Court Opinion

ID: 4552768
Source: CourtListenerOpinion
Date Created: 2020-08-03 16:00:40.298599+00
Date Added: 2024-06-11T09:24:38.641115
License: Public Domain

Case: 19-1419    Document: 64     Page: 1   Filed: 08/03/2020

   United States Court of Appeals
       for the Federal Circuit
                  ______________________

          ILLUMINA, INC., SEQUENOM, INC.,
                 Plaintiffs-Appellants

                             v.

         ARIOSA DIAGNOSTICS, INC., ROCHE
        SEQUENCING SOLUTIONS, INC., ROCHE
            MOLECULAR SYSTEMS, INC.,
                 Defendants-Appellees
                ______________________

                        2019-1419
                  ______________________

    Appeal from the United States District Court for the
 Northern District of California in No. 3:18-cv-02847-SI,
 Senior Judge Susan Y. Illston.
                 ______________________

            OPINION ISSUED: March 17, 2020
           OPINION MODIFIED: August 3, 2020 *
                ______________________

     EDWARD R. REINES, Weil, Gotshal & Manges LLP, Red-
 wood Shores, CA, argued for plaintiffs-appellants. Also
 represented by CHRISTOPHER SHAWN LAVIN, DEREK C.
 WALTER; ZACHARY TRIPP, Washington, DC.

    *   This opinion has been modified and reissued fol-
 lowing a petition for rehearing filed by Defendants-Appel-
 lees.
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 2                  ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

     DARALYN JEANNINE DURIE, Durie Tangri LLP, San
 Francisco, CA, argued for all defendants-appellees. De-
 fendant-appellee Ariosa Diagnostics, Inc. also represented
 by DAVID FLOYD MCGOWAN, LAURA MILLER.

     ROBERT J. GUNTHER, JR., Wilmer Cutler Pickering Hale
 and Dorr LLP, New York, NY, for defendants-appellees
 Roche Sequencing Solutions, Inc., Roche Molecular Sys-
 tems, Inc. Also represented by OMAR KHAN, CHRISTOPHER
 R. NOYES; THOMAS SAUNDERS, Washington, DC.
                  ______________________

     Before LOURIE, MOORE, and REYNA, Circuit Judges.
     Opinion for the court filed by Circuit Judge LOURIE.
      Dissenting opinion filed by Circuit Judge REYNA.
 LOURIE, Circuit Judge.
     Illumina, Inc. and Sequenom, Inc. (collectively, “Illu-
 mina”) appeal from a decision of the United States District
 Court for the Northern District of California that claims 1–
 2, 4–5, and 9–10 of U.S. Patent 9,580,751 (the “’751 pa-
 tent”) and claims 1–2 and 10–14 of U.S. Patent 9,738,931
 (the “’931 patent”) are invalid under 35 U.S.C. § 101 as di-
 rected to an ineligible natural phenomenon. Illumina, Inc.
 v. Ariosa Diagnostics, Inc., 356 F. Supp. 3d 925 (N.D. Cal.
 2018) (“Decision”). Because we conclude that the claims
 are directed to patent-eligible subject matter, we reverse.
                        BACKGROUND
     “In 1996, Drs. Dennis Lo and James Wainscoat discov-
 ered cell-free fetal DNA in maternal plasma and serum, the
 portion of maternal blood samples that other researchers
 had previously discarded as medical waste.” Ariosa Diag-
 nostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1373 (Fed.
 Cir. 2015). They applied for a patent, and, in 2001, they
 obtained U.S. Patent 6,258,540, which claimed a method
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                   3

 for detecting the small fraction of paternally inherited cell-
 free fetal DNA in the plasma and serum of a pregnant
 woman. Id. In 2015, we held that the claims of that patent
 were invalid under 35 U.S.C. § 101 because they were di-
 rected to “matter that is naturally occurring”—i.e., the nat-
 ural phenomenon that cell-free fetal DNA exists in
 maternal blood. Id. at 1376.
     The present case involves two patents that are unre-
 lated to the patent held invalid in Ariosa, but rather claim
 priority from a European patent application filed in 2003.
 The ’751 and ’931 patents at issue in this case, which are
 related to each other and have largely identical specifica-
 tions, begin by acknowledging the natural phenomenon
 that was at issue in Ariosa: “[I]t has been shown that in the
 case of a pregnant woman extracellular fetal DNA is pre-
 sent in the maternal circulation and can be detected in ma-
 ternal plasma . . . .” ’751 patent col. 1 ll. 23–25. The
 patents then identify a problem that was the subject of fur-
 ther research on cell-free fetal DNA in maternal blood:
     [T]he major proportion (generally >90%) of the ex-
     tracellular DNA in the maternal circulation is de-
     rived from the mother. This vast bulk of maternal
     circulatory extracellular DNA renders it difficult, if
     not impossible, to determine fetal genetic alterna-
     tions [sic] . . . from the small amount of circulatory
     extracellular fetal DNA.
Id. col. 1 ll. 42–50. In simple terms, the problem that the
 inventors encountered was that, although it was known
 that cell-free fetal DNA existed in the mother’s blood-
 stream, there was no known way to distinguish and sepa-
 rate the tiny amount of fetal DNA from the vast amount of
 maternal DNA.
      The inventors of the ’751 and ’931 patents attempted to
 find a solution to that problem. First, they made a discov-
 ery:
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     An examination of circulatory extracellular fetal
     DNA and circulatory extracellular maternal DNA
     in maternal plasma has now shown that, surpris-
     ingly, the majority of the circulatory extracellular
     fetal DNA has a relatively small size of approxi-
     mately 500 base pairs or less, whereas the majority
     of circulatory extracellular maternal DNA in ma-
     ternal plasma has a size greater than approxi-
     mately 500 base pairs.
Id. col. 1 ll. 54–61. To arrive at that discovery, the inven-
 tors examined five pregnancies and found that cell-free fe-
 tal DNA fragments “were almost completely of sizes
 smaller than 500 base pairs.” ’751 patent col. 4 ll. 50–53.
 Moreover, the inventors found that 70% of all DNA frag-
 ments smaller than 300 base pairs were fetal. Id.
     Having made that discovery regarding the relative size
 distributions of cell-free fetal and maternal DNA frag-
 ments in a pregnant mother’s bloodstream, the inventors
 used their discovery to develop a solution to the identified
 problem of distinguishing the fetal DNA from the maternal
 DNA:
     This surprising finding forms the basis of the pre-
     sent invention according to which separation of cir-
     culatory extracellular DNA fragments which are
     smaller than approximately 500 base pairs pro-
     vides a possibility to enrich for fetal DNA se-
     quences from the vast bulk of circulatory
     extracellular maternal DNA.
Id. col. 2 ll. 1–6.
     The claims of the ’751 and ’931 patents are directed to
 that solution. Specifically, they claim methods of prepar-
 ing a fraction of cell-free DNA that is enriched in fetal
 DNA. The methods of preparation include size discrimina-
 tion of the DNA based on size parameters that the inven-
 tors selected to balance the need to remove enough longer
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                    5

 maternal DNA fragments to enrich the sample but also
 leave behind enough shorter fetal DNA fragments to allow
 for testing. As explained in the patent, “depending on the
 downstream application” of the enriched mixture, the size
 parameter is not fixed at either 500 or 300 base pairs but
 can be even smaller. See ’751 patent col. 4 ll. 57–59.
     Claim 1 of the ’751 patent, the only independent claim,
 includes an inventor-chosen size parameter of 500 base
 pairs to allow for selective removal of longer DNA frag-
 ments from the mixture:
        1. A method for preparing a deoxyribonucleic
     acid (DNA) fraction from a pregnant human female
     useful for analyzing a genetic locus involved in a
     fetal chromosomal aberration, comprising:
        (a) extracting DNA from a substantially cell-free
     sample of blood plasma or blood serum of a preg-
     nant human female to obtain extracellular circula-
     tory fetal and maternal DNA fragments;
        (b) producing a fraction of the DNA extracted in
     (a) by:
          (i) size discrimination of extracellular circula-
     tory DNA fragments, and
          (ii) selectively removing the DNA fragments
     greater than approximately 500 base pairs,
        wherein the DNA fraction after (b) comprises a
     plurality of genetic loci of the extracellular circula-
     tory fetal and maternal DNA; and
       (c) analyzing a genetic locus in the fraction of
     DNA produced in (b).
 ’751 patent col. 7 l. 54–col. 8 l. 57. In contrast, claim 1 of
 the ’931 patent imposes a different size parameter, namely,
 300 base pairs:
       1. A method, comprising:
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        (a) extracting DNA comprising maternal and fe-
     tal DNA fragments from a substantially cell-free
     sample of blood plasma or blood serum of a preg-
     nant human female;
        (b) producing a fraction of the DNA extracted in
     (a) by:
           (i) size discrimination of extracellular circula-
     tory fetal and maternal DNA fragments, and
          (ii) selectively removing the DNA fragments
     greater than approximately 300 base pairs,
        wherein the DNA fraction after (b) comprises ex-
     tracellular circulatory fetal and maternal DNA
     fragments of approximately 300 base pairs and less
     and a plurality of genetic loci of the extracellular
     circulatory fetal and maternal DNA fragments; and
       (c) analyzing DNA fragments in the fraction of
     DNA produced in (b).
 ’931 patent col. 7 l. 58–col. 8 l. 63.
      Dependent claims in each patent place further limita-
 tions on the size discrimination and selective removal pro-
 cesses recited in step (b) of the method claims. For
 example, dependent claim 7 of the ’751 patent recites that
 “the size discrimination in (b) comprises centrifugation,”
 and claim 8 further limits it to “density gradient centrifu-
 gation.” ’751 patent col. 9 ll. 1–4. Likewise, dependent
 claims 4–10 of the ’931 patent recite that step (b) can com-
 prise “chromatography,” “electrophoresis,” “centrifuga-
 tion,” and/or “nanotechnological means.” ’931 patent col. 9
 ll. 1–14.
     Illumina filed suit against Ariosa Diagnostics, Inc.,
 Roche Sequencing Solutions, Inc., and Roche Molecular
 Systems, Inc. (collectively, “Roche”) alleging infringement
 of the ’751 and ’931 patents. Roche moved for summary
 judgment that the asserted claims are invalid under 35
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                   7

 U.S.C. § 101. The district court granted Roche’s motion for
 summary judgment, holding that the claims of the ’751 and
 ’931 patents are directed to ineligible subject matter. De-
 cision, 356 F. Supp. 3d at 935. The court entered judgment
 in favor of Roche, and Illumina appealed. We have juris-
 diction under 28 U.S.C. § 1295(a)(1).
                          DISCUSSION
      We review a grant of summary judgment according to
 the law of the regional circuit. Kaneka Corp. v. Xiamen
 Kingdomway Grp. Co., 790 F.3d 1298, 1303 (Fed. Cir. 2015)
 (citing Halo Elecs., Inc. v. Pulse Elecs., Inc., 769 F.3d 1371,
 1377 (Fed. Cir. 2014)). In the Ninth Circuit, a grant of
 summary judgment is reviewed de novo. Leever v. Carson
 City, 360 F.3d 1014, 1017 (9th Cir. 2004) (citing Hargis v.
 Foster, 312 F.3d 404, 409 (9th Cir. 2002)). Summary judg-
 ment is appropriate when “there is no genuine dispute as
 to any material fact and the movant is entitled to judgment
 as a matter of law.” Fed. R. Civ. P. 56.
                                I
     Section 101 provides that “Whoever 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 . . . .” 35 U.S.C. § 101.
 Given the expansive terms of § 101, “Congress plainly con-
 templated that the patent laws would be given wide scope”;
 the legislative history likewise indicated that “Congress in-
 tended statutory subject matter to ‘include anything under
 the sun that is made by man.’” Diamond v. Chakrabarty,
 447 U.S. 303, 308–09 (1980) (internal citation omitted).
     The Supreme Court has held that § 101 “contains an
 important implicit exception. ‘[L]aws of nature, natural
 phenomena, and abstract ideas’ are not patentable.” Mayo
 Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66,
 70 (2012) (alteration in original) (quoting Diamond v.
 Diehr, 450 U.S. 175, 185 (1981)). These exceptions exist
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 8                  ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 because monopolizing the basic tools of scientific work
 “might tend to impede innovation more than it would tend
 to promote it.” Id. at 71. However, the Supreme Court has
 advised that these exceptions must be applied cautiously,
 as “too broad an interpretation of this exclusionary princi-
 ple could eviscerate patent law.” Id.
     Laws of nature and natural phenomena are not patent-
 able, but applications and uses of such laws and phenom-
 ena may be patentable. A claim to otherwise statutory
 subject matter does not become ineligible by its use of a law
 of nature or natural phenomenon. See Diehr, 450 U.S. at
 187; Parker v. Flook, 437 U.S. 584, 590 (1978). On the other
 hand, adding “conventional steps, specified at a high level
 of generality,” to a law of nature or natural phenomenon
 does not make a claim to the law or phenomenon patenta-
 ble. Mayo, 566 U.S. at 82.
     To distinguish claims to patent-eligible applications of
 laws of nature and natural phenomena from claims that
 impermissibly tie up such laws and phenomena, we apply
 the two-part test set forth by the Supreme Court. First, we
 examine whether the claims are “directed to” a law of na-
 ture or natural phenomenon. Alice Corp. Pty. Ltd. v. CLS
 Bank Int’l, 573 U.S. 208, 217 (2014). If—and only if—they
 are, then we proceed to the second inquiry, where we ex-
 amine whether the limitations of the claim apart from the
 law of nature or natural phenomenon, considered individ-
 ually and as an ordered combination, “‘transform the na-
 ture of the claim’ into a patent-eligible application.” Id.
 (quoting Mayo, 566 U.S. at 78).
                              II
     This is not a diagnostic case. And it is not a method of
 treatment case. It is a method of preparation case.
     Under Mayo, we have consistently held diagnostic
 claims unpatentable as directed to ineligible subject mat-
 ter. See Athena Diagnostics, Inc. v. Mayo Collaborative
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 Servs., LLC, 927 F.3d 1333, 1352 (Fed. Cir. 2019) (Moore,
 J., dissenting from denial of rehearing en banc) (“Since
 Mayo, we have held every single diagnostic claim in every
 case before us ineligible.”); see also, e.g., Athena Diagnos-
 tics, Inc. v. Mayo Collaborative Servs., LLC, 915 F.3d 743
 (Fed. Cir. 2019); Cleveland Clinic Found. v. True Health
 Diagnostics LLC, 859 F.3d 1352 (Fed. Cir. 2017); Cleveland
 Clinic Found. v. True Health Diagnostics LLC, 760 F. App’x
 1013 (Fed. Cir. 2019). In contrast, we have held that
 method of treatment claims are patent-eligible. See Endo
 Pharm. Inc. v. Teva Pharm. USA, Inc., 919 F.3d 1347 (Fed.
 Cir. 2019); Natural Alternatives Int’l, Inc. v. Creative Com-
 pounds, LLC, 918 F.3d 1338 (Fed. Cir. 2019); Vanda
 Pharm. Inc. v. West-Ward Pharm. Int’l Ltd., 887 F.3d 1117
 (Fed. Cir. 2018). The claims in this case do not fall into
 either category, and we consider the claims under the Al-
 ice/Mayo test.
     Here, it is undisputed that the inventors of the ’751 and
 ’931 patents discovered a natural phenomenon. But at step
 one of the Alice/Mayo test, “it is not enough to merely iden-
 tify a patent-ineligible concept underlying the claim; we
 must determine whether that patent-ineligible concept is
 what the claim is ‘directed to.’” Rapid Litig. Mgmt. Ltd. v.
 CellzDirect, Inc., 827 F.3d 1042, 1050 (Fed. Cir. 2016). The
 focus of the dispute in this case is whether the claims of the
 ’751 and ’931 patents are “directed to” the natural phenom-
 enon, i.e., whether they claim the discovered natural phe-
 nomenon itself versus eligible subject matter that exploits
 the discovery of the natural phenomenon.
     As an initial matter, there are differences between the
 district court and the parties about how to articulate the
 natural phenomenon that the inventors discovered. The
 district court appeared to find that the relevant natural
 phenomenon is either the “testable quantity” of fetal DNA
 or “test results” obtained from that fetal DNA. Decision,
356 F. Supp. 3d at 933. Roche’s articulation of the natural
 phenomenon was a moving target throughout its briefing
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 10                 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 and at oral argument, but appears to be the “size distribu-
 tion” of fetal to maternal cell-free DNA in a mother’s blood
 reflected in Table 1 of the specification, with a particular
 focus on the number “500 base pairs” as the critical divid-
 ing line between the two. See Appellee’s Br. 14, 18, 21; Oral
 Arg. 27:58, 28:35, 29:16. And Illumina asserts more simply
 that the inventors’ discovery was that “fetal cell-free DNA
 tends to be shorter than maternal cell-free DNA.” Appel-
 lant’s Br. 24; see also id. at 8 (“[I]n a sample of cell-free
 DNA from a pregnant woman, the DNA that arises from
 the fetus is smaller on average than the DNA that arises
 from the mother.”).
      We take note of Roche’s inability—despite its status as
 the party challenging the validity of the patents—to
 clearly identify the natural phenomenon that forms the ba-
 sis of its challenge. But, ultimately, we find that the par-
 ties’ respective articulations reflect distinctions without
 differences. For simplicity, we adopt Illumina’s articula-
 tion of the natural phenomenon, i.e., that cell-free fetal
 DNA tends to be shorter than cell-free maternal DNA in a
 mother’s bloodstream. We thus turn to the crucial question
 on which this case depends: whether the claims are “di-
 rected to” that natural phenomenon. We conclude that the
 claims are not directed to that natural phenomenon but ra-
 ther to a patent-eligible method that utilizes it.
     The claims in this case are directed to methods for pre-
 paring a fraction of cell-free DNA that is enriched in fetal
 DNA. The methods include specific process steps—size dis-
 criminating and selectively removing DNA fragments that
 are above a specified size threshold—to increase the rela-
 tive amount of fetal DNA as compared to maternal DNA in
 the sample. ’751 patent col. 7 ll. 63–67. The size thresholds
 in the claims—500 base pairs in the ’751 patent and 300
 base pairs in the ’931 patent—are not dictated by any nat-
 ural phenomenon, particularly because the size distribu-
 tions of fetal and maternal cell-free DNA overlap each
 other (i.e., there are maternal DNA fragments shorter than
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                  11

 300 base pairs). The claimed size thresholds are human-
 engineered parameters that optimize the amount of mater-
 nal DNA that is removed from the mixture and the amount
 of fetal DNA that remains in the mixture in order to create
 an improved end product that is more useful for genetic
 testing than the original natural extracted blood sample.
      Moreover, the claimed methods achieve more than
 simply observing that fetal DNA is shorter than maternal
 DNA or detecting the presence of that phenomenon. The
 claims include physical process steps that change the com-
 position of the mixture, resulting in a DNA fraction that is
 different from the naturally occurring fraction in the
 mother’s blood. The dependent claims further illustrate
 the concrete nature of the claimed process steps. For ex-
 ample, claims 7–8 of the ’751 patent and claims 8–9 of the
 ’931 patent require that the size discrimination step com-
 prise “centrifugation,” and specifically “density gradient
 centrifugation.” ’751 patent col. 9 ll. 1–4; ’931 patent col. 9
 ll. 9–12. Other dependent claims in the ’931 patent com-
 prise other discrimination and separation means, such as
 “high performance liquid chromatography” (claims 4–5),
 “capillary electrophoresis” (claims 6–7), or “nanotechnolog-
 ical means” (claim 10). These dependent claims are sup-
 ported by the specification’s description of the physical
 means by which the size discrimination and selective re-
 moval step of the claims can be achieved:
     The size separation of the extracellular DNA in
     said serum or plasma sample can be brought about
     by a variety of methods, including but not limited
     to: chromatography or electrophoresis such as chro-
     matography on agarose or polyacrylamide gels, ion-
     pair reversed-phase high performance liquid chro-
     matography [], capillary electrophoresis in a self-
     coating, low-viscosity polymer matrix [], selective
     extraction in microfabricated electrophoresis de-
     vices [], microchip electrophoresis on reduced vis-
     cosity polymer matrices [], adsorptive membrane
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 12                  ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

      chromatography [] and the like; density gradient
      centrifugation []; and methods utilising [sic] nano-
      technological means such as microfabricated en-
      tropic trap arrays [] and the like.
 ’931 patent col. 2 l. 61–col. 3 l. 18 (citations omitted); see
 also id. col. 4 ll. 15–22 (“3. The gel was electrophoresed at
 80 Volt for 1 hour. 4. The Gel [sic] was cut into pieces cor-
 responding to specific DNA sizes . . . .”). As described by
 the specification, the inventors used these concrete process
 steps, not merely to observe the presence of the phenome-
 non that fetal DNA is shorter than maternal DNA, but ra-
 ther to exploit that discovery in a method for preparation
 of a mixture enriched in fetal DNA.
      Roche insists that the claims in this case are no more
 eligible than the claims at issue in Ariosa. We disagree. In
 Ariosa, the relevant independent claims were directed to a
 method “for detecting a paternally inherited nucleic acid”
 (claims 1 and 24) or a method “for performing a prenatal
 diagnosis” (claim 25). See Ariosa, 788 F.3d at 1373–74.
 The only operative steps in the claims were “amplifying”
 (i.e., making more of) the cell-free fetal DNA and then “de-
 tecting [it],” “subjecting [it] . . . to a test,” or “performing
 nucleic acid analysis on [it] to detect [it].” Id. We found
 those claims ineligible because, like the invalid diagnostic
 claims at issue in Mayo, Athena, and Cleveland Clinic, they
 were directed to detecting a natural phenomenon after a
 sample has been prepared or extracted. In essence, the in-
 ventors in Ariosa discovered that cell-free fetal DNA exists,
 and then obtained patent claims that covered a method di-
 rected to starting with a sample that contains cell-free fetal
 DNA and seeing that that the cell-free fetal DNA exists.
     Here, in contrast, the claims are directed to more than
 just the correlation between a DNA fragment’s size and its
 tendency to be either fetal or maternal, a correlation which
 is not even mentioned in the claims. The claims do not
 cover a method for detecting whether a cell-free DNA
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                  13

 fragment in a previously-prepared sample is fetal or ma-
 ternal based on the natural size distribution of cell-free
 DNA fragments; rather, the claimed methods exploit that
 natural size distribution during the sample preparation
 steps to remove some maternal DNA from the mother’s
 blood. Even the “analyzing” step of the claims is not di-
 rected to analyzing the discovered natural phenomenon,
 but to analyzing something else entirely, namely, “fetal
 chromosomal aberrations.” See ’751 patent col. 7 ll. 55–56,
 col. 8 ll. 56–57, col. 9 ll. 5–8; ’931 patent col. 9 ll. 17–24.
 Thus, the claims in this case are different from the claims
 that we held invalid in Ariosa.
      Roche also argues, based on the Supreme Court’s deci-
 sion in Association for Molecular Pathology v. Myriad Ge-
 netics, Inc., that “a naturally occurring DNA segment is a
 product of nature and not patent eligible merely because it
 has been isolated.” 569 U.S. 576, 580 (2013). But the
 claims here are not directed to the cell-free fetal DNA itself.
 The Supreme Court in Myriad expressly declined to extend
 its holding to method claims reciting an innovative process
 used to isolate DNA. See id. at 595–96. The Court stated:
     It is important to note what is not implicated by
     this decision. First, there are no method claims be-
     fore this Court. Had Myriad created an innovative
     method of manipulating genes while searching for
     the BRCA1 and BRCA2 genes, it could possibly
     have sought a method patent. But the processes
     used by Myriad to isolate DNA were well under-
     stood by geneticists at the time of Myriad’s patents,
     were well understood, widely used, and fairly uni-
     form insofar as any scientist engaged in the search
     for a gene would likely have utilized a similar ap-
     proach, and are not at issue in this case.
Id. (internal quotation marks omitted). Thus, in Myriad,
 the claims were ineligible because they covered a gene that
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 14                 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 the inventors isolated but did not invent, rather than an
 innovative process for isolating a gene.
      Here, we encounter the opposite situation, i.e., the
 claims do not cover separated cell-free fetal DNA itself but
 rather a process for selective removal of non-fetal DNA to
 enrich a mixture in fetal DNA. That process includes size
 parameters that the inventors engineered to balance the
 practicalities of the specific problem that they were facing,
 namely, removing enough cell-free maternal DNA to enrich
 the mixture while leaving enough cell-free fetal DNA to al-
 low for testing. Thus, the Supreme Court’s decision in Myr-
 iad is not on point in this case where the inventors claimed
 to have conceived and reduced to practice, not the sepa-
 rated DNA, but a method that uses unconventional size pa-
 rameters to perform the separation.
     In our view, CellzDirect, while not directly on point, is
 instructive. In CellzDirect, the inventors discovered the
 natural phenomenon “that some fraction of hepatocytes are
 capable of surviving multiple freeze-thaw cycles.” 827 F.3d
 at 1045. Having made that discovery, they patented an
 “improved process of preserving hepatocytes,” that com-
 prises freezing hepatocytes, thawing the hepatocytes, re-
 moving the non-viable hepatocytes, and refreezing the
 viable hepatocytes. Id. We found that their claimed inven-
 tion was patent-eligible because it was “not simply an ob-
 servation or detection of the ability of hepatocytes to
 survive multiple freeze-thaw cycles. Rather, the claims are
 directed to a new and useful method of preserving hepato-
 cyte cells.” Id. at 1048.
     The inventors in CellzDirect did not invent hepatocytes
 or impart to hepatocytes an ability to survive cycles of
 freezing and thawing. Id. at 1045. Rather, they discovered
 that hepatocytes naturally have that ability, and they ex-
 ploited that phenomenon in a patent-eligible method. So
 too here, the inventors of the ’751 and ’931 patents obvi-
 ously did not invent cell-free fetal DNA or the relative size
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                15

 distribution of fetal and maternal cell-free DNA in mater-
 nal blood. And, like in CellzDirect, the inventors used their
 discovery to invent a method of preparing a fraction of DNA
 that includes physical process steps with human-engi-
 neered size parameters to selectively remove some mater-
 nal DNA in blood to produce a mixture enriched in fetal
 DNA.
      Roche argues that the techniques for size discriminat-
 ing and selectively removing DNA fragments that are used
 to practice the invention were well-known and conven-
 tional. And we recognize, of course, that the inventors of
 the ’751 and ’931 patents did not invent centrifugation,
 chromatography, electrophoresis, or nanotechnology. 1 But
 conventional separation technologies can be used in uncon-
 ventional ways. And Roche, the party challenging the va-
 lidity of the patents and thus bearing the burden of proof
 on its § 101 challenge, has presented no evidence that
 thresholds of 500 base pairs and 300 base pairs were con-
 ventional for separating different types of cell-free DNA
 fragments. Thus, the claims are directed to a human-engi-
 neered method rather than the natural size distributions
 of cell-free DNA. Moreover, while such conventionality
 considerations may be relevant to the inquiry under Al-
 ice/Mayo step two, or to other statutory considerations such
 as obviousness that are not at issue before us in this case,
 they do not impact the Alice/Mayo step one question
 whether the claims themselves are directed to a natural
 phenomenon. Again, CellzDirect is instructive, where we
 acknowledged that the inventors had not invented the well-
 known processes of “freezing” and “thawing,” but only in

     1   We note, without deciding, that Illumina argues
 that claim 11 of the ’931 patent requires the use of micro-
 arrays, which it claims was a methodology not previously
 used with cell-free DNA. Appellant’s Br. 40.
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 16                 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 the context of the Alice/Mayo step two inquiry. 827 F.3d at
 1050–51.
     Rather than focusing on what the inventors of the ’751
 and ’931 patents did not invent, we focus our Alice/Mayo
 step one analysis on what the inventors did purport to in-
 vent and what they claimed in their patents: methods for
 preparing a fraction of cell-free DNA by the physical pro-
 cess of size discriminating and selectively removing DNA
 fragments longer than a specified human-engineered
 threshold. Those methods are “directed to” more than
 merely the natural phenomenon that the inventors discov-
 ered. Accordingly, we conclude at step one of the Al-
 ice/Mayo test that the claims are not directed to a patent-
 ineligible concept, and we need not reach step two of the
 test.
                              III
      In Ariosa, we recognized that the inventors had made
 a discovery with implications that would allow what had
 previously been discarded as medical waste to be used as a
 tool for determining fetal characteristics. 788 F.3d at 1373.
 We acknowledged the profound impact that the discovery
 had on the field of prenatal medicine, including that it “cre-
 ated an alternative for prenatal diagnosis of fetal DNA that
 avoids the risks of widely-used techniques that took sam-
 ples from the fetus or placenta.” Id. Nevertheless, under
 guidance from the Supreme Court, we determined that the
 discovery of that natural phenomenon, no matter how sig-
 nificant it was to the medical field, was not itself patenta-
 ble, and neither was a method for detecting it. Id. at 1379–
 80.
      The invention in this case is the product of further re-
 search on cell-free fetal DNA. This time, the inventors dis-
 covered that, not only does the fetal DNA exist in the
 bloodstream of a pregnant mother, but it has characteris-
 tics that make it distinguishable, and therefore separable,
 from the maternal DNA.             Again, regardless how
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                17

 groundbreaking this additional discovery may have been,
 the inventors were not entitled to patent the natural phe-
 nomenon that cell-free fetal DNA tends to be shorter than
 cell-free maternal DNA. “Groundbreaking, innovative, or
 even brilliant discovery does not by itself satisfy the § 101
 inquiry.” Myriad, 569 U.S. at 591. Thus, they could not
 claim a method directed to the natural phenomenon, e.g., a
 method for determining whether a fragment of cell-free
 DNA is fetal or maternal based on its length. And they did
 not attempt to patent such a method.
     The inventors here patented methods of preparing a
 DNA fraction. The claimed methods utilize the natural
 phenomenon that the inventors discovered by employing
 physical process steps and human-engineered size param-
 eters to selectively remove larger fragments of cell-free
 DNA and thus enrich a mixture in cell-free fetal DNA.
 Though we make no comment on whether the claims at is-
 sue will pass muster under challenges based on any other
 portion of the patent statute, under § 101 the claimed
 methods are patent-eligible subject matter.
                         CONCLUSION
     We conclude that the claims of the ’751 and ’931 pa-
 tents are directed to patent-eligible subject matter under
 35 U.S.C. § 101. We therefore reverse the district court’s
 grant of summary judgment and remand for further pro-
 ceedings.
                REVERSED AND REMANDED
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    United States Court of Appeals
        for the Federal Circuit
                  ______________________

           ILLUMINA, INC., SEQUENOM, INC.,
                  Plaintiffs-Appellants

                             v.

          ARIOSA DIAGNOSTICS, INC., ROCHE
         SEQUENCING SOLUTIONS, INC., ROCHE
             MOLECULAR SYSTEMS, INC.,
                  Defendants-Appellees
                 ______________________

                        2019-1419
                  ______________________

    Appeal from the United States District Court for the
 Northern District of California in No. 3:18-cv-02847-SI,
 Senior Judge Susan Y. Illston.
                 ______________________

 REYNA, Circuit Judge, dissenting.
     The claims, written description, and legal precedent
 converge to a conclusion that the ’751 and ’931 patents 1
 cover patent ineligible subject matter. The asserted claims
 are directed to a natural phenomenon, the patents’ sole
 claimed advance is the discovery of that natural

     1   U.S. Patent Nos. 9,580,751 and 9,738,931. The pa-
 tents contain nearly identical written descriptions and
 claims. For economy, this opinion will reference only the
 ’751 patent.
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 2                  ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 phenomenon, and the application of the natural phenome-
 non utilizes routine steps and conventional procedures that
 are well known in the art.
     The patents in this appeal proclaim a surprising dis-
 covery that has advanced the medical arts in an area of
 great need. Without doubt, scientists are entitled to great
 credit and recognition for such a discovery. But, under U.S.
 patent law, they are not entitled to a patent.
                         DISCUSSION
     I. The Claims are Directed to a Natural Phenomenon
      At the time of the invention, skilled artisans were
 aware that cell-free fetal DNA (“cff-DNA”) existed; that cff-
 DNA could be detected in a sample of a pregnant woman’s
 blood or serum; and that cff-DNA was useful for reliably
 analyzing fetal genetic markers (for detecting certain dis-
 eases and disorders). ’751 patent at col. 1 ll. 22–34. But
 for some genetic markers found in the genomes of both the
 mother and the fetus, skilled artisans faced a problem: the
 relatively small amount of cff-DNA compared to the
 amount of maternal extracellular DNA in the mother’s
 blood made it difficult to identify and analyze genetic alter-
 ations in the fetus. Id. at col. 1 ll. 41–50.
      The patent informs us that the problem was overcome
 when the inventors made a “surprising” discovery. Id. at
 col. 1 ll. 54–61. The inventors discovered that cff-DNA
 tends to be shorter than cell-free maternal DNA in a
 mother’s blood. See ’751 patent at col. 1 ll. 54–67; see also
 Maj. Op. at 3–4, 8. The written description explains that
 the majority of cff-DNA in the mother’s blood plasma “has
 a relatively small size of approximately 500 base pairs or
 less, whereas the majority of circulatory extracellular ma-
 ternal DNA in maternal plasma has a size greater than ap-
 proximately 500 base pairs.” Id. at col. 1 ll. 54–61. The
 written description states that “[t]his surprising finding
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                   3

 forms the basis of the present invention.” Id. at col. 2 ll. 1–
 2 (emphasis added).
     As explained in detail below, it is to this precise sur-
 prising discovery of size discrepancy of cff-DNA in a
 mother’s blood—an undisputed natural phenomenon—
 that the claims at issue are directed. These claims, thus,
 do not escape Alice step one.
                 A. The Claimed Method Steps
                Involve a Natural Phenomenon
      The first step of the Alice test requires that we deter-
 mine whether the claims at issue are “directed to” a natural
 phenomenon. Alice Corp. Pty. Ltd. v. CLS Bank Intern, 573
U.S. 208, 217–18 (2014). To make this determination, the
 Supreme Court has analyzed whether the claims “in-
 volved” patent-ineligible subject matter. Id. at 219; see also
id. at 218–20 (citing Gottschalk v. Benson, 409 U.S. 63, 71–
 72 (1972), and Bilski v. Kappos, 561 U.S. 593, 599 (2010)).
 In Alice, the Court determined that the claims were di-
 rected to an abstract idea because the claims “involve” the
 abstract idea of “intermediated settlement,” a concept the
 Court deemed a “fundamental economic practice.” Alice,
573 U.S. at 219. Like in Alice, the claims here are directed
 to a natural phenomenon because they involve a funda-
 mental natural phenomenon, that cff-DNA tends to be
 shorter than cell-free maternal DNA in a mother’s blood, to
 produce a “mixture” of naturally-occurring substances.
     For example, the preamble of claim 1 of the ’751 patent
 informs us that the patent claims a method for preparing a
 DNA “fraction” from a pregnant human female that can be
 used for diagnostic purposes. 2 The remainder of claim 1

     2   Claim 1 recites:
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 4                    ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 recites the method steps for producing the fraction and an-
 alyzing it. Each step involves the DNA taken from the
 blood plasma or serum of a pregnant human female. The
 DNA itself is not changed or altered.
    The first step is achieved by (a) extracting DNA from a
 substantially cell-free sample of blood plasma or blood se-
 rum taken from a pregnant female. That sample is then

     A method for preparing a deoxyribonucleic acid
     (DNA) fraction from a pregnant human female use-
     ful for analyzing a genetic locus involved in a fetal
     chromosomal aberration, comprising:
         (a) extracting DNA from a substantially
         cell-free sample of blood plasma or blood se-
         rum of a pregnant human female to obtain
         extracellular circulatory fetal and mater-
         nal DNA fragments;
         (b) producing a fraction of the DNA ex-
         tracted in (a) by:
              (i) size discrimination of extracellu-
              lar circulatory DNA fragments,
              and
              (ii) selectively removing the DNA
              fragments greater than approxi-
              mately 500 base pairs, wherein the
              DNA fraction after (b) comprises a
              plurality of genetic loci of the extra-
              cellular circulatory fetal and ma-
              ternal DNA; and
         (c) analyzing a genetic locus in the fraction
         of DNA produced in (b).
 ’751 patent at col. 7 ll. 54-67, col. 8 ll. 53-57; cf. ’931 patent
 at col. 7 ll. 58-67, col. 8 ll. 57-63 (claim 1).
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                   5

 used to (b) produce a “fraction” of the DNA extracted in the
 first step (a). The fraction is produced via (i) size discrimi-
 nation of the extracellular circulatory DNA fragments, and
 (ii) selective removal of DNA fragments greater than ap-
 proximately 500 base pairs. Claim 1 states that after the
 extraction, size discrimination, and selection and removal
 steps are completed, the fraction comprises “a plurality of
 genetic loci of the extracellular circulator fetal and mater-
 nal DNA.” ’751 patent at col. 8 ll. 53–55. The Majority
 describes the resulting fraction as “a mixture enriched in
 fetal DNA.” Maj. Op. at 12. But this mixture is made of
 the same natural substances present in the original sam-
 ple.
      In sum, the claimed method begins with extracting a
 sample of blood plasma or serum from a pregnant mother
 that consists wholly of various naturally occurring sub-
 stances, including cff-DNA. ’751 patent at col. 7. ll. 58–61.
 The claimed method separates those naturally occurring
 substances by size, leaving a “fraction” of the original sam-
 ple that is predominantly cff-DNA. Id. at col. 7 ll. 63–67,
 col. 8 ll. 53–55. The claimed method ends with analyzing
 the components of the “fraction,” which contains cff-DNA.
Id. at col. 8 ll. 56–57. The substances present throughout
 the process are naturally occurring substances, and the
 claimed method steps do not alter those substances. Thus,
 under the Supreme Court’s step-one analysis, the claimed
 method steps “involve” natural phenomenon and are,
 therefore, directed to a natural phenomenon. 3

     3    The dependent claims add detail such as tech-
 niques for conducting each method step and the detection
 of specific chromosomal aberrations. For example, claim 7
 of the ’751 patent specifies centrifugation for the size dis-
 crimination step and claim 10 specifies for the detection of
 a fetal chromosomal aberration causing Down Syndrome.
 ’751 patent at col. 9 ll. 1-2, 7-8.
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 6                   ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

     B. The Claimed Advance is a Natural Phenomenon
     My conclusion that the method steps are directed to a
 natural phenomenon is bolstered by our precedent that
 looks to the “claimed advance” for determining whether a
 claim is directed to patent ineligible subject matter. E.g.,
 Athena, 915 F.3d 743, 750 (Fed. Cir. 2019) (Lourie, J.); Ge-
 netic Techs. Ltd. v. Merial L.L.C., 818 F.3d 1369, 1375 (Fed.
 Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788
F.3d 1371 (Fed. Cir. 2015).
     In Ariosa, we concluded that the claims were directed
 to a natural phenomenon relying, in part, on the patent’s
 disclosure that the natural phenomenon was a “surprising
 and unexpected finding.” 788 F.3d at 1376 (citation and
 quotation omitted). In Athena, we concluded that the
 claimed advance was “only in the discovery of the natural
 law” by relying, in part, on the patent’s disclosure that the
 inventors “surprisingly found” the natural law. 915 F.3d
 at 751 (citation and quotation omitted). In Cleveland
 Clinic, we concluded that the claims were directed to a nat-
 ural law relying, in part, on the patent’s disclosure that
 “the inventions are ‘based on the discovery’” of the natural
 law. 859 F.3d at 1360–61 (citation omitted).
     Here, the claimed advance is the inventors’ “surpris-
 ing[]” discovery of a natural phenomenon—that cff-DNA
 tends to be shorter than cell-free maternal DNA in a
 mother’s bloodstream. See ’751 patent at col. 1 ll. 54–61.
 Like in Ariosa and Athena, the patent’s written description
 identifies only the natural phenomenon as the “surprising
 finding.” Id. at col. 1 l. 54–col. 2 l. 6. And the patent ex-
 plains that the natural phenomenon “forms the basis of the
 present invention,” like the patent in Cleveland Clinic. Id.
 at col. 2 ll. 1–6. It is undisputed that the surprising discov-
 ery is a natural phenomenon. See Maj. Op. at 3–4, 9. The
 claimed advance is, therefore, the discovery of the natural
 phenomenon.
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                 7

     The conclusion that the claimed advance is the discov-
 ery of a natural phenomenon is supported by the fact that
 the claimed method steps begin and end with a naturally
 occurring substance. See Ariosa, 788 F.3d at 1376. In Ari-
 osa, we found ineligible process claims directed to a method
 of detecting paternally inherited cff-DNA. Id. The claimed
 method steps began with a naturally occurring blood sam-
 ple and ended with cff-DNA, itself a naturally occurring
 substances. Id. In this case, as in Ariosa, the inventors did
 not create or alter via the claimed method steps any of the
 genetic information encoded in the cff-DNA in the claimed
 method steps. Id.
     The Majority avoids our claimed advance precedent by
 reasoning that these claims belong in a distinct category of
 process claims for “method[s] of preparation.” 4 See Maj.
 Op. at 8. But characterizing the claims as a “method of
 preparation” does not render inapplicable this court’s prec-
 edent including Athena, Roche Molecular, Cleveland
 Clinic, Genetic Techs., and Ariosa. 5 Id. Our precedent does
 not support such cherry picking. A “method of prepara-
 tion” is treated no differently than any other process claim
 under our law. The statute provides that the term “pro-
 cess” in § 101 encompasses all “process, art or method”

     4   Cf. Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc., 827
F.3d 1042, 1050 (Fed. Cir. 2016) (reciting in claim 1’s pre-
 amble “[a] method of producing a desired preparation”).
     5   Athena Diagnostics, Inc. v. Mayo Collaborative
 Servs., LLC, 915 F.3d 743 (Fed. Cir. 2019); Roche Molecu-
 lar Sys., Inc. v. Cepheid, 905 F.3d 1363 (Fed. Cir. 2018);
 Cleveland Clinic Found. v. True Health Diagnostics LLC,
 859 F.3d 1352 (Fed. Cir. 2017); Genetic Techs. Ltd. v.
 Merial L.L.C., 818 F.3d 1369 (Fed. Cir. 2016); Ariosa Diag-
 nostics, Inc. v. Sequenom, Inc., 788 F.3d 1371 (Fed.
 Cir. 2015).
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 8                   ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 claims. 35 U.S.C. § 100(b). It makes no distinction based
 on how the process or method is characterized.
     Here, the Majority fails to adequately address the
 claimed advance inquiry. E.g., Maj. Op. at 8–13. Yet, the
 Majority maintains that the claimed methods are not di-
 rected to the natural phenomenon—under the Alice/Mayo
 step-one inquiry—because they “include physical process
 steps” that “achieve more than simply observing that fetal
 DNA is shorter than maternal DNA or detecting the pres-
 ence of that phenomenon.” Maj. Op. at 11. The problem
 with this approach is that it conflates the Alice/Mayo step-
 one analysis with the step-two analysis by focusing on
 whether and how the claimed “physical process steps”
 transform the invention into more than an observation of
 the natural phenomenon. See Alice, 573 U.S. 217–18. The
 Supreme Court describes step two of the analysis as “a
 search for an ‘inventive concept’—i.e., an element or com-
 bination of elements that is ‘sufficient to ensure that the pa-
 tent in practice amounts to significantly more than a patent
 upon the [ineligible concept] itself.’” Id. (emphasis added)
 (quoting Mayo Collaborative Services v. Prometheus Labor-
 atories, Inc., 566 U.S. 66, 72–73 (2012)).
     The Majority also suggests that the claimed advance is
 an improvement in “size discriminat[ion]” and “selective[]
 remov[al]” techniques. See Maj. Op. at 9–11. The Majority
 reasons that the inventors used “specific process steps” of
 “size discriminating and selectively removing DNA frag-
 ments that are above a specified size threshold” and that
 these “concrete process steps . . . exploit [the natural phe-
 nomenon] in a method for preparation of a mixture en-
 riched in fetal DNA.” Id. at 9–10, 12. But whether the
 claimed method steps are specific and concrete is not the
 point of analysis for the “directed to” inquiry or for deter-
 mining the claimed advance at step one. See Athena, 915
F.3d at 752 (concluding that the claims’ specific and con-
 crete nature “does not disturb our conclusion at step one”).
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                      9

      The claimed advance suggested by the Majority, an im-
 provement in the underlying DNA-processing technology,
 is not supported by the claims or the written description.
 As discussed below, the written description identifies the
 claimed method steps as well-known or performed using
 commercially available tools or kits. See ’751 patent at col.
 2 l. 49–col. 3 l. 18, col. 3 ll. 49–50, col. 3 l. 65–col. 4 l. 13,
 col. 5 ll. 45–50. Where a written description identifies a
 technology as well-known or performed using commercially
 available tools or kits, that technology cannot logically con-
 stitute a claimed advance. Ariosa, 788 F.3d at 751; see also
 Athena, 915 F.3d at 751 (identifying the claimed “immuno-
 logical assay techniques [as] known per se in the art” and
 therefore not the claimed advance); Cleveland Clinic, 859
F.3d at 1361 (relying on the patent’s disclosure of “commer-
 cially available testing kits” for detecting the natural law).
     Table 1, below, highlights the commercially available
 tools and kits that are identified in the written description
 as used to perform each claimed method step.
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 10                     ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

      Table 1: Performance of Claimed Method Steps

                                    Commercially Available
      Claimed Method Step
                                        Tool or Kit

                                          QIAgen Maxi kit
       Claim 1(a), “extracting
                                    (’751 patent at col. 3 ll. 49–
               DNA”
                                                50)

                                     Invitrogen 1% agarose gel
                                    (’751 patent at col. 3 ll. 66–
                                                67)
                                    New England Biolabs 100
       Claim 1(b)(i), “size dis-        base pair ladder
            crimination”              (id. at col. 4 ll. 4–5)
          Claim 1(b)(ii), “selec-     Lamda Hind III digest
          tively removing”          (’751 patent at col. 4 ll. 5–
                                                6)
                                        QIAEX Gel Extraction
                                                 kit
                                      (id. at col. 4 ll. 10–12)

                                     Applied Biosystems (ABI)
                                     7000 Sequence Detection
                                              System
                                    (’751 patent at col. 4 ll. 14-
      Step (c), “analyzing a ge-                38)
             netic locus”
                                       TaqMan System and
                                      TaqMan Minor Groove
                                               Binder
                                      (id. at col. 4 ll. 19–38)

     The Majority turns to attorney argument to save these
 claims. It reasons that Roche “has presented no evidence
 that thresholds of 500 base pairs and 300 base pairs were
 conventional for separating different types of cell-free DNA
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                 11

 fragments.” Maj. Op. at 15. But whether a claim is di-
 rected to patent ineligible subject matter depends on the
 claims and the written description, and not attorney argu-
 ment. The absence, or silence, of conventionality of an as-
 pect of an invention in the written description does not
 render that aspect unconventional. There is nothing in the
 patent itself to indicate that size selection based on 500 and
 300 base pairs was an unconventional human engineered
 parameter or that this aspect of the invention is the
 claimed advance. This explains why the Majority’s re-
 peated statements concerning human engineered parame-
 ters are unsupported by citations to the specification. See
 Maj. Op. at 10, 14–17. The claimed DNA-processing tech-
 nologies do not, therefore, constitute the claimed advance.
 See Cleveland Clinic, 859 F.3d at 1361.
     The Majority relies on CellzDirect. See Maj. Op. at 14–
 15. But CellzDirect is distinct from this case. In CellzDi-
 rect, the inventors created a new and useful cryopreserva-
 tion technique comprising multiple free-thaw cycles. 827
F.3d at 1048. The claimed invention went beyond applying
 a known laboratory technique to a newly discovered natu-
 ral phenomenon and, instead, created an entirely new la-
 boratory technique. Id. Unlike in CellzDirect, the claimed
 method steps here are not new, nor are the claimed tech-
 niques used in a new or unconventional way. The method
 steps do not recite or recognize the creation of a new labor-
 atory technique. The Majority recognizes that the inven-
 tors “did not invent centrifugation, chromatography,
 electrophoresis, or nanotechnology”—the claimed tech-
 niques described in the written description. Maj. Op. at 15.
     The Majority further reasons that the claimed method
 steps of size discrimination and selective removal “change
 the composition of the mixture, resulting in a DNA fraction
 that is different from the naturally-occurring fraction in
 the mother’s blood.” Id. at 9–10. On this basis, the Major-
 ity concludes that the claimed method in the patent
 “achieves more than simply observing that fetal DNA is
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 12                 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 shorter than maternal DNA, or detecting the presence of
 that phenomenon.” Id.
     The Majority’s position is declaratory, but not logical.
 That the claimed process changes the composition of a sam-
 ple of naturally occurring substances, but does not alter the
 naturally occurring substances themselves, is not suffi-
 cient to render the claimed process patent eligible. See Ge-
 netic Techs., 818 F.3d at 1374 (holding ineligible the
 claimed process for using PCR to amplify genomic DNA in
 a sample before detecting it); Ariosa, 788 F.3d at 1373
 (holding ineligible the claimed process for using PCR to
 amplify cff-DNA in a sample before detecting it).
     Here, the claimed method steps of size discrimination
 and selective removal do not alter the naturally occurring
 substances in the sample of blood plasma or serum from a
 pregnant mother. Importantly, the majority correctly un-
 derstands that the patent does not claim the fraction in
 terms of chemical composition, as a naturally occurring
 substance that has been chemically altered by the method
 steps. Cf. Association for Molecular Pathology v. Myriad
 Genetics, Inc., 569 U.S. 576, 593 (2013) (“Myriad’s claims
 are simply not expressed in terms of chemical composition,
 nor do they rely in any way on the chemical changes that
 result from the isolation of a particular section of DNA.”).
      The Majority also suggests that the claimed methods
 are not directed to the natural phenomenon because the
 “correlation” that “a DNA fragment’s size and its tendency
 to be either fetal or maternal” is not recited in the claim.
 Maj. Op. at 12–13. Neither our precedent nor that of the
 Supreme Court imposes such a requirement. Requiring a
 recitation of the natural phenomenon leads to the “drafts-
 man’s art” problem, where a claim drafter has written a
 claim that is devoted to an ineligible concept, but the
 drafter managed to avoid reciting the ineligible concept it-
 self. It was this recognition of “the draftsman’s art” that
 motivated the Supreme Court to adopt the step-two,
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                 13

 inventive concept inquiry. Mayo, 566 U.S. at 72 (citing
 Parker v. Flook, 437 U.S. 584, 593 (1978)); see also Dia-
 mond v. Diehr, 450 U.S. 175, 188–89 (1981).
      The Majority’s category-based approach also allows
 claim draftsmanship to evade § 101’s safeguard at the step-
 one inquiry. In Myriad, the Court concluded that the
 claims at issue were “concerned primarily” with a patent-
 ineligible product of nature and recognized that “separat-
 ing [a] gene from its surrounding genetic material is not an
 act of invention.” 569 U.S. at 591. Here, the separation of
 genetic material from its surroundings is plainly the focus
 of the claims at issue. Yet, the Majority distinguishes Myr-
 iad on the sole ground that these claims have been drafted
 as method claims rather than composition of matter
 claims. In any event, whether a patent claim recites a pro-
 cess or a composition of matter does not impact the step-
 one, “directed to” inquiry because this inquiry applies
 equally to composition of matter and process claims. 6 I see
 no principled reason why under the facts of this case Myr-
 iad should or should not apply simply because this case
 presents a method claim and not a composition of matter
 claim. Regardless of whether the asserted claims are to a
 composition of matter or a “method of preparation,” the
 purpose of § 101 remains the same: to safeguard against

     6   E.g., Myriad, 569 U.S. at 591 (analyzing the “focus”
 of the relevant composition of matter claims), Mayo, 566
U.S. at 72-73 (analyzing the “focus” of the relevant process
 claims); Bilski, 561 U.S. at 609–13 (analyzing whether the
 process claims involved an abstract idea); Diehr, 450 U.S.
 at 192 (analyzing whether the process claims were “drawn
 to” a mathematical formula or a patent-eligible process ap-
 plying that formula); Funk Bros. Seed Co. v. Kalo Inoculant
 Co., 333 U.S. 127, 132 (1948) (analyzing eligibility of “prod-
 uct claims”).
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 14                  ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 claims that monopolize a law of nature, natural phenome-
 non, or abstract idea. See Alice, 573 U.S. at 216.
          II. The Claims Do Not Survive Step Two
     Step two of the Alice inquiry is a search for other ele-
 ments that transform ineligible claims into significantly
 more than a patent upon the natural law or phenomenon.
 See Mayo, 566 U.S. at 72–73. Mayo made clear that trans-
 formation into a patent eligible application requires “more
 than simply stat[ing] the law of nature while adding the
 words ‘apply it.’” Id. at 72.
      In step two, we ask: “[w]hat else is there in the claims
 before us?” Id. at 78. This question is a lifeline, one that
 is limited to “additional features” of the claim that trans-
 forms the nature of the claim into a patent-eligible appli-
 cation. Id. at 77; Ariosa, 788 F.3d at 1377.
     For method claims that encompass natural phenom-
 ena, the method steps are the additional features that must
 be new and useful. See Parker v. Flook, 437 U.S. 584, 591
 (1978) (“The process itself, not merely the mathematical al-
 gorithm, must be new and useful.”). We must assess
 whether the additional features are new and useful within
 the field generally, not in the context of their particular ap-
 plication to the newly discovered phenomenon. See Roche
 Molecular, 905 F.3d at 1372; see also Athena, 915 F.3d at
 754.
     The method steps under review do not transform the
 nature of the claims into patent-eligible applications. The
 three claimed method steps of (a) extracting DNA, (b) pro-
 ducing a fraction of DNA by size discrimination, and (c) an-
 alyzing a genetic locus are not new, either alone or in
 combination. As illustrated above in Table 1, the written
 description indicates that the laboratory techniques of the
 claimed method are commercially available. And the writ-
 ten description explains that step (b)’s requirement of pro-
 ducing a fraction by size discrimination “can be brought
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                 15

 about by a variety of methods.” ’751 patent at col. 2 ll. 49–
 51.
      Contrary to the majority’s belief, that the size discrim-
 ination and selective removal method steps were applied
 for the first time to the newly discovered natural phenom-
 enon does not render those steps transformative, new and
 useful, under the Alice/Mayo step-two inquiry. See Roche
 Molecular, 905 F.3d at 1372; see also Athena, 915 F.3d at
 754. In Roche Molecular, we held that the method claims
 at issue, which involved PCR amplification of DNA, did not
 contain an inventive concept even though the inventors
 were the first to use PCR to detect the claimed natural phe-
 nomenon. 905 F.3d at 1372. We reasoned that the claims
 did not contain an inventive concept because they did not
 “disclose any ‘new and useful’ improvement to PCR proto-
 cols or DNA amplification techniques in general.” Id. see
 also Athena, 915 F.3d at 754 (noting that “to supply an in-
 ventive concept, the sequence of claimed steps must do
 more than adapt a conventional assay to a newly discov-
 ered natural law”).
      Like in Roche Molecular, the claimed method steps
 here do not disclose any new and useful improvement to
 DNA separation techniques. And they do not disclose an
 unconventional assay to apply the newly discovered natu-
 ral phenomenon. As noted above in the step-one discus-
 sion, the Majority reasons that Roche has presented “no
 evidence that thresholds of 500 base pairs and 300 base
 pairs were conventional for separating different types of
 cell-free DNA fragments.” Maj. Op. at 15. But, like in
 Roche, the addition of these so-called thresholds—which
 are claimed as approximations conforming to the natural
 phenomenon—are nothing more than an adaptation of
 commercially available DNA separation techniques to the
 natural phenomenon.
    The dependent claims also fail to transform the nature
 of the claims because they too rely on the same
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 16                    ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 commercially available, routine, and conventional tech-
 niques as claim 1, only they provide more specificity on
 which techniques to use (e.g., ’751 patent, claim 7, identi-
 fying “density gradient centrifugation” for the size discrim-
 ination method).
      For example, the written description describes two ex-
 amples where experiments illustrate the application of the
 natural phenomenon. ’751 patent at col. 3 l. 30–col. 6 l. 46.
 The results of Example 1, as captured in Table 1, demon-
 strate that “DNA fragments originating from the fetus
 were almost completely of sizes smaller than 500 base pairs
 with around 70% being of fetal origin for sizes smaller than
 300 base pairs.” Id. at col. 4 l. 50–col. 5 l. 7. The results of
 Example 2 demonstrate that fetal alleles for “D21S11,” a
 genetic marker found in the human chromosome related to
 Down Syndrome, could be detected in cell-free DNA sam-
 ples from which fragments greater than 500 base pairs or
 300 base pairs had been removed. The patent explains that
 both experiments were conducted using known laboratory
 techniques and commercially available testing kits. E.g.,
 id. at col. 3 ll. 49–50, col. 3 l. 65–col. 4 l. 13, col. 5 ll. 45–50;
 see also id. at col. 2 l. 61–col. 3 l. 18.
      Simply appending routine, conventional steps to a nat-
 ural phenomenon, specified at a high level of generality, is
 not enough to supply an inventive concept. Thus, the
 claims of the patent in this appeal that are directed to pa-
 tent ineligible subject matter are not transformed into sig-
 nificantly more than a patent upon the natural law or
 phenomenon. See Mayo, 566 U.S. at 72–73.
                         III. Preemption
     The Supreme Court has made clear that the principle
 of preemption is the basis for the judicial exceptions to pa-
 tentability. Alice, 573 U.S. at 216–17. As Mayo empha-
 sized, “there is a danger that the grant of patents that tie
 up the[] use [of laws of nature] will inhibit future innova-
 tion premised upon them.” 566 U.S. at 86.
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     Here, the claims are drafted in a manner that tie up
 future innovations premised upon the natural phenomenon
 because no skilled artisan would be entitled to rely on the
 natural phenomenon to isolate cff-DNA. That a skilled ar-
 tisan could isolate or enrich cff-DNA using some unclaimed
 technique is not dispositive for preemption. See Athena Di-
 agnostics, Inc. v. Mayo Collaborative Servs., 927 F.3d 1333,
 1351 (Fed. Cir. 2019) (Chen, J., concurring in the denial of
 the petition for rehearing en banc) (“That claims 7 and 9 do
 not preempt all ways of observing the law of nature isn’t
 decisive, as none of the steps recited therein add anything
 inventive to the claims.”). As in Athena, the only claimed
 advance here is the discovery of the natural phenomenon,
 and as drafted, these claims significantly preempt use of
 that natural phenomenon.
                         CONCLUSION
     Much of what we are as humans has its source in our
 respective DNA, including particular genetic aberrations.
 The development of medical and scientific procedures to de-
 tect and diagnose genetic aberrations, like those involved
 in the patents in this appeal, count among the great discov-
 eries of modern medicine. Such procedures may qualify for
 a patent, but DNA itself, or a segment of DNA that dis-
 closes an aberration, like the entirety of the human ge-
 nome, does not.
     I dissent because while I do not doubt that process
 claims that are directed to natural phenomenon could be
 patent eligible subject matter, this is not such a case.