Court Opinion

ID: 3192523
Source: CourtListenerOpinion
Date Created: 2016-04-08 15:01:19.130694+00
Date Added: 2024-06-11T14:36:12.242878
License: Public Domain

United States Court of Appeals
      for the Federal Circuit
                ______________________

       GENETIC TECHNOLOGIES LIMITED,
               Plaintiff-Appellant

                           v.

     MERIAL L.L.C., BRISTOL-MYERS SQUIBB
                   COMPANY,
               Defendants-Appellees
              ______________________

                 2015-1202, 2015-1203
                ______________________

    Appeals from the United States District Court for the
District of Delaware in Nos. 1:12-cv-00396-LPS, 1:12-cv-
00394-LPS Chief Judge Leonard P. Stark.
                 ______________________

                Decided: April 8, 2016
                ______________________

   BENJAMIN B. LIEB, Sheridan Ross, PC, Denver, CO,
argued for plaintiff-appellant. Also represented by
ROBERT R. BRUNELLI, HIWOT M. COVELL.

    GREGORY A. CASTANIAS, Jones Day, Washington, DC,
argued for defendant-appellee Merial L.L.C. Also repre-
sented by JOHN PATRICK ELSEVIER, PHILIP SHENG, San
Diego, CA; JUDY CATHERINE JARECKI-BLACK, Merial
Limited, Atlanta, GA.
2             GENETIC TECHNOLOGIES LIMITED   v. MERIAL L.L.C.

   AMY K. WIGMORE, Wilmer Cutler Pickering Hale and
Dorr LLP, Washington, DC, argued for defendant-
appellee Bristol-Myers Squibb Company. Also represented
by THOMAS SAUNDERS, TRACEY COTE ALLEN; WILLIAM F.
LEE, ALLISON TRZOP, Boston, MA.
                 ______________________

    Before PROST, Chief Judge, DYK, and TARANTO, Circuit
                          Judges.
DYK, Circuit Judge.
    Genetic Technologies Limited (“GTG”) brought suit
against Merial L.L.C. (“Merial”) and Bristol-Myers Squibb
(“BMS”) (together, “appellees”). GTG alleged that appel-
lees had infringed U.S. Patent No. 5,612,179 (“the ’179
patent”), which relates to methods of detecting genetic
variations. The district court granted appellees’ motions
to dismiss for failure to state a claim and entered final
judgment that claims 1–25 and 33–36 of the ’179 patent
are ineligible for patenting under 35 U.S.C. § 101. For
purposes of this appeal, the parties have stipulated that
claim 1 is representative of all of the invalidated claims.
Because we agree that claim 1 is directed to unpatentable
subject matter, we affirm.
                       BACKGROUND
     The ’179 patent claims methods of analyzing sequenc-
es of genomic deoxyribonucleic acid (“DNA”). Genetic
information is encoded in DNA, which carries instructions
for the development and function of all life. DNA se-
quences spell out instructions for synthesis of shorter
sequences of ribonucleic acid (“RNA”), which in turn
provide templates for synthesis of proteins. An individu-
al’s complete set of DNA is known as his genome, and a
particular sequence of DNA within the genome that codes
for a given protein (or functional RNA molecule) is re-
ferred to as a gene. Genes are the individual units defin-
GENETIC TECHNOLOGIES LIMITED   v. MERIAL L.L.C.           3

ing heredity, and a person’s overall collection of genes is
known as his genotype. The site on a chromosome occu-
pied by a particular gene is the genetic locus. Genes
typically contain both coding regions, called exons, and
non-coding regions, called introns. Exons are regions of
the DNA sequence of the gene that are expressed, i.e.,
ultimately “decoded” and translated into the protein
sequence. Introns are regions that are not expressed;
these regions do not code for protein.
    Each individual has his own unique genotype, inher-
ited from his two parents. Variation of the precise genetic
sequence within a particular gene among different people
is known as genetic polymorphism, and the various alter-
native forms (mutations) of the gene are referred to as
individual alleles. Detection of specific alleles can be
useful for a variety of purposes, including diagnosis and
treatment of genetic disorders and diseases correlated
with those alleles, e.g., sickle-cell anemia, hemophilia,
and cystic fibrosis.
    In the 1980s, Dr. Malcolm J. Simons, the named in-
ventor of the ’179 patent, working with GTG, 1 discovered
an interesting feature of genomic DNA. Dr. Simons
discovered that certain DNA sequences in coding regions
(exons) of certain genes are correlated with non-coding
regions (introns) within the same gene, non-coding re-
gions in different genes, or non-coding regions of the
genome that are not part of any gene. Non-coding DNA
regions between genes are referred to by the ’179 patent
as “intergenic spacing sequences” and have been referred
to colloquially as “junk DNA,” because, at least historical-

   1  Dr. Simons’s work was done for a predecessor
company, GeneType, AG. For simplicity we refer to both
GTG and GeneType as “GTG.”
4             GENETIC TECHNOLOGIES LIMITED    v. MERIAL L.L.C.

ly, they appeared to serve no function. ’179 patent col. 5
ll. 42–46.
     Dr. Simons found that the correlated coding and non-
coding regions tend to be inherited together, with only
rare shuffling. In other words, the regions are in “linkage
disequilibrium,” meaning that the coding and non-coding
regions appear “linked” together in individuals’ genomes
more often than probability would dictate. ’179 patent
col. 5 ll. 20–32; see also, e.g., Henderson’s Dictionary of
Biology 366 (14th ed. 2008) (“[L]inkage disequilibrium [is
a] condition in which certain alleles at two linked loci are
non-randomly associated with each other.”). The correlat-
ed coding and non-coding regions may be linked even
though the two sequences are located far apart from one
another on the chromosome.
    Dr. Simons concluded that alleles of a particular gene
may be detected, using well-established laboratory tech-
niques, not by looking for the coding region of the gene
itself but instead by amplifying and analyzing non-coding
regions known to be linked to the coding region. Between
1989 and 1992, Dr. Simons and GTG filed several patent
applications related to the discovery. One of these appli-
cations ultimately became the ’179 patent. Claim 1 of the
’179 patent recites:
    1. A method for detection of at least one coding re-
    gion allele of a multi-allelic genetic locus compris-
    ing:
        a) amplifying genomic DNA with a primer pair
    that spans a non-coding region sequence, said
    primer pair defining a DNA sequence which is in
    genetic linkage with said genetic locus and con-
    tains a sufficient number of non-coding region se-
    quence nucleotides to produce an amplified DNA
    sequence characteristic of said allele; and
GENETIC TECHNOLOGIES LIMITED   v. MERIAL L.L.C.          5

       b) analyzing the amplified DNA sequence to
   detect the allele.
’179 patent col. 59 ll. 57–67. Claim 1 is thus broad in
scope; it encompasses methods of detecting a coding
region allele by amplifying and analyzing any linked non-
coding region, which could be found within the same gene
as the coding region, within a different gene, or within an
intergenic region.
    According to GTG, the methods of the ’179 patent
have various advantages over prior art methods involving
direct analysis of a coding region. For example, GTG
stated that “analysis of relatively short regions of non-
coding sequences, of a size which can be amplified, can
provide more information than prior art analyses such as
cDNA RFLP analyses which involve the use of significant-
ly larger DNA sequences . . . .” ’179 Patent Prosecution
History, Applicant’s Amendment and Remarks of Jan. 14,
1993, at 6.
     In 2011, GTG sued several pharmaceutical and bio-
technology companies, including Merial and BMS, in the
United States District Court for the District of Colorado
for infringement of the ’179 patent. GTG’s claims against
Merial and BMS were severed and transferred to the
District of Delaware. GTG alleged infringement of at
least one claim of the ’179 patent and, in BMS’s case,
infringement of a second patent not at issue in this ap-
peal. Merial and BMS subsequently moved to dismiss
under Federal Rule of Civil Procedure 12(b)(6) (“Rule
12(b)(6)”) for failure to state a claim, arguing that the
claims of GTG’s patents covered ineligible subject matter
under 35 U.S.C. § 101.
    After briefing and oral argument, the district court
granted defendants’ motions, holding that claim 1 of the
’179 patent is invalid for claiming a law of nature, which
is patent-ineligible subject matter. “A claim is unpatent-
6            GENETIC TECHNOLOGIES LIMITED   v. MERIAL L.L.C.

able if it merely informs a relevant audience about certain
laws of nature, even newly-discovered ones, and any
additional steps collectively consist only of well-
understood, routine, conventional activity already en-
gaged in by the scientific community. The claim involved
here, claim 1 of the ’179 patent, does just that and no
more.” Genetic Techs. Ltd. v. Bristol-Myers Squibb Co., 72
F. Supp. 3d 521, 527 (D. Del. 2014) (citing Mayo Collabo-
rative Servs. v. Prometheus Labs., Inc., 132 S. Ct. 1289,
1298 (2012)). The district court did not evaluate the
validity of other claims of the ’179 patent under § 101,
noting that GTG had not specified which of those claims it
was asserting against Merial and BMS.
    GTG, Merial, and BMS subsequently stipulated that,
for purposes of appeal, claim 1 is representative of claims
2–25 and 33–36 of the ’179 patent with respect to eligibil-
ity under § 101. GTG also covenanted not to assert the
remaining claims, 26–32, of the ’179 patent. Upon the
parties’ request, the district court dismissed GTG’s in-
fringement claims against Merial and BMS and entered
judgment that claims 1–25 and 33–36 of the ’179 patent
are invalid for claiming unpatentable subject matter.
GTG appeals. We have jurisdiction under 28 U.S.C.
§ 1295(a)(1).
                       DISCUSSION
                             I
    We review de novo the dismissal for failure to state a
claim under Rule 12(b)(6). Content Extraction & Trans-
mission LLC v. Wells Fargo Bank, Nat’l Ass’n, 776 F.3d
1343, 1346 (Fed. Cir. 2014); Sands v. McCormick, 502
F.3d 263, 267 (3d Cir. 2007). Patent eligibility under
35 U.S.C. § 101 is a question of law that we review de
novo. OIP Techs., Inc. v. Amazon.com, Inc., 788 F.3d
1359, 1362 (Fed. Cir. 2015); Content Extraction, 776 F.3d
at 1346.
GENETIC TECHNOLOGIES LIMITED      v. MERIAL L.L.C.        7

    We have repeatedly recognized that in many cases it
is possible and proper to determine patent eligibility
under 35 U.S.C. § 101 on a Rule 12(b)(6) motion. See, e.g.,
OIP Techs., 788 F.3d at 1362; Content Extraction, 776
F.3d at 1351; buySAFE, Inc. v. Google, Inc., 765 F.3d
1350, 1355 (Fed. Cir. 2014). In many cases, too, evalua-
tion of a patent claim’s subject matter eligibility under
§ 101 can proceed even before a formal claim construction.
“[C]laim construction is not an inviolable prerequisite to a
validity determination under § 101.” Bancorp Servs.,
L.L.C. v. Sun Life Assurance Co. of Canada (U.S.), 687
F.3d 1266, 1273 (Fed. Cir. 2012); see also Content Extrac-
tion, 776 F.3d at 1349. Here, there is no claim construc-
tion dispute relevant to the eligibility issue.
                             II
    Section 101 establishes that “any new and useful pro-
cess, machine, manufacture, or composition of matter, or
any new and useful improvement thereof” may be eligible
for a patent, subject to the conditions and requirements of
the Patent Act. 35 U.S.C. § 101. But the Supreme Court
has “long held that this provision contains an important
implicit exception: Laws of nature, natural phenomena,
and abstract ideas are not patentable.” Ass’n for Molecu-
lar Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107,
2116 (2013) (quoting Mayo, 132 S. Ct. at 1293). “Phenom-
ena of nature, though just discovered, mental processes,
and abstract intellectual concepts are not patentable, as
they are the basic tools of scientific and technological
work.” Gottschalk v. Benson, 409 U.S. 63, 67 (1972).
“Groundbreaking, innovative, or even brilliant discovery
does not by itself satisfy the § 101 inquiry.” Myriad, 133
S. Ct. at 2117.
   In the past several years, most notably in its Mayo
and Alice decisions, the Supreme Court has articulated a
now well-established two-step test for patent eligibility
8             GENETIC TECHNOLOGIES LIMITED    v. MERIAL L.L.C.

under § 101. The test “distinguish[es] patents that claim
laws of nature, natural phenomena, and abstract ideas
from those that claim patent-eligible applications of those
concepts.” Alice Corp. Pty. Ltd. v. CLS Bank Int’l, 134 S.
Ct. 2347, 2355 (2014) (citing Mayo, 132 S. Ct. at 1296–97).
As set forth in Alice:
    First, we determine whether the claims at issue
    are directed to one of those patent-ineligible con-
    cepts. If so, we then ask, what else is there in the
    claims before us? . . . We have described step two
    of this analysis as a search for an inventive con-
    cept—i.e., an element or combination of elements
    that is sufficient to ensure that the patent in prac-
    tice amounts to significantly more than a patent
    upon the ineligible concept itself.
Id. (alterations, citations, and quotation marks omitted).
    As noted above, claim 1 of the ’179 patent is the only
claim before us. We begin at step one of the Mayo/Alice
test and ask first whether claim 1 is directed to a patent-
ineligible concept—e.g., a law of nature, natural phenom-
enon, or abstract idea. Alice, 134 S. Ct. at 2355. We find
that it is. Claim 1 is directed to the relationship between
non-coding and coding sequences in linkage disequilibri-
um and the tendency of such non-coding DNA sequences
to be representative of the linked coding sequences—a law
of nature.
    Claim 1 recites a method of detecting an allele of in-
terest at a multi-allelic locus (i.e., a location on the chro-
mosome where multiple variations of a particular gene
are known) by amplifying a sequence of non-coding region
DNA known to be linked with the allele and then analyz-
ing the non-coding region to detect the allele. In some-
what plainer terms, claim 1 covers a method of detecting
a coding region of a person’s genome by amplifying and
GENETIC TECHNOLOGIES LIMITED     v. MERIAL L.L.C.             9

analyzing a linked non-coding region of that person’s
genome.
     Claim 1 covers any comparison, for any purpose, of
any non-coding region sequence known to be linked with a
coding region allele at a multi-allelic locus. The ’179
patent states that “[t]he method can be used to detect
alleles of genetic loci for any eukaryotic organism,” ’179
patent col. 4 ll. 12–13, and “is generally applicable to
detection of any type of genetic trait,” id. at col. 46 ll. 8–9.
The ’179 patent does not limit its scope to methods of
detecting any particular alleles linked to any particular
non-coding sequences, although the specification does
provide some examples of linked alleles known to be
diagnostic of inherited diseases such as cystic fibrosis and
muscular dystrophy. See generally, ’179 patent col. 43
l. 43–col. 46 l. 6. Claim 1 broadly covers essentially all
applications, via standard experimental techniques, of the
law of linkage disequilibrium to the problem of detecting
coding sequences of DNA.
    The product of the method of claim 1 is information
about a patient’s natural genetic makeup—at least one
coding region allele. The claim relies on the existence of
linkage disequilibrium between the non-coding and coding
regions—i.e., the tendency of these regions to be linked.
Linkage disequilibrium is indisputably a universal,
inherent feature of human DNA, and the ’179 patent itself
notes that the claims are based on this fact. “The present
invention is based on the discovery that amplification of
intron sequences that exhibit linkage disequilibrium with
adjacent and remote loci can be used to detect alleles of
those loci.” ’179 patent col. 4 ll. 28–31.
    Claim 1 of the ’179 patent is in this respect quite simi-
lar to the claims invalidated in Mayo itself. In Mayo, the
Supreme Court considered method claims that likewise
required analysis of a biological sample (the blood of a
10            GENETIC TECHNOLOGIES LIMITED   v. MERIAL L.L.C.

patient being treated with a thiopurine drug) and in
which the focus of the claimed advance over the prior art
was allegedly newly discovered information about human
biology: the likelihood that a patient could suffer toxic
side effects from particular doses of the drug. Mayo, 132
S. Ct. at 1296–97. “Claim 1, for example, states that if
the levels of 6-TG in the blood (of a patient who has taken
a dose of a thiopurine drug) exceed about 400 pmol per
8 x 108 red blood cells, then the administered dose is likely
to produce toxic side effects.” Id. The Court concluded
that the claims were necessarily directed to an underlying
law of nature or natural phenomenon, even if implemen-
tation of the method involves substantial human labor
and ingenuity:
     While it takes a human action (the administration
     of a thiopurine drug) to trigger a manifestation of
     this relation in a particular person, the relation
     itself exists in principle apart from any human ac-
     tion. The relation is a consequence of the ways in
     which thiopurine compounds are metabolized by
     the body—entirely natural processes. And so a
     patent that simply describes that relation sets
     forth a natural law.
Id. at 1297. We agree with the district court that “just as
the relationship at issue in Mayo was entirely a conse-
quence of the body’s natural processes for metabolizing
thiopurine, so too is the correlation here (between varia-
tions in the non-coding regions and allele presence in the
coding regions) a consequence of the naturally occurring
linkages in the DNA sequence.” Genetic Techs., 72
F. Supp. 3d at 530.
    In our court’s recent Ariosa v. Sequenom decision, we
considered genetic testing method claims remarkably
similar to the claim here and found, at step one of the
Mayo/Alice test, that they too were directed to unpatenta-
GENETIC TECHNOLOGIES LIMITED   v. MERIAL L.L.C.           11

ble subject matter. Ariosa Diagnostics, Inc. v. Sequenom,
Inc., 788 F.3d 1371, 1373–74, 1376 (Fed. Cir. 2015). The
claims in Ariosa covered a method of detecting fetal DNA
by amplifying and analyzing cell-free fetal DNA
(“cffDNA”) sampled from a pregnant woman’s blood. Id.
at 1373–74. The court found that “the claims are directed
to matter that is naturally occurring” and that the inven-
tors there did not purport to “create[] or alter[] any of the
genetic information encoded in the cffDNA.” Id. at 1376.
The focus of the claimed advance over the prior art was
allegedly newly discovered information about human
biology: paternally inherited cffDNA is to be found in
maternal blood (using established detection techniques).
So too in the present case: the patent claim focuses on a
newly discovered fact about human biology (the linkage of
coding and non-coding regions of DNA), involves no crea-
tion or alteration of DNA sequences, and does not purport
to identify novel detection techniques.
    The similarity of claim 1 to the claims evaluated in
Mayo and Ariosa requires the conclusion that claim 1 is
directed to a law of nature. The sole function of the
“primer pair defining a DNA sequence which is in genetic
linkage with [a multi-allelic] genetic locus” is to amplify a
sequence of non-coding DNA in linkage disequilibrium
with a sequence of coding DNA of interest. ’179 patent
col. 59 ll. 60–62. “The method comprises amplifying
genomic DNA with a primer pair that spans an intron
sequence and defines a DNA sequence in genetic linkage
with an allele to be detected.” Id. at col. 4 ll. 37–39. The
claim is directed to a natural law—the principle that
certain non-coding and coding sequences are in linkage
disequilibrium with one another. 2 We hold that claim 1 is

    2  At various points in its briefs, GTG appears to
concede that claim 1 is directed to a law of nature. See,
12            GENETIC TECHNOLOGIES LIMITED   v. MERIAL L.L.C.

directed to unpatentable subject matter at the first step of
the Mayo/Alice test.
                               III
    We thus proceed to step two of the Mayo/Alice analy-
sis. At step two, after identifying a claim directed to
unpatentable subject matter, “we must examine the
elements of the claim to determine whether it contains an
inventive concept sufficient to transform the claimed
abstract idea [or law of nature] into a patent-eligible
application.” Alice, 134 S. Ct. at 2357 (internal quotation
marks omitted) (citing Mayo, 132 S. Ct. at 1294, 1298).
“The question . . . is whether the claims do significantly
more than simply describe [a] natural relation[].” Mayo,
132 S. Ct. at 1297. The inventive concept necessary at
step two of the Mayo/Alice analysis cannot be furnished
by the unpatentable law of nature (or natural phenome-
non or abstract idea) itself. That is, under the Mayo/Alice
framework, a claim directed to a newly discovered law of
nature (or natural phenomenon or abstract idea) cannot
rely on the novelty of that discovery for the inventive
concept necessary for patent eligibility; instead, the
application must provide something inventive, beyond
mere “well-understood, routine, conventional activity.”
Mayo, 132 S. Ct. at 1294; see also Myriad, 133 S. Ct. at
2117; Ariosa, 788 F.3d at 1379. “[S]imply appending

e.g., Appellant’s Br. at 8 (“The District Court found that
the Discovery was a natural phenomenon: ‘The correla-
tions between variations in non-coding regions of DNA—
formerly known as “junk DNA”—and variations in coding
regions of DNA—specifically, alleles—are natural phe-
nomena. . . .’ [T]his finding is correct . . . .”); id. at 17
(“[T]he natural phenomenon underlying Claim 1 is the
Discovery [of linkage disequilibrium between coding and
non-coding regions] . . . .”).
GENETIC TECHNOLOGIES LIMITED       v. MERIAL L.L.C.           13

conventional steps, specified at a high level of generality,
to laws of nature, natural phenomena, and abstract ideas
cannot make those laws, phenomena, and ideas patenta-
ble.” Mayo, 132 S. Ct. at 1300. Claims directed to laws of
nature are ineligible for patent protection when, “(apart
from the natural laws themselves) [they] involve well-
understood, routine, conventional activity previously
engaged in by researchers in the field.” Mayo, 132 S. Ct.
at 1294.
    We conclude that the additional elements of claim 1
are insufficient to provide the inventive concept necessary
to render the claim patent-eligible.
                               A
    We look first at the physical steps by which claim 1
implements the natural law of linkage disequilibrium
between coding and non-coding regions to determine
whether they provide more than “well-understood, rou-
tine, conventional activity” already engaged in by those in
the field. Id. Claim 1 contains two implementation steps,
“amplifying genomic DNA with a primer pair” and “ana-
lyzing the amplified DNA sequence to detect the allele.”
’179 patent col. 59 ll. 57–67.
    The first claimed step of “amplifying” genomic DNA
with a primer pair was indisputably well known, routine,
and conventional in the field of molecular biology as of
1989, when the first precursor application to the ’179
patent was filed. GTG concedes that “[t]he general labor-
atory technique of primer pair amplification of DNA,
admittedly, was known as of the Filing Date.” Appellant’s
Br. at 4. The ’179 patent repeatedly characterizes primer
pair amplification as prior art. “The method is commonly
referred to as the polymerase chain reaction sequence
amplification method or PCR.” ’179 patent col. 2 ll. 53–
55; see also id. at col. 3 ll. 5–8 and ll. 39–45 (listing specif-
ic primer pair amplification techniques known in the art);
14            GENETIC TECHNOLOGIES LIMITED    v. MERIAL L.L.C.

col. 12 ll. 47–64 (same). To overcome an examiner’s claim
rejection for lack of enablement under 35 U.S.C. § 112,
GTG expressly argued during prosecution of the ’179
patent        that    “amplification . . . [was   a]     tech-
nique[] . . . readily practiced by those in skill at the time
the application was filed.” ’179 Patent Prosecution Histo-
ry, Applicant’s Amendment and Remarks of Jan. 14, 1993,
at 7–8.
     The second physical implementation step, “analyzing”
amplified DNA to provide a user with information about
the amplified DNA, including its sequence, was also
clearly well known, routine, and conventional at the time
the ’179 patent was filed.           GTG concedes that
“[t]echniques to analyze amplified DNA were . . . admit-
tedly known.” Appellant’s Br. at 4. Moreover, the Back-
ground section of the ’179 patent acknowledges as prior
art the claimed two-step combination of amplification of
DNA and subsequent analysis of its sequence. “A number
of techniques have been employed to detect allelic vari-
ants of genetic loci including analysis of restriction frag-
ment length polymorphic (RFLP) patterns, use of
oligonucleotide probes, and DNA amplification methods.”
’179 patent col. 1 ll. 50–53; see also col. 10 ll. 6–34 (dis-
cussing methods of analyzing amplified DNA, including
“sequencing the amplified DNA sequence”). GTG granted
during prosecution of the ’179 patent that it did not
invent any new physical techniques. “Applicant has not
invented a new way to analyze genetic loci. Rather Appli-
cant has found that when prior art techniques are applied
to the non-coding sequences, the result can be more
informative than analysis of the coding regions.” ’179
Patent Prosecution History, Applicant’s Amendment and
Remarks of Jan. 14, 1993, at 6.
   Thus the physical steps of DNA amplification and
analysis of the amplified DNA to provide a user with the
sequence of the non-coding region do not, individually or
GENETIC TECHNOLOGIES LIMITED      v. MERIAL L.L.C.         15

in combination, provide sufficient inventive concept to
render claim 1 patent eligible. 3 In this regard, claim 1 of
the ’179 patent is directly comparable to the claims inval-
idated in Ariosa. Ariosa, 788 F.3d at 1377 (“Using meth-
ods like PCR to amplify and detect cffDNA was well-
understood, routine, and conventional activity in 1997.”).
                              B
     GTG argues that claim 1 provides more: once the non-
coding DNA has been amplified and sequenced, an in-
struction to users to “analyz[e] the amplified DNA se-
quence to detect the [coding region] allele.” ’179 patent
col. 59 ll. 66–67 (emphasis added). “[T]he analysis limita-
tion of Claim 1 requires that analysis to be performed
upon the amplified, i.e., man-made, non-coding DNA to
detect the coding region allele. [This and other] limita-
tions do not recite the Discovery [of linkage disequilibri-
um between coding and non-coding regions] or the
Observation [of using a non-coding polymorphism to learn
about a coding region allele] . . . .” Appellant’s Reply Br.
at 15. GTG argues that, at the time the ’179 patent was

    3   We are not persuaded by GTG’s arguments that
claim 1 is inventive because it involves analysis of man-
made amplified DNA. While the man-made amplified
non-coding DNA may have an “altered methylation sta-
tus,” Appellant’s Br. at 22, its sequence is identical to that
of naturally occurring DNA, unlike the cDNA held to be
patent-eligible in Myriad, 133 S. Ct. at 2119. As with the
claims to genomic DNA invalidated in Myriad, claim 1 “is
concerned primarily with the information contained in the
genetic sequence, not with the specific chemical composi-
tion of a particular molecule,” and any minor chemical
differences are irrelevant. Id. at 2118; see also In re
Roslin Inst. (Edinburgh), 750 F.3d 1333, 1337 (Fed. Cir.
2014).
16            GENETIC TECHNOLOGIES LIMITED   v. MERIAL L.L.C.

filed, “no one had before analyzed man-made non-coding
DNA in order to detect a coding region allele,” and that
this additional feature, at least, provides sufficient in-
ventive concept to pass step two of the Mayo/Alice test.
Appellant’s Br. at 4.
    We disagree. The term “to detect the allele” (in the
sense of examining the non-coding region to detect an
allele in the coding region) is a mental process step, one
that provides claim 1 with a purpose but does not create
the requisite inventive concept, because it merely sets
forth a routine comparison that can be performed by the
human mind. As we held in Cybersource, “[m]ethods
which can be performed entirely in the human mind are
unpatentable not because there is anything wrong with
claiming mental method steps as part of a process con-
taining non-mental steps, but rather because computa-
tional methods which can be performed entirely in the
human mind are the types of methods that embody the
‘basic tools of scientific and technological work’ that are
free to all men and reserved exclusively to none.” Cyber-
Source Corp. v. Retail Decisions, Inc., 654 F.3d 1366, 1373
(Fed. Cir. 2011) (citing Benson, 409 U.S. at 67); see also
Diamond v. Diehr, 450 U.S. 175, 187 (1981); SmartGene,
Inc. v. Advanced Biological Labs., SA, 555 F. App’x 950,
955 (Fed. Cir. 2014).
     Mayo itself considered and rejected diagnostic and
therapeutic method claims that combined routine and
conventional physical implementation of a law of nature
with a simple mental process step. An exemplary claim
evaluated in Mayo recited “[a] method of optimizing
therapeutic efficacy for treatment of [a] gastrointestinal
disorder, comprising: (a) administering a [thiopurine]
drug . . . and (b) determining the level of [a metabo-
lite] . . . wherein” a certain low metabolite level indicated
a need to increase drug dosage and a certain high metabo-
lite level indicated a need to decrease drug dosage. Mayo,
GENETIC TECHNOLOGIES LIMITED    v. MERIAL L.L.C.           17
132 S. Ct. at 1295. Mayo held that the “‘wherein’ clauses
simply tell a doctor about the relevant natural laws, at
most adding a suggestion that he should take those laws
into account when treating his patient.” Id. at 1297.
That is, “these clauses tell the relevant audience about
the laws while trusting them to use those laws appropri-
ately where they are relevant to their decisionmaking
(rather like Einstein telling linear accelerator operators
about his basic law and then trusting them to use it
where relevant).” Id.
     Here, the phrase “to detect the allele” in claim 1 of the
’179 patent also merely informs the relevant audience—
e.g., doctors or others seeking to make a genetic diagno-
sis—to apply a law of nature for a purpose—detecting a
polymorphism within a coding region of an allele of inter-
est. The limitation “to detect the allele” merely asks the
user to compare the non-coding sequence he has amplified
and analyzed with a library of non-coding sequences
known to be in linkage disequilibrium with certain coding
region alleles. This instruction to undertake a simple
comparison step does not represent an unconventional,
inventive application sufficient to make the claim patent-
eligible. “[T]o transform an unpatentable law of nature
into a patent-eligible application of such a law, one must
do more than simply state the law of nature while adding
the words ‘apply it.’” Mayo, 132 S. Ct. at 1294 (citing
Benson, 409 U.S. at 71–72).
    Ariosa is again relevant. The claims challenged and
invalidated in Ariosa included claims 21 and 25 of U.S.
Patent No. 6,258,540, methods of “performing a prenatal
diagnosis.” Ariosa, 788 F.3d at 1374. To various routine
and conventional steps of physical implementation (am-
plifying DNA in a blood sample and then performing
analysis of that DNA to detect DNA of a particular
origin), these claims also added a mental process step
(performing a prenatal diagnosis based on the DNA
18           GENETIC TECHNOLOGIES LIMITED    v. MERIAL L.L.C.

detected). The mental process of “performing a prenatal
diagnosis” based on the DNA detected is directly compa-
rable to claim 1’s mental process of detecting the allele.
The addition of this mental process step to the routine
and conventional physical activity of amplification and
analysis of DNA did not distinguish claims 21 and 25,
which were invalidated with the other claims of the ’540
patent. Ariosa, 788 F.3d at 1378.
    Our decision in In re BRCA1- & BRCA2-Based Hered-
itary Cancer Test, 774 F.3d 755 (Fed. Cir. 2014), is also
instructive. Claim 8 of U.S. Patent No. 5,753,441 evalu-
ated in that case recited a method of screening for altera-
tions of the BRCA1 gene that included the steps of
“amplifying all or part of a BRCA1 gene from [a] sample
using a set of primers to produce amplified nucleic acids
and sequencing the amplified nucleic acids” and “compar-
ing” the sequence with wild-type BRCA1. Id. at 761–62.
We held that claim to be invalid because it was directed to
an abstract idea and did not add enough to distinguish it
from a claim to the abstract idea. Id. at 762–65. An
aspect of our analysis there supports our analysis of the
law-of-nature issue here. We noted that “[t]he non-
patent-ineligible elements of claim[] . . . 8 do not add
‘enough’ to make the claim[] as a whole patent-
eligible. . . . The [physical implementation steps] of
claim[] . . . 8 do nothing more than spell out what practi-
tioners already knew—how to compare gene sequences
using routine, ordinary techniques.” Id. at 764. Claim 8,
which combined conventional physical implementation of
a law of genetics with a simple mental process step of
“comparing,” was held to be patent-ineligible. Id. at 765.
    To be sure, it seems to be true, as GTG alleges, that at
the time the ’179 patent was filed, no one was “using the
non-coding sequence as a surrogate marker for the coding
region allele.” Appellant’s Reply Br. at 7. Claim 1 was
found by the patent examiner to be novel over the prior
GENETIC TECHNOLOGIES LIMITED   v. MERIAL L.L.C.           19

art and survived multiple rounds of reexamination. But
the novelty of looking to non-coding DNA to detect a
coding region allele of interest resides in the novelty of
the newly discovered natural law of linkage disequilibri-
um between coding and non-coding regions and adds little
more than a restatement of the natural law itself. We
thus hold that the simple mental process step of “de-
tect[ing] the allele” in claim 1, either alone or in combina-
tion with the physical steps described above, does not
supply sufficient inventive concept to make the claim
patent-eligible under § 101.
    As a final matter, we note that GTG’s attempts to dis-
tinguish this case on the ground that the method of claim
1 is useful have no basis in case law or in logic. Claim 1
stands rejected under § 101 as ineligible for claiming
unpatentable subject matter, not for lack of utility. The
method claims of Mayo and Ariosa were apparently also
useful, and also invalid. Mayo, 132 S. Ct. at 1294 (“[This
case] concerns patent claims covering processes that help
doctors who use thiopurine drugs to treat patients with
autoimmune diseases determine whether a given dosage
level is too low or too high.”); Ariosa, 788 F.3d at 1380
(“We do not disagree that detecting cffDNA in maternal
plasma or serum that before was discarded as waste
material is a positive and valuable contribution to science.
But even such valuable contributions can fall short of
statutory patentable subject matter, as it does here.”)
Utility is not the test for patent-eligible subject matter.
See Bilski, 561 U.S. at 659 (Breyer, J., concurring).
                       CONCLUSION
    For the foregoing reasons, we hold that claim 1 of the
’179 is invalid under 35 U.S.C. § 101 as directed to patent-
ineligible subject matter. We therefore affirm the district
court’s grant of appellees’ motions to dismiss under Rule
12(b)(6).
20            GENETIC TECHNOLOGIES LIMITED   v. MERIAL L.L.C.

                           AFFIRMED
                             COSTS
     Costs to appellees.