Court Opinion

ID: 4517001
Source: CourtListenerOpinion
Date Created: 2020-03-17 16:00:35.100836+00
Date Added: 2024-06-11T09:15:26.192662
License: Public Domain

Case: 19-1419    Document: 55     Page: 1   Filed: 03/17/2020

   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.
                 ______________________

                 Decided: March 17, 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.

     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.
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 2                  ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

     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
 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
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                   3

 natural phenomenon that cell-free fetal DNA exists in ma-
 ternal 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:
     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
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 4                       ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

     approximately 500 base pairs or less, whereas the
     majority of circulatory extracellular maternal DNA
     in maternal plasma has a size greater than approx-
     imately 500 base pairs.
 Id. col. 1 ll. 54–61. Having made that discovery, they used
 it to develop a solution to the identified problem of distin-
 guishing fetal DNA from maternal DNA in the mother’s
 bloodstream:
     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. Claim 1 is the only independent claim in each pa-
 tent:
        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
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          (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.
        1. A method, comprising:
        (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,”
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 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
 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
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 contemplated that the patent laws would be given wide
 scope”; 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) (internal cita-
 tion 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
 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
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 8                  ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 examine whether the limitations of the claim apart from
 the law of nature or natural phenomenon, considered indi-
 vidually and as an ordered combination, “‘transform the
 nature 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
 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 bucket, 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
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 ’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
 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.
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     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. Those process
 steps change the composition of the mixture, resulting in a
 DNA fraction that is different from the naturally-occurring
 fraction in the mother’s blood. Thus, the process achieves
 more than simply observing that fetal DNA is shorter than
 maternal DNA or detecting the presence of that phenome-
 non.
     The dependent claims further illustrate the concrete
 nature of the claimed process steps. For example, claims
 7–8 of the ’751 and claims 8–9 of the ’931 patent require
 that the size discrimination step comprise “centrifugation,”
 and specifically “density gradient centrifugation.” ’751 pa-
 tent col. 9 ll. 1–4; ’931 patent col. 9 ll. 9–12. Other depend-
 ent claims in the ’931 patent comprise other discrimination
 and separation means, such as “high performance liquid
 chromatography” (claims 4–5), “capillary electrophoresis”
 (claims 6–7), or “nanotechnological means” (claim 10).
 These dependent claims are supported by the specifica-
 tion’s description of the physical means by which the size
 discrimination and selective removal 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
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     viscosity polymer matrices [], adsorptive mem-
     brane chromatography [] and the like; density gra-
     dient centrifugation []; and methods utilising [sic]
     nanotechnological means such as microfabricated
     entropic 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. In es-
 sence, the inventors in Ariosa discovered that cell-free fetal
 DNA exists, and then obtained patent claims that covered
 only the knowledge that it exists and a method to see that
 it 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. And the
 claims do not merely cover a method for detecting whether
 a cell-free DNA fragment is fetal or maternal based on its
 size. Rather the claimed method removes some maternal
 DNA from the mother’s blood to prepare a fraction of cell-
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 12                  ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 free DNA that is enriched in fetal DNA. Thus, the claims
 in this case are different from the claims that we held in-
 valid 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 a process used to iso-
 late 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 . . . are not at issue
      in this case.
 Id. Thus, in Myriad, the claims were ineligible because
 they covered a gene rather than a process for isolating it.
 Here, we encounter the opposite situation, i.e., the claims
 do not cover cell-free fetal DNA itself but rather a process
 for selective removal of non-fetal DNA to enrich a mixture
 in fetal DNA. Thus, the Supreme Court’s decision in Myr-
 iad is not on point.
     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
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 invention was patent-eligible because it was “not simply an
 observation or detection of the ability of hepatocytes to sur-
 vive 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
 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 to selectively remove
 some maternal 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
 while such considerations may be relevant to the inquiry
 under Alice/Mayo step two, or to other statutory considera-
 tions such as obviousness that are not at issue before us in
 this case, they do not impact the Alice/Mayo step one ques-
 tion whether the claims themselves are directed to a natu-
 ral phenomenon. Again, CellzDirect is instructive, where
 we acknowledged that the inventors had not invented the

     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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 14                 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 well-known processes of “freezing” and “thawing,” but only
 in 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 threshold. Those meth-
 ods are “directed to” more than merely the natural phe-
 nomenon that the inventors discovered. Accordingly, we
 conclude at step one of the Alice/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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 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 to selectively remove larger frag-
 ments of cell-free DNA and thus enrich a mixture in cell-
 free fetal DNA. Though we make no comment on whether
 the claims at issue 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
Case: 19-1419    Document: 55      Page: 16   Filed: 03/17/2020

    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.
                 ______________________

 REYNA, Circuit Judge, dissenting.
     The Majority holds that the asserted patents are di-
 rected to patent-eligible subject matter. I respectfully dis-
 agree and dissent. I conclude that the claims are directed
 to a natural phenomenon. The patents’ only claimed ad-
 vance is the discovery of that natural phenomenon. The
 claims, the written description, and the legal precedent ap-
 plicable to this case all support the conclusion that the pa-
 tents are ineligible.
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 2                     ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

                I.    The ’751 and ’931 Patents 1
      At the time of the invention, skilled artisans knew that
 cell-free fetal DNA (“cff-DNA”) existed, that it could be de-
 tected in a sample of a pregnant woman’s blood or serum,
 and that it was useful for reliably analyzing fetal genetic
 markers (for detecting certain diseases and disorders).
 ’751 patent col. 1 ll. 22–34. But for some genetic markers
 that are 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 maternal extracellular
 DNA in the mother’s blood made it difficult to identify and
 analyze genetic alterations in the fetus. Id. at col. 1 ll. 41–
 50.
      The patent maintains that the problem was overcome
 when the inventors made a “surprising” discovery. Id. at
 col. 1 ll. 54–61. The inventors discovered a natural phe-
 nomenon: that cff-DNA tends to be shorter than cell-free
 maternal DNA in a mother’s blood. See id. at col. 1 ll. 54–
 67; see also Maj. Op. at 3–4, 8. The written description ex-
 plains that the majority of cff-DNA in the mother’s blood
 “has a relatively small size of approximately 500 base pairs
 or less, whereas the majority of circulatory extracellular
 maternal DNA in maternal plasma has a size greater than
 approximately 500 base pairs.” Id. at col. 1 ll. 54–61. The
 written description states that “[t]his surprising finding
 forms the basis of the present invention.” Id. at col. 2 ll. 1–
 2 (emphasis added).
     Other than the surprising discovery, nothing else in
 the specification or the record before us indicates there was
 anything new or useful about the claimed invention. In two

     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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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                         3

 examples, the patent describes experiments that illustrate
 the natural phenomenon and a potential application. Id.
 at col. 3 l. 30–col. 6 l. 46. The results of Example 1, as cap-
 tured in Table 1, demonstrate that “DNA fragments origi-
 nating 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 bases.” 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 samples from which fragments greater
 than 500 base pairs or 300 base pairs had been removed.
 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.
      The claims recite nearly identical method steps. The
 method steps of the ’751 patent separate DNA fragments
 greater than or equal to 500 base pairs. The method steps
 of the ’931 patent separate DNA fragments greater than or
 equal to 300 base pairs.
     For example, claim 1 of the ’751 patent recites the fol-
 lowing method:
     1. 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:
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 4                    ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

              (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 plu-
     rality of genetic loci of the extracellular circulatory
     fetal and maternal DNA; and
         (c) analyzing a genetic locus in the fraction
         of DNA produced in (b).
 Id. at col. 7 ll. 54–67, col. 8 ll. 53–57; cf., ’931 patent col. 7
 ll. 58–67, col. 8 ll. 57–63 (claim 1).
     The dependent claims for each patent add detail such
 as techniques for conducting each method step and the de-
 tection of specific chromosomal aberrations. For example,
 claim 7 of the ’751 patent specifies centrifugation for the
 size discrimination step and claim 10 specifies for the de-
 tection of a fetal chromosomal aberration causing Down
 Syndrome. ’751 patent col. 9 ll. 1–2, 7–8.
           II. The Claims Are Not Patent Eligible
     The Majority sidesteps well-established precedent by
 reasoning that the claims in this case belong in a unique
 “bucket” reserved for patents that claim “a method of prep-
 aration.” 2 See Maj. Op. at 8. By placing this case in that
 bucket and not in a “diagnostic case” bucket, the Majority
 summarily dismisses precedent like Athena, Roche

     2  Cf., Rapid Litig. Mgmt. Ltd. v. CellzDirect, Inc., 827
F.3d 1042, 1046 (Fed. Cir. 2016) (reciting in claim 1’s pre-
 amble “[a] method of producing a desired preparation”).
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                 5

 Molecular, Cleveland Clinic, Genetic Techs., Ariosa, 3 and
 others. Id. Our precedent, however, does not support the
 Majority’s per se grouping of claims. A “method of prepa-
 ration case” is treated no differently than any other process
 claim under our law.
     35 U.S.C. § 101 grants patent rights to “[w]hoever in-
 vents or discovers any new and useful process[ 4], machine,
 manufacture, or composition of matter, or any new and
 useful improvement thereof.” See Ass’n for Molecular Pa-
 thology v. Myriad Genetics, Inc., 569 U.S. 576, 589 (2013).
 Laws of nature, natural phenomena, and abstract ideas,
 however, are not patent-eligible subject matter. Id.
     To determine whether a patent claims a patent-eligible
 application of a natural phenomenon or impermissibly mo-
 nopolizes a natural phenomenon, we apply the two-step
 test set forth by the Supreme Court. Alice Corp. v. CLS
 Bank Int’l, 573 U.S. 208, 217–18 (2014). In the first step,
 we determine whether the claims at issue are “directed to”
 a patent-ineligible concept. Id. If they are, we consider in
 the second step whether the additional claim elements—
 both individually and “as an ordered combination”—“trans-
 form the nature of the claim” into a patent-eligible applica-
 tion. Id.

     3   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).
     4   The term “process,” as recited in § 101, encom-
 passes all “process, art or method” claims. 35 U.S.C.
 § 100(b).
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 6                  ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

              A. The Claims are Directed to a
           Patent-Ineligible Natural Phenomenon
     The claims are directed to a natural phenomenon be-
 cause the patent’s claimed advance is the discovery of that
 natural phenomenon. The Majority disregards well-estab-
 lished precedent for conducting the Alice, step one, “di-
 rected to” inquiry by failing to consider the patent’s claimed
 advance.
     The Supreme Court first articulated the “directed to”
 inquiry in Alice, 573 U.S. at 217–218. To make that deter-
 mination, the Court analyzed whether the claims “in-
 volved” patent-ineligible subject matter (there, an abstract
 idea). Id. at 218–220 (citing Gottschalk v. Benson, 409 U.S.
63, 71–72 (1972), and Bilski v. Kappos, 561 U.S. 593, 599
 (2010)).
     In the three years following Alice, this court addressed
 numerous § 101 cases without articulating a more definite
 “directed to” inquiry. Instead, we performed step one of the
 patent-eligibility inquiry by comparing the claims at issue
 to the claims held eligible or ineligible in earlier Supreme
 Court and Federal Circuit cases. See, e.g., In re Smith, 815
F.3d 816, 818 (Fed. Cir. 2016); buySAFE, Inc. v. Google,
 Inc., 765 F.3d 1350, 1353 (Fed. Cir. 2014).
     Since 2016, in a string of cases reciting process claims,
 we began conducting the “directed to” inquiry by asking
 whether the “claimed advance” of the patent “improves
 upon a technological process or [is] merely an ineligible
 concept.” Athena, 915 F.3d at 750 (Lourie, J.); Genetic
 Techs., 818 F.3d at 1375.
     To determine a process’s “claimed advance,” we review
 the claims and the written description. Athena, 915 F.3d
 at 750. If a written description highlights the discovery of
 a natural phenomenon—e.g., by describing the natural
 phenomenon as the only “surprising” or “unexpected” as-
 pect of the invention or that the invention is “based on the
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                  7

 discovery” of a natural law—the natural phenomenon
 likely constitutes the claimed advance. See Ariosa, 788
F.3d at 1376; Athena, 915 F.3d at 751; Cleveland Clinic,
859 F.3d at 1360 –61.
     In Ariosa, we concluded that the claims were directed
 to a natural phenomenon based in part on the patent’s dis-
 closure 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 a natural
 law” based in part on the patent’s disclosure that the in-
 ventors “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 natural law
 relying, in part, on the patent’s disclosure that “the inven-
 tions 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 col. 1 ll. 54–61. Like
 in Ariosa and Athena, the patent’s written description iden-
 tifies the natural phenomenon as the only “surprising find-
 ing.” Id. at col. 1 l. 54–col. 2 l. 6. And the patent explains
 that the natural phenomenon “forms the basis of the pre-
 sent invention,” like the patent in Cleveland Clinic. Id. at
 col. 2 ll. 1–6. It is undisputed that the surprising discovery
 is a natural phenomenon. See Maj. Op. at 3–4, 8. The
 claimed advance is, therefore, the natural phenomenon.
     This conclusion is bolstered by the fact that the claimed
 method steps begin and end with a naturally occurring sub-
 stance, as in Ariosa. 788 F.3d at 1376. In Ariosa, 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 sample and
 ended with cff-DNA, both naturally occurring substances.
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 8                   ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 Id. The inventors did not create or alter any of the genetic
 information encoded in the cff-DNA in the claimed method
 steps. Id.
     Likewise, the claimed method here begins and ends
 with a naturally occurring substance. The claimed method
 begins with extracting a sample of blood plasma or serum
 from a pregnant mother that consists wholly of various nat-
 urally occurring substances, including cff-DNA. ’751 pa-
 tent col. 7. ll. 58–61. The claimed method separates those
 naturally occurring substances by size, leaving a “fraction”
 of the original sample 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 con-
 tains cff-DNA. Id. at col. 8 ll. 56–57. The substances pre-
 sent throughout the process are naturally occurring
 substances, and the claimed method steps do not alter
 those substances. The claimed method is therefore di-
 rected to a natural phenomenon.
      The Majority fails to identify the claimed advance
      The Majority’s step one analysis ignores the claimed
 advance inquiry altogether. Contrary to the Majority’s con-
 clusion, the claims here are not directed to “a patent-eligi-
 ble method that utilizes [the natural phenomenon].” Maj.
 Op. at 8–9. Although the Majority states that the claims
 “are directed to methods for preparing a fraction of cell-free
 DNA that is enriched in fetal DNA” (id. at 9), the Majority
 fails to address with specificity the patent’s claimed ad-
 vance.
      Instead, the Majority only seems to suggest that the
 claimed advance is an improvement in “size discrimi-
 nat[ion]” and “selective[] remov[al]” techniques. See id. at
 9–10. The Majority reasons that the inventors used “spe-
 cific process steps” of “size discriminating and selectively
 removing DNA fragments that are above a specified size
 threshold” and that these “concrete process steps . . . exploit
 [the natural phenomenon] in a method for preparation of a
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                         9

 mixture enriched in fetal DNA.” Id. at 10–11. But whether
 the steps are concrete is not the appropriate analysis for
 determining the claimed advance.
     Where a written description identifies a technology as
 well-known or performed using commercially available
 tools or kits, that technology cannot logically constitute a
 claimed advance. Ariosa, 788 F.3d at 751; see also Athena,
915 F.3d at 751 (identifying the claimed “immunological
 assay techniques [as] known per se in the art” and there-
 fore not the claimed advance); Cleveland Clinic, 859 F.3d
 at 1361 (relying on the patent’s disclosure of “commercially
 available testing kits” for detecting the natural law).
      Here, the claimed advance is not an improvement in
 the underlying DNA-processing technology, as hinted by
 the Majority. The written description identifies the
 claimed method steps as well-known or performed using
 commercially available tools or kits. See ’751 patent 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. For example, the table 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.

           Performance of Claimed Method Steps

                                    Commercially Available
      Claimed Method Step
                                        Tool or Kit

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

                                    Invitrogen 1% agarose gel
                                     (’751 patent 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 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 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 selection of 300 and 500 base pairs resulted from using
 commercially available DNA size-markers. See id. at col. 4
 ll. 3–9. The claimed DNA-processing technologies do not,
 therefore, constitute the claimed advance. See Cleveland
 Clinic, 859 F.3d at 1361.
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.               11

     The Majority relies on CellzDirect. See Maj. Op. at 12–
 13. But CellzDirect is different from this case. In CellzDi-
 rect, the inventors created a new and useful cryopreserva-
 tion technique comprising multiple freeze-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 CellzDirect, the claimed
 method steps here are not new nor are the claimed tech-
 niques used in a new or unconventional way. The Majority
 recognizes that the inventors “did not invent centrifuga-
 tion, chromatography, electrophoresis, or nanotechnol-
 ogy”—the claimed techniques described in the written
 description. Maj. Op. at 13.
          The Majority’s remaining reasoning fails
     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 10. On this basis, the Majority
 concludes that the claimed method in the patent “achieves
 more than simply observing that fetal DNA is shorter than
 maternal DNA, or detecting the presence of that phenome-
 non.” Id.
     The Majority’s reasoning is shortsighted. A process
 that merely changes the composition of a sample of natu-
 rally occurring substances, without altering the naturally
 occurring substances themselves, is not patent eligible. See
 Genetic Techs., 818 F.3d at 1374 (using PCR to amplify ge-
 nomic DNA in a sample before detecting it); Ariosa, 788
F.3d at 1373 (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. Cf., Myriad, 569 U.S. at 593 (“Myriad’s
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 12                 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

 claims are simply not expressed in terms of chemical com-
 position, nor do they rely in any way on the chemical
 changes that result from the isolation of a particular sec-
 tion of DNA.”).
      The Majority attempts to distinguish Myriad, reason-
 ing that the claims at issue in Myriad were not method
 claims. Maj. Op. at 12 (citing Myriad, 569 U.S. at 595).
 But I see no principled reason why, under the facts of this
 case, Myriad should or should not apply simply because
 this case presents a method claim and not a composition of
 matter claim. Whether the asserted claims recite a compo-
 sition of matter or a “method of preparation,” the purpose
 of § 101 remains the same, to safeguard against claims that
 monopolize a law of nature, natural phenomenon, or ab-
 stract idea. See Alice, 573 U.S. at 216 (“We have described
 the concern that drives this exclusionary principal as one
 of pre-emption.”).
     Because the patent’s claimed advance is the discovery
 of the natural phenomenon, the claims are directed to a
 natural phenomenon under the step one inquiry.
      B. The Claims Fail to Recite an Inventive Concept
     Step two of the Alice inquiry is a search for other ele-
 ments that transform the ineligible claims into signifi-
 cantly more than a patent upon the natural law or
 phenomenon. See Mayo Collaborative Servs. v. Prometheus
 Labs., Inc., 566 U.S. 66, 72–73. Mayo made clear that
 transformation 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.
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.                  13

     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 fail to 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. The written description indicates that the la-
 boratory techniques of the claimed method are commer-
 cially available techniques. And the written description
 explains that step (b)’s producing a fraction by size discrim-
 ination “can be brought about by a variety of methods.”
 ’751 patent col. 2 ll. 49–51.
     For step two purposes, that the size discrimination and
 selective removal method steps were never before applied
 to the newly discovered natural phenomenon does not ren-
 der those steps new and useful. 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 in-
 ventive concept notwithstanding that the inventors were
 the first to use PCR to detect the claimed natural phenom-
 enon. Id. We reasoned that the claims did not contain an
 inventive concept because they did not “disclose any ‘new
 and useful’ improvement to PCR protocols or DNA amplifi-
 cation techniques in general.” Id.; see also Athena, 915
F.3d at 754 (noting that “to supply an inventive concept the
 sequence of claimed steps must do more than adapt a con-
 ventional assay to a newly discovered natural law”).
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 14                 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.

    Like in Roche Molecular, the claimed method steps
 here do not disclose any new and useful improvement to
 DNA separation techniques. They do not disclose an un-
 conventional assay to the newly discovered natural phe-
 nomenon. Instead, they adapt 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 commer-
 cially available, routine, and conventional techniques as
 claim 1, only they provide more specificity on which tech-
 niques to use (e.g., ’751 patent, claim 7, identifies “density
 gradient centrifugation” for the claimed size discrimination
 method).
     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, under
 step two, the claims of the patent in this appeal that are
 directed to patent ineligible subject matter are not trans-
 formed and made eligible under Alice step two.
                       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 216–217. 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.
     Here, the claims are drafted in a manner that tie up
 future innovation 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 with denial of
 the petition for rehearing en banc) (“That claims 7 and 9 do
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 ILLUMINA, INC. v. ARIOSA DIAGNOSTICS, INC.               15

 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.”). Like 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.
     I do not doubt that process claims that involve natu-
 rally occurring phenomena from beginning to end could be
 directed to patent eligible subject matter, but this is not
 such a case.