contacting MuSK or an epitope thereof having a 125I label, with bodily fluid; (2) immunoprecipitating any anti- body/MuSK complex; and (3) monitoring for the label on the complex, wherein the presence of the label indicates the presence of a MuSK-related disorder. The specification of the ’820 patent further explains what the steps of iodination and immunoprecipitation en- tail. First, MuSK is iodinated using radioactive 125I. Id. col. 10 ll. 50–52. Then iodinated MuSK is separated from any free 125I by gel filtration. Id. col. 10 ll. 55–56. Next, the 125I-labeled MuSK is added to a small volume of the patient’s bodily fluid and left overnight. Id. col. 10 ll. 56– 58. If MuSK autoantibodies are present in the patient’s bodily fluid, they will bind to the 125I-labeled MuSK. Any 125I-labeled MuSK in the sample is then immunoprecipi- tated by adding a secondary antibody that binds to any

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MuSK autoantibodies present. Id. col. 10 ll. 58–60. The resulting precipitate is finally centrifuged, washed, and counted for radioactivity, which may be indicative of MG. Id. col. 10 ll. 60–61. It is undisputed that iodination and immunoprecipita- tion were known techniques at the time of the invention. The ’820 patent specification states that “[t]he actual steps of detecting autoantibodies in a sample of bodily fluids may be performed in accordance with immunological assay techniques known per se in the art,” such as radioimmuno- assays. Id. col. 3 ll. 33–37. With respect to the relevant individual steps in the radioimmunoassay, the specifica- tion also discloses that “[i]odination and immunoprecipita- tion are standard techniques in the art.” Id. col. 4 ll. 10– 11. Claim 6 is additionally at issue in this appeal and de- pends from claim 3. While claim 6 also involves detecting MuSK autoantibodies by contacting a patient’s bodily fluid with MuSK or an epitope thereof, the labelling occurs somewhat differently than in claims 7–9. Instead of label- ing MuSK with a radioisotope, claim 3 recites that the sec- ondary antibody is “tagged or labeled with a reporter molecule.” Id. col. 12 ll. 47–49. Claim 6 additionally re- quires that “the intensity of the signal from the [secondary] antibody is indicative of the relative amount of the anti- MuSK autoantibody in the bodily fluid when compared to a positive and negative control reading.” Id. col. 12 ll. 57– 61. This claimed technique exemplifies the ELISA method, 2 which, like radioimmunoassays, the ’820 patent specification lists as an example of “immunological assay techniques known per se in the art.” Id. col. 3 ll. 33–36.

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B. The district court concentrated its analysis on claims 7–9. Athena did not present any arguments specific to claim 6. Applying the test for subject matter eligibility es- tablished by the Supreme Court in Mayo Collaborative Ser- vices v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012) and Alice Corp. v. CLS Bank International, 573 U.S. 208 (2014), the court first concluded that the claims were di- rected to a law of nature, Decision, 275 F. Supp. 3d at 312. According to the court, the claims focused on the interac- tion of 125I-labeled MuSK with MuSK autoantibodies in bodily fluid, an interaction which occurs naturally. Id. at 310. The district court also determined that the claims lacked an inventive concept, as the recited steps involved only standard techniques in the art. Id. at 312–13. The district court thus dismissed Athena’s complaint for failure to state a claim. Athena appealed. We have ju- risdiction under 28 U.S.C. § 1295(a)(1). II. DISCUSSION We review the district court’s dismissal for failure to state a claim under regional circuit law. BASCOM Glob. Internet Servs., Inc. v. AT&T Mobility LLC, 827 F.3d 1341, 1347 (Fed. Cir. 2016). The First Circuit reviews such dis- missals de novo, accepts all well-pleaded facts alleged in the complaint to be true, and draws all reasonable infer- ences in favor of the non-movant. In re Loestrin 24 Fe An- titrust Litig., 814 F.3d 538, 549 (1st Cir. 2016). Patent eligibility under § 101 is a question of law based on under- lying facts, see Aatrix Software, Inc. v. Green Shades Soft- ware, Inc., 882 F.3d 1121, 1125 (Fed. Cir. 2018); Berkheimer v. HP Inc., 881 F.3d 1360, 1364–65 (Fed. Cir. 2018), that may be resolved on a Rule 12(b)(6) motion when the undisputed facts require a holding of ineligibility, SAP Am., Inc. v. Investpic, LLC, 898 F.3d 1161, 1166 (Fed. Cir. 2018).

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Section 101 provides that “[w]hoever invents or discov- ers 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 condi- tions and requirements of this title.” 35 U.S.C. § 101. Given the expansive terms of § 101, “Congress plainly con- templated that the patent laws would be given wide scope”; some of the legislative history likewise indicated that “Con- gress intended statutory subject matter to ‘include any- thing under the sun that is made by man.’” Diamond v. Chakrabarty, 447 U.S. 303, 308–09 (1980). Under the law as set forth by the Supreme Court, § 101, while broad, “contains an important implicit excep- tion. ‘[L]aws of nature, natural phenomena, and abstract ideas’ are not patentable.” Mayo, 566 U.S. at 70 (alteration in original) (quoting Diamond v. Diehr, 450 U.S. 175, 185 (1981)). These exceptions exist because monopolizing the basic tools of scientific work “might tend to impede innova- tion more than it would tend to promote it.” Id. at 71. How- ever, the Supreme Court has advised that these exceptions must be applied cautiously, as “too broad an interpretation of this exclusionary principle could eviscerate patent law.” Id. Laws of nature are not patentable, but applications of such laws may be patentable. A claim to otherwise statu- tory subject matter does not become ineligible by its use of a law of nature. See Diehr, 450 U.S. at 187; Parker v. Flook, 437 U.S. 584, 590 (1978). But, on the other hand, adding “conventional steps, specified at a high level of generality,” to a law of nature does not make a claim to the law of na- ture patentable. Mayo, 566 U.S. at 82. To distinguish claims to patent-eligible applications of laws of nature from claims that impermissibly tie up such laws, we apply the two-part test set forth by the Supreme Court. First, we examine whether the claims are “directed to” a law of nature. Alice, 573 U.S. at 217. If they are, then

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we proceed to the second inquiry, where we ask whether the limitations of the claim apart from the law of nature, considered individually and as an ordered combination, “‘transform the nature of the claim’ into a patent-eligible application.” Id. (quoting Mayo, 566 U.S. at 78). To so transform the claim, the additional limitations must “en- sure that the patent in practice amounts to significantly more than a patent upon the natural law itself.” Mayo, 566 U.S. at 73. We first address claims 7–9 and then turn to claim 6. A. Athena argues that claims 7–9 are not directed to a natural law at step one because they recite innovative, spe- cific, and concrete steps that do not preempt a natural law. Rather, Athena contends that the claims are directed to a new laboratory technique that makes use of man-made molecules. Mayo responds that the claims are directed to a natural law: the correlation between naturally-occurring MuSK autoantibodies and MuSK-related neurological diseases like MG. According to Mayo, the remaining steps apart from the natural law are concededly standard immunoas- say techniques that still leave the claim directed to a natu- ral law. Indeed, Mayo argues that the specificity and concreteness of the claimed steps are irrelevant to whether a claim is directed to a natural law. And, as in Mayo, Mayo contends that it makes no difference to eligibility that the claimed diagnostic method uses man-made materials. We ultimately agree with Mayo that, under Mayo, the claims are directed to a natural law. As an initial matter, we must identify what the relevant natural law is. Here, it is the correlation between the presence of naturally-oc- curring MuSK autoantibodies in bodily fluid and MuSK-

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related neurological diseases like MG. 3 This correlation exists in nature apart from any human action. There can thus be no dispute that it is an ineligible natural law. However, as Athena correctly observes, not every claim that involves a natural law is directed to a natural law. “[A]ll inventions at some level embody, use, reflect, rest upon, or apply laws of nature, natural phenomena, or ab- stract ideas.” Mayo, 566 U.S. at 71. The Supreme Court’s two-step test thus “plainly contemplates that the first step of the inquiry is a meaningful one, i.e., that a substantial class of claims are not directed to a patent-ineligible con- cept.” Enfish, LLC v. Microsoft Corp., 822 F.3d 1327, 1335 (Fed. Cir. 2016). The step one “directed to” inquiry focuses on the claim as a whole. E.g., Elec. Power Grp., LLC v. Alstom S.A., 830 F.3d 1350, 1353 (Fed. Cir. 2016). To determine whether a claim is directed to an ineligible concept, we have fre- quently considered whether the claimed advance improves upon a technological process or merely an ineligible con- cept, based on both the written description and the claims. See Cleveland Clinic Found. v. True Health Diagnostics LLC, 859 F.3d 1352, 1361 (Fed. Cir. 2017); Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc., 827 F.3d 1042, 1047–49 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1376 (Fed. Cir. 2015); see also McRO, Inc. v.

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Bandai Namco Games Am. Inc., 837 F.3d 1299, 1314–15 (Fed. Cir. 2016); Elec. Power Grp., 830 F.3d at 1354. For example, in CellzDirect we considered claims that covered a method for producing a preparation of a type of liver cell (called hepatocytes) that involved multiple freeze- thaw cycles. 827 F.3d at 1046, 1048. Although the inven- tors discovered the cells’ ability to survive multiple freeze- thaw cycles, a discovery that the district court understood to be a natural law, we concluded that the claims were not directed to that natural law. Id. at 1048–50. This was be- cause the claims as a whole recited “a new and improved way of preserving hepatocyte cells for later use,” “not simply an observation or detection of the ability of hepato- cytes to survive multiple freeze-thaw cycles.” Id. at 1048. The claimed advance harnessed a natural law to produce a technological improvement that was patent eligible. See id. at 1048–49; see also, e.g., Enfish, 822 F.3d at 1335–39 (holding improvement in computer-related technology not directed to abstract idea). In contrast, in Cleveland Clinic we reiterated that claims that merely recite observing naturally occurring bi- ological correlations “with no meaningful non-routine steps in between” are directed to a natural law. 859 F.3d at 1361; see Ariosa, 788 F.3d at 1376. There, the specification indi- cated that the claimed inventors discovered a natural cor- relation between a molecule called MPO and cardiovascular disease. Cleveland Clinic, 859 F.3d at 1360–61. The claims at issue recited detecting MPO or other MPO-related products in a patient sample and then predicting a patient’s risk of having or developing cardio- vascular disease. Id. at 1361. As the claims only covered the correlation between MPO and cardiovascular disease, an ineligible discovery, together with “well-known tech- niques to execute the claimed method,” we held that the claims were directed to a natural law. Id.

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The claims at issue here involve both the discovery of a natural law and certain concrete steps to observe its oper- ation. Claim 9, the most specific claim at issue, recites the following method to detect MuSK autoantibodies: (1) mix- ing MuSK or an epitope thereof having a 125I label with bodily fluid; (2) immunoprecipitating any resulting anti- body/MuSK complex; and (3) monitoring for the label on the complex. ’820 patent col. 12 l. 62–col. 13 l. 9. The claim then concludes in the wherein clause with a statement of the natural law, i.e., the discovery that MuSK autoantibod- ies naturally present in a patient sample, detected with the 125I label bound to the MuSK/antibody complex, indicate that the patient is suffering from a MuSK-related neuro- logical disorder. Id. col. 13 ll. 2–5. As in Cleveland Clinic and Ariosa, we conclude that claims 7–9 are 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 apply conven- tional techniques to detect that natural law. The specifica- tion of the ’820 patent highlights the discovery of the natural law, explaining that “[t]he present inventors sur- prisingly found that many of the 20% of MG patients [who] do not exhibit any autoantibodies to [the acetylcholine re- ceptor], instead have . . . antibodies directed against the ex- tracellular [amino]-terminal domains of MuSK.” Id. col. 1 ll. 54–57. Further, the specification describes the claimed concrete steps for observing the natural law as conven- tional. It teaches that “[t]he actual steps of detecting auto- antibodies in a sample of bodily fluids may be performed in accordance with immunological assay techniques known per se in the art,” including radioimmunoassays and ELISA. Id. col. 3 ll. 33–37. Likewise, the specification identifies “[i]odination and immunoprecipitation” as “standard techniques in the art.” Id. col. 4 ll. 10–12. The ’820 patent thus describes the claimed invention princi- pally as a discovery of a natural law, not as an improve- ment in the underlying immunoassay technology.

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Consistent with the specification, the claims are directed to that law. Athena argues that the claims at issue, like the claims in CellzDirect, are directed to an innovative laboratory technique, not a law of nature. However, Athena does not point to any innovation other than its discovery of the nat- ural law. CellzDirect did not suggest that appending standard techniques to detect a natural law rendered claims not directed to a natural law; rather, we expressly distinguished the eligible claims in that case from ineligi- ble claims that “amounted to nothing more than observing or identifying the ineligible concept itself.” 827 F.3d at 1048. In that case, we concluded that the “end result” of the claims at issue was “not simply an observation or de- tection” of a natural law. Id. We cannot so conclude here, since the claims before us only involve detecting a natural law “with no meaningful non-routine steps.” Cleveland Clinic, 859 F.3d at 1361. Athena also points to the specificity of the claimed con- crete steps, contending that they preempt no natural law and therefore the claims cannot be directed to a natural law. Although we agree that claim 9 leaves open to the public other ways of interrogating the correlation between MuSK autoantibodies and MuSK-related disorders with- out practicing the claim’s concrete steps, that does not dis- turb our conclusion at step one. Preemption is sufficient to render a claim ineligible under § 101, but it is not neces- sary. Flook, 409 U.S. at 71–72 (holding claim involving mathematical formula invalid under § 101 that did not preempt a mathematical formula); Ariosa, 788 F.3d at 1379; In re BRCA¹- & BRCA²-Based Hereditary Cancer Test Patent Litig., 774 F.3d 755, 764 n.⁴ (Fed. Cir. 2014). The claims here are directed to a natural law because they recite only the natural law together with standard tech- niques for observing it. That the routine steps are set forth with some specificity is not enough to change that conclu- sion.

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Finally, Athena argues that the claims at issue differ from prior diagnostic claims we have held ineligible under § 101 because they require labeling MuSK with a man- made substance. We disagree. As Mayo argues, the use of a man-made molecule is not decisive if it amounts to only a routine step in a conventional method for observing a nat- ural law. For example, Mayo involved claims requiring ad- ministering a man-made molecule (a drug “providing” 6- thioguanine) to a patient. 566 U.S. at 74–75. Some of the claims in Ariosa likewise required amplification through the polymerase chain reaction, which makes use of man- made reagents, see U.S. Patent 6,258,540 col. 5 ll. 6–26, or using a specific probe that binds to DNA, 788 F.3d at 1374. And the claims in BRCA1 also involved hybridizing a syn- thetic DNA probe to a DNA strand. BRCA1, 774 F.3d at 763–64. Nonetheless, in each of these cases either the Su- preme Court or this court held the claims directed to a nat- ural law and invalid under § 101. Mayo, 566 U.S. at 92; Ariosa, 788 F.3d at 1380; BRCA1, 774 F.3d at 765. We thus reaffirm that use of a man-made molecule in a method claim employing standard techniques to detect or observe a natural law may still leave the claim directed to a natural law. We consider it important at this point to note the dif- ference between the claims before us here, which recite a natural law and conventional means for detecting it, and applications of natural laws, which are patent-eligible. See Vanda Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117, 1133–36 (Fed. Cir. 2018) (holding that method of treatment by administering drug at certain dosage ranges based on a patient’s genotype was not directed to a natural law). Claiming a natural cause of an ailment and well-known means of observing it is not eligible for patent because such a claim in effect only encompasses the natu- ral law itself. But claiming a new treatment for an ailment, albeit using a natural law, is not claiming the natural law.

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As we conclude that claims 7–9 are directed to a natu- ral law, we turn to the second step of the Mayo/Alice test. 4 B. At step two, “we consider the elements of each claim both individually and ‘as an ordered combination’ to deter- mine whether the additional elements ‘transform the na- ture of the claim’ into a patent-eligible application.” Alice,

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573 U.S. at 217 (quoting Mayo, 566 U.S. at 78, 79). “Purely ‘conventional or obvious’ ‘[pre]-solution activity’ is nor- mally not sufficient to transform an unpatentable law of nature into a patent-eligible application of such a law.” Mayo, 566 U.S. at 79 (second alteration in original) (quot- ing Flook, 437 U.S. at 590). The transformative “inventive concept” supplied by the claim elements not drawn to inel- igible subject matter must be “sufficient to ensure that the patent in practice amounts to significantly more than a pa- tent upon the [ineligible concept] itself.” Alice, 573 U.S. at 217–18 (quoting Mayo, 566 U.S. at 73). 1. Athena argues that the claims provide an inventive concept: an innovative sequence of steps involving man- made molecules. Prior to its discovery, Athena contends that there was no disclosed method to detect MuSK auto- antibodies. In addition, Athena argues that the existence of factual disputes precluded dismissal under Rule 12(b)(6). Mayo responds that the claims lack an inventive con- cept because the specification describes the steps for de- tecting MuSK autoantibodies as standard techniques in the art. Furthermore, Mayo argues that no factual issues precluded the district court’s dismissal under Rule 12(b)(6). We agree with Mayo that the steps of the claims not drawn to ineligible subject matter, whether viewed individ- ually or as an ordered combination, only require standard techniques to be applied in a standard way. As previously discussed, the specification of the ’820 patent plainly states that “[t]he actual steps of detecting autoantibodies in a sample of bodily fluids may be performed in accordance with immunological assay techniques known per se in the art,” such as radioimmunoassays. ’820 patent col. 3 ll. 33– 37. Iodination and immunoprecipitation are likewise de- scribed as standard techniques. Id. col. 4 ll. 9–12. Because the specification defines the individual immunoprecipita- tion and iodination steps and the overall

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radioimmunoassay as conventional techniques, the claims fail to provide an inventive concept. Cleveland Clinic, 859 F.3d at 1362; Ariosa, 788 F.3d at 1378. Our decisions in CellzDirect and BASCOM are con- sistent with the principle that applying standard tech- niques in a standard way to observe a natural law does not provide an inventive concept. In CellzDirect, we considered a combination of claimed steps involving two freeze/thaw cycles. 827 F.3d at 1051. We held that this combination of steps was not conventional because the prior art methods only disclosed using one freeze/thaw cycle and, in fact, taught away from using multiple freeze/thaw cycles. Id. Similarly, in BASCOM we held that the ordered combina- tion of claim limitations was not routine and conventional because they placed a filtering tool at a specific location that improved on prior art technology. 827 F.3d at 1350. The inventive concept was “found in the non-conventional and non-generic arrangement of known, conventional pieces.” Id. In contrast, claims 7–9 of the ’820 patent em- ploy a conventional technique for detecting autoantibodies, a radioimmunoassay, which the specification acknowl- edges was “known per se in the art.” ’820 patent col. 3 ll. 33–37. The individual constituent steps of that technique, iodination and immunoprecipitation, are similarly de- scribed as standard. Id. col. 4 ll. 9–12. Thus, unlike the claimed limitations at issue in CellzDirect and BASCOM, the recited steps here were conventional both as an ordered combination and individually. Athena also argues that the claimed steps were uncon- ventional because they had not been applied to detect MuSK autoantibodies prior to Athena’s discovery of the correlation between MuSK autoantibodies and MG. Even accepting that fact, we cannot hold that performing stand- ard techniques in a standard way to observe a newly dis- covered natural law provides an inventive concept. This is because “[t]he inventive concept necessary at step two . . . cannot be furnished by the unpatentable law of nature

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. . . itself.” Genetic Techs. Ltd. v. Merial L.L.C., 818 F.3d 1369, 1376 (Fed. Cir. 2016); see Mayo, 566 U.S. at 73 (con- sidering whether the “claimed processes (apart from the natural laws themselves)” were routine and conventional). Rather, to supply an inventive concept the sequence of claimed steps must do more than adapt a conventional as- say to a newly discovered natural law; it must represent an inventive application beyond the discovery of the natural law itself. Because claims 7–9 fail to recite such an appli- cation, they do not provide an inventive concept. Similar to its step one argument, Athena further ar- gues that the claims recite an inventive concept because they use a man-made molecule, i.e., labeled MuSK. Athena analogizes its methods involving labeled MuSK to the com- position claims involving cDNA held eligible in Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 594–95 (2013). However, the method claims at issue here are unlike the claims held eligible in Myriad, which recited a new composition of matter that was not a natural product. Id. For the same reasons that we have concluded that attaching a label to MuSK did not make the claims directed to an eligible concept at step one, we conclude that appending labeling techniques to a natural law does not provide an inventive concept where, as here, the specifica- tion describes 125I labeling as a standard practice in a well-known assay. 2. Athena also argues that the district court needed to conduct fact-finding before resolving the § 101 issue. But, unlike in Aatrix, 882 F.3d at 1128, Athena directs us to no factual allegations in its complaint—amended three times—that the radioimmunoassay technique recited in claims 7–9 is anything other than standard and “known per se in the art.” ’820 patent, col. 3 ll. 33–37. Instead, Athena relies on an expert declaration submitted with its opposi- tion to Mayo’s motion to dismiss, asserting that iodination

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and immunoprecipitation were not routine as applied to the claimed invention. In dismissing Athena’s complaint under Rule 12(b)(6), the district court did not consider the declaration. Athena argues that was error. We disagree. In the First Circuit, under Rule 12(b)(6) a district court may generally “consider only facts and documents that are part of or incorporated into the complaint; if matters out- side the pleadings are considered, the motion must be de- cided under the more stringent standards applicable to a Rule 56 motion for summary judgment.” Trans-Spec Truck Serv., Inc. v. Caterpillar Inc., 524 F.3d 315, 321 (1st Cir. 2008). Certain documents, like the ’820 patent here, are also considered to “merge[] into the pleadings” where the “complaint’s factual allegations are expressly linked to” and dependent upon a document, the authenticity of which is undisputed. Id. (quoting Beddall v. State St. Bank & Trust Co., 137 F.3d 12, 16–17 (1st Cir. 1998)). District courts in the First Circuit have discretion whether to convert a motion to dismiss into a motion for summary judgment. Id. (citing Fed. R. Civ. P. 12(d)). “[I]f the district court chooses . . . to ignore supplementary ma- terials submitted with the motion papers and determine the motion under the Rule 12(b)(6) standard, no conversion occurs and the supplementary materials do not become part of the record for purposes of the Rule 12(b)(6) motion.” Id. We conclude that the district court did not abuse its discretion in declining to consider Athena’s expert declara- tion and convert the motion into one for summary judg- ment. The declaration does not “merge into the pleadings,” as the complaint does not reference it or otherwise depend on it. Nor is the declaration an official public record, an- other type of document a court may consider with the pleadings. See Watterson v. Page, 987 F.2d 1, 3–4 (1st Cir. 1993).

20 ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES

Athena does not expressly argue that the district court abused its discretion, but does contend, primarily citing non-binding authority, that the plaintiff may freely allege facts without support in responding to a motion to dismiss as long as those facts are consistent with the complaint, see Early v. Bankers Life & Casualty Co., 959 F.2d 75, 79 (7th Cir. 1992), and that its expert declaration alleged such con- sistent facts that create a dispute of material fact. Even assuming this general principle applies in the First Circuit—an assumption that Athena meagerly sup- ports—the district court did not need to consider the alle- gations in the expert declaration because they were not consistent with the complaint read in light of the ’820 pa- tent. These technical allegations include: (1) that detect- ing MuSK autoantibodies required the “creative step” of breaking up MuSK into smaller fragments, J.A. 623, 625; (2) that identifying a specific site on MuSK to label would not have been routine because many factors contribute to whether a binding site for a label is adequate, J.A. 626–28; and (3) that immunoprecipitation is generally uncertain and not routine, J.A. 630. None of these details are recited in the claims of the ’820 patent: no claim requires breaking MuSK into fragments as opposed to using the entire MuSK protein; no claim is limited to a particular MuSK binding site; and no claim recites any detail with respect to im- munoprecipitation. Those omissions are consistent with the specification’s description of iodination, immunoprecip- itation, and the overall radioimmunoassay as standard techniques. Because Athena’s expert declaration made al- legations inconsistent with the ’820 patent, the district court was not obliged to accept them as true. For these reasons, the district court did not err in dismissing Athena’s complaint under Rule 12(b)(6). C. Claim 6 recites a method for detecting MuSK autoanti- bodies different from claims 7–9. While claims 7–9 recite

ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES 21

a radioimmunoassay, claim 6 recites an ELISA method. Like radioimmunoassays, the specification describes ELISA as an “immunological assay technique[] known per se in the art.” ’820 patent col. 3 ll. 32–36. The main tech- nical difference pertinent to this appeal between an ELISA and a radioimmunoassay is that in an ELISA, the second- ary antibody rather than the antigen is labeled. Athena argues that since the district court did not spe- cifically analyze claim 6, which involves a different tech- nology, and implicitly treated claims 7–9 as representative, we should remand at least with respect to claim 6. Mayo responds that the district court properly grouped claim 6 with claims 7–9 because Athena grouped them together, and that Athena waived any separate arguments regard- ing claim 6 by not specifically addressing that claim in its briefing. During the district court proceedings, Athena repre- sented that it would not assert claims 1–5 and 10–12, and Mayo then moved to dismiss Athena’s complaint, specifi- cally addressing claims 6–9. In its response, Athena did not make any particularized arguments regarding claim 6, and, in an earlier response, indicated that the same argu- ments pertaining to claims 7–9 were also applicable to claim 6. See J.A. 180 (“While the claim does not require radioactive MuSK or complexes, many other arguments re- lating to claims 7-9 apply to claim 6.”). The district court did not address claim 6 in its order beyond listing it among the other claims. Decision, 275 F. Supp. 3d at 309–10. Given this history, we agree with Mayo that Athena waived its arguments specific to claim 6 by not making them before the district court. We apply regional circuit law to the issue of waiver, as it is not unique to patent law. Riverwood Int’l Corp. v. R.A. Jones & Co., 324 F.3d 1346, 1352 (Fed. Cir. 2003) (citing Midwest Indus., Inc. v. Kara- van Trailers, Inc., 175 F.3d 1356, 1359 (Fed. Cir. 1999) (en banc in relevant part)). In the First Circuit, an argument

22 ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES

may be deemed waived that was not presented to the dis- trict court. Butler v. Deutsche Bank Tr. Co. Ams., 748 F.3d 28, 36 (1st Cir. 2014). Although Athena recognized that claim 6 was at issue, it concededly did not present any spe- cific arguments concerning the eligibility of claim 6. Ap- pellant’s Br. 15. It was not incumbent on the district court to address arguments that Athena did not make. We thus find no error in the district court considering claims 7–9 as representative of claim 6. Even if we had reached the is- sue, we would hold claim 6 ineligible. The specification de- scribes ELISA as an “immunological assay technique[] known per se in the art.” ’820 patent col. 3 ll. 32–36. Claim 6 merely recites the application of this standard technique to observe a natural law. This does not provide an in- ventive concept under step two. CONCLUSION We have considered Athena’s remaining arguments but find them unpersuasive. Because claims 6–9 of the ’820 patent recite only a natural law together with conventional steps to detect that law, they are ineligible under § 101. For the foregoing reasons, we affirm the judgment of the district court. AFFIRMED

United States Court of Appeals for the Federal Circuit ______________________

ATHENA DIAGNOSTICS, INC., OXFORD UNIVERSITY INNOVATION LTD., MAX-PLANCK- GESELLSCHAFT ZUR FORDERUNG DER WISSENSCHAFTEN E.V., Plaintiffs-Appellants

v.

MAYO COLLABORATIVE SERVICES, LLC, DBA MAYO MEDICAL LABORATORIES, MAYO CLINIC, Defendants-Appellees ______________________

2017-2508 ______________________

Appeal from the United States District Court for the District of Massachusetts in No. 1:15-cv-40075-IT, Judge Indira Talwani. ______________________ NEWMAN, Circuit Judge, dissenting. Until discovery of the diagnostic method described in U.S. Patent No. 7,267,820 (“the ’820 patent”), some 20% of patients suffering from the neurological disorder Myasthe- nia Gravis were not capable of being diagnosed. My col- leagues rule that this new diagnostic method is not patent- eligible, although new and unobvious. However, “[t]his new and improved technique, for producing a tangible and useful result, falls squarely outside those categories of in- ventions that are ‘directed to’ patent-ineligible concepts.” Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc., 827 F.3d 1042,

2 ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES

1050 (Fed. Cir. 2016). The court again departs from the cautious restraints in the Supreme Court’s Mayo/Alice ap- plication of laws of nature and abstract ideas. This court’s decisions on the patent-ineligibility of di- agnostic methods are not consistent, and my colleagues to- day enlarge the inconsistencies and exacerbate the judge- made disincentives to development of new diagnostic meth- ods, with no public benefit. I respectfully dissent. The claims are for a multi-step method of di- agnosis, not a law of nature The ’820 inventors did not patent their scientific dis- covery of MuSK autoantibodies. Rather, they applied this discovery to create a new method of diagnosis, for a previ- ously undiagnosable neurological condition. The district court summarized this new diagnostic method as follows: For the 20% of Myasthenia Gravis patients who do not have the AChR [acetylcholine receptor] autoan- tibodies, the ’820 patent inventors discovered that they had IgG [immunoglobulin G] antibodies that attack the N-terminal domains of muscle specific tyrosine kinase (“MuSK”), a receptor that is located on the surface of neuromuscular junctions. . . . [A] radioactive label is attached to MuSK (or a frag- ment thereof) and is then introduced to a sample of bodily fluid. . . . [T]he MuSK autoantibodies, if pre- sent, attach to the labeled fragment . . . [and] is im- munoprecipitated, the presence of the radioactive label on any antibody indicates that the person is suffering from Myasthenia Gravis.

ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES 3

Dist. Ct. Order, at 307–08 1 (citing ’820 patent, col. 1, ll. 55– 61). The claims recite the method, including preparation of the new radioactive entities and their chemical reactions to detect autoantibodies to the protein muscle-specific ty- rosine kinase (MuSK). At issue are patent claims 7–9, shown with claim 1 (not in suit) from which they depend: 1. A method for diagnosing neurotransmission or developmental disorders related to muscle specific tyrosine kinase (MuSK) in a mammal comprising the step of detecting in a bodily fluid of said mam- mal autoantibodies to an epitope of muscle specific tyrosine kinase (MuSK). 7. A method according to claim 1, comprising contacting MuSK or an epitope or antigenic deter- minant thereof having a suitable label thereon, with said bodily fluid, immunoprecipitating any antibody/MuSK com- plex or antibody/MuSK epitope or antigenic deter- minant complex from said bodily fluid and monitoring for said label on any of said anti- body/MuSK complex or antibody/MuSK epitope or antigen determinant complex, wherein the presence of said label is indicative of said mammal is suffering from said neurotransmis- sion or developmental disorder related to muscle specific tyrosine kinase (MuSK). 8. A method according to claim 7 wherein said label is a radioactive label.

1 Athena Diagnostics, Inc. v. Mayo Collaborative Servs., LLC, 275 F. Supp. 3d 306 (D. Mass. 2017) (“Dist. Ct. Order”).

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9. A method according to claim 8 wherein said label is 125I [iodine isotope 125]. The reaction between the antibody and the MuSK protein was not previously known, nor was it known to form a la- beled MuSK or its epitope, nor to form the antibody/MuSK complex, immunoprecipitate the complex, and monitor for radioactivity, thereby diagnosing these previously undiag- nosable neurotransmission disorders. Claims 7–9 require specific steps by which the diagnos- tic method is performed. The panel majority ignores these steps, and instead holds that “claims 7–9 are 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 apply conventional techniques to detect that nat- ural law.” Maj. Op. at 12. This analysis of patent-eligibil- ity is incorrect, for the claim is for a multi-step method of diagnosing neurotransmission disorders related to muscle specific tyrosine kinase, by detecting autoantibodies using a series of chemical and biological steps as set forth in the claims. Eligibility is determined for the claim considered as a whole, including all its elements and limitations. Claim limitations cannot be discarded when determining eligibility under Section 101, as explained in Diamond v. Diehr, 450 U.S. 175 (1981): In determining the eligibility of respondents’ claimed process for patent protection under § 101, their claims must be considered as a whole. It is inappropriate to dissect the claims into old and new elements and then to ignore the presence of the old elements in the analysis. Id. at 188; see Parker v. Flook, 437 U.S. 584, 594 (1978) (“[A] patent claim must be considered as a whole.”); see also Aro Mfg. Co. v. Convertible Top Replacement Co., 365 U.S. 336, 344 (1961) (“[I]f 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

ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES 5

viewed, is within the grant.”); Mercoid Corp. v. Minneap- olis-Honeywell Regulator Co., 320 U.S. 680, 684 (1944) (“[A] patent on a combination is a patent on the assembled or functioning whole, not on the separate parts.”). The requirement that a claim is considered as a whole was not changed by the Mayo/Alice protocol of searching for an inventive concept within a claim that is directed to a law of nature or an abstract idea. It is incorrect to excise from the claims any steps that are performed by conven- tional procedures. This is misconstruction of claims, and misapplication of Section 101. As reiterated in Bilski v. Kappos, 561 U.S. 593 (2010): Section 101 is a dynamic provision designed to en- compass new and unforeseen inventions. A cate- gorical rule denying patent protection for inventions in areas not contemplated by Congress . . . would frustrate the purposes of the patent law. Id. at 605 (internal citations and quotation marks omitted). Applied to the ’820 patent, the claimed method is a new method of diagnosing Myasthenia Gravis. After eliminat- ing the “conventional” procedures, my colleagues rule that this new method is a “law of nature.” However, these in- ventors are not claiming the scientific fact of a newly de- scribed autoantibody; they are claiming a new multi-step diagnostic method. This is not a law of nature, but a man- made reaction sequence employing new components in a new combination to perform a new diagnostic procedure. Section 101 describes patent-eligible subject matter in broad and general terms Section 101 does not exclude new methods of diagnosis of human ailments. 35 U.S.C. § 101 Inventions Patentable Whoever invents or discovers any new and useful process, machine, manufacture, or composition of

⁶ ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES

matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title. Section 101 recites the subject matter of patent law, as dis- tinguished from copyright law, which is also authorized by Article I, Section 8. This framework is “cast in broad terms,” as the Court observed in Diamond v. Chakrabarty, 447 U.S. 303 (1980): The subject-matter provisions of the patent law have been cast in broad terms to fulfill the consti- tutional and statutory goal of promoting “the Pro- gress of Science and the useful Arts” with all that means for the social and economic benefits envi- sioned by Jefferson. Broad general language is not necessarily ambiguous when congressional objec- tives require broad terms. Id. at 315. The Court has often discussed the exceptions to patent eligibility, stating that: “Phenomena of nature, though just discovered, mental processes, and abstract intellectual con- cepts are not patentable, as they are the basic tools of sci- entific and technological work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972). “Thus, a new mineral discovered in the earth or a new plant found in the wild is not patentable subject matter. Likewise, Einstein could not patent his cel- ebrated law that E=mc2; nor could Newton have patented the law of gravity. Such discoveries are ‘manifestations of . . . nature, free to all men and reserved exclusively to none’.” Chakrabarty, 447 U.S. at 309 (quoting Funk Bros. Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 130 (1948)). In Funk Brothers the Court explained: The qualities of these bacteria, like the heat of the sun, electricity, or the qualities of metals, are part of the storehouse of knowledge of all men. They are manifestations of laws of nature, free to all men

ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES 7

and reserved exclusively to none. He who discovers a hitherto unknown phenomenon of nature has no claim to a monopoly of it which the law recognizes. If there is to be invention from such a discovery, it must come from the application of the law of nature to a new and useful end. Id. at 130. The Court early drew the distinction between scientific knowledge and its technological application. An oft-cited example is the case of O’Reilly v. Morse, 56 U.S. 62 (15 How.) (1854), where the Court declined patent-eligibility of Morse’s claim 8 to “electro-magnetism, however developed for marking or printing intelligible characters, signs, or let- ters, at any distances,” id. at 112–13, but sustained Morse’s claims to “us[ing] [] the motive power of magnetism . . . as means of operating or giving motion to machinery, which may be used to imprint signals . . . for the purpose of tele- graphic communication at any distances.” Id. at 85; see id. at 112. The Court criticized the breadth of Morse’s claim 8, and stated: In fine he claims an exclusive right to use a manner and process which he has not described and indeed had not invented, and therefore could not describe when he obtained his patent. Id. at 113; see Adam Mossoff, O’Reilly v. Morse, George Ma- son Law & Econ. Research Paper No. 14-22 (Aug. 18, 2014), available at http://ssrn.com/abstract=2448363. In Mackay Radio & Telegraph Co. v. Radio Corp. of America, 306 U.S. 86 (1939), the Court explained that: “While a scientific truth, or the mathematical expression of it, is not patenta- ble invention, a novel and useful structure created with the aid of knowledge of scientific truth may be.” Id. at 94. These principles are the foundation of the truism that nat- ural phenomena and abstract ideas are not patent-eligible.

⁸ ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES

As science and its applications advanced, particularly in the new fields of digital electronics and biotechnology, the jurisprudence kept pace. In Chakrabarty the Court considered a man-made bacterium, and held that eligibility under Section 101 applies to “anything under the sun that is made by man.” 447 U.S. at 309. The most recent Court updates are Mayo Collaborative Services v. Prometheus Laboratories, Inc., 566 U.S. 66 (2012) (biotechnology), and Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 573 U.S. 208 (2014) (digital electronics). The Court reviewed Section 101 eligibility in these new fields, building on the vast body of jurisprudence since the first patent was analyzed by Thomas Jefferson as Secretary of State in 1790. See generally Ten Law Professors Br.; 2 Five Life Sciences Patent Practitioners Br. 3 These amici curiae explain the policy concern for preemption of scientific prin- ciples, and apply this concern to the case at bar, advising that the scientific information of the new autoantibody and its protein reactivity is available to all, and that the ’820 patent claims 7–9 “did not preempt any ‘law of nature’ upon which the claimed diagnostic method relied.” Five Life Sci- ences Patent Practitioners Br. at 1. In Alice, the Court summarized the procedural frame- work for eligibility for patenting: First, we determine whether the claims at issue are directed to one of those patent-ineligible concepts. 132 S. Ct., at 1296–1297. If so, we then ask, “[w]hat else is there in the claims before us?” 132

2 Amici Curiae Ten Law Professors, ECF No. 54 (Nov. 13, 2017) (“Ten Law Professors Br.”). 3 Amici Curiae Five Life Sciences Patent Practition- ers, ECF No. 52 (Nov. 13, 2017) (“Five Life Sciences Patent Practitioners Br.”).

ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES 9

S. Ct., at 1297. To answer that question, we con- sider the elements of each claim both individually and “as an ordered combination” to determine whether the additional elements “transform the nature of the claim” into a patent-eligible applica- tion. 132 S. Ct., at 1298, 1297. Alice, 573 U.S. at 217 (quoting Mayo). This analysis comports with precedent, and the Court reiterated its caution that “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 ab- stract ideas.” Mayo, 566 U.S. at 71; see Alice, 573 U.S. at 217 (“At the same time, we tread carefully in construing this exclusionary principle lest it swallow all of patent law.”). We have echoed this concern, stating in Rapid Lit- igation Management, 827 F.3d at 1050, “[a]t step one, therefore, it is not enough to merely identify a patent-inel- igible concept underlying the claim; we must determine whether that patent-ineligible concept is what the claim is ‘directed to,’” (quoting Alice, 573 U.S. at 217). The panel majority departs from this guidance, for the claimed diagnostic method as a whole satisfies step one. The majority does not distinguish between the question of whether the claimed method as a whole is eligible, and the question of whether the separate steps use conventional procedures. Instead, my colleagues hold that since the sep- arate procedures are conventional, it is irrelevant that the method as a whole is a new method. The majority miscon- strues the claims, in holding that claims 7–9 are directed to the “concept” of “the correlation between the presence of naturally-occurring MuSK autoantibodies in bodily fluid and MuSK-related neurological diseases like MG.” Maj. Op. at 9–10. The claimed method determines whether this correlation is present, for diagnostic purposes, but the con- cept itself is not claimed.

10 ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES

It is incorrect to separate the claim steps into whether a step is performed by conventional techniques, and then to remove those steps from the claims and their “conjunc- tion with all of the other steps” for the purpose of Section 101 analysis. Diehr, 450 U.S. at 187. All of the claim steps must be considered in the claimed combination. “It is in- appropriate to dissect the claims into old and new elements and then to ignore the presence of the old elements in the analysis.” Id. at 188. The Court explained that a new pro- cess may be a combination of known steps: This is particularly true in a process claim because a new combination of steps in a process may be pa- tentable even though all the constituents of the combination were well known and in common use before the combination was made. Id. The Court stated that: The “novelty” of any element or steps in a process, or even of the process itself, is of no relevance in determining whether the subject matter of a claim falls within the § 101 categories of possibly patent- able subject matter. Id. at 188–89. The Court again recognized this principle in KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398 (2007), stating that: [I]nventions in most, if not all, instances rely upon building blocks long since uncovered, and claimed discoveries almost of necessity will be combinations of what, in some sense, is already known. Id. at 418–19. This court applied this principle in McRO, Inc. v. Bandai Namco Games America Inc., 837 F.3d 1299, 1313 (Fed. Cir. 2016) (internal quotation marks omitted) and cautioned that “courts must be careful to avoid over- simplifying the claims by looking at them generally and failing to account for the specific requirements of the claims”—a caution disregarded today.

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The panel majority contravenes the requirements of precedent, now holding that all of the steps of claims 7–9— that is, radioactive labelling, complexing, precipitating, and monitoring—are removed from consideration in the Section 101 analysis because they use conventional proce- dures; the majority holds that “[t]he ’820 patent thus de- scribes the claimed invention principally as a discovery of a natural law, not as an improvement in the underlying immunoassay technology.” Maj. Op. at 12. However, that is not the claimed invention. In Mayo, 566 U.S. at 71, the Court cautioned that “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.” Applying 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. Claims 7–9 recite a combination of technologic steps, all of which are limitations to the claims and cannot be disregarded whether for patentability or pa- tent-eligibility or infringement. The court today violates this rule, in holding that because “the . . . individual steps . . . [of] ‘[i]odination and immunoprecipitation are standard techniques in the art,’” Maj. Op. at 6, these steps do not count under Section 101. Id. at 12–13. Section 101 does not turn on whether any claim steps are “standard techniques.” The appropriate analysis of the role of conventional process steps in claims to a new method is under Sections 102 and 103, not Section 101. The amici curiae raise strong concerns for the consequences for biomedical diagnostics This court’s decisions have not been consistent. To- day’s decision is not consistent with, for example, Rapid Litigation Management, 827 F.3d at 1048, where the court

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held that although the general type of cell was known, and the manipulation of these specific cells was conducted in a conventional manner, the overall method was eligible un- der Section 101. Amici curiae point out that the public interest is poorly served by adding disincentive to the development of new diagnostic methods. This is a severe criticism; and when presented by the entire industry, and stressed by thought- ful scholars, it warrants judicial attention. The Biotechnology Innovation Organization 4 pleads for consistency in judge-made law, citing the unabated uncertainty about the patent-eligibility of many biotechnological inventions, with diagnos- tic and prognostic methods being particularly af- fected. The unstable state of patent-eligibility jurisprudence affects modern biotechnologies rang- ing from biomarker-assisted methods of drug treat- ment to companion diagnostic tests, fermentation products, industrial enzyme technology, and marker-assisted methods of plant breeding. BIO Br. at 1. International concerns are presented by The Chartered Institute of Patent Attorneys, 5 an organization of the United Kingdom, stating that this decision conflicts with the eligibility of diagnostic methods under the Patent Cooperation Treaty and the European Patent Convention, and is inconsistent with the obligations of the United States under Article 27 and Note 5 of the Agreement on Trade-Related Aspects of Intellectual Property Rights

4 Amicus Curiae Biotechnology Innovation Organi- zation, ECF No. 53 (Nov. 13, 2017) (“BIO Br.”). 5 Amicus Curiae The Chartered Institute of Patent Attorneys, ECF No. 51 (Nov. 13, 2017) (“CIPA Br.”).

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(TRIPS) administered by the World Trade Organization. CIPA Br. at 2. Amici curiae Five Life Sciences Patent Practitioners point out that “The Supreme Court has recognized that pa- tent ineligibility determinations (by courts or the Patent Office) have the potential to inhibit innovation,” Five Life Sciences Patent Practitioners Br. at 6 (citing Bilski v. Kap- pos, 561 U.S. 593, 605 (2010)). They state concerns of the inventing/investing communities with respect to the future of diagnostics, because “[medical] diagnostic methods . . . are so tightly bound to underlying natural laws and phe- nomen[a], they are especially susceptible to undue expan- sion of the eligibility standards implemented to protect the judicial exceptions as they have been explicated by the Su- preme Court.” Id. at 6–7. Amici curiae Ten Law Professors direct us to the cost to develop and commercialize a new diagnostic, reported as $50-100 million, see Ten Law Professors Br. at 18–19 (cit- ing Diaceutics Group, Mystery Solved! What is the Cost to Develop and Launch a Diagnostic? (2013), available at https://www.diaceutics.com/?expert-insight=mystery- solved-what-is-the-cost-to-develop-and-launch-a-diagnos- tic). Undoubtedly there are a variety of interests in diagnos- tic procedures, and we take note that amicus curiae ARUP Laboratories6 states that diagnostic tests should not be pa- tentable at all. See generally ARUP Br. However, for pro- cedures that require extensive development and federal approval, unpredictability of patent support is a

14 ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES

disincentive to development of new diagnostic methods. 7 The loser is the afflicted public, for diagnostic methods that are not developed benefit no one. 8 The judicial obligation is to provide stable, consistent application of statute and precedent, to implement the leg- islative purpose. With all respect to my colleagues on this panel, they misapply precedent and misinterpret the stat- ute, adding discrepancies and disincentives to this im- portant area of biomedicine. Claims 7–9 meet the Section 101 eligibility rules, for the claims are to a new and useful method. Applying the statute correctly, diagnostic claims should be evaluated for novelty and unobviousness, speci- ficity and enablement. A method that meets these statu- tory criteria is within the system of patents, whether the diagnosed event occurs in the human body or in an

ATHENA DIAGNOSTICS v. MAYO COLLABORATIVE SERVICES 15

extraneous device. From my colleagues’ contrary conclu- sion, I respectfully dissent.

Footnotes

[1] An epitope, also known as an antigenic determi- nant, is a segment of a protein recognized by an antibody. See Bruce Alberts, Molecular Biology of the Cell 449–50 (6th ed. 2015). The specification of the ’820 patent dis- closed that autoantibodies in MG patients recognize a MuSK epitope located on the protein’s extracellular amino- terminal domain. ’820 patent col. 1 ll. 54–57.

[2] ELISA stands for enzyme-linked immunosorbent assay. The technical details of this assay are not relevant to this appeal.

[3] We note that the district court held that the “focus of the claims” was the binding of MuSK to MuSK antibod- ies in bodily fluid. Decision, 275 F. Supp. 3d at 310. Our cases have not described a claim to the binding of two mol- ecules during a sequence of chemical manipulations (here, after MuSK labeling and before immunoprecipitation) as a claim to a natural law, even if such binding occurs accord- ing to natural laws. We need not resolve that issue here, as we agree with Mayo’s identification of the natural law.

[4] The dissent states much that one can agree with from the standpoint of policy, and history, including that “the public interest is poorly served by adding disincentive to the development of new diagnostic methods.” Dissent at 12. We would add further that, in our view, providing pa- tent protection to novel and non-obvious diagnostic meth- ods would promote the progress of science and useful arts. But, whether or not we as individual judges might agree or not that these claims only recite a natural law, cf. Berk- heimer v. HP Inc., 890 F.3d 1369, 1374 (Fed. Cir. 2018) (Lourie, J., concurring in the denial of rehearing en banc) (discussing traditional laws of nature such as “Ohm’s Law, Boyle’s Law, [and] the equivalence of matter and energy”), the Supreme Court has effectively told us in Mayo that cor- relations 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,” id. at 79 (second alteration in original) (quoting Flook, 437 U.S. at 590). We have since confirmed that applying some- what specific yet conventional techniques (such as the pol- ymerase chain reaction) to detect a newly discovered natural law does not confer eligibility under § 101. Ariosa, 788 F.3d at 1377; see also Cleveland Clinic, 859 F.3d at 1356, 1362 (addressing other conventional techniques such as flow cytometry). Our precedent leaves no room for a dif- ferent outcome here.

[6] Amicus Curiae ARUP Laboratories, ECF No. 76 (Feb. 6, 2018) (“ARUP Br.”).

[7] This court has invalidated patents on new diagnos- tic methods in Roche Molecular Sys., Inc. v. CEPHEID, 905 F.3d 1363, 1374 (Fed. Cir. 2018); Cleveland Clinic Found. v. True Health Diagnostics LLC, 859 F.3d 1352, 1363 (Fed. Cir. 2017); Genetic Techs. Ltd. v. Merial L.L.C., 818 F.3d 1369, 1380 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Se- quenom, Inc., 788 F.3d 1371, 1378 (Fed. Cir. 2015); In re BRCA1- & BRCA2-Based Hereditary Cancer Test Patent Litig., 774 F.3d 755, 765 (Fed. Cir. 2014).

[8] It is estimated that 66% of all medical treatment decisions are based on the results of in vitro diagnostic test- ing. Ulrich-Peter Rohr, et al., The Value of In Vitro Diagnostic Testing in Medical Practice: A Status Report, 11 PLoS One 1, 2, 11, 13 (2016), https://www.ncbi.nlm.nih.gov/pmc/arti- cles/PMC4778800/pdf/pone.0149856.pdf. See Ten Law Professors Br. at 18.