Trials@uspto.gov
`571-272-7822
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` Paper 10
`
`Date: July 12, 2021
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`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PROGENITY, INC.,
`Petitioner,
`v.
`NATERA, INC.,
`Patent Owner.
`____________
`
`IPR2021-00282
`Patent 10,266,893 B2
`____________
`
`
`
`Before GRACE KARAFFA OBERMANN, ZHENYU YANG, and
`RYAN H. FLAX, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`571-272-7822
`
` Paper 10
`
`Date: July 12, 2021
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PROGENITY, INC.,
`Petitioner,
`v.
`NATERA, INC.,
`Patent Owner.
`____________
`
`IPR2021-00282
`Patent 10,266,893 B2
`____________
`
`
`
`Before GRACE KARAFFA OBERMANN, ZHENYU YANG, and
`RYAN H. FLAX, Administrative Patent Judges.
`
`YANG, Administrative Patent Judge.
`
`
`
`
`DECISION
`Denying Institution of Inter Partes Review
`35 U.S.C. § 314
`
`
`
`
`
`
`
`
`
`IPR2021-00282
`Patent 10,266,893 B2
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`
`INTRODUCTION
`I.
`Progenity, Inc. (“Petitioner”) filed a Petition, seeking an inter partes
`review of claims 1–11 and 13 of U.S. Patent No. 10,266,893 B2 (Ex. 1001,
`“the ’893 patent”). Paper 2 (“Pet.”). Natera, Inc. (“Patent Owner”) filed a
`Preliminary Response. Paper 6 (“Prelim. Resp.”). With our authorization
`(Paper 7), Petitioner filed a Reply (Paper 8) and Patent Owner filed a
`Sur-reply (Paper 9).
`We have authority under 35 U.S.C. § 314, which provides that an
`inter partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a).
`For the reasons provided below, we determine Petitioner has not
`demonstrated a reasonable likelihood that it would prevail with respect to at
`least one claim challenged in the Petition. Accordingly, we deny institution
`of an inter partes review.
`
`A. Related Matters
`According to the parties, the ’893 patent is the subject of Natera, Inc.
`v. Progenity, Inc., No. 6:20-cv-00532 (W.D. Tex.); Natera, Inc. v.
`Progenity, Inc., No. 3:20-cv-1634 (N.D. Tex.); Progenity, Inc. v. Natera,
`Inc., No. 3:20-cv-01252 (S.D. Cal.). Pet. 4–5; Paper 5, 1.
`Petitioner also filed IPR2021-00266, IPR2021-00267,
`IPR2021-00279, IPR2021-00280, and IPR2021-00281, challenging the
`claims of other patents of Patent Owner. Paper 5, 1–2.
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`B. The ’893 Patent
`The ’893 patent issued from an application that claims priority to a
`series of earlier applications, including certain provisional applications filed
`in 2005. Ex. 1001, code 60. Petitioner, however, asserts that the challenged
`claims are not entitled to a priority date earlier than March 17, 2008. Pet. 14
`(citing Ex. 1002, 337–38, 415–16). Patent Owner does not dispute this
`argument. Prelim. Resp. 1, 9. Thus, for purposes of this Decision, we
`analyze the patentability of the challenged claims, accepting March 17, 2008
`as the priority date.
`The ’893 patent discloses a system and method for cleaning
`“incomplete or noisy genetic data using secondary genetic data as a source
`of information,” and for determining “chromosome copy number using said
`genetic data.” Ex. 1001, 11:37–40.
`The ’893 patent explains that a human being normally has “two sets
`of 23 chromosomes in every diploid cell, with one copy coming from each
`parent. Aneuploidy, the state of a cell with extra or missing
`chromosome(s),” is responsible for “a large percentage of failed
`implantations and miscarriages, and some genetic diseases.” Id. at 2:53–60.
`For example, a child with Down syndrome has three copies of
`chromosome 21, i.e., trisomy 21. Id. at 5:41–42.
`“[P]renatal diagnosis can alert physicians and parents to abnormalities
`in growing fetuses.” Id. at 4:33–34. “Unfortunately, standard methods
`require invasive testing and carry a roughly 1 percent risk of miscarriage.”
`Id. at 4:37–39. According to the ’893 patent, “[a] need exists for a method of
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`prenatal diagnosis that mitigates these risks.” Id. at 4:51–52. The ’893 patent
`explains:
`It has recently been discovered that cell-free fetal DNA and intact
`fetal cells can enter maternal blood circulation. Consequently,
`analysis of these cells can allow early Non-Invasive Prenatal
`Genetic Diagnosis (NIPGD). A key challenge in using NIPGD is
`the task of identifying and extracting fetal cells or nucleic acids
`from the mother’s blood.
`Id. at 4:53–58, see also id. at 11:27–29 (“In the case of prenatal or
`pre-implantation genetic diagnoses a complicating factor is the relative
`paucity of genetic material available.”).
`The ’893 patent states that “[g]iven the inherently noisy nature of the
`measured genetic data in cases where limited genetic material is used for
`genotyping, there is a great need for a method which can increase the fidelity
`of, or clean, the primary data.” Id. at 11:29–33. According to the ’893 patent,
`the techniques disclosed therein are “for cleaning genetic data,” relevant in,
`among others, “non-invasive prenatal diagnosis, where a small quantity of
`fetal genetic material is isolated from maternal blood.” Id. at 11:45–51.
`C. Illustrative Claim
`Claim 1, the only independent claim of the ’893 patent, is illustrative
`of the claimed subject matter. The parties label the four steps recited in
`claim 1 as steps (a) through (d). For consistency, we do the same. Claim 1,
`with the labels added in brackets, is reproduced below.
`A method for measuring the amounts of fetal
`1.
`chromosome segments in a maternal blood sample, comprising:
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`[a] obtaining cell-free DNA comprising fetal and maternal
`chromosome segments from the maternal blood sample;
`[b] performing universal amplification on the chromosome
`segments to generate amplified chromosome segments;
`[c] performing clonal amplification on
`the amplified
`chromosome segments to generate clonally amplified
`chromosome segments; and
`[d] measuring the amounts of clonally amplified fetal
`chromosome segments by performing next-generation
`sequencing.
`Id. at 79:47–60.
`
`D. Asserted Grounds of Unpatentability
`Petitioner asserts the following grounds of unpatentability:
`Claims Challenged
`35 U.S.C.
`§1
`103(a)
`
`References
`Lo,2 Robertson3
`
`1–11, 13
`
`
`1 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29,
`125 Stat. 284, 287–88 (2011), amended 35 U.S.C. § 103, effective
`March 16, 2013. Because the ’893 patent has an effective filing date prior to
`March 16, 2013, we apply the pre-AIA version of § 103.
`2 U.S. Patent Publication No. 2009/0029377 A1, published Jan. 29, 2009
`(Ex. 1007).
`3 Robertson et al., Genome-Wide Profiles of STAT1 DNA Association
`Using Chromatin Immunoprecipitation and Massively Parallel Sequencing,
`4 NATURE METHODS 651–57 (2007) (Ex. 1009).
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`Claims Challenged
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`35 U.S.C.
`References
`§1
`Shimkets,4 Nishigaki,5 Bianchi6
`103(a)
`1–3, 7–11, 13
`In support of their respective positions, Petitioner relies on the
`Declaration of Chunming Ding, Ph.D. (Ex. 1005), and Patent Owner relies
`on the Declaration of John Quackenbush, Ph.D. (Ex. 2001).7
`II. ANALYSIS
`A. Claim Construction
`In an inter partes review, we construe a claim term “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 that standard, the words of a claim “are generally given their ordinary
`and customary meaning,” which is “the meaning that the term would have to
`a person of ordinary skill in the art in question at the time of the invention,
`i.e., as of the effective filing date of the patent application.” Phillips v. AWH
`Corp., 415 F.3d 1303, 1312–13 (Fed. Cir. 2005) (en banc).
`Petitioner argues that (1) the term “universal amplification” refers to
`“techniques that amplify a pool of chromosome segments in the reaction
`
`
`4 PCT Application No. WO 2005/039389 A2, published May 6, 2005
`(Ex. 1010).
`5 Nishigaki et al., Random PCR-Based Genome Sequencing: A Non-Divide-
`And-Conquer Strategy, 7 DNA RES. 19–26 (2000) (Ex. 1012).
`6 Bianchi, Circulating Fetal DNA: Its Origin and Diagnostic Potential—A
`Review, 25 PLACENTA, SUPP. A, TROPHOBLAST RES. S93–S101 (2004)
`(Ex. 1011).
`7 The Quackenbush Declaration was originally filed in support of Patent
`Owner’s Preliminary Response in IPR2021-00266. See Ex. 2001, cover
`page, caption.
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`mixture in an unbiased manner, as opposed to amplifying targeted
`sequences;” and (2) the term “clonal amplification,” also known as “cluster
`amplification,” refers to “amplification techniques that generate identical
`copies of a single chromosome segment and co-locates them together in a
`clonal population.” Pet. 10–12. Petitioner also argues that “[a] POSA would
`have understood the term ‘next-generation sequencing’ to include any of
`various commercially-available techniques used to sequence DNA in a high-
`throughput, massively parallel manner, including sequencing-by-synthesis,”
`for example, “by the Illumina/Solexa or 454 Life Sciences platforms.” Id. at
`13.
`
`Patent Owner states that for purposes of its Preliminary Response, it
`does not dispute Petitioner’s proposed constructions of these terms. Prelim.
`Resp. 4. On this record, and for purposes of this Decision, we adopt
`Petitioner’s proposed constructions because they are consistent with intrinsic
`and extrinsic evidence.
`Petitioner also proposes that we construe step 1(d): “measuring the
`amounts of clonally amplified fetal chromosome segments by performing
`next-generation sequencing.” Pet. 12–13. According to Petitioner, “[a]
`POSA would have understood this step to mean quantifying or measuring
`through the use of next-generation sequencing the amounts of clonally
`amplified fetal chromosome segments that were previously amplified
`through clonal amplification.” Id. Patent Owner does not dispute, and for
`purposes of this Decision, we adopt, Petitioner’s proposed construction.
`The parties, however, dispute the scope of step 1(d), as construed.
`Petitioner argues that step 1(d) can be satisfied by measuring the amounts of
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`clonally amplified maternal and fetal chromosome segments together, and
`does not require measurements that separately quantify fetal and maternal
`DNA. Id. at 12–13. Patent Owner counters that although “the claims
`encompass measuring fetal and maternal chromosome segments together,”
`step 1(d) “cannot be satisfied by a process in which the amounts of fetal and
`maternal DNA are always aggregated and never segregated into amounts
`attributable to the fetus and amounts attributable to the mother.” Prelim.
`Resp. 4–5. We agree with Patent Owner.
`We agree with Patent Owner that claim 1 requires specifically
`measuring amounts of fetal chromosome segments, not merely measuring
`some amounts of mixed DNA that includes fetal chromosome segments.
`We find support for our conclusion in the claim language itself. After all,
`both the preamble and step 1(d) require “measuring the amounts of clonally
`amplified fetal chromosome segments.” Ex. 1001, 79:47–48, 58–59
`(emphasis added). Thus, although claim 1, with the open-ended
`“comprising” transitional phrase, “does not preclude the measuring of the
`‘fetal and maternal chromosome segments’ together” (Pet. 17), the plain
`language of step 1(d) is specifically directed to “measuring the amounts of
`clonally amplified fetal chromosome segments.” Stated somewhat
`differently, the words “measuring the amounts” signals a measurement taken
`of the species that follows those words in the claim.
`The language of claims 8 and 9, which Petitioner relies on, do not
`result in a different determination. Claim 8 depends from claim 1 and further
`recites “wherein the clonally amplified maternal chromosome segments are
`measured along with the clonally amplified fetal chromosome segments by
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`performing next-generation sequencing.” Petitioner argues that “[c]laim 8
`demonstrates that the measuring step of claim 1 can be satisfied by the use
`of next-generation sequencing to simultaneously measure the amounts of the
`clonally amplified maternal chromosome segments along with the clonally
`amplified fetal chromosome segments.” Pet. 12 (emphasis added).
`Petitioner’s statement is not incorrect; but it does not change our
`determination of the scope of step 1(d), because measuring clonally
`amplified maternal and fetal chromosome segments simultaneously means
`measuring them at the same time, it does not necessarily require measuring
`them together. Even were we to read simultaneous measurement to allow
`that the fetal and maternal DNA may be measured together, it would not
`change our understanding of claim 1 based on that claim’s language: claim 1
`still requires specifically quantifying clonally amplified fetal chromosome
`segments. In other words, claim 1 requires determining how much such fetal
`DNA is present, regardless of whether maternal DNA is also measured,
`together or separate.
`The same rationale also applies to claim 9. Petitioner also points to
`dependent claim 9 and invokes the principle of claim differentiation. In our
`view, under the doctrine of claim differentiation, claim 1 does not require
`“measuring the amounts of clonally amplified maternal chromosome
`segments and comparing the measured amounts of clonally amplified
`maternal chromosome segments with the measured amounts of clonally
`amplified fetal chromosome segments,” the additional limitation recited in
`claim 9. Petitioner does not sufficiently explain why claim 9 “further
`confirms” step 1(d) “does not require separately quantifying the amounts of
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`clonally amplified fetal chromosome segments from the amounts of clonally
`amplified maternal chromosome segments.” Id. at 13.
`In sum, although we adopt Petitioner’s proposed construction of
`step 1(d), we reject its argument that step 1(d) can be satisfied by a process
`that is unable to distinguish the amounts of clonally amplified fetal
`chromosome segments from the amounts of clonally amplified maternal
`chromosome segments.
`On this record, and for purposes of this Decision, there is no need to
`expressly construe any other claim term. Wellman, Inc. v. Eastman Chem.
`Co., 642 F.3d 1355, 1361 (Fed. Cir. 2011) (stating claim terms need only be
`construed to the extent necessary to resolve the controversy).
`B. Obviousness over Lo and Robertson
`1. Prior Art Disclosures
`i. Lo
`Lo relates to “the diagnostic testing of fetal chromosomal aneuploidy
`by determining imbalances between different nucleic acid sequences, and
`more particularly to the identification of trisomy 21 (Down syndrome) and
`other chromosomal aneuploidies via testing a maternal sample (e.g. blood).”
`Ex. 1007 ¶ 3.
`Lo teaches methods for determining “whether an increase or decrease
`(diseased state) of a clinically-relevant chromosomal region exists compared
`to a non-diseased state.” Id. ¶ 50. According to Lo:
`This determination may be done by using a parameter of an
`amount of a clinically-relevant chromosomal region in relation
`to
`other
`non-clinically-relevant
`chromosomal
`regions
`(background regions) within a biological sample. Nucleic acid
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`molecules of the biological sample are sequenced, such that a
`fraction of the genome is sequenced, and the amount may be
`determined from results of the sequencing. One or more cutoff
`values are chosen for determining whether a change compared to
`a reference quantity exists (i.e. an imbalance), for example, with
`regards to the ratio of amounts of two chromosomal regions (or
`sets of regions).
`
`Id.
`
`Lo states that sequencing is done using massively parallel sequencing
`on, for example, the 454 platform or Illumina Genome Analyzer (or Solexa
`platform). Id. ¶ 56. According to Lo, “[e]ach of these platforms sequences
`clonally expanded or even non-amplified single molecules of nucleic acid
`fragments.” Id.
`Lo reports prenatal diagnosis of fetal trisomy 21 in eight pregnant
`women, “[f]our of them were each carrying a fetus with trisomy 21 and the
`other four were each carrying a euploid fetus.” Id. ¶¶ 92, 93. There, “[t]he
`maternal plasma DNA was . . . used for massively parallel sequencing by the
`Illumina Genome Analyzer according to manufacturer’s instructions.” Id.
`¶ 92. Specifically, “approximately 50 ng of maternal plasma DNA was used
`for DNA library preparation.” Id. ¶ 93. Maternal plasma DNA fragments
`were blunt-ended and ligated to Solexa adaptors. Id. Afterwards, “[t]he
`adaptor-ligated DNA was hybridized to the surface of flow cells, and DNA
`clusters were generated using the Illumina cluster station, followed by 36
`cycles of sequencing on the Illumina Genome Analyzer.” Id.
`Lo explains that “[i]n this study, to reduce the complexity of the data
`analysis, only sequences that have been mapped to a unique location in the
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`repeat-masked human genome reference are further considered.” Id. ¶ 94.
`According to Lo:
`The total number of uniquely mappable sequences for each
`specimen was counted. The number of sequences uniquely
`aligned to chromosome 21 was expressed as a proportion to the
`total count of aligned sequences for each specimen. As maternal
`plasma contains fetal DNA among a background of DNA of
`maternal origin, the trisomy 21 fetus would contribute extra
`sequenced tags originating from chromosome 21 due to the
`presence of an extra copy of chromosome 21 in the fetal genome.
`Hence, the percentage of chromosome 21 sequences in maternal
`plasma from a pregnancy carrying a trisomy 21 fetus would be
`higher than that from a pregnancy with a euploid fetus.
`
`Id.
`
`Lo also teaches another way to analyze the data. In this approach, Lo
`teaches determining the percentages of maternal plasma DNA sequences
`aligned to each of the 24 chromosomes (22 autosomes and X and Y
`chromosomes) in two pregnant women, one carrying a trisomy 21 fetus and
`the other carrying a euploid fetus. Id. ¶ 98. Lo shows “[t]he differences (%)
`of the percentage representation per chromosome between the maternal
`plasma DNA specimens of the above two cases.” Id. ¶ 99. According to Lo,
`“there is an over-representation of chromosome 21 sequences by 11% in the
`plasma of the pregnant woman carrying a trisomy 21 fetus when compared
`with the pregnant woman carrying a euploid fetus. For the sequences aligned
`to other chromosomes, the differences between the two cases were within
`5%.” Id. ¶ 102.
`Lo explains that “[a]s the percentage representation for chromosome
`21 is increased in the trisomy 21 compared with the euploid maternal plasma
`samples, the difference (%) could be alternatively referred as the degree of
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`over-representation in chromosome 21 sequences.” Id. According to Lo, “the
`degree of over-representation of chromosome 21 sequences in maternal
`plasma is related to the fractional concentration of fetal DNA in the maternal
`plasma sample.” Id. ¶ 104, see also id. ¶ 114 (“The degree of
`over-representation [of the sequenced tags aligned to chromosome 21] is
`dependent on the fetal DNA percentage in the maternal plasma DNA
`sample.”). Thus, Lo concludes that “cut-off values in the degree of
`chromosome 21 sequence over-representation relevant to the fractional fetal
`DNA concentrations could be determined to identify pregnancies involving
`trisomy 21 fetuses.” Id. ¶ 104.
`
`ii. Robertson
`Robertson teaches a method, “combining chromatin
`immunoprecipitation (ChIP) and massively parallel sequencing to identify
`mammalian DNA sequences bound by transcription factors in vivo.”
`Ex. 1009, 651. To construct an Illumina library, Robertson teaches
`“following the manufacturer’s instructions” to (1) ligate Illumina adapters to
`the ends of prepared DNA; (2) enrich adaptor-modified DNA fragments by
`PCR using Illumina PCR primer 1.1 and 2.1; and (3) perform cluster
`generation and sequencing on the Illumina cluster station and 1G analyzer.
`Id. at 656.
`
`2. Discussion
`i. Prior-Art Status of Lo
`Lo published from Application No. 12/178,181 (“the ’181
`application”). Ex. 1007, code 21. The ’181 application, filed on July 23,
`2008, claims priority to Provisional Application No. 60/951,438 (“Lo
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`Provisional”), filed on July 23, 2007. Id., codes 22, 60. Because the ’181
`application was filed after March 17, 2008, the priority date of the
`challenged claims, Lo qualifies as prior art under § 102(e) only if it can
`claim priority to Lo Provisional. The parties disagree on this issue, with
`Petitioner arguing that Lo is entitled to the 2007 priority date, and Patent
`Owner contending that Petitioner has not met its burden of establishing such
`priority. Pet. 24–28; Prelim. Resp. 15–27.
`We do not need to resolve this issue because, even if Lo can claim
`priority to Lo Provisional, and thus, qualifies as prior art, as explained
`below, Petitioner has not shown sufficiently that the combination of Lo and
`Robertson teaches step 1(d).
`ii. Obviousness Challenge Based on Lo
`Petitioner argues that claims 1–11 and 13 of the ’893 patent would
`have been obvious over the combination of Lo and Robertson. Pet. 33–51.
`Based on this record, and for at least the following reasons, we determine
`Petitioner has not established a reasonable likelihood that it would prevail in
`this assertion. Our analysis below focuses on claim 1, the only independent
`claim, and most specifically on step 1(d), the dispositive issue for this
`challenge.
`Step 1(d) recites “measuring the amounts of clonally amplified fetal
`chromosome segments by performing next-generation sequencing.”
`Petitioner argues that “Lo teaches the use of the Illumina and 454 NGS
`platforms (among others) to perform next-generation sequencing on
`‘clonally expanded’ (i.e., clonally amplified) nucleic acid fragments.”
`Pet. 41 (citing EX1007 ¶¶ 56, 70, 73, 92, 93). Petitioner states that “Lo
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`measured the clonally amplified maternal chromosome segments along with
`the clonally amplified fetal chromosome segments.” Id. According to
`Petitioner, this falls within the scope of step 1(d). Id. We are not persuaded.
`Lo teaches prenatal diagnosis by calculating the percentage
`representation of a particular chromosome (e.g., chromosome 21), which is
`the proportion of the number of sequences uniquely aligned to that
`chromosome to the total count of sequences. Ex. 1007 ¶¶ 94, 98. Lo
`specifically states its analysis “does not require the need to distinguish or
`identify fetal from maternal sequences after sequencing.” Id. ¶ 94. In other
`words, Lo teaches measuring clonally amplified fetal and maternal
`sequences together as an aggregate, without the ability to discern specific
`amounts of either. Lo describes this as an advantage of its method because it
`overcomes problems of past methods due to low concentrations of fetal
`DNA in maternal plasma. Id. ¶ 16 (“The sequencing advantageously
`maximizes the amount of genetic information that could be inferred from the
`limited amount of fetal nucleic acids which exist as a minor population in a
`biological sample containing maternal back ground nucleic acids.”), see also
`id. ¶ 13 (the same).
`As explained above, step 1(d) cannot be satisfied by a process that is
`unable to distinguish measured amounts of clonally amplified fetal
`chromosome segments from those of clonally amplified maternal
`chromosome segments. See II.A. Thus, Lo’s method measuring the amounts
`of clonally amplified fetal and maternal sequences together without
`“distinguish[ing] or identify[ing] fetal from maternal sequences,” that is,
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`without specifically quantifying the fetal sequence, does not, by itself, fall
`within the scope of step 1(d). See Ex. 1007 ¶ 94.
`Relying on Lo’s teaching of fetal fraction, Petitioner argues that Lo
`discloses “separately quantifying the fetal and maternal cfDNA chromosome
`segments in the maternal blood plasma samples.” Pet. 41 (citing Ex. 1007
`¶¶ 17, 52, 81, 96, 97, Fig. 3B). We agree with Petitioner; yet this argument
`does not help Petitioner’s case.
`Lo states that because “[t]he sequences mapped to the Y chromosome
`would be fetal-specific,” the percentage of sequences mapped to the Y-
`chromosome can be used to “calculate the fractional fetal DNA
`concentration in the original maternal plasma specimen.” Ex. 1007 ¶ 96
`(emphasis added), see also id. ¶ 17 (identifying “a percentage of fetal DNA
`in the biological sample,” which is “received from a pregnant female”)
`(emphasis added), ¶ 81 (the same).
`Step 1(d), however, requires “measuring the amounts of clonally
`amplified fetal chromosome segments.” Petitioner does not point to any
`competent evidence or persuasively argue that the fetal fraction in the
`maternal plasma remains the same after the universal amplification and
`clonal amplification steps of claim 1. Thus, even though Lo teaches, as
`Petitioner puts it, “separately quantifying the fetal and maternal cfDNA
`chromosome segments in the maternal blood plasma samples” (Pet. 41
`(emphasis added)), we are not persuaded that, on this record, this is the same
`as separately quantifying the clonally amplified fetal and maternal DNA, as
`challenged claim 1 requires.
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`We note that in the Reply, Petitioner cites Lo as “distinguishing ‘the
`[post-clonal amplification] sequences mapped to the Y-chromosome’ as
`‘fetal specific.’” Reply 4 (quoting Ex. 1007 ¶ 96) (brackets added by
`Petitioner). The language in the added brackets, however, is simply nowhere
`to be found in Lo; and Petitioner does not explain the support for this
`addition.
`In sum, Lo’s method measures the amounts of clonally amplified fetal
`and maternal sequences together without distinguishing the two amounts.
`And because Petitioner only points to the fetal fraction in the original
`maternal plasma, and not after the amplification steps, it has not met its
`burden in showing that Lo teaches step 1(d). As a result, on this record,
`Petitioner has not established a reasonable likelihood that it would prevail in
`this challenge.
`C. Obviousness over Shimkets, Nishigaki, and Bianchi
`1. Prior Art Disclosures
`Shimkets
`i.
`Shimkets describes “Sequence-Based Karyotyping methods for the
`detection of genomic abnormalities, for diagnosis of hereditary disease, or
`for diagnosis of spontaneous genomic mutations.” Ex. 1010, Abstract.
`According to Shimkets:
`The current invention provides for a method of karyotyping a
`genome of a test cell (e.g., eukaryotic or prokaryotic) by
`generating a pool of fragments of genomic DNA by a random
`fragmentation method, determining the DNA sequence of at least
`20 base pairs of each fragment, mapping the fragments to the
`genomic scaffold of
`the organism, and comparing
`the
`distribution of the fragments relative to a reference genome or
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`relative to the distribution expected by chance. The number of a
`plurality of sequences mapping within a given window in the
`population is compared to the number of said plurality of
`sequences expected to have been sampled within that window or
`to the number determined to be present in a karyotypically
`normal genome of the species of the cell. A difference in the
`number of the plurality of sequences within the window present
`in the population from the number calculated to be present in the
`genome of the cell indicates a karyotypic abnormality.
`Id. at 2:20–30.
`Shimkets also teaches complex sample sequencing that “can be used
`for detection of pathogens in blood, water, air, soil, food, and for
`identification of all organisms in a sample without any prior knowledge.” Id.
`at 21:10–12. In this method, “populations of organisms can be identified by
`preparing a mixed DNA and cDNA sample, sequencing random fragments
`from the DNA and RNA in the sample, and mapping sequences to a
`hierarchical database of all known sequences.” Id. at 21:12–15. Shimkets
`teaches “a cell-free sample (e.g., blood, water, air, food, or soil) can be used
`to generate 1 million sequence reads.” Id. at 21:16–17.
`ii. Bianchi
`Bianchi reviews the state of diagnostic technology regarding fetal
`DNA present in maternal blood, and concludes “[f]etal cell-free nucleic
`acids have potential for non-invasive monitoring of placental pathology.”
`Ex. 1011, S93.
`Bianchi emphasizes the need for non-invasive methods for prenatal
`diagnosis because of the risks associated with invasive techniques. Id.
`Bianchi states that “multiple studies show that both intact fetal cells and cell-
`free nucleic acids circulate freely in maternal blood.” Id. Specifically, there
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`are “surprisingly high mean concentrations of fetal DNA in maternal plasma
`DNA” and “[s]ignificantly more fetal DNA . . . present in the cell-free
`plasma (or serum) of pregnant women as compared with the fetal DNA
`extracted from the cellular fraction of maternal blood.” Id.
`According to Bianchi, the fractional concentration of fetal DNA in
`plasma is 0.39–11.9 % (mean 3.4 %) and 2.33–11.4 % (mean 6.2 %) in early
`pregnancy and late pregnancy, respectively. Id. at S94. Bianchi explains that
`in a study where “the median circulating fetal DNA concentrations in fresh
`2nd trimester plasma samples from pregnant women” were measured, “there
`appeared to be about twice as much fetal DNA present in the pregnant
`woman when the fetus had trisomy 21.” Id. at S96.
`Bianchi states that “[c]ompared with the analysis of fetal nucleated
`cells in the maternal blood, which in many cases requires the use of
`sophisticated fetal cell enrichment procedures, maternal plasma/serum DNA
`analysis has the advantage of being rapid, reliable, reproducible, and easily
`carried out for a large number of samples.” Id. at S93–S94.
`iii. Nishigaki
`Nishigaki teaches Random PCR-based Genome Sequencing (RGS).
`EX1012, 19. According to Nishigaki, “[t]he most important step in RGS . . .
`is sequencing based on random PCR. Sequence data obtained in this manner
`will accumulate and cover most of the genome.” Id. Nishigaki explains that
`Random PCR “requires only a set of non-specific primers and a template
`DNA.” Id. Nishigaki notes that “RGS needs only a small amount of genomic
`DNA owing to PCR amplification.” Id. at 24.
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`2. Discussion
`Petitioner argues that claims 1–3, 7–11, and 13 of the ’893 patent
`would have been obvious over the combination of Shimkets, Nishigaki, and
`Bianchi. Pet. 51–67. Based on this record, and for at least the following
`reasons, we determine Petitioner has not established a reasonable likelihood
`that it would prevail in this assertion. We, again, focus on claim 1, the only
`independent claim.
`Petitioner argues that the combination of Shimkets, Nishigaki, and
`Bianchi teaches the preamble and each step of claim 1. Id. at 55–60.
`Petitioner also asserts that an ordinarily skilled artisan would have had a
`reason to combine the teachings of these references and would have had a
`reasonable expectation of success in doing so. Id. at 51–54.
`Patent Owner challenges Petitioner’s mapping of prior art disclosures
`to steps 1(b) and 1(d). Prelim. Resp. 37–39, 61–64. We do not need to
`address these issues because we agree with Patent Owner that “Petitioner has
`not provided any competent evidence that a POSITA would have a
`reasonable expectation of success in extending Shimkets’ method for
`aneuploidy detection to mixed cell-free DNA in a maternal blood sample.”
`Id. at 39.
`Petitioner argues that “a POSA would have had good reason to
`employ th[e] sequence-based karyotyping . . . as taught by Shimkets, using a
`maternal blood sample comprising cfDNA from the fetus and mother, as
`identified by Bianchi.” Pet. 52. According to Petitioner, an ordinarily skilled
`artisan would have had a reasonable expectation of success because
`“Shimkets taught its method could be applied to prenatal testing and
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`suggested obtaining DNA for chromosomal analysis from a cell-free blood
`sample.” Id. (citing Ex. 1010, 3:9–13, 7:28–8:1, 16:20–26, 21:10–24,
`58:5–9, claims 17–18), see also id. at 55 (“Shimkets taught that a ‘cell-free
`sample (e.g., blood . . .) can be used to generate 1 million sequence reads,’
`and that its methodology could be used for prenatal diagnosis.”) (citing
`Ex. 1010
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