Document ID: s3://data.kl3m.ai/documents/govinfo/USCOURTS/USCOURTS-ca13-19-01419/USCOURTS-ca13-19-01419-0/pdf.json

Parties Involved:
Ariosa Diagnostics, Inc.
Appellee
Illumina, Inc.
Appellant
Roche Molecular Systems, Inc.
Appellee
Roche Sequencing Solutions, Inc.
Appellee
Sequenom, Inc.
Appellant

Document Text:

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, Redwood 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. Defendant-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 Systems, 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, “Illumina”) 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 patent”) 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 directed 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 discovered 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 Diagnostics, 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 cellfree 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 directed to “matter that is naturally occurring”—i.e., the 

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natural phenomenon that cell-free fetal DNA exists in maternal blood. Id. at 1376.

The present case involves two patents that are unrelated 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 specifications, 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 present in the maternal circulation and can be detected in maternal plasma . . . .” ’751 patent col. 1 ll. 23–25. The 

patents then identify a problem that was the subject of further research on cell-free fetal DNA in maternal blood: 

[T]he major proportion (generally >90%) of the extracellular DNA in the maternal circulation is derived from the mother. This vast bulk of maternal 

circulatory extracellular DNA renders it difficult, if 

not impossible, to determine fetal genetic alternations [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 bloodstream, there was no known way to distinguish and separate 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 discovery:

An examination of circulatory extracellular fetal 

DNA and circulatory extracellular maternal DNA 

in maternal plasma has now shown that, surprisingly, the majority of the circulatory extracellular 

fetal DNA has a relatively small size of 

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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. col. 1 ll. 54–61. Having made that discovery, they used 

it to develop a solution to the identified problem of distinguishing fetal DNA from maternal DNA in the mother’s 

bloodstream:

This surprising finding forms the basis of the present invention according to which separation of circulatory extracellular DNA fragments which are 

smaller than approximately 500 base pairs provides a possibility to enrich for fetal DNA sequences 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 preparing a fraction of cell-free DNA that is enriched in fetal 

DNA. Claim 1 is the only independent claim in each patent:

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 pregnant human female to obtain extracellular circulatory fetal and maternal DNA fragments;

(b) producing a fraction of the DNA extracted in 

(a) by:

(i) size discrimination of extracellular circulatory 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 circulatory 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 fetal DNA fragments from a substantially cell-free 

sample of blood plasma or blood serum of a pregnant human female;

(b) producing a fraction of the DNA extracted in 

(a) by:

(i) size discrimination of extracellular circulatory 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 extracellular 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 limitations on the size discrimination and selective removal processes 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 centrifugation.” ’751 patent col. 9 ll. 1–4. Likewise, dependent 

claims 4–10 of the ’931 patent recite that step (b) can comprise “chromatography,” “electrophoresis,” “centrifugation,” 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. Decision, 356 F. Supp. 3d at 935. The court entered judgment 

in favor of Roche, and Illumina appealed. We have jurisdiction 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 judgment 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 discovers 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 “Congress intended 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 

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 principle could eviscerate patent law.” Id. 

Laws of nature and natural phenomena are not patentable, but applications and uses of such laws and phenomena 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 patentable. 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 nature 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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examine whether the limitations of the claim apart from 

the law of nature or natural phenomenon, considered individually and as an ordered combination, “‘transform the 

nature of the claim’ into a patent-eligible application.” Id.

(quoting Mayo, 566 U.S. at 78).

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 matter. 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 Diagnostics, 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 Compounds, 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 Alice/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 identify 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 phenomenon, i.e., whether they claim the discovered natural phenomenon 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 distribution” 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 dividing 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.” Appellant’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 basis of its challenge. But, ultimately, we find that the parties’ respective articulations reflect distinctions without 

differences. For simplicity, we adopt Illumina’s articulation 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 “directed to” that natural phenomenon. We conclude that the 

claims are not directed to that natural phenomenon but rather to a patent-eligible method that utilizes it. 

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The claims in this case are directed to methods for preparing a fraction of cell-free DNA that is enriched in fetal 

DNA. The methods include specific process steps—size discriminating and selectively removing DNA fragments that 

are above a specified size threshold—to increase the relative 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 phenomenon.

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 patent col. 9 ll. 1–4; ’931 patent col. 9 ll. 9–12. Other dependent 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 specification’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 chromatography on agarose or polyacrylamide gels, ionpair reversed-phase high performance liquid chromatography [], capillary electrophoresis in a selfcoating, low-viscosity polymer matrix [], selective 

extraction in microfabricated electrophoresis devices [], microchip electrophoresis on reduced 

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viscosity polymer matrices [], adsorptive membrane chromatography [] and the like; density gradient 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 corresponding to specific DNA sizes . . . .”). As described by 

the specification, the inventors used these concrete process 

steps, not merely to observe the presence of the phenomenon that fetal DNA is shorter than maternal DNA, but rather 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 “detecting [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 essence, 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 cellCase: 19-1419 Document: 55 Page: 11 Filed: 03/17/2020
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free DNA that is enriched in fetal DNA. 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 decision in Association for Molecular Pathology v. Myriad Genetics, 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 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 before 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 Myriad 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 comprises freezing hepatocytes, thawing the hepatocytes, removing 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 survive multiple freeze-thaw cycles. Rather, the claims are 

directed to a new and useful method of preserving hepatocyte 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 exploited that phenomenon in a patent-eligible method. So 

too here, the inventors of the ’751 and ’931 patents obviously did not invent cell-free fetal DNA or the relative size 

distribution of fetal and maternal cell-free DNA in maternal 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 discriminating and selectively removing DNA fragments that are used 

to practice the invention were well-known and conventional. 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 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 

1 We note, without deciding, that Illumina argues 

that claim 11 of the ’931 patent requires the use of microarrays, which it claims was a methodology not previously 

used with cell-free DNA. Appellant’s Br. 40. 

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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 invent and what they claimed in their patents: methods for 

preparing a fraction of cell-free DNA by the physical process of size discriminating and selectively removing DNA 

fragments longer than a specified threshold. Those methods are “directed to” more than merely the natural phenomenon 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 “created an alternative for prenatal diagnosis of fetal DNA that 

avoids the risks of widely-used techniques that took samples 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 significant it was to the medical field, was not itself patentable, and neither was a method for detecting it. Id. at 1379–

80.

The invention in this case is the product of further research on cell-free fetal DNA. This time, the inventors discovered that, not only does the fetal DNA exist in the 

bloodstream of a pregnant mother, but it has characteristics 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 phenomenon 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 fragments of cell-free DNA and thus enrich a mixture in cellfree 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 patents 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 proceedings.

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 Majority holds that the asserted patents are directed to patent-eligible subject matter. I respectfully disagree and dissent. I conclude that the claims are directed 

to a natural phenomenon. The patents’ only claimed advance is the discovery of that natural phenomenon. The

claims, the written description, and the legal precedent applicable to this case all support the conclusion that the patents are ineligible.

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

I. The ’751 and ’931 Patents1

At the time of the invention, skilled artisans knew that 

cell-free fetal DNA (“cff-DNA”) existed, that it could be detected 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 phenomenon: 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 explains 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 patents contain nearly identical written descriptions and 

claims. For economy, this opinion will reference only the 

’751 patent.

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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 captured in Table 1, demonstrate 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 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 following method:

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 pregnant human female to obtain 

extracellular circulatory fetal and maternal DNA fragments;

(b) producing a fraction of the DNA extracted in (a) by:

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(i) size discrimination of extracellular circulatory 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 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 detection 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 detection 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 preparation.”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 preamble “[a] method of producing a desired preparation”). 

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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 preparation case” is treated no differently than any other process 

claim under our law. 

35 U.S.C. § 101 grants patent rights to “[w]hoever invents 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 Pathology 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 monopolizes 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”—“transform the nature of the claim” into a patent-eligible application. Id.

3 Athena Diagnostics, Inc. v. Mayo Collaborative 

Servs., LLC, 915 F.3d 743 (Fed. Cir. 2019); Roche Molecular 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 Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371 (Fed. 

Cir. 2015). 4 The term “process,” as recited in § 101, encompasses 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 because the patent’s claimed advance is the discovery of that 

natural phenomenon. The Majority disregards well-established precedent for conducting the Alice, step one, “directed 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 determination, the Court analyzed whether the claims “involved” 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” aspect of the invention or that the invention is “based on the 

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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 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 a natural 

law” based 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 natural 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’ “surprising[]” 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 identifies the natural phenomenon as the only “surprising finding.” Id. at col. 1 l. 54–col. 2 l. 6. And the patent explains 

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 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 substance, 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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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 naturally occurring substances, including cff-DNA. ’751 patent 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 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. The claimed method is therefore directed 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 conclusion, the claims here are not directed to “a patent-eligible 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 advance. 

Instead, the Majority only seems to suggest that the 

claimed advance is an improvement in “size discriminat[ion]” and “selective[] remov[al]” techniques. See id. at 

9–10. The Majority reasons that the inventors used “specific 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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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 therefore 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

Claimed Method Step Commercially Available 

Tool or Kit

Claim 1(a), “extracting 

DNA”

QIAgen Maxi kit 

(’751 patent col. 3 ll. 49–

50)

Claim 1(b)(i), “size discrimination”

Claim 1(b)(ii), “selectively removing”

Invitrogen 1% agarose gel

(’751 patent col. 3 ll. 66–

67)

New England Biolabs 100 

base pair ladder

(id. at col. 4 ll. 4–5)

Lamda Hind III digest

(’751 patent col. 4 ll. 5–6)

QIAEX Gel Extraction 

kit

(id. at col. 4 ll. 10–12)

Step (c), “analyzing a genetic locus”

Applied Biosystems (ABI)

7000 Sequence Detection 

System

(’751 patent col. 4 ll. 14–

38)

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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The Majority relies on CellzDirect. See Maj. Op. at 12–

13. But CellzDirect is different from this case. In CellzDirect, the inventors created a new and useful cryopreservation 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 natural phenomenon and, instead, created an entirely new laboratory technique. Id. Unlike CellzDirect, the claimed 

method steps here are not new nor are the claimed techniques used in a new or unconventional way. The Majority 

recognizes that the inventors “did not invent centrifugation, chromatography, electrophoresis, or nanotechnology”—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 phenomenon.” Id. 

The Majority’s reasoning is shortsighted. A process 

that merely changes the composition of a sample of naturally 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 genomic 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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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 attempts to distinguish Myriad, reasoning 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 composition 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 abstract 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 elements that transform the ineligible claims into significantly 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 transforms the nature of the claim into a patent-eligible application. Id. at 77; Ariosa, 788 F.3d at 1377. 

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For method claims that encompass natural phenomena, 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 algorithm, 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 application 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) producing a fraction of DNA by size discrimination, and (c) analyzing a genetic locus are not new, either alone or in 

combination. The written description indicates that the laboratory techniques of the claimed method are commercially available techniques. And the written description 

explains that step (b)’s producing a fraction by size discrimination “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 render 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 inventive concept notwithstanding that the inventors were 

the first to use PCR to detect the claimed natural phenomenon. 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 amplification 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 conventional assay to a newly discovered natural law”).

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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 unconventional assay to the newly discovered natural phenomenon. 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 commercially available, routine, and conventional techniques as 

claim 1, only they provide more specificity on which techniques 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 natural 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 transformed 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 patentability. Alice, 573 U.S. at 216–217. As Mayo emphasized, “there is a danger that the grant of patents that tie 

up the[] use [of laws of nature] will inhibit future innovation 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 artisan could isolate or enrich cff-DNA using some unclaimed 

technique is not dispositive for preemption. See Athena Diagnostics, 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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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 naturally occurring phenomena from beginning to end could be 

directed to patent eligible subject matter, but this is not 

such a case.

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