Ravgen, Inc.

Patent Trials and Appeals Board

Oct 19, 2021

IPR2021-00789 (P.T.A.B. Oct. 19, 2021)

Trials@uspto.gov Paper 21
571-272-7822 Date: October 19, 2021

UNITED STATES PATENT AND TRADEMARK OFFICE
____________

BEFORE THE PATENT TRIAL AND APPEAL BOARD
____________

QUEST DIAGNOSTICS INCORPORATED,
Petitioner,

v.

RAVGEN, INC.,
Patent Owner.
____________

IPR2021-00789
Patent 7,332,277 B2
____________

Before ZHENYU YANG, TIMOTHY G. MAJORS, and DAVID COTTA,
Administrative Patent Judges.

MAJORS, Administrative Patent Judge.

DECISION
Denying Institution of Inter Partes Review
35 U.S.C. § 314
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I. INTRODUCTION
Quest Diagnostics Incorporated (“Petitioner” or “Quest”),1 on April
19, 2021, filed a Petition to institute inter partes review of claims 1–7, 49–
54, 116–124, and 134–137 of U.S. Patent No. 7,332,277 B2 (Ex. 1101, “the
’277 patent”). Paper 4 (“Pet.” or “Petition”). Ravgen, Inc. (“Patent
Owner”)2 filed a Preliminary Response. Paper 9 (“Prelim. Resp.”). With
our authorization, Petitioner and Patent Owner filed a respective Preliminary
Reply and Preliminary Sur-Reply addressing certain matters raised in the
Preliminary Response. Paper 15 (Order authorizing briefing); Paper 17
(“Prelim. Reply”); Paper 18 (“Prelim. Sur-Reply”).
Under 35 U.S.C. § 314(a), inter partes review may not be instituted
unless the Petition “shows that there is a reasonable likelihood that the
petitioner would prevail with respect to at least 1 of the claims challenged in
the petition.” Petitioner has not on this record established a reasonable
likelihood of prevailing on the grounds advanced here. Thus, for reasons
explained below, we do not institute inter partes review of claims 1–7, 49–
54, 116–124, and 134–137 of the ’277 patent.
A. Related Patents & Proceedings
The ’277 patent issued February 19, 2008, from U.S. Patent
Application No. 10/661,165 (“the ’165 Application”), filed September 11,
2003. Ex. 1101, codes (21), (22), (45). The ’165 Application is a
continuation-in-part of Application No. PCT/US03/06198, filed February

1 Petitioner identifies itself as the real party-in-interest. Pet. 5.
2 Patent Owner identifies itself as the real party-in-interest. Paper 5, 1.
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28, 2003, which claims priority to other applications with filing dates in
2002 and 2003, and two provisional applications filed May 8, 2002, and
March 1, 2002. Id. at codes (60), (62). Petitioner identifies multiple
lawsuits involving the ’277 patent. Pet. 5–6. Those lawsuits include:
Ravgen, Inc. v. Quest Diagnostics, No. 6:20-cv-00972-ADA (W.D. Tex.)
(“the Quest lawsuit”), and Ravgen, Inc. v. Natera, Inc. and NSTX, No. 1:20-
cv-00692-ADA (W.D. Tex.) (“the Natera lawsuit”). Id. (listing other
lawsuits).3
Petitioner and Patent Owner also identify other matters involving the
’277 patent pending before the Patent Office. Pet. 6; Paper 5, 1; Paper 10, 1.
Different claims of the ’277 patent are challenged in IPR2021-00788 and
IPR2021-00790 (both filed by Petitioner),4 IPR2021-00902 and IPR2021-
01054 (both filed by Laboratory Corporation of America), and IPR2021-
01272 (filed by Illumina, Inc.). Paper 5, 1; Paper 10, 1. In addition to the
above, Patent Owner identifies Ex Parte Reexamination Control No.
90/014,792 as relating to the present proceeding. Paper 10, 1.

3 Related U.S. Patent No. 7,727,720 is also asserted in the related lawsuits, it
is challenged by Petitioner in IPR2021-00791, and is subject to Ex Parte
Reexamination Control No. 90/014,703. IPR2021-00791, Paper 6, 1.
4 Petitioner asserts that it was justified in filing three petitions against the
’277 patent. See generally Paper 3 (citing, inter alia, the number of claims,
and complexity; ranking the 788 petition first in priority). Patent Owner
argues that three petitions from Petitioner were unnecessary and, thus, that at
least the 789 and 790 petitions should be denied. See generally Paper 8. We
concurrently deny the 789 and 790 petitions on their merits, leaving only the
788 case. We, therefore, decline to further address Patent Owner’s argument
that the petitions should be denied for being excessive in number.
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B. Asserted Grounds of Unpatentability
Petitioner asserts two grounds of unpatentability in this Petition
(Pet. 8), which are provided in the table below:
Claims Challenged 35 U.S.C. § Reference(s)/Basis
1–7, 50–52, 116–124,
134–137

103(a)5 Adinolfi,6 Pertl7
49, 53, 54 103(a) Adinolfi, Pertl, Ross8
Petitioner relies on the declaration of Ronald J. Wapner, M.D.
(Ex. 1102), and Patent Owner responds with a declaration from Brian Van
Ness, Ph.D. (Ex. 2001).
C. Technology Overview & the ’277 Patent
The ’277 patent relates generally to non-invasive methods for DNA
sampling and to detection of genetic abnormalities in a fetus. Ex. 1101,
1:31–39. The ’277 patent explains that a variety of invasive and non-

5 The Leahy-Smith America Invents Act, Pub. L. No. 112-29, 125 Stat. 284
(2011) (“AIA”), amended 35 U.S.C. §§ 102 and 103. Based on the filing
date of the ’277 patent, we apply the pre-AIA versions of §§ 102 and 103.
6 Matteo Adinolfi et al., Rapid Detection of Aneuploidies by Microsatellite
and the Quantitative Fluorescent Polymerase Chain Reaction, 17:13
PRENATAL DIAGNOSIS 1299–1311 (1997) (Ex. 1112, “Adinolfi”).
7 Barbara Pertl et al., Detection of male and female fetal DNA in maternal
plasma by multiplex fluorescent polymerase chain reaction amplification of
short tandem repeats, 106 HUM. GENET. 45–49 (2000) (Ex. 1111, “Pertl”).
8 Phillip Ross et al., Quantitative Approach to Single-Nucleotide
Polymorphism Analysis Using MALDI-TOF Mass Spectrometry, 29
BIOTECHNIQUES 620–29 (2000) (Ex. 1113, “Ross”).
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invasive techniques are available for prenatal diagnosis, including
amniocentesis, and those that use fetal blood cells or cell-free fetal DNA in
maternal blood. Id. at 2:53–57, 5:7–59.
As discussed below, the claims challenged here relate to methods of
quantitating ratios of alleles (e.g., alternative versions of genes) in samples
from a pregnant female that contain a mixture of fetal and maternal DNA
and, from those ratios, detecting fetal chromosomal abnormalities. Dr. Van
Ness explains that, with prior methods, “DNA in a mixed sample of
unknown proportions of fetal and maternal DNA could not easily be
distinguished in a way that would inform chromosomal abnormalities in the
fetus.” Ex. 2001 ¶ 22 (citing Ex. 1101, 67:11–22). According to the ’277
patent, with the methods claimed “[t]he percentage of fetal DNA present in
the sample from the pregnant female can be calculated by determining the
ratio of alleles at a heterozygous locus of interest on a chromosome that is
not typically associated with a chromosomal abnormality.” Ex. 1101,
67:18–22; id. at 70:19–23 (“[T]he present invention provides a method that
allows the ratio of maternal to fetal alleles at loci of interest, including SNPs,
to be calculated.”). The ’277 patent discloses methods that purport to allow
for determination of fetal chromosomal abnormalities based on allelic ratios
in mixed samples with both fetal and maternal DNA. See, e.g., id. at 67:57–
68:19 (showing quantification of ratios of alleles in maternal samples with
40% fetal DNA; noting, in one example, “if the fetal DNA is 40% of the
DNA in the maternal blood, the expected ratio without a trisomy is 0.25”).
We provide a brief overview of chromosomes and alleles, with
reference to the testimony from Dr. Wapner.
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Chromosomes are the biological structures that carry an individual’s
genes—normal human cells contain 23 pairs of chromosomes, for a total of
46 chromosomes. Ex. 1102 ¶ 31. Generally each pair has one chromosome
inherited from the individual’s father and one from the mother. Id.
An “allele” is one or more alternate versions of a particular locus on a
chromosome (e.g., a gene or portion of a gene). Id. ¶ 34. This is illustrated
on the chromosome pair shown in Figure 2 (reproduced below).

Ex. 1102 ¶ 35. Figure 2 above from Dr. Wapner’s Declaration depicts a
chromosome pair with “Allele D” on the left and “Allele d” on the right—
both alleles reflecting a hypothetical locus or gene shaded in light blue on
corresponding portions of the chromosome pair. Id. If two alleles are the
same at a given locus, they are considered “homozygous” at that locus (e.g.,
D, D; or d, d); if the alleles are different at that locus (like shown above with
D, d), they are “heterozygous.” Id. ¶ 36.
One form of chromosomal abnormality is “aneuploidy,” which is a
numerical abnormality where there are too few or too many chromosomes.
Id. ¶ 38. One type of aneuploidy is “trisomy,” where the individual has
three copies of a chromosome instead of the usual two. Down Syndrome is
a type of trisomy and individuals with Down Syndrome have three copies of
chromosome 21. Id. ¶ 39. This is shown in the Figure 4 below.
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Ex. 1102 ¶ 39. Figure 4 from Dr. Wapner’s Declaration is reproduced
above, and it depicts a “[n]ormal” pair of chromosomes on the left (with
alleles “D” and “d” at a heterozygous locus for that pair), and a set of three
chromosomes are shown on the right for “Trisomy” (with an additional
allele “d” at the locus on the extra chromosome at the far right). Id.
D. Challenged Claims
Twenty-six of the ’277 patent’s one hundred and forty claims are
challenged here. Pet. 1. Independent claim 1 is illustrative of the claims
challenged in this Petition and reads as follows:
1. A method for detecting the presence or absence of a fetal
chromosomal abnormality, said method comprising:
quantitating a ratio of the relative amount of alleles at a
heterozygous locus of interest in a mixture of template DNA,
wherein said mixture comprises maternal DNA and fetal DNA,
and wherein said mixture of maternal DNA and fetal DNA has
been obtained from a sample from a pregnant female, and further
wherein said heterozygous locus of interest has been identified
by determining the sequence of alleles at the locus of interest,
and wherein said ratio indicates the presence or absence of a fetal
chromosomal abnormality.
Ex. 1101, 469:10–21.
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Independent claim 116 includes limitations similar to claim 1, and is
reproduced below.
116. A method for detecting the presence or absence of a fetal
chromosomal abnormality, said method comprising:
(a) determining the sequence of alleles of a locus of
interest from template DNA, wherein the template DNA
comprises a mixture of fetal DNA and maternal DNA, and
wherein the template DNA is from a sample from a pregnant
female,
(b) quantitating a ratio of the relative amount of the alleles
in the mixture of fetal DNA and maternal DNA at a heterozygous
locus of interest in the mixture that was identified by step (a), and
wherein said ratio indicates the presence or absence of a fetal
chromosomal abnormality.
Id. at 477:1–13.
E. Prosecution History
The independent claims challenged here (claims 1 and 116)
correspond, respectively, to claims 1 and 152 that were pending during
prosecution of the ’277 patent. Ex. 1103, 526.9 The Examiner rejected
pending claims 1 and 152 as obvious over either “Umansky” or “Amicucci,”
in combination with “Saiki.” Id. at 909–910, 943–944.
We discuss the rejection of claim 1 based on the Umansky-Saiki
combination as illustrative. The Examiner determined that Umansky taught
a method with all the limitations of claim 1, but was “silent as regards how
to express the relative amount of the alleles at the heterogeneous locus of

9 Citations to the prosecution history (Ex. 1103) use the page numbers added
to the exhibit copy rather than the original pagination.
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interest.” Id. at 909 (citing teaching in Umansky about detection of inherited
diseases (e.g., Marfan Syndrome or Sickle Cell Anemia) of the fetus by
analysis of fetal DNA in a maternal fluid sample). According to the
Examiner, Saiki taught methods for diagnosing “sickle cell anemia wherein
the relative amount of the alleles at a heterozygous locus of interest are
determined . . . and results of the assay are expressed as a ratio.” Id. at 910.
Applicant responded with an amendment to both claims 1 and 152.
Id. at 536, 554. Applicant then made several responsive remarks. First,
applicant stated that “[c]laim 1 has been amended to more clearly indicate
that the alleles, which are quantified and used to calculate a ratio, comprise a
mixture of maternal DNA and fetal DNA.” Id. at 559 (stating same for
claim 152). Second, applicant argued that the combination of Umansky and
Saiki “does not teach or suggest a method comprising all of the [claim]
elements.” Id. at 563. In particular, Applicant argued that Saiki relied on
“determining the relative amount of alleles in a homogeneous sample, and
expressing the results of the assay as a ratio,” such that the ratio “is
calculated using a homogeneous DNA sample, and the ratio calculated
represents alleles from a single individual.” Id. Applicant asserted that,
“[i]n contrast, the methods [of the claims] taught herein comprise calculating
a ratio of the relative amount of alleles in a heterogeneous mixture of DNA,
i.e., maternal DNA and fetal DNA,” where “[t]he methods taught in the
present invention comprise determining a ratio, wherein the ratio represents
alleles from both the mother and the fetus.” Id. at 563–64. According to
applicant, Umansky and Saiki “fail[ed] to teach or suggest this element,
either alone or in combination.” Id. at 564 (“Thus, the methods described in
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the present application detect chromosomal abnormalities using a method
that comprises, inter alia, quantitating a ratio of alleles in a heterogeneous
mixture of DNA, wherein the ratio represents alleles from more than one
individual.”).
Shortly thereafter, the Examiner allowed the claims. Ex. 1103, 519–
520. The Examiner’s Reasons for Allowance stated that the claims are
“deemed to be allowable in light of applicant’s amendment filed 30 MAY 07
and the persuasive argument(s) therein.” Id. at 521.
II. ANALYSIS
A. Principles of Law
“In an [inter partes review], the petitioner has the burden from the
onset to show with particularity why the patent it challenges is
unpatentable.” Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed.
Cir. 2016) (citing 35 U.S.C. § 312(a)(3) (requiring inter partes review
petitions to identify “with particularity . . . the evidence that supports the
grounds for the challenge to each claim”)).
A claim is unpatentable under 35 U.S.C. § 103(a) if the differences
between the subject matter sought to be patented and the prior art are such
that the subject matter as a whole would have been obvious at the time the
invention was made to a person having ordinary skill in the art to which that
subject matter pertains. KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
(2007). The question of obviousness is resolved on the basis of underlying
factual determinations including: (1) the scope and content of the prior art;
(2) any differences between the claimed subject matter and the prior art;
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(3) the level of ordinary skill in the art; and (4) secondary considerations of
nonobviousness when presented. Graham v. John Deere Co., 383 U.S. 1,
17–18 (1966).
A. Person of Ordinary Skill in the Art (“POSA”)
In determining the level of skill in the art, we consider the problems
encountered in the art, the art’s solutions to those problems, the rapidity with
which innovations are made, the sophistication of the technology, and the
educational level of active workers in the field. Custom Accessories, Inc. v.
Jeffrey-Allan Indus., Inc., 807 F.2d 955, 962 (Fed. Cir. 1986).
Petitioner contends:
A person of ordinary skill in the art (“POSA”) in the field of the
’277 Patent would be a Ph.D., M.D. or M.D./Ph.D., with a
doctoral degree or Board certification in medical genetics,
human genetics, molecular genetics, clinical genetics or related
fields, with 2-3 years of relevant research experience in an
academic or industry setting in, e.g., prenatal diagnosis or cancer
diagnosis.
Pet. 32–33 (citing Ex. 1102 ¶ 64). Patent Owner does not directly oppose
this definition. Prelim. Resp. 17. Patent Owner’s own proposal is similar
but describes the fields of advanced study as including “area[s] such as
genetics, biochemistry, molecular biology, cell biology, or microbiology.”
Id. Patent Owner proposes that a POSA would have “at least one to two
years of work” in those areas and, alternatively, that a POSA “could have a
Bachelor’s degree in one of the foregoing areas and at least three to four
years of work in” such areas. Id. (citing Ex. 2001 ¶ 19).
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Petitioner’s proposal of the POSA level is more precise and appears to
be generally consistent with the prior art. Accordingly, we adopt it for
purposes of this Decision. Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed.
Cir. 2001) (explaining that specific findings regarding ordinary skill level
are not required “where the prior art itself reflects an appropriate level and a
need for testimony is not shown”) (quoting Litton Indus. Prods., Inc. v. Solid
State Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985)).
B. Claim Construction
We interpret a claim “using the same claim construction standard that
would be used to construe the claim in a civil action under 35 U.S.C.
282(b).” 37 C.F.R. § 42.100(b) (2020). Under this standard, we construe
the claim “in accordance with the ordinary and customary meaning of such
claim as understood by one of ordinary skill in the art and the prosecution
history pertaining to the patent.” Id. “[W]e need only construe terms ‘that
are in controversy, and only to the extent necessary to resolve the
controversy.’” See Nidec Motor Corp. v. Zhongshan Broad Ocean Motor
Co. Ltd., 868 F.3d 1013, 1017 (Fed. Cir. 2017) (quoting Vivid Techs., Inc. v.
Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999)).
According to Petitioner, “no terms need to be construed for purposes
of resolving the issues in this Petition because the prior art discloses all
limitations under any plausible construction.” Pet. 33. Patent Owner, in
discussing the prosecution history and in its merits argument, raises an issue
that touches on claim interpretation, which we address in Section II(D).
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C. Overview of the Asserted Prior Art
1. Adinolfi (Exhibit 1112)
Adinolfi is a publication from 1997 and relates to a method for rapid
detection of aneuploidies using quantitative fluorescent polymerase chain
reaction (“QF-PCR”). Ex. 1112, 1299. Adinolfi uses QF-PCR to analyze
short tandem repeats (“STRs”)10 to detect fetal aneuploidies, such as on
chromosomes 21 and 13. Id.
Adinolfi teaches amplification of STRs by PCR, and detection of
fluorescent activity for the STRs. Id. at 1301 (disclosing “incorporation of
fluorochromes into the products of PCR amplification via . . . primers
specific for each STR”). Adinolfi discloses that fluorescent activity for two
different alleles at one locus will generate two “peaks” following
amplification and DNA scanning. Id.; see also id. at Fig. 1. According to
Adinolfi, “in normal heterozygotes the ratio of the fluorescent activity of the
two peaks should be close to 1:1.” Id. (“If the STR marker is highly
polymorphic, few normal subjects should be homozygotes and show one
peak of activity (Figs. 1 and 2).”). However, “[i]n a trisomic patient, the
three doses of an STR marker can be detected either as three peaks . . . with
a ratio of 1:1:1 (trisomic allelic) or as a pattern of two peaks with a ratio of
2:1 (trisomic diallelic).” Id.
To illustrate the differences in normal diploid samples and samples
indicating trisomy in the fetus as taught in Adinolfi, we reproduce excerpts

10 STRs are short sequences of DNA, normally of 2–5 base pairs in length,
which are repeated numerous times. Ex. 1101, 74:14–19.
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of Adinolfi’s Figure 1 below, with annotations in red added by Petitioner.

Pet. 26; Ex. 1112, 1301 (Fig. 1). The annotated image above is a schematic
representation of testing samples “A” and “B” with results of electrophoresis
on the left, and fluorescent intensities (represented as peaks for a control and
respective maternal and paternal STRs) depicted on the right. Ex. 1112,
1301. As shown, sample “A” includes two different peaks of roughly equal
height representing the relative amount of two different fetal alleles, which
Petitioner annotates in red as being a “Heterozygous Ratio 1:1.” Id.; Pet. 26.
Sample B includes a single, larger fluorescent peak, which Petitioner
annotates as having a value of “2” (intensity of 2:1 relative to control) and as
showing a “Homozygous Ratio.” Pet. 26; Ex. 1112, 1301. Adinolfi
describes these samples as being “Normal Diploid Samples.” Id.
Adinolfi also discloses conducting QF-PCR on samples and
generating fluorescent peaks that are indicative of trisomy (e.g., Down
Syndrome) in a fetus. Ex. 1112, 1301–02. This is shown in another excerpt
of Adinolfi’s Fig. 1, with annotations in red provided by Petitioner.
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Id.; Pet. 28. The excerpt above shows electrophoresis results on the left, in
the middle, three equally-sized fluorescent peaks for sample “A” in a
“Trisomic Ratio 1:1:1” and, at the far right, sample “B” with one large peak
and one smaller peak, reflecting a “Trisomic Ratio 2:1.” Id.; Ex. 1112,
1301. Thus, as depicted, the trisomic patient produces either three peaks that
represent three different alleles (a ratio of 1:1:1 in sample A), or two peaks
at a ratio of 2:1 that represent duplicate copies of one STR allele and only a
single copy of another allele (as in sample B). Id.; see also Ex. 1102 ¶ 55.
Adinolfi teaches taking fetal samples through invasive techniques
(e.g., obtaining amniotic fluid samples, chorionic villus samples, or
umbilical cord blood samples). Ex. 1112, 1306–07. Adinolfi discloses
“maternal contamination” was present in a few samples. Id. at 1307.
According to Adinolfi, “[o]ne amniotic fluid sample” was “visibly
contaminated with [maternal] blood” and “showed an unusual triallelic
pattern with the chromosome 13 markers.” Id. Adinolfi teaches that
“[s]ince in the case of contaminated samples, we always analyse the
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maternal STR profile, it was possible to exclude trisomy 13 and conclude
that the unusual pattern was due to maternal contamination.” Id.
2. Pertl (Exhibit 1111)
Pertl is a study published in 2000, and relates to methods for detecting
fetal DNA in maternal plasma. Ex. 1111, 45. The purpose of Pertl’s “study
was to develop a fluorescent polymerase chain reaction (PCR) assay for the
detection of circulating fetal DNA in maternal plasma.” Id. According to
Pertl, “[m]ultiplex fluorescent PCR was used to detect fetus-specific alleles
in the corresponding maternal plasma samples” and “[f]etus-specific alleles
were found in all maternal plasma samples studied.” Id.
Pertl teaches that “[t]his approach may have implications for non-
invasive prenatal diagnosis.” Id. at 45. According to Pertl, the “results
demonstrate the feasibility of detection of male and female fetal DNA in
maternal plasma with the use of highly polymorphic STR markers and
fluorescent multiplex PCR.” Id. at 48. Pertl discloses that “the potential of
quantitative analysis of fetal DNA in maternal plasma/serum using
fluorescent PCR has still to be investigated.” Id.
3. Ross (Exhibit 1113)
Ross is a research report from 2000 relating to quantitative approaches
to single-nucleotide polymorphism analysis using MALDI-TOF Mass
Spectrometry. Ex. 1113, 620. Ross teaches that “quantitative genotyping or
allele detection in pools can be performed with ostensibly the same
chemistry and MALDI-TOF instrumentation that is used for high-throughput
analysis of SNPs from single individuals.” Id. at 628.
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D. Obviousness over Adinolfi in View of Pertl
Petitioner asserts that claims 1–7, 50–52, 116–124, and 134–137 are
unpatentable as obvious over Adinolfi in view of Pertl. Pet. 33–59; see id. at
33–48 (claim 1), 55–58 (claim 116), 48–55, 59 (dependent claims).
The asserted prior art is summarized above. We start with Petitioner’s
contentions for independent claims 1 and 116 and then move to Patent
Owner’s responsive arguments and our analysis for those claims.
1. Claims 1 and 116
We discuss Petitioner’s challenge to claim 1 in greater detail below,
but Petitioner summarizes it as follows:
In sum, Adinolfi discloses an effective technique for
identifying and quantifying chromosomal abnormalities in fetal
DNA; Pertl discloses the benefit of using that technique on
maternal plasma containing a mixture of maternal and fetal
DNA—namely, using such a mixture was safer and less invasive
than using DNA obtained by amniocentesis. . . . Accordingly, a
POSA would have been motivated to combine Adinolfi with
Pertl [to meet the limitations of claim 1].
Pet. 46–47.
To show that Adinolfi and Pertl teach the subject matter of claim 1,
Petitioner breaks claim 1 into six parts (1[A] through 1[F]). Pet. 34–44.
Petitioner argues, without dispute, that Adinolfi discloses claim 1’s preamble
of a “method for detecting the presence or absence of a fetal chromosomal
abnormality.” Id. at 34–35 (citing Ex 1112, 1305 (Fig. 3)).11

11 Absent a dispute, we need not decide whether this preamble language is
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Petitioner argues that Adinolfi discloses what Petitioner has
designated part “1[B]” of claim 1, reciting “quantitating a ratio of the
relative amount of alleles at a heterozygous locus of interest.” Id. at 35–37.
According to Petitioner, Adinolfi meets this claim language because it
teaches, inter alia, using QF-PCR to produce fluorescent peaks for
heterozygous alleles that will exhibit a 1:1 ratio in normal samples and a
trisomic ratio (1:1:1 or 2:1) in samples with a trisomy. Id. (“Experimental
data in Adinolfi discloses both a 1:1:1[] ratio and a 2:1 ratio in fetal DNA.”)
(citing, for example, Ex. 1112, 1301–02, Figs. 2A and 2B). Petitioner cites
similar teachings in Adinolfi as meeting part 1[F] of claim 1, which recites
“wherein said ratio indicates the presence or absence of a fetal chromosomal
abnormality.” Id. at 43–44 (“Adinolfi further discloses that a 1:1:1 ratio or a
2:1 ratio indicates the presence of a trisomy, a fetal chromosomal
abnormality.”) (citing Ex. 1112, 1301; Ex. 1102 ¶¶ 74–76, 90–91).
Petitioner argues that Adinolfi also discloses parts 1[D] and 1[E] of
claim 1. Id. at 39–44; Ex. 1102 ¶¶ 82–89. According to Petitioner, Adinolfi
discloses obtaining a sample from a pregnant female as in part 1[D], and
determining the sequences of heterozygous alleles at a locus of interest for
part 1[E]. Pet. 39 (citing Adinolfi’s “samples obtained by amniocentesis,
which must come from a pregnant female”), 40–41 (“Absent such

limiting. In addressing the different portions of the claim, Petitioner also
makes several assertions to the effect that some of the techniques disclosed
in Adinolfi or Pertl are the same as those described in the Specification. See,
e.g., 35–36 (“[T]he method disclosed in Adinolfi is identical to the QF-PCR
method described in the alleged novel embodiment of the ’277 patent.”)
(citing Ex. 1101, 74:14–75:17). We discuss below.
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sequencing [of alleles], one could not perform the PCR analysis” nor use the
specific primers in Adinolfi) (citing Ex. 1112, 1301 (Table 1 (listing loci)).
That leaves claim 1’s recitation of “in a mixture of template DNA,
wherein said mixture comprises maternal DNA and fetal DNA,” which
language Petitioner designates as part 1[C]. Pet. 37–39. Relevant to part
1[C], Petitioner contends that, during prosecution, Patent Owner obtained
the ’277 patent based on the argument “that the prior art did not teach the
limitation of a mixture of template DNA, wherein said mixture comprises
maternal DNA and fetal DNA.”12 Id. at 37. And Petitioner contends its
asserted art teaches what was argued as missing during prosecution. Id.
To show that the art asserted here meets the language of part 1[C] of
claim 1, Petitioner first cites Adinolfi’s disclosure that one fetal sample
taken from the womb was visibly contaminated with maternal blood, which
sample exhibited “an unusual triallelic pattern.” Id. at 37–38 (citing
Ex. 1112, 1307). Petitioner contends “Adinolfi was able to confirm the third
peak was attributable to a maternal allele in the maternal DNA” and rule out
trisomy in the contaminated sample. Id. Recognizing that Adinolfi’s
method was, however, not made for testing mixtures of both maternal and
fetal DNA, Petitioner cites to Pertl. Pet. 38, 45. Petitioner contends Pertl
discloses the use of QF-PCR for the express purposes of detecting fetal

12 We disagree with this characterization of the file history as discussed
further below; see also Pet. 48 (asserting “[d]uring prosecution, PO
expressly stated that the claims were not obvious . . . because none of the
references disclosed the use of samples containing a mix of fetal and
maternal DNA.”).
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DNA in samples that include both maternal DNA and fetal DNA. Id. at 38–
39 (citing Ex. 1111, 45–46); Ex. 1102 ¶ 81.
Petitioner, therefore, contends that Adinolfi and Pertl together teach
the method of claim 1, and Petitioner argues a POSA would have been
motivated to combine those references with a reasonable expectation of
success. Pet. 44–48. According to Petitioner, although Adinolfi’s testing
involved taking samples invasively (i.e., via amniocentesis), it was known
that invasive techniques posed greater risks in pregnancy. Id. at 45. And,
Petitioner argues, Pertl disclosed non-invasive approaches that were capable
of detecting fetal alleles in maternal plasma, and also suggested free fetal
DNA could be an alternative source of fetal DNA for prenatal diagnosis. Id.
at 46 (citing Ex. 1111, 45); Ex. 1102 ¶¶ 94–95.
Patent Owner raises several counterarguments. Prelim. Resp. 18–32.
Patent Owner contends the Petition does not establish that Adinolfi and Pertl
render obvious all of claim 1’s limitations. Id. at 19–20 (“Petitioner here
fails to map the asserted prior art onto the Challenged Claims,” instead
“breaking [the claim language] into small disjointed pieces” and “never
identifies how the supposed combination . . . would meet the limitations of
the claims read as a whole.”); see also id. at 20–23 (“Petitioner fails to show
that Adinolfi discloses quantitating the ratio as claimed” because, e.g.,
“Adinolfi’s expected 1:1 ratio applies only to fetal DNA samples (that
include alleles only from the fetus)—not mixed samples (that include alleles
from both the fetus and the mother.”), 26 (“Petitioner fails to show that Pertl
discloses quantitating any ratio, much less the ratio claimed in the ’277
patent.”), 27 (“Petitioner fails to explain how a POSA would have combined
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Adinolfi and Pertl to reconcile their teachings and arrive at the Challenged
Claims” because, e.g., “Adinolfi’s ratio of alleles is potentially useful only
for assessing chromosomal abnormalities in a sample of fetal DNA, without
maternal DNA” and “Pertl does not disclose quantitating any ratio at all.”);
Ex. 2001 ¶¶ 53–66.
Patent Owner also argues that the Petition does not establish a
sufficient motivation to combine Adinolfi and Pertl with a reasonable
expectation of arriving at the claimed subject matter. Prelim. Resp. 29–32.
Patent Owner contends that Adinolfi focused its design on only fetal DNA—
describing maternal DNA as contamination—yet Petitioner posits that
Adinolfi’s method would somehow be modified to intentionally add
contaminating genetic material. Id. at 29–30. Patent Owner contends
“Adinolfi was unable to apply its quantitative analysis to mixed samples and
instead required a [separate] workaround . . . to draw a conclusion in view of
the unreliable ratios obtained.” Id. at 31. And, to the extent Pertl is relied
upon, Patent Owner highlights Pertl’s disclosure that the potential of
quantitative analysis on fetal DNA in maternal plasma “has still to be
investigated.” Id. (citing Ex. 1111, 48).
Based on the grounds advanced and the preliminary record here, we
determine that Petitioner has not met its institution burden. We agree in
general with Patent Owner that, when claim 1’s method is considered as a
whole, Petitioner has not shown that all its subject matter is taught in the
asserted combination of Adinolfi and Pertl. In particular, we reference the
following language of claim 1, which Patent Owner calls out in its papers:
“quantitating a ratio of the relative amount of alleles at a heterozygous locus
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of interest in a mixture of template DNA, wherein said mixture comprises
maternal DNA and fetal DNA . . . wherein said ratio indicates the presence
or absence of a fetal chromosomal abnormality.” Prelim. Resp. 18–20; see
supra Section I(D). On this record, considering this language in context and
in view of the intrinsic evidence, especially the prosecution history, we
determine this claim language requires that the quantitated ratio is a ratio of
alleles from both maternal and fetal DNA in the mixture. And it is that
quantitated ratio that must “indicate[] the presence or absence of a fetal
chromosomal abnormality.”
As an initial matter, Petitioner’s challenge here does not account
adequately for the amendment and argument made during prosecution in
route to securing allowance of the challenged claims. To the extent
Petitioner mentions the prosecution history, we do not agree with its
characterizations. Petitioner suggests that the issue during prosecution was
whether the art taught samples containing both fetal and maternal DNA.
Pet. 24–25, 37, 48. But considering Patent Owner’s argument and Dr. Van
Ness’s testimony, and upon our review of the relevant file history, the
challenged claims were amended (with related argument from applicant)
specifically to address and overcome a different issue. Prelim. Resp. 10–12;
Ex. 2001 ¶¶ 22–37.
From our review of the prosecution history, it is clear that the issue
applicant’s arguments and amendments sought to overcome was whether the
asserted prior art taught quantitating a ratio of the relative amount of alleles
in a mixed sample—where the ratio represents alleles not just from one
individual, but alleles from both the mother and the fetus. See, e.g.,
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Ex. 1103, 563–64. Indeed, the applicant argued explicitly that the claims
were amended “to indicate more clearly that the alleles, which are quantified
and used to calculate a ratio, comprises a mixture of maternal DNA and fetal
DNA.” Id. at 559 (explaining amendment to pending claims 1 and 152).
And, if that left any doubt, applicant argued expressly that, “[i]n contrast” to
the cited prior art, “the methods taught herein comprise calculating a ratio of
the relative amount of alleles in a heterogeneous mixture of DNA . . .
wherein the ratio represents alleles from both the mother and the fetus.”
Id. at 563–564 (emphasis added); see also id. (“[T]he methods described in
the present application detect chromosomal abnormalities using a method
that comprises . . . quantitating a ratio of alleles in a heterogeneous mixture
of DNA, wherein the ratio represents alleles from more than one
individual. This element is neither taught nor suggested” by the cited prior
art) (emphasis added).
Those representations make sense when considering the art cited
against the applicant during prosecution, and why applicant believed they
were needed to distinguish that art. The Examiner cited Umansky or,
alternatively, Amicucci as teaching the claimed subject matter, including the
language that “template DNA comprises a mixture of maternal DNA and
fetal DNA.” Id. at 910 (“This limitation is inherent to Umansky in that both
maternal and fetal free DNA present in the maternal blood stream will pass
over into [a] maternal urine” sample); see also id. at 943–44 (making similar
findings for Amicucci). The issue, thus, was not (as Petitioner suggests)
whether the prior art taught methods for detecting fetal chromosomal
abnormalities in a sample that included both fetal and maternal DNA. The
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Examiner determined, and the applicant did not dispute, that Umansky and
Amicucci taught that. See, e.g., id. at 909–10. The deficiency of Umansky
(or Amicucci), according to the Examiner, was that neither taught how to
express the relative amounts of alleles in ratios as claimed to indicate the
abnormality. Id. For that, the Examiner turned to Saiki as teaching
quantitating the amounts of alleles and expressing as a ratio to indicate a
chromosomal abnormality (i.e., sickle cell anemia). Id. But Saiki’s
deficiency, applicant later argued after amending and clarifying its claim
scope, was that it only taught how to calculate ratios indicative of a
chromosomal abnormality in a homogeneous DNA sample—where “the
ratio calculated represents alleles from a single individual.” Id. at 563
(emphasis added). Thus, applicant’s repeated representations that the
claimed invention was, in direct contrast, drawn to quantitating ratios that
represent the alleles from more than one individual (i.e., mother and fetus)
was key to the alleged distinction of the claims over the cited art. And, after
such argument, the claims were allowed.
Petitioner contends that certain disclosures in the Specification are
allegedly comparable to some of the techniques in Adinolfi or Pertl. See,
e.g., Pet. 36–37 (citing Ex. 1101, 75:2–4). But we are not persuaded on this
record that such disclosures change the result on the meaning of claim 1
when the aforementioned amended claim language and prosecution history
is taken into account. Even if, for argument’s sake, these disclosures in the
Specification might be read as relating to quantitating alleles of a single
individual or using homogeneous samples, such disclosures would appear to
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be related to alternative embodiments outside the scope of these claims
based on the file history as discussed above.13
Turning to Petitioner’s asserted prior art, Petitioner admits that
“Adinolfi was not specifically designed to test a mixture of maternal and
fetal DNA and largely involved fetal samples obtained via amniocentesis.”
Pet. 45. Insofar as Adinolfi quantitated allelic ratios and used those ratios as
indicating a fetal chromosomal abnormality, its rapid detection method is
limited to samples comprising only fetal DNA. Pet. 44 (citing Adinolfi’s
detected ratios of 1:1 as indicating a normal sample, and 1:1:1 or 2:1 as
indicating trisomy); Prelim. Resp. 21 (“Adinolfi’s Figure 1 (in which the
peaks correspond only to alleles from the same individual (i.e., the fetus))”).
We agree with Dr. Van Ness that Adinolfi’s conclusions about the presence
of trisomy based on an observed ratio of 1:1:1 or 2:1 “is valid . . . only if the
observed peaks reflect alleles from the same individual (i.e., the fetus), in
which case only a 1:1 ratio would be normal at a heterozygous locus.”
Ex. 2001 ¶ 57; see also id. ¶ 58 (“This is in contrast to the ’277 Patent,
which recognized that the expected ratio of alleles in a mixed sample
changes in accordance with changes in the sample’s proportion of fetal

13 We find, on this record, the statements in the prosecution history are also
clear about the scope of claims 1 and 152 (claims 1 and 116) in contrast to
the cited art, where ratios indicating a chromosomal abnormality were
quantitated for alleles only on one subject’s DNA, likely also amounting to a
disclaimer against recapturing such scope. Continental Circuits LLC v. Intel
Corp., 915 F.3d 788, 798 (Fed. Cir 2019) (“[T]o operate as a disclaimer, the
statement in the prosecution history must be clear and unambiguous, and
constitute a clear disavowal of scope.”).
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DNA.”). These teachings of Adinolfi do not meet the limitations of claim 1,
which recite, inter alia, “quantitating a ratio of the relative amount of alleles
. . . in a mixture of template DNA, wherein the mixture comprises maternal
DNA and fetal DNA . . . and wherein said ratio indicates the presence or
absence of a fetal chromosomal abnormality.”
We also agree with Patent Owner that Adinolfi’s disclosure of a
“contaminated” sample does not satisfy the limitations of claim 1. Prelim.
Resp. 23–25. As discussed above (Section II(C)(1)), Adinolfi describes one
fetal sample taken via amniocentesis that was visibly contaminated with
maternal blood. Ex. 1112, 1307. And Adinolfi reports that QF-PCR
revealed an “unusual triallelic pattern” (i.e., three peaks) with that sample.
Id. Even if that were considered quantitating a ratio of alleles in a mixed
sample of both fetal and maternal DNA, it still does not meet the claim
language because Adinolfi does not teach that such “ratio indicates the
presence or absence of a fetal chromosomal abnormality” as claimed (what
Petitioner calls part “1[F]” of claim 1). If anything, as explained by Patent
Owner, reliance on that triallelic pattern would have incorrectly led to a
diagnosis of aneuploidy. Prelim. Resp. 24. Indeed, Adinolfi did not rely on
that pattern and instead, only through a separate “workaround” analyzing the
maternal DNA profile, was Adinolfi able to rule out trisomy and determine
that the contaminated sample actually contained a fetal sample with a normal
chromosome count. Id., Ex. 1112, 1307; Ex. 2001 ¶¶ 44–46, 61–62.
Petitioner relies on Pertl primarily for its disclosures of detecting fetal
alleles in mixed samples with both fetal and maternal DNA. Pet. 38–39. As
argued persuasively by Patent Owner, Petitioner does not contend or show
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that Pertl teaches “quantitating a ratio of the relative amount of alleles at a
heterozygous locus of interest” in a mixed sample or “wherein said ratio
indicates the presence or absence of a fetal chromosomal abnormality.”
Prelim. Resp. 26. We agree with Patent Owner that “Pertl’s goal was simply
detection, aiming ‘to develop a fetal DNA detection method that can be used
independently of the fetal gender.’” Id. (quoting (with Patent Owner’s
emphasis) Ex. 1111, 46); Ex. 2001 ¶ 64. Pertl does not, therefore, close the
gaps between Adinolfi’s disclosures and claim 1 as discussed above. To the
extent Pertl even mentions any quantitative analysis, it states that “the
potential of quantitative analysis of fetal DNA in maternal plasma/serum
using fluorescent PCR has still to be investigated.” Ex. 1111, 48 (emphasis
added). This statement, coming three years after Adinolfi and made by one
of Adinolfi’s co-authors, undermines Petitioner’s position that Adinolfi and
Pertl would have been predictably combined with a reasonable expectation
of success of arriving at the claimed subject matter.
Finally, we also agree with Patent Owner that “Petitioner fails to
explain how a POSA would have combined Adinolfi and Pertl to reconcile
their teachings and arrive at the Challenged Claims.” Prelim. Resp. 27. The
Petition itself must lay out its challenge with sufficient “particularity.”
Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd., 821 F.3d 1359,
1369 (Fed. Cir. 2016) (“It is of the utmost importance that petitioners in the
IPR proceedings adhere to the requirement that the initial petition identify
‘with particularity’ the “evidence that supports the grounds for the challenge
to each claim.’”) (quoting 35 U.S.C. § 312(a)(3)). Adinolfi’s ratio of alleles
was capable of indicating trisomy (or absence of trisomy) in samples of fetal
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DNA without contaminating maternal DNA. And Pertl, although it discloses
detecting fetal alleles in samples with both maternal and fetal DNA, does not
disclose quantitating allelic ratios in such samples to indicate any
abnormality as claimed. On this record, the Petition simply does not provide
a sufficient and persuasive evidence-backed theory on how Adinolfi and
Pertl would be combined to predictably quantitate ratios of heterozygous
alleles in a mixed sample such that the ratio indicates whether a
chromosomal abnormality is present. Doing so might be straightforward.
Yet it might also be the case that there were known or unknown
complexities still to be explored; as noted above, Pertl remarked years after
Adinolfi that quantitative analysis of fetal DNA in maternal plasma using
QF-PCR had not yet been investigated. Ex. 1111, 48. Put differently, we
are not persuaded on this record that Petitioner has shown how the art would
have been combined with a reasonable expectation of success in arriving at
the claimed subject matter.
For the above reasons, Petitioner has not established a reasonable
likelihood of prevailing on its challenge to claim 1 on this record.
Petitioner’s arguments against claim 116 parallel its arguments for claim 1.
Pet. 55–58 (incorporating argument and evidence against claim 1). Patent
Owner’s rebuttal addresses claims 1 and 116 together. See, e.g., Prelim.
Resp. 18–20. We determine that substantially the same relevant limitations
of claim 1 addressed above appear in claim 116, and our reasoning from
above applies to Petitioner’s challenge to claim 116. Thus, Petitioner has
not met its institution burden on claim 116 on this record.
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2. Dependent claims
Petitioner contends that dependent claims 2–7, 50–52, 117–124, and
134–137 are also unpatentable for obviousness over Adinolfi and Pertl. Pet.
48–55, 58–59. Petitioner incorporates its discussion for the relevant
independent claims from above. See, e.g., id. at 48. Petitioner’s challenge
to the dependent claims is insufficient on this record to remedy the
deficiencies noted above with its contentions on independent claims 1 and
116. In re Fritch, 972 F.2d 1260, 1266 (Fed. Cir. 1992) (“[D]ependent
claims are nonobvious if the independent claims from which they depend are
nonobvious.”). We, thus, determine that Petitioner has not met its burden
here to show that the challenged dependent claims are unpatentable.
3. Secondary Considerations of Nonobviousness
Patent Owner contends that secondary considerations show that the
claims are nonobvious. Prelim. Resp. 6–10. We do not further address
Patent Owner’s argument because Petitioner has not met its institution
burden on other issues necessary to prevail on the obviousness challenge.
See Hamilton Beach Brands, Inc. v. f’real Foods, LLC, 908 F.3d 1328, 1343
(Fed. Cir. 2018) (holding “objective indicia of nonobviousness” “need not
[be] address[ed]” because the court “affirm[ed] the Board’s findings
regarding the failure of the prior art to teach or suggest all [claim]
limitations”).
E. Obviousness over Adinolfi, Pertl, and Ross
Petitioner asserts that claims 49, 53, and 54, which all depend from
claim 1, would have been obvious Adinolfi and Pertl, in further view of
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Ross. Pet. 59–66. Petitioner relies on the combination of Adinolfi and Pertl
as disclosing all of claim 1’s limitations. Id. at 60 (incorporating prior
discussion). Petitioner’s argument on the dependent claims and Ross do not
remedy the deficiencies noted above on independent claim 1. We, thus,
determine that Petitioner has not met its burden to show that the challenged
dependent claims are unpatentable on this record.
III. CONCLUSION
Petitioner has not established a reasonable likelihood of prevailing in
showing that the challenged claims are unpatentable.14
IV. ORDER
In consideration of the foregoing, it is hereby:
ORDERED that the Petition is denied, and we do not institute inter
partes review of any claim of the ’277 patent based on the grounds asserted
in this Petition.

14 Considering the merits, Petitioner has not met its institution burden on this
record. We decline to reach the argument that the Petition should be denied
on the basis of discretion under § 314(a). Prelim. Resp. 32–42.
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FOR PETITIONER:

Colleen Superko
Wenli Gu
WILMER CUTLER PICKERING HALE AND DORR LLP
colleen.superko@wilmerhale.com
wenli.gu@wilmerhale.com

FOR PATENT OWNER:
Brian D. Matty
Theodoros Konstantakopoulos
DESMARAIS LLP
bmatty@desmaraisllp.com
tkonstantakopoulos@desmaraisllp.com