\ PORATED?
`
`USINS. FOV
`ey
`57]-272-7822
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`Paper 9
`Entered: February 8, 2023
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`TWINSTRAND BIOSCIENCES, INC.,
`Petitioner,
`
`V.
`
`GUARDANT HEALTH,INC.,
`Patent Owner.
`
`IPR2022-01400
`Patent 11,149,306 B2
`
`Before SUSAN L. C. MITCHELL, TINA E. HULSE,and
`MICHAEL A. VALEK, Administrative Patent Judges.
`
`VALEK, Administrative Patent Judge.
`
`DECISION
`Granting Institution of Inter Partes Review
`3S US.C. $ 314
`
`

`

`IPR2022-01400
`Patent 11,149,306 B2
`
`I.
`
`INTRODUCTION
`
`TwinStrand Biosciences,Inc. (‘Petitioner’) filed a Petition requesting
`
`an inter partes review of claims 1—29 of U.S. Patent No. 11,149,306 B2
`
`(Ex. 1001, “the ’306 patent’’). Paper 2 (“Pet.”). Guardant Health, Inc.
`
`(“Patent Owner’) filed a Preliminary Response. Paper 6 (“Prelim. Resp.”).
`
`With our authorization, Petitioner filed a Reply to Patent Owner’s
`
`Preliminary Response (Paper 7) and Patent Ownerfiled a Sur-reply to the
`
`Reply (Paper8).
`
`Considering the arguments and evidence of record, we determine that
`
`the Petition demonstrates “a reasonable likelihood that [P]etitioner would
`
`prevail with respect to at least 1 of the claims challenged in the petition.”
`
`35 U.S.C. § 314(a). Accordingly, we institute an inter partes review.
`
`A.
`
`Related Proceedings
`
`Theparties state that the °306 patent has been asserted in 7winsStrand
`
`Biosciences, Inc. et al. vy. Guardant Health, Inc., 1-21-cv-01126 (D. Del.)
`
`and ///umina, Inc. vy. Guardant Health, Inc., 22-cv-00334 (D. Del.). Pet. 70;
`
`Paper4, 1.
`
`The parties identify the following IPRs involving patents related to the
`
`°306 patent: IPR2022-00746, IPR2022-01115, IPR2022-00747, IPR22-
`
`01116, and IPR2022-01152. Pet. 70; Paper 4, 1. Patent Owneradditionally
`
`identifies a numberof IPRsthatit has filed, 1.e., IPR2022-00449, IPR2022-
`
`00450, IPR2022-00816, IPR2022-00817, IPR2022-00935, IPR2022-01158,
`
`IPR2022-01159, and IPR2022-01388, as related matters. Paper 4, 1.
`
`B.
`
`The ’306 Patent
`
`Genetic testing is useful for a numberof diagnostic methods.
`
`Ex. 1001, 1:25—26. Disorders that are caused by rare genetic mutations(e.g.,
`
`sequencevariations) or changes in epigenetic markers, such as cancer and
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`

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`IPR2022-01400
`Patent 11,149,306 B2
`
`partial or complete aneuploidy, may be detected or more accurately
`
`characterized with DNA sequenceinformation. /d. at 1:26-30.
`
`Early detection and monitoring of genetic diseases is often useful and
`
`needed in the successful treatment or managementof a disease. Ex. 1001,
`
`1:31-33. According to the 306 patent, one approach may include
`
`monitoring a sample derived from cell-free nucleic acids, which are
`
`polynucleotides that can be found in different types of bodily fluids. /d. at
`
`1:33-36. Cell-free DNA (“cfDNA”) may contain genetic aberrations, such
`
`as copy numbervariation or sequence variation, associated with a particular
`
`disease. /d. at 1:36—43.
`
`The ’306 patent explains that many methods have been developed to
`
`estimate copy numbervariation. Ex. 1001, 1:46-47. According to the
`
`Specification, most of those methods involve preparing a sample by
`
`converting the original nucleic acids into a sequenceablelibrary, followed by
`
`massively parallel sequencing, and then conducting a bioinformatic analysis
`
`to estimate the copy numbervariation at one or more loci. /d. at 1:51—55.
`
`The °306 patentstates that although known methods for detecting
`
`cfDNAare able to reduce the errors introduced by the sample preparation
`
`and sequencing processes for the molecules that are converted and
`
`sequenced, these methodsare not able to infer the counts of molecules that
`
`were converted, but not sequenced. Ex. 1001, 1:59-63. The ’306 patent
`
`states this inability to count converted but unsequenced molecules “can
`
`dramatically and adversely affect the sensitivity that can be achieved.”/d. at
`
`1:63-67. Accordingly, the °306 patent relates to a method of tagging and
`
`counting both halves of double-stranded DNA and estimating the number of
`
`unseen molecules based on the numberof Pairs (i.e., molecules where both
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`

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`IPR2022-01400
`Patent 11,149,306 B2
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`strands were identified) and Singlets (i.e., molecules where only one strand
`
`wasidentified) detected in a particular region. See id. at 2:1—18.
`
`C.
`
`Illustrative Claims
`
`Petitioner challenges claims 1—29 of the ’306 patent. Of these, claims
`
`1 and 17 are independent. Claims | and 17 read as follows:
`
`1. A method, comprising:
`
`(a) providing a population of cell-free deoxyribonucleic acid
`(cfDNA) molecules havingfirst and second complementary
`strands;
`
`(b) tagging a plurality of the cfDNA moleculesin the
`population with duplex tags comprising molecular barcodes
`to produce tagged parent polynucleotides, wherein the
`duplex tags are attached at both ends of a molecule of the
`plurality of the cfDNA molecules, wherein the plurality of
`the cfDNA molecules are tagged with n different
`combinations of molecular barcodes, wherein n is at least 2
`and no more than 100,000*z, wherein z is a mean of an
`expected numberof duplicate molecules in the population of
`cf{DNA molecules that map to identical start and stop
`positions on a reference sequence;
`
`(c) amplifying a plurality of the tagged parent polynucleotides
`to produce amplified progeny polynucleotides;
`
`(d) sequencingat least a subset of the amplified progeny
`polynucleotides to produce a set of sequence reads; and
`
`(e) reducing or tracking redundancyofa plurality of sequence
`reads from the set of sequence reads using at least sequence
`information from the molecular barcodes of the duplex tags
`to determine distinct cDNA molecules from among the
`tagged parent polynucleotides, wherein the distinct cfDNA
`molecules are determined based on (1) paired reads
`corresponding to sequence reads generated fromafirst
`tagged strand and a second tagged complementary strand
`derived from cfDNA molecules from among the tagged
`parent polynucleotides, or (11) unpaired reads corresponding
`to sequence reads generated fromafirst tagged strand
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`

`

`IPR2022-01400
`Patent 11,149,306 B2
`
`having no second tagged complementary strand derived
`from cfDNA molecules from among the tagged parent
`polynucleotides, wherein reducing or tracking the
`redundancyof the plurality of sequence reads comprises
`mappingat least a subset of the plurality of sequence reads
`to the reference sequence.
`
`17. A method, comprising:
`
`(a) tagging a population of double-strandedcell-free
`deoxyribonucleic acid (cfDNA) molecules obtained or
`derived from a sample of a subject with a set of tags
`comprising molecular barcodes to produce tagged parent
`polynucleotides;
`
`(b) amplifying a plurality of the tagged parent polynucleotides
`to produce amplified progeny polynucleotides;
`
`(c) sequencingat least a subset of the amplified progeny
`polynucleotides to produce a set of sequence reads; and
`
`(d) sorting a plurality of sequence reads from the set of
`sequence readsinto (1) families comprising paired reads
`corresponding to sequence reads generated fromafirst
`tagged strand and a second tagged complementary strand
`derived from double-stranded cfDNA molecules from
`among the tagged parent polynucleotides, and (11) families
`comprising unpaired reads corresponding to sequence reads
`generated fromafirst tagged strand having no second tagged
`complementary strand derived from double-stranded cfDNA
`molecules from amongthe tagged parent polynucleotides.
`
`Ex. 1001, 61:6—43 (claim 1), 62:45—65 (claim 17).
`
`D.
`
`The Asserted Grounds of Unpatentability
`
`Petitioner asserts that claims 1-29 would have been unpatentable on
`
`the following grounds:
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`

`

`IPR2022-01400
`Patent 11,149,306 B2
`
`
`1-3, 5,7, 9-14, 17-
`
`
`
`27,29 15, 16, 28 Narayan, Schmitt, and Kivioja®
`
`Petitioner also relies upon the Declaration of Paul T. Spellman, Ph.D.
`
`(Ex. 1002) (“Spellman Declaration”).
`
`Before turning to our analysis of these grounds, we address Patent
`
`Owner’s argumentthat, notwithstanding the merits of the Petition, we
`
`should exercise discretion to deny institution under 35 U.S.C. § 325(d).
`
`' The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, 125
`Stat. 284 (2011), amended 35 U.S.C. $103, effective March 16,
`2013. The ’306 patent claims priority to a series of applications the earliest
`of which is a provisional application filed on December 28, 2013. Ex. 1001
`code (60). Because the AIA becameeffective before the filing of the earliest
`of the application to which the ’306 patent claims priority, we apply the AIA
`version ofthe statute.
`? Narayanet al., Ultrasensitive Measurement ofHotspot Mutations in Tumor
`DNA in Blood Using Error-Suppressed Multiplexed Deep Sequencing,
`72(14) CANCER RES. 3492-98 (Ex. 1082) (“Narayan’’).
`3 Schmitt et al., WO 2013/142389 A1, published Sept. 26, 2013 (Ex. 1009)
`(“Schmitt”).
`+ Meyeret al., Parallel Tagged Sequencing on the 454 Platform, 3(2)
`NATURE PROTOCOLS 267-78 (2008) (Ex. 1005) (“Meyer”).
`> Craig et al., Jdentification ofGenetic Variants Using Bar-coded
`Multiplexed Sequencing, 5(10) NATURE METHODS 887-93 (2008) (Ex. 1007)
`(“Craig’’).
`° Kivioja et al., Counting Absolute Numbers ofMolecules Using Unique
`Molecular Identifiers, 9 NATURE METHODS 72-76 (2012) (Ex. 1006)
`(“Kivioja’).
`
`

`

`IPR2022-01400
`Patent 11,149,306 B2
`
`II.
`
`DISCRETITION UNDER35 U.S.C. § 325(d)
`
`Patent Owner argues that we should exercise discretion to deny
`
`institution because “[t]he same art and arguments presentedin this petition
`
`were considered and rejected by the Office multiple times” and Petitioner
`
`has “failed to .. . demonstrate material error.” Prelim. Resp. 1—2. Petitioner
`
`disagrees. See Pet. 21-24.
`
`A.—Legal Standard
`
`Section 325(d) provides that the Director may elect not to institute a
`
`proceedingif the challenge to the patent is based on matters previously
`
`presented to the Office. The statute states, in pertinent part, “[i]n
`
`determining whetherto institute .
`
`.
`
`. the Director may take into account
`
`whether, and reject the petition .
`
`.
`
`. because, the same or substantially the
`
`sameprior art or arguments previously were presented to the Office.”
`
`35 U.S.C. § 325(d).
`
`The question of whether a petition presents art or argumentsthat are
`
`“the same or substantially the same”as art or arguments previously
`
`presented to the Office is a factual inquiry, which may be resolved by
`
`referenceto the factors set forth in Becton, Dickinson.’ The precedential
`
`section of that decision sets forth the following non-exclusive factors for
`
`consideration:
`
`(a) the similarities and material differences between the
`asserted art and the prior art involved during examination;
`(b) the cumulative nature of the asserted art and the prior art
`evaluated during examination;
`
`Becton, Dickinson & Co. v. B. Braun Melsungen AG, IPR2017-01586,
`Paper 8 (PTAB Dec. 15, 2017) (precedential as to § HII.C.5, first paragraph)
`(“Becton, Dickinson’).
`
`

`

`IPR2022-01400
`Patent 11,149,306 B2
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`(c) the extent to which the asserted art was evaluated during
`examination, including whether the prior art was the basis for
`rejection;
`(d) the extent of the overlap between the arguments made
`during examination and the mannerin whichPetitionerrelies
`on the prior art or Patent Owner distinguishesthe priorart;
`(e) whether Petitioner has pointed out sufficiently how the
`Examinererred in its evaluation of the asserted prior art; and
`(f) the extent to which additional evidence andfacts
`presented in the Petition warrant reconsideration of the prior art
`or arguments.
`
`Becton, Dickinson, 17-18.
`
`AdvancedBionics® sets out a two-part framework for analyzing these
`
`factors. In the first part, we consider factors (a), (b), and (d) to determine
`
`whether the art and arguments presented in the petition are the same or
`
`substantially the same as those previously presented to the Office. Advanced
`
`Bionics, 8-10. “Tf, after review of factors (a), (b), and (d), it is determined
`
`that the same or substantially the same art or arguments previously were
`
`presented to the Office,” then we move on to the secondpart of the analysis
`
`to determine “whether the petitioner has demonstrated a material error by the
`
`Office” in view offactors (c), (e), and (f). /d.
`
`B.
`
`Advanced Bionics Part One
`
`Patent Ownerarguesthat the disclosure in “Schmitt was considered
`
`by the Examiner and applied as the primary reference in prosecution.”
`
`Prelim. Resp. 10. We agree. Both parties acknowledge that Schmitt shares
`
`its specification with U.S. Patent No. 10,752,951 (“Salk”). Pet. 22; Prelim.
`
`Resp. 5. And it is undisputed that the Examiner asserted Salk in anticipation
`
`8 Advanced Bionics, LLC v. MED-EL Electromedizinishe Gerdte GmbH,
`IPR2019-01469, Paper 6 at 10 (Feb. 13, 2020) (precedential) (“Advanced
`Bionics’’).
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`

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`IPR2022-01400
`Patent 11,149,306 B2
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`and obviousnessrejections during prosecution. Pet. 17-18; Prelim. Resp. 6
`
`(citing Ex. 1066, 539-41, 672-74). Thus, there is no dispute that the same
`
`disclosure the Petition relies upon in Schmitt was both before, and evaluated
`
`by,’ the Examiner during prosecution.
`
`Narayan, Craig, and Kivioja were also before the Examiner during
`
`prosecution. Each of these references waslisted in an IDS. Ex. 1066, 122—
`
`221; see also Pet. 21 (acknowledgingthis fact). Thus, all of the same
`
`references in three of the Petition’s four grounds and covering all but two of
`
`the challenged claims were previously presented to the Office. For these
`
`reasons, we determine that, on the whole, the Petition presents the same or
`
`substantially the sameart as that previously presented to the Office and
`
`proceed to the second part of the Advanced Bionics framework.
`
`C.
`
`Advanced Bionics Part Two
`
`During prosecution, the Examinerrejected the then-pending claims
`
`as anticipated by and obviousover Salk, finding that Salk disclosed or
`
`rendered obviouseach of the recited method steps. Ex. 1066, 539-40. Patent
`
`Owner’s initial response (id. at 554—65) did not succeed in overcoming those
`
`rejections. /d. at 671—75 (maintaining rejections).
`
`Patent Ownernext responded by amending claim element 1(b) to
`
`recite tagging with n different combinations of barcodes, “wherein n isat
`
`least 2 and no more than 100,000*z, wherein z is a mean of an expected
`
`number of duplicate molecules in the population of cfDNA moleculesthat
`
`map to identical start and stop positions on a reference sequence.” /d. at 687.
`
`Patent Owner argued that this amendmentdistinguished Salk °951. /d. at
`
`” Wewill address the extent of the Examiner’s evaluation of Schmitt’s
`disclosure (1.e., Becton, Dickinson Factor (c)) when weturn to the second
`part of the Advanced Bionics analysis.
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`

`

`IPR2022-01400
`Patent 11,149,306 B2
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`694. Patent Owneralso argued that Salk was not prior art becauseits priority
`
`applications did not provide written description support for “cfDNA”and
`
`“circulating DNA”asrecited in Salk’s claims. Ex. 1066, 692—93. For
`
`support, Patent Ownerpointed to the Board’s statementin the final written
`
`decision in IPR2019-00652 (the “’652 IPR”) that “Schmitt [’188]'° does not
`
`expressly teach that the target polynucleotide is cfDNA.’” /d. at 693
`
`(quoting Ex. 1074, 31). The Examiner subsequently withdrew the rejections
`
`without expressly noting the reasons for allowance. See id. at 708 (notice of
`
`allowance).
`
`Petitioner urges that the Examiner erred in a numberofrespects. See
`
`Pet. 21-24; Reply 4—5. Most of these alleged errors relate to arguments
`
`Patent Owner madeinits first response to the Examiner’s rejections. As
`
`noted above, those initial arguments were not successful in overcoming the
`
`rejections, and the Examinerdid notarticulate any particular reasons for
`
`allowing the claims.
`
`Nevertheless, based on its showing in Ground 1, we determinethat
`
`Petitioner has sufficiently demonstrated a material error during the
`
`examination of claim 1. Claim | and its dependent claims were allowed
`
`shortly after Patent Owner’s amendmentto recite a range of barcode
`
`combinations n between 2 and 100,000*z in element 1(b). This suggests the
`
`Examiner determined that Salk and Schmitt ?188 did not disclose or suggest
`
`the recited range. As explained below, however, the record at this stage of
`
`the proceeding supports Petitioner’s argument that the numberof barcode
`
`10 The “Schmitt” referenced in the °652 IPR decision is U.S. Patent No.
`9,752,188 (‘Schmitt ?188”). Ex. 1074, 3 n. 2. Schmitt ’188 claimspriority to
`the international application publication (1.e., WO2013/142,389) referred to
`as “Schmitt” in this proceeding. Ex. 2008, code (87).
`
`10
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`IPR2022-01400
`Patent 11,149,306 B2
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`combinations for Schmitt’s 3-mer hybrid tag embodimentfalls within the
`
`recited range regardless of the value of z. See infra § IIL.E.1. To the extent
`
`the Examinerdid not appreciate the relevance of the “hybrid method using a
`
`combination of sheared ends and shorter n-mertags (such as | or 2 or 3 or 4
`
`or more degenerate or semi-degenerate bases)” taught in Salk and
`
`Schmitt ?188 to claim element 1(b), this constitutes material error. Ex. 2012
`
`9:20—24; Ex. 1083 § 30. Moreover, the Petition presents additional evidence
`
`regarding element 1(b), e.g., Ex. 1002 4 166, that warrants reconsideration
`
`of Schmitt in this proceeding.
`
`Wealso note that Patent Owner’s argument during prosecution that
`
`Salk was not prior art because it lacks written description support for cfDNA
`
`is a different issue than whether the challenged claims are obvious over
`
`Schmitt and Narayan and the other referencescited in the Petition. The
`
`Examiner’s rejection relied at least in part on the disclosure in Salk’s claims.
`
`See Ex. 1066, 674. The Petition, however, relies on the disclosure in
`
`Schmitt’s specification (and even more specifically on the disclosure in a
`
`priority application, provisional application 61/625,623 (“Schmitt-623”(Ex.
`
`1083)). See infra § III.D.2. At this stage of the proceeding, Patent Owner
`
`does not dispute that the disclosure in Schmitt is prior art to the challenged
`
`claims. Moreover, as explained below,the Petition relies on Narayan’s
`
`disclosure of cfDNA in combination with Schmitt.!'! Thus, to the extent the
`
`'! Tn this regard, Petitioner’s obviousness theory is consistent with the
`ground on which claims were determined to be unpatentable in the *652 IPR.
`There, the panel determined that “although Schmitt [’188] does not
`expressly teach that the target polynucleotide is cfDNA, [other references
`cited in combination with Schmitt ’?188] teach the extraction and analysis of
`cfDNA.” Ex. 1074, 29; see also id. at 51 (finding, based on the record in that
`proceeding, “that an ordinarily skilled artisan screening cfDNA for cancer
`
`11
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`IPR2022-01400
`Patent 11,149,306 B2
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`Examinerdid not consider the disclosure in Salk’s specification to be prior
`
`art, or did not consider whether it would have been obvious to apply the
`
`methodology taught in Salk and Schmitt to cfDNA based on the teachings in
`
`other references such as Narayan,this was also a materialerror.
`
`For these reasons, we find that Petitioner has demonstrated a material
`
`error, and therefore, will not exercise discretion to deny institution of inter
`
`partes review under 35 U.S.C. § 325(d).
`
`Il. ANALYSIS
`
`A.—Legal Standard
`
`A patent claim is unpatentable under 35 U.S.C. § 103 if the
`
`differences between the claimed invention and the prior art are such that the
`
`claimed invention, as a whole, would have been obviousat the time the
`
`invention was madeto a person having ordinary skill in the art to which the
`
`subject matter pertains. See KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 406
`
`(2007). The question of obviousnessis resolved on the basis of underlying
`
`factual determinations, including: (1) the scope and content of the priorart;
`
`(2) any differences between the claimed subject matter and the priorart; (3)
`
`the level of skill in the art; and (4) objective evidence of nonobviousness.
`
`Graham vy. John Deere Co., 383 U.S. 1, 17-18 (1966).
`
`“[A] patent composed of several elements is not proved obvious
`
`merely by demonstrating that each of its elements was, independently,
`
`knownin the prior art.” KSR, 550 U.S. at 418. “[I]t can be important to
`
`identify a reason that would have prompted a person of ordinary skill in the
`
`relevant field to combine the elements in the way the claimed new invention
`
`mutations ... would have looked to Schmitt’s DCS method” to reduceerrors
`and improve detection).
`
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`does.” /d. Moreover, a person of ordinary skill in the art must have had a
`
`reasonable expectation of success of doing so. PAR Pharm., Inc. v. TWI
`
`Pharms., Inc., 773 F.3d 1186, 1193 (Fed. Cir. 2014).
`
`B.
`
`Person of Ordinary Skill in the Art
`
`Petitioner asserts that a person of ordinary skill in the art (“POSA”) at
`
`the time of the invention would have had
`
`(1) a Ph.D. in molecular biology, genetics, bioinformatics, or a
`related field, and have at least about two years of experience in
`the use and development of sequencing technologies; or (11) a
`Master’s degree in one of the samefields with at least aboutfive
`years of the same experience.
`
`Pet. 18 (citing Ex. 1002 §§] 27-30). Patent Owner doesnot offer a proposed
`
`definition of the level of ordinary skill in the art at this stage of the
`
`proceeding.
`
`On this record, we adopt Petitioner’s uncontested definition of the
`
`level of ordinary skill in the art. We further note that the priorart itself is
`
`sufficient to demonstrate the level of skill in the art at the time of the
`
`invention. See Okajima v. Bourdeau, 261 F.3d 1350, 1355 (Fed. Cir. 2001)
`
`(explaining that specific findings regarding ordinary skill level are not
`
`required “wherethe priorart itself reflects an appropriate level and a need
`
`for testimony 1s not shown”(quoting Litton Indus. Prods., Inc. v. Solid State
`
`Sys. Corp., 755 F.2d 158, 163 (Fed. Cir. 1985))).
`
`C.
`
`Claim Construction
`
`In an inter partes review, the Board applies the same claim
`
`construction standard that would be used to construe the claim inacivil
`
`action under 35 U.S.C. § 282(b). See 37 C.F.R. § 100(b). Underthat
`
`standard, claim terms “are generally given their ordinary and customary
`
`meaning” as understood by a person of ordinary skill in the art at the time of
`
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`Patent 11,149,306 B2
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`the invention. Phillips v. AWH Corp., 415 F.3d 1303, 1312-13 (Fed. Cir.
`
`2005) (en banc).
`
`Element 1(b) recites a range of “different combinations of molecular
`
`barcodes” between 2 and “no more than 100,000*z, wherein zis a mean of
`
`an expected number of duplicate molecules in the population of cfDNA
`
`molecules that map to identical start and stop positions on a reference
`
`sequence.” Ex. 1001, 61:15—21. Petitioner does not specify any formal claim
`
`construction, but contends a “POSA would understandthat the population of
`
`cf{DNA molecules that map to identical start and stop positions will vary,
`
`depending on the numberof haploid gene equivalents (HGEs) in the
`
`sample.” Pet. 19 (citing Ex. 1002 4¥ 131-133). Moreover, Petitioner
`
`contends that Schmitt discloses tagging with barcodes having a number of
`
`combinationsthat falls within the recited range regardless of the value ofz.
`
`See id. at 29 (arguing that Schmitt discloses the use of “3-mer barcodes”
`
`having “4,096 different combinations” that “would fall between 2 and
`
`100,000*z” regardless of “whether zis 1, 10, 100, 800, etc.”’). Patent Owner
`
`disputes Petitioner’s showing for element 1(b), but does not seek any claim
`
`construction at this stage. Prelim. Resp. 19.
`
`As explained below and based on the current record, Petitioner has
`
`shown sufficiently for institution that Schmitt discloses the use of barcodes
`
`having a numberof different combinationsthat falls within the recited range
`
`regardless of the value of z. For this reason,it is unnecessary to expressly
`
`construe “z” or any other aspect of element 1(b) to decide the issues
`
`presented in the Petition. To the extent Patent Ownerdisagrees, it will have
`
`the opportunity to addressthis issueattrial.
`
`Neither party refers to any other claim term in the claim construction
`
`sections of their papers. See Pet. 18-19; Prelim. Resp. 19. We agreethatit is
`
`14
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`Patent 11,149,306 B2
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`unnecessary to expressly construe any claim term for purposes of rendering
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`this Decision. See Wellman, Inc. v. Eastman Chem. Co., 642 F.3d 1355,
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`1361 (Fed. Cir. 2011) (“[C]laim terms need only be construed ‘to the extent
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`necessary to resolve the controversy.’”
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`(quoting Vivid Techs., Inc. v. Am.
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`Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999))).
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`D.
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`Cited References
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`1.
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`Narayan
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`Narayan is a journalarticle titled “Ultrasensitive Measurementof
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`Hotspot Mutations in Tumor DNA in Blood Using Error-Suppressed
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`Multiplexed Deep Sequencing,” and bearing a 2012 publication date.
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`Ex. 1082, 3492.!? Patent Owner doesnot dispute that Narayanis prior art in
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`its Preliminary Response.
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`According to Narayan, “[d]etection of cell-free tumor DNA in the
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`blood has offered promise as a cancer biomarker, but practical clinical
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`implementations have been impeded bythe lack of a sensitive and accurate
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`method for quantification that is also simple, inexpensive, and readily
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`scalable.” /d. Narayan describes “an approach that uses next-generation
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`sequencing [“NGS”] to quantify the small fraction of DNA molecules that
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`contain tumor-specific mutations within a background of normal DNA in
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`plasma.” /d.
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`2.
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`Schmitt
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`Schmitt is an international patent application entitled “Methods of
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`Lowering the Error Rate of Massively Parallel DNA Sequencing Using
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`Duplex Consensus Sequencing,” and published on September 26, 2013.
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`” Unless stated otherwise, citations to page numbersrefer to the reference
`page numbers.
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`Ex. 1009, code (43). Petitioner contends that Schmitt is prior art under 35
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`U.S.C. § 102(a)(1) and (a)(2), relying on the fact that Schmitt claims priority
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`to Schmitt-623. Pet. 20-21. Petitioner contends that Schmitt is prior art as of
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`the filing date of Schmitt-623, 1.e., April 17, 2012, because the disclosures
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`Petitioner relies upon in Schmitt “were carried forward from Schmitt-623”
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`and “Schmitt-623 provides §112 support for at least on[e] claim in Schmitt.”
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`7d. (internal quotations omitted). Patent Owner does not dispute these
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`contentions in its Preliminary Response."
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`Schmitt describes a method called Duplex Consensus Sequencing
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`(“DCS”) that, according to Schmitt, “greatly reduces sequencing errors by
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`independently tagging and sequencing each of the two strands of a DNA
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`duplex.” Ex. 1083, 47 (Abstract). Because the two strands of DNA are
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`complementary, true mutations can be found at the same position on both
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`strands. /d. As Schmitt explains:
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`Comparing the sequence obtained from each of the two strands
`comprising a single molecule of duplex DNA facilitates
`differentiation of sequencing errors from true mutations. When
`an apparent mutation is, due to a PCR or sequencingerror, the
`substitution will only be seen on a single strand. In contrast,
`with a true DNA mutation, complementary substitutions will be
`present on both strands.
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`Id. | 62. According to Schmitt, its DCS “method uniquely capitalizes on the
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`redundant information stored in double-stranded DNA,thus overcoming
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`'5 The Petition cites to the disclosure in Schmitt-623, rather than Schmitt
`itself, as support for the asserted grounds. See, e.g., Pet. 27-61 (citing
`Ex. 1083 to support statements regarding the teachings in Schmitt). The
`Preliminary Responsealso cites Schmitt-623 to respond to Petitioner’s
`allegations. Prelim. Resp. 25 n.3. For ease of reference, we too cite to
`Schmitt-623. For purposes of our present analysis, we consider the
`disclosure in Schmitt-623 to be representative of the teachings in Schmitt.
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`technical limitations of prior methods ofutilizing data from only one of the
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`two strands.” /d. at 47 (Abstract).
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`In Schmitt’s DCS method, double-stranded DNA molecules are
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`ligated to single molecule identifier (“SMI’’) adapter molecules. Ex. 1083
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`4] 9-10. In one embodiment, “[s]heared double-stranded DNA that has been
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`end-repaired and T-tailed 1s combined with A-tailed SMI adaptors and
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`ligated.” /d. § 11, Fig. 1. In this embodiment, “every adaptor contains a
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`unique, double-stranded, complementary n-mer random tag on each end.”
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`Id.; see also § 16 (describing the embodiment in Example 1 in which “the
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`SMI sequence is a random degenerate nucleotide n-mer sequence whichis
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`12 nucleotides in length’’). In another embodiment, Schmitt discloses a
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`“hybrid method using a combination of sheared ends and shorter n-mer tags
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`(such as 1 or 2 or 3 or 4 or more degenerate or semi-degenerate bases)”to
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`“serve as unique molecular identifiers.” /d. § 30. The labeled DNA
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`fragments are then amplified (e.g., by PCR) and sequenced. /d.
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`42
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`Schmitt teaches that sequence reads are “groupedinto families of
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`paired target nucleic acid strands based on a commonset of SMI sequences”
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`to produce “an error corrected double-stranded consensus sequence.”
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`Ex. 1083 4 43, 60. This data processing is described in Schmitt’s
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`Example 1. See id. ¥§| 60-69. There, “[rJeads having common(i.e., identical)
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`SMI sequences were grouped together, and were collapsed to generate a
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`consensusread.” /d. § 60. “PCR consensus sequences arising from two
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`complementary strands of duplex DNA”are then identified “by virtue of the
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`complementary SMIs”that “identify the “partner SMI.”’ /d. J 63; see also
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`id. { 13, Fig. 3 (showing how sequence reads “sharing a unique set of SMI
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`tags are grouped into paired families with membershaving strand identifiers
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`in either the aB or Ba orientation”). “Following partnering of two strands by
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`virtue of their complementary SMIs, the sequences of the strands are
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`compared. Sequencereadsat a given position are kept only if the read data
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`from each of the two paired strands is in agreement.” /d.; see also id. J 60,
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`68 (“Sequence reads were considered only when the read data from each of
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`the two strandsis in perfect agreement’).
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`3.
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`Meyer
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`Meyeris a journalarticle titled “Parallel tagged sequencing on the 454
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`platform” and bearing a 2008 publication date. Ex. 1005, 267. Patent Owner
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`does not dispute that Meyeris prior art in its Preliminary Response.
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`Meyerrelates to a methodcalled parallel tagged sequencing that
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`allows for parallel sequencing of large numbers of double-stranded DNA
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`samples on a next-generation sequencing system called the 454 Platform.
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`Id., Abstr. According to Meyer, the method involves blunt end repairing
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`each DNA sample and then ligating sample-specific barcoding adapters to
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`both ends of blunt-end repaired DNA molecules. /d. at 268, Fig. 1. The
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`adapters “comprise single self-hybridized oligos containing a sequence tag
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`and an SrfI restriction site.” /d. at 267. The barcoded samples are pooled in
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`equimolarratios, and untagged molecules are excluded from sequencing
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`through dephosphorylation and restriction digestion. /d., Fig. 1. The sample
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`pool is then sequenced and the sequencereadsare sorted accordingto their
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`tag sequences and the source of each DNA canthen betraced using the tag
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`sequences. /d.
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`4.
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`Craig
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`Craig is a journalarticle titled “Identification of genetic variants using
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`bar-coded multiplexed sequencing,” and bearing an October 2008
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`publication date. Ex. 1007, 887. Patent Owner doesnot dispute that Craig is
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`prior art in its Preliminary Response.
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`Craig relates to “a generalized framework for multiplexed
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`resequencing of targeted human genome regions on the I[lumina Genome
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`Analyzer using degenerate indexed DNAbarcodesligated to fragmented
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`DNAbefore sequencing” for simultaneously sequencing DNA from multiple
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`individuals. Ex. 1007, 887. Craig refers to these bar codesas “indexes” and
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`describes the use of “a six-base index with built-in redundancyfor error
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`correction.” /d. According to Craig, “only 48 of the 4,096 possible
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`nucleotide combinations” were synthesized for use in their experiment.
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`Craig explains that this design “allowed usto control, tolerate and measure
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`error base calling of the index” because “one, and in somecases two,
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`sequencing errors could be tolerated without an index being incorrectly
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`identified as being a different valid index. /d. at 888; see also id. at 13"*
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`(Supplementary Table 4 describing the design of the “DNA Indexes
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`Appended to Each Adapter’).
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`J.
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`Kivioja
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`Kivioja is a journal article titled “Counting absolute numbers of
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`molecules using unique molecular identifiers,” and bearing a November
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`2011 publication date. Ex. 1006, 72. Patent Owner doesnot dispute that
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`Kivioja is prior art in its Preliminary Response.
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`According to Kivioja, [d]etermining the relative abundance of two
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`dif