‘Trialsiauspto. gov
`
`571-272-7822
`
`Paper 41
`Entered: January 26, 2024
`
`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.
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. $ 318(a)
`Denying Patent Owner’s Motionto Strike
`Denying Patent Owner’s Motion to Exclude
`37 CER. $ 42.64(c)
`
`
`
`571-272-7822
`
`Paper 41
`Entered: January 26, 2024
`
`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.
`
`JUDGMENT
`Final Written Decision
`Determining No Challenged Claims Unpatentable
`35 U.S.C. $ 318(a)
`Denying Patent Owner’s Motionto Strike
`Denying Patent Owner’s Motion to Exclude
`37 CER. $ 42.64(c)
`
`
`
`IPR2022-01400
`Patent 11,149,306 B2
`
`I.
`
`INTRODUCTION
`
`TwinStrand Biosciences, Inc. (“Petitioner”) filed a Petition requesting
`
`an interpartes review of claims 1—29 of U.S. Patent No. 11,149,306 B2
`
`(Ex. 1001, “the *306 patent”). Paper 2 (“Pet.”’). We instituted trial on all of
`
`the grounds in the Petition. Paper 9, 44 (“Dec.”’).
`
`Guardant Health, Inc. (“Patent Owner”) subsequentlyfiled its
`
`Responseto the Petition (Paper 18, “Resp.”’), Petitionerfiled its Reply
`
`(Paper 25, “Reply”) and Patent Ownerfiled its Sur-reply (Paper 30, “Sur-
`
`reply.”). In addition, with our authorization, Patent Ownerfiled a motion to
`
`strike certain exhibits submitted with the Reply (Paper 29, “MTS”), which
`
`Petitioner has opposed (Paper 31, “MTS Opp.”). Patent Owneralso filed a
`
`motion to exclude (Paper 32 (“MTE”)), which Petitioner has opposed (Paper
`
`34 (“MTE Opp.”). We held a hearing on November 17, 2023, anda
`
`transcript is ofrecord. Paper 40 (“Tr.”).
`
`After considering the parties’ arguments and evidence,wefind that
`
`Petitioner has not shownby a preponderanceofthe evidencethat the
`
`challenged claims ofthe ’306 patent are unpatentable. See 35 U.S.C.
`
`§ 316(e). Moreover, we deny Patent Owner’s motionsto strike and exclude.
`
`I. BACKGROUND
`
`A.
`
`Real Parties in Interest
`
`Petitioneridentifies itselfas areal party in interest andthe University
`
`of Washingtonas a potentialreal party in interest. Pet. 69. Patent Owner
`
`identifies itselfas a real party in interest. Paper 19, 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.,
`
`sequence variations) or changes in epigenetic markers, such as cancer and
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`
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`IPR2022-01400
`Patent 11,149,306 B2
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`partial or complete aneuploidy, may be detected or more accurately
`
`characterized with DNA sequence information./d. at 1:26—30.
`
`Early detection and monitoring of genetic diseasesis often useful and
`
`neededin the successful treatment or managementof a disease. Ex. 1001,
`
`1:31—33. According to the ?306 patent, one approach mayinclude
`
`monitoring a sample derived from cell-free nucleic acids, which are
`
`polynucleotides that can be found in different types ofbodily fluids. /d. at
`
`1:33—36. Cell-free DNA (“cfDNA”) may contain genetic aberrations, such
`
`as copy numbervariation or sequencevariation, 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 ofthose 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 estimatethe copy numbervariation at oneor moreloci. /d. at 1:51—55.
`
`The ’306 patentstates that although known methodsfor detecting
`
`cfDNAare able to reduce the errors introduced by the sample preparation
`
`and sequencingprocesses for the molecules that are converted and
`
`sequenced, these methods are notable to infer the counts ofmolecules 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 oftagging and
`
`counting both halves of double-stranded DNA and estimating the numberof
`
`unseen molecules based on the numberofPairs (1.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 (1.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 ofthe ’306 patent. Ofthese, claims
`
`1 and 17 are independent. Claims 1 and 17 read as follows:
`
`1. A method, comprising:
`
`(a) providing a population ofcell-free deoxyribonucleic acid
`(cf{DNA) molecules havingfirst and second complementary
`strands;
`
`(b) tagginga plurality ofthe 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 ofthe
`plurality ofthe cf(DNA molecules, wherein the plurality of
`the cfDNA molecules are tagged with n different
`combinations ofmolecular barcodes, whereinnis at least 2
`and no more than 100,000*z, wherein z is a mean of an
`expected numberof duplicate moleculesin the population of
`cf{DNA molecules that map to identical start and stop
`positions on areference sequence;
`
`(c) amplifying a plurality ofthe tagged parent polynucleotides
`to produce amplified progeny polynucleotides;
`
`(d) sequencingat least a subset ofthe 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 readsusing at least sequence
`information from the molecular barcodes ofthe duplex tags
`to determine distinct cfDNA 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 anda second tagged complementary strand
`derived from cfDNA molecules from among the tagged
`parent polynucleotides, or (11) unpaired reads corresponding
`to sequence reads generated from a first tagged strand
`
`
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`IPR2022-01400
`Patent 11,149,306 B2
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`having no second tagged complementary strand derived
`from cf{DNA molecules from among thetagged parent
`polynucleotides, wherein reducingor tracking the
`redundancy ofthe plurality of sequence reads comprises
`mappingat least a subset ofthe plurality of sequence reads
`to the reference sequence.
`
`17. A method, comprising:
`
`(a) taggingapopulation of double-strandedcell-free
`deoxyribonucleic acid (cfDNA) molecules obtained or
`derived from a sample ofa subject withaset of tags
`comprising molecular barcodesto produce tagged parent
`polynucleotides;
`
`(b) amplifying a plurality ofthe tagged parent polynucleotides
`to produce amplified progeny polynucleotides;
`
`(c) sequencingat least a subset ofthe amplified progeny
`polynucleotides to produce a set of sequencereads; and
`
`(d) sortingaplurality of sequence reads from the set of
`sequence readsinto (1) families comprising paired reads
`corresponding to sequencereads generated fromafirst
`tagged strand anda 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 ofUnpatentability
`
`Petitioner asserts that claims 1—29 are unpatentable on the following
`
`grounds:
`
`
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`IPR2022-01400
`Patent 11,149,306 B2
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`1-3, 5, 7,9-14, 17—
`27,29
`
`103
`
`Narayan? and Schmitt?
`
`
`
`Narayan, Schmitt, and Meyer’
`Narayan, Schmitt, and
`103
`Craig>
`15, 16, 28|=103.—S—s| Narayan, Schmitt, and Kivioja°
`
`In support ofthese grounds, Petitioner relies upon the Declaration ofPaulT.
`
`Spellman, Ph.D. (Ex. 1002), submitted with the Petition, and the
`
`Declarations ofRahul Satiyja, D.Phil. (Ex. 1098) and Aleksandar Rajkovic,
`
`M.D., Ph.D. (Ex. 1099), submitted with the Reply. Patent Ownerrelies on
`
`the Declarations ofDr. John Quackenbush (Ex. 20115) and Dr. Ian
`
`Hageman (Ex. 2016).
`
`' 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 claimspriority to a series of applicationsthe earliest
`of whichis a provisionalapplication filed on December 28, 2013. Ex. 1001
`code (60). Because the AIA became effective before thefiling ofthe earliest
`of the application to which the ’306 patent claimspriority, we apply the AIA
`version ofthe statute.
`? Narayanet al., Ultrasensitive Measurement ofHotspotMutations in Tumor
`DNAin Blood Using Error-SuppressedMultiplexedDeep Sequencing,
`72(14) CANCER RES. 3492—98 (Ex. 1082) (“Narayan”).
`> Schmitt et al., WO 2013/142389 A1, published Sept. 26, 2013 (Ex. 1009)
`(‘Schmitt’).
`4 Meyeret al., Parallel TaggedSequencing on the 454 Platform, 3(2)
`NATURE PROTOCOLS 267—78 (2008) (Ex. 1005) (“Meyer”).
`> Craig et al., /dentification ofGenetic Variants Using Bar-coded
`Multiplexed Sequencing, 5(10) NATURE METHODS 887-93 (2008) (Ex. 1007)
`(“Craig”).
`° Kivioja et al., CountingAbsolute Numbers ofMolecules Using Unique
`Molecular Identifiers, 9 NATURE METHODS 72—76 (2012) (Ex. 1006)
`(“Kivioja’).
`
`
`
`IPR2022-01400
`Patent 11,149,306 B2
`
`I. ANALYSIS
`
`A.
`
`Legal Standard
`
`A patent claim is unpatentable under 35 U.S.C. § 103 ifthe
`
`differences between the claimed invention andthepriorart are such that the
`
`claimed invention, as a whole, would have been obviousat thetimethe
`
`invention was made to a person having ordinary skill in the art to which the
`
`subject matter pertains. See KSR Int’] Co. v. Teleflex Inc., 550 U.S. 398, 406
`
`(2007). The question of obviousnessis resolved on the basis ofunderlying
`
`factual determinations, including: (1) the scope and content ofthe priorart;
`
`(2) any differences between the claimed subject matter andthepriorart; (3)
`
`the level of skill in the art; and (4) objective evidence ofnonobviousness.
`
`Graham v. John Deere Co. , 383 U.S. 1, 17-18 (1966).
`
`“[A] patent composedofseveral 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 ofordinary skill in the
`
`relevantfield to combinethe elements in the way the claimed new invention
`
`does.” /d. Moreover, a person ofordinary skill in the art must have hada
`
`reasonable expectation of success of doing so. PAR Pharm., Inc. v. TWi
`
`Pharms., Inc., 773 F.3d 1186, 1193 (Fed. Cir. 2014).
`
`B.—PersonofOrdinary Skill in the Art
`
`Relying on Dr. Spellman’s testimony, Petitioner asserts that a person
`
`of ordinary skill in the art (“POSA”) at thetime ofthe 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
`
`
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`IPR2022-01400
`Patent 11,149,306 B2
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`Master’s degree in one ofthe samefields with at least aboutfive
`years of the same experience.
`
`Pet. 18 (citing Ex. 1002 49 27-30). Patent Owneragrees that a POSA would
`
`have had the knowledge suggested by Dr. Spellman, andits declarants apply
`
`“Dr. Spellman’s definition of a POSA in their analyses.” Resp. 6—7.
`
`Weadopt Petitioner’s uncontested definition ofthe level of ordinary
`
`skill in the art. This definition 1s supported by the record (Ex. 1002 44] 27—
`
`30) and consistent with the disclosure in the ’306 patent and references cited
`
`in the Petition.
`
`C.
`
`Claim Construction
`
`In an interpartes review, the Board applies the same claim
`
`construction standard that would be used to construe the claim in a civil
`
`action under 35 U.S.C. § 282(b). See 37 C.F.R. § 100(b). Under that
`
`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
`
`the invention. Phillips v. AWH Corp., 415 F.3d 1303, 1312-13 (Fed. Cir.
`
`2005) (en banc).
`
`In our Institution Decision, we noted Petitioner’s assertions regarding
`
`a POSA’s understanding of “z” in element 1(b) and its contention that
`
`Schmitt discloses a numberofdifferent combinations of molecular barcodes
`
`that was within the range recited in element 1(b) regardless ofthe z value.
`
`Dec. 14 (citing Pet. 19). Based on therecordat that time, we explained that
`
`[flor this reason, it is unnecessary to expressly construe ‘z’ or any other
`
`aspect of element 1(b) to decides the issues present in the Petition.” /d. We
`
`also noted that, at least at the institution stage, neither side had proposedany
`
`express claim construction./d.
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`
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`In its Response, Patent Ownerasserts that “[n]o specific construction
`
`is believed necessary here to determinethat the recited termsare disclosed in
`
`the cited prior art.” Resp. 7. Nevertheless, Patent Owneroffers a
`
`“discussion”to “provide[] context” regardingits interpretation of certain
`
`terms relating to tagging of cfDNA molecules in element 1(b). /d. at 7-8.
`
`According to Patent Owner,“claim construction must begin with the words
`
`of the claims themselves,” and here the “language of claim 1 distinguishes
`
`the duplex tags” comprising molecular barcodes in element 1(b) “from the
`
`cfDNA molecules” to which they are attached. /d. at 8 (quoting Amgen Inc.
`
`v. Hoechst Marion Roussel, Inc. ,457 F.3d 1293, 1301 (Fed. Cir. 2006). In
`
`particular, Patent Ownerpointsto the fact that claim 1 “expressly recites
`
`“wherein the duplex tags are attached to both ends of a molecule ofthe
`
`plurality ofthe cfDNA molecules.”/d. (quoting Ex. 1001, 61:13-14).
`
`Petitioner does not directly reply to Patent Owner’s argument that the
`
`claim language distinguishes between the duplex tags and cfDNA
`
`molecules. See generally Reply. Instead, Petitioner contends that Patent
`
`Owner“ignoresthe [’]306 patent’s definition ofduplex tags.” Reply 8.
`
`Moreover, Petitioner contendsthat the ’306 patent “admits” that its methods
`
`encompassthe tagging methodology,1.¢., “Schmitt’s hybrid tagging
`
`embodiment,”it relies upon in the Petition. /d. at 9.
`
`Thus, while neither party proposes any formal claim construction,
`
`some oftheir arguments regarding the application of Schmitt’s teachings to
`
`element 1(b) present issues relating to the properinterpretation of element
`
`1(b). We address those issues below in context ofthe parties’ other
`
`argumentsrelating to element 1(b). No other claim construction is necessary
`
`for this decision.
`
`
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`IPR2022-01400
`Patent 11,149,306 B2
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`D.
`
`CitedReferences
`
`l.
`
`Narayan
`
`Narayan is a journal articletitled “Ultrasensitive Measurement of
`
`Hotspot Mutations in Tumor DNAin Blood Using Error-Suppressed
`
`Multiplexed Deep Sequencing,” and bearing a 2012 publication date.
`
`Ex. 1082, 3492.’ Patent Ownerdoesnotdispute, and we agree, that Narayan
`
`is prior art to the challenged claimshere.
`
`According to Narayan,“[d]etection of cell-free tumor DNAin the
`
`blood has offered promise as a cancer biomarker, but practical clinical
`
`implementations have been impeded by the lack ofa sensitive and accurate
`
`method for quantification that is also simple, inexpensive, and readily
`
`scalable.” /d. Narayan describes “an approachthat uses next-generation
`
`sequencing to quantify the small fraction ofDNA moleculesthat contain
`
`tumor-specific mutations within a background ofnormal DNA in plasma.”
`
`Id.
`
`2.
`
`Schmitt
`
`Schmitt is an international patent application entitled “Methods of
`
`Lowering the Error Rate ofMassively Parallel DNA Sequencing Using
`
`Duplex Consensus Sequencing,” and published on September 26, 2013.
`
`Ex. 1009, code (43). Petitioner contends that Schmitt is prior art under
`
`35 U.S.C. § 102(a)(1) and (a)(2), relying on the fact that Schmittclaims
`
`priority to Schmitt-623. Pet. 20—21. Petitioner contends that Schmitt is prior
`
`art as of the filing date of Schmitt-623, 1.¢e., April 17, 2012, becausethe
`
`disclosures Petitioner relies upon in Schmitt “were carried forward from
`
`7 Unless stated otherwise,citations to page numbersrefer to the reference
`page numbers.
`
`10
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`IPR2022-01400
`Patent 11,149,306 B2
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`Schmitt-623”and “Schmitt-623 provides §112 support for at least on[e]
`
`claim in Schmitt.” /d. (internal quotations omitted). Patent Ownerdoes not
`
`dispute these contentions and we agree that Schmitt is prior art to the
`
`challenged claimshere.®
`
`Schmitt describes a method called Duplex Consensus Sequencing
`
`(“DCS”) that, according to Schmitt, “greatly reduces sequencingerrors by
`
`independently tagging and sequencing each ofthe two strands ofa DNA
`
`duplex.” Ex. 1083, 47 (Abstr.). Because the two strands ofDNA are
`
`complementary, true mutations can be found at the same position on both
`
`strands. /d. As Schmitt explains:
`
`Comparing the sequence obtained from each ofthe twostrands
`comprising a single molecule of duplex DNAfacilitates
`differentiation of sequencing errors from true mutations. When
`an apparent mutation is, due toa PCRor sequencingerror, the
`substitution will only be seen on a single strand. In contrast,
`with atrue DNA mutation, complementary substitutions will be
`present on bothstrands.
`
`Id. ¥ 62. According to Schmitt, its DCS “method uniquely capitalizes on the
`
`redundantinformation stored in double-stranded DNA, thus overcoming
`
`technical limitations ofprior methodsofutilizing data from only one ofthe
`
`two strands.” /d. at 47 (Abstr.).
`
`In Schmitt's DCS method, double-stranded DNA molecules are
`
`ligated to single molecule identifier (“SMI”) adapter molecules. Ex. 1083
`
`8 The Petition cites to the disclosure in Schmitt-623, ratherthan Schmitt
`itself, as support for the asserted grounds. See, e.g., Pet. 27-61 (citing
`Ex. 1083 to support statements regarding theteachings in Schmitt). The
`Preliminary Responsealso cites Schmitt-623 to respondto Petitioner’s
`allegations. Prelim. Resp. 25 n.3. For ease ofreference, we too cite to
`Schmitt-623. For purposes of our present analysis, we consider the
`disclosure in Schmitt-623 to be representative ofthe teachings in Schmitt.
`
`11
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`4] 9-10. In one embodiment, “[s]heared double-stranded DNA that has been
`
`end-repaired and T-tailed is combined with A-tailed SMIadaptors and
`
`ligated.” /d. § 11, Fig. 1. In this embodiment, “every adaptor contains a
`
`unique, double-stranded, complementary n-mer'!”! random tag on each end.”
`
`Id.; see also § 16 (describing the embodiment in Example 1 in which “the
`
`SMI sequence is arandom degenerate nucleotide n-mer sequence whichis
`
`12 nucleotides in length’). In another embodiment, Schmitt discloses a
`
`“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)” to
`
`“serve as unique molecularidentifiers.” /d. 430. The labeled DNA
`
`fragments are then amplified (e.g., by PCR) and sequenced./d. § 42
`
`Schmittteaches that sequence readsare “grouped into families of
`
`paired target nucleic acid strands based on a commonset of SMI sequences”
`
`to produce “an error corrected double-stranded consensus sequence.”
`
`Ex. 1083 {§ 43, 60. This data processing is described in Schmitt's
`
`Example 1. See id. 44 60-69. There, “[r]eads having common(1.e., identical)
`
`SMI sequences were groupedtogether, and were collapsed to generate a
`
`consensusread.” /d. § 60. “PCR consensus sequencesarising from two
`
`complementary strands of duplex DNA”are then identified “by virtue ofthe
`
`complementary SMIs”that “identify the ‘partner SMI.” /d. 463; see also
`
`id. ¥ 13, Fig. 3 (showing how sequence reads“sharing a unique set of SMI
`
`tags are groupedinto paired families with membershaving strandidentifiers
`
`in either the aor Ba orientation’). “Following partnering oftwo strands by
`
`virtue oftheir complementary SMIs, the sequences ofthe strandsare
`
`? An n-meris a sequence wheren is the numberofnucleotides. A 3-mer,for
`example, is a sequence ofthree nucleotides.
`
`12
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`compared. Sequencereadsat a given position are kept only ifthe read data
`
`from each ofthe twopaired strandsis in agreement.” /d.; see also id. J§ 60,
`
`68 (“Sequence reads were considered only whenthe read data from each of
`
`the twostrandsis in perfect agreement’).
`
`3.
`
`Meyer
`
`Meyeris a journalarticle titled “Parallel tagged sequencing on the 454
`
`platform”andbearing a 2008 publication date. Ex. 1005, 267. Patent Owner
`
`does not dispute, and we agree, that Meyeris prior art to the challenged
`
`claims here.
`
`Meyerrelates to a methodcalled parallel tagged sequencing that
`
`allowsfor parallel sequencing of large numbersof double-stranded DNA
`
`samples on a next-generation sequencing system called the 454 Platform.
`
`Id., Abstr. According to Meyer, the method involvesblunt end repairing
`
`each DNAsample and then ligating sample-specific barcoding adapters to
`
`both endsofblunt-end repaired DNA molecules. /d. at 268, Fig. 1. The
`
`adapters “comprise single self-hybridized oligos containing a sequence tag
`
`and an Srfl restriction site.” /d. at 267. The barcoded samples are pooled in
`
`equimolar ratios, and untagged molecules are excluded from sequencing
`
`through dephosphorylation and restriction digestion. /d., Fig. 1. The sample
`
`pool is then sequenced and the sequencereadsare sorted accordingto their
`
`tag sequences and the source of each DNAcanthen be traced using the tag
`
`sequences. /d.
`
`4.
`
`Craig
`
`Craig is a journal article titled “Identification of genetic variants using
`
`bar-coded multiplexed sequencing,” and bearing an October 2008
`
`publication date. Ex. 1007, 887. Patent Owner doesnotdispute, and we
`
`agree, that Craig is prior art to the challengedclaims here.
`
`13
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`Craig relates to “a generalized framework for multiplexed
`
`resequencingoftargeted human genomeregionson the I]lumina Genome
`
`Analyzer using degenerate indexed DNAbarcodesligated to fragmented
`
`DNAbefore sequencing” for simultaneously sequencing DNA from multiple
`
`individuals. Ex. 1007, 887. Craig refers to these bar codes as “indexes” and
`
`describes the use of “a six-base index with built-in redundancyforerror
`
`correction.” /d. According to Craig, “only 48 ofthe 4,096 possible
`
`nucleotide combinations” were synthesized for use in their experiment.
`
`Craig explains that this design “allowed us to control, tolerate and measure
`
`error base calling ofthe index” because “one, andin some cases two,
`
`sequencing errors could be tolerated without an index being incorrectly
`
`identified as being a different valid index./d. at 888; see also id. at 131°
`
`(Supplementary Table 4 describing the design ofthe “DNAIndexes
`
`Appended to Each Adapter’).
`
`J.
`
`Kivioja
`
`Kivioja is a journalarticle titled “Counting absolute numbers of
`
`molecules using unique molecularidentifiers,” and bearing a November
`
`2011 publication date. Ex. 1006, 72. Patent Owner doesnotdispute, and we
`
`agree, that Kivioja is prior art to the challenged claimshere.
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`According to Kivioja, [d]etermining the relative abundance oftwo
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`different molecular species or the absolute numberofmolecules [ofDNA] in
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`a single sample is challenging.” Ex. 1006, 72. Kivioja describes “an absolute
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`counting methodthat can use amplification but does not require detecting
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`each original molecule or keeping track ofthe numberof copies made.”/d.
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`In Kivioja’s method, “each molecule in a population is first made unique” by
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`'0 This refers to the page numberaddedto the exhibit.
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`14
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`IPR2022-01400
`Patent 11,149,306 B2
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`labeling it with a unique molecular identifier (““UMI’’). /d. “Upon deep
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`sequencing, each UMI will be observed multiple times, and the numberof
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`original DNA molecules can be determined simply by counting each UMI
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`only once. However, long before all UMIs are observed, increasingly precise
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`estimates ofthe absolute molecule number can be made.”/d. (citing Online
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`Methods).
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`In its Online Methods section, Kivioja teachesthat “the original
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`numberofmolecules in a sample can be estimated as the sum of observed
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`and unobserved UMIs”and “[the number ofunobserved UMIscan be
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`estimated based on the distribution ofthe copy numbersofthe observed
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`UMIs.” See Ex. 1006, 4-5'! (explaining that “the number ofmolecules from
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`each gene wasestimated by fitting a zero-truncated Poissondistribution to
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`the UMI copy numberdistribution using the generalized additive models for
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`location, scale and shape (GAMLSS)R package and adding the predicted
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`numberofunobserved UMIs to the observed UMI count’).
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`E.
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`Ground 1: Obviousness over Narayan and Schmitt
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`Petitioner asserts that claims 1—3, 5, 7, 9-14, 17-27 and 29 are
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`unpatentable as obvious over Narayan and Schmitt. Pet. 25—58. Patent
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`OwneropposesPetitioner’s assertions. Resp. 10-60.
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`For the reasons explained below,wefind that Petitioner has not
`
`shownby a preponderance ofthe evidence that any ofthese claims would
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`have been obviousover the asserted combination ofNarayan and Schmitt.
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`Morespecifically, for independent claim 1, and those claimsthat depend
`
`from claim 1, Petitioner has not sufficiently shown that any ofthese
`
`references teach or suggest “tagging a plurality ofthe cfDNA molecules. ..
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`'l This refers to the page numberaddedto the exhibit.
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`15
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`Patent 11,149,306 B2
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`with duplex tags comprising molecular barcodes . .. wherein the duplex tags
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`are attached to both ends ofa molecule ofthe plurality ofthe cfDNA
`
`molecules,” as recited in element 1(b). Ex. 1001, 61:10—14. For independent
`
`claim 17 and those claims that depend from claim 17, Petitioner has not
`
`sufficiently shown that any ofthese references teach or suggest “sorting a
`
`plurality of sequencereads from the set of sequence readsinto (1) families
`
`comprising paired reads... and (11) families comprising unpaired reads”as
`
`recited in element 17(d). Ex. 1001, 62:55—65 (emphasis added). Because
`
`these issues are dispositive forall of the challenged claims, our analysis
`
`below focuses on the parties’ arguments and evidencepertaining to these
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`claim elements.
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`1.
`
`Analysis ofClaims 1-3, 5, 7, 9-14, and 29
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`Petitioner contendsclaim 1 is rendered obvious by the application of
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`Schmitt's DCS methodto screen cfDNAfor canceras taught in Narayan.
`
`See Pet. 25, 34. That is, Petitioner asserts that “Narayan disclosesisolating
`
`cfDNA. .. from the blood of cancerpatient, sequencingit, and analyzing
`
`the sequence reads.” /d. at 26. In the asserted combination, Petitioner
`
`contends a POSA would have substituted Schmitt’s DCS methodfor the
`
`sequencing method used in Narayan./d. at 34. Accordingto Petitioner,
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`“Schmitt alone”disclosesall ofthe steps, 1e., “tagging, amplifying,
`
`sequencing, and reducing or tracking redundancy of sequencing reads,” of
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`the method in claim 1. /d.
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`Regarding element 1(b), Petitioner relies on Schmitt’s teaching ofa
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`“hybrid method’ oftagging, which uses a combination ofthe ends ofthe
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`DNAfragments and‘a shorter n-mer tag’” such as a “3-mer barcode”that
`
`“together with the sequence information within the target DNA,serve as
`
`“unique molecularidentifiers.’” Pet. at 8—9 (quoting Ex. 1083 {§ 30, 47, 75
`
`16
`
`
`
`S
`
`SMF Satan ts Ga
`ati” idenivier
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`2
`i
`
`Target ONA
`
`.
`i
`
`SR we? pata satya
`Bia" igdeninver
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`
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`IPR2022-01400
`Patent 11,149,306 B2
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`(emphasis omitted)). We refer to this as “Schmitt’s hybrid method”or
`
`“Schmitt’s hybrid embodiment”herein.
`
`Petitioner’s declarant, Dr. Spellman, provides the following diagram
`
`depicting Schmitt’s hybrid embodiment.
`
`
`
`Id. at 9 (citing Ex. 1002 4 89). In Dr. Spellman’s diagram above,“the ends
`
`of the DNA fragmentare designated ‘L’ and ‘R,’ and the 3-mer molecular
`
`barcodes are labeled “X’ and ‘Y.’” /d.
`
`Petitioner asserts that Schmitt’s hybrid embodimentdiscloses
`
`“duplex tags comprising molecular barcodes’ that are ‘attached to both
`
`ends’ ofa cfDNA molecule” as thosetermsare recited in element1(b).
`
`Pet. 27. Petitioner contendsthat “duplex tags”are “tags that differently label
`
`the complementary strands... of a double-stranded molecule.” /d. (quoting
`
`Ex. 1001, 17:9-13). Accordingto Petitioner,
`
`Schmitt's hybrid tag embodimentdifferently labels the
`complementary strands by tagging both ends ofthe molecule
`and relying on the asymmetrical nature ofthe duplex tags. And
`Schmitt's hybrid tag embodiment comprises molecular
`barcodes because the duplex tags comprise both the fragment
`DNAend sequences[i.e., L and R in the diagram above] and “a
`
`17
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`IPR2022-01400
`Patent 11,149,306 B2
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`shorter n-mertag”[1.e., X and Y in the diagram] to serve as
`“unique molecularidentifiers.”
`
`7d. (citing Ex. 1002 4 162; Ex. 1083 4§ 11, 30).
`
`For the “n different combinations ofmolecular barcodes” requirement
`
`of element 1(b), Petitioner points to Schmitt’s disclosure of “3-mer
`
`barcodes.” Pet. 28—29. Petitioner contendsthat this 3-mer barcodeprovides a
`
`total of4,096 “different combinations ofmolecular barcodes, considering
`
`the tagging occurs on both ends ofthe target molecule.” /d. at 28 (citing
`
`Ex. 1002 §] 164) (internal quotations omitted). Based on this calculation,
`
`Petitioner urges that Schmitt discloses an “n”with the recited range of “at
`
`least 2 andno more than 100,000*z” regardless ofthe z value for a given
`
`sample. /d. at 29 (citing Ex. 1002 4§ 166-167).
`
`In response, Patent Ownerurgesthat “[t]he petition materials fail to
`
`establish the cited prior art discloses or teaches the tagging step of claim 1,”
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`1.e., element 1(b). Resp. 10. Patent Owner contends “[t|he petition materials
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`acknowledge SMIs as the ‘molecular barcodes’ in Schmitt, and they
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`acknowledge hybrid SMIs as the combination of shear sequence and
`
`exogenous n-mer sequence, but they improperly and inconsistently map only
`
`the exogenous 3-merportion ofthe hybrid SMIin the discussion ofthe
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`challenged claims.”/d. (citing Pet. 28—29).
`
`Morespecifically, Patent Ownerarguesthat claim 1 does not
`
`encompass Schmitt’s hybrid embodiment because “even ifthe hybrid SMI
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`sequencesare viewed as molecular barcodes in Schmitt’s DCS process,
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`those are not contained in adapter molecules or duplex tagsthat are attached
`
`tothe DNA molecules.”/d. at 18 (citing Ex. 2015 9 59). According to Patent
`
`Owner,“the language of claim 1 specifies that the duplex tags are attached
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`to the cfDNA molecules and distinguishes the “cfDNA molecules’ from the
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`18
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`IPR2022-01400
`Patent 11,149,306 B2
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`‘duplex tags” with the molecular barcodes.” /d. (citing Ex. 2015 4 60); see
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`alsoid. at 8 (discussed supra § I(C)). But in Schmitt’s hybrid embodiment,
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`the SMI includes both the n-mer and a portion ofthe endogenous end
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`sequence ofthe DNA molecule. /d.; see also id. at 16—17 (citing testimony
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`from Dr. Spellman that Patent Owner contends “acknowledgesthe
`
`combination ofthe endogenousshear sequence and exogeneous3-mer
`
`sequence together provide the SMI used for grouping and matching in
`
`Schmitt’s DCS process”). Thus, urges Patent Owner, Petitioner’s attempt to
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`mapthis “amalgamation of sequencesthat together function as the SMI”to
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`the duplex tag in element 1(b) “improperly conflates the DNA molecule with
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`the attached duplex tags.” /d. at 19 (citing Ex. 1002 § 162.).
`
`Patent Owneralso asserts that Petitioner has not shownthat the
`
`numberof different combinations ofthe SMIin Schmitt’s hybrid
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`embodimentis within the recited range for “n” because Dr. Spellman’s
`
`calculations only consider the nucleotides in the 3-mertag and not those in
`
`the “shear sequences ofthe DNA molecule. .
`
`. included in the hybrid
`
`SMIs.” /d. at 20-21.
`
`In reply, Petitioner asserts that Patent Owner’s arguments ignorethe
`
`°306 “patent’s definition ofduplex tags” as “tags that differently label the
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`complementary strands of a double-stranded molecule.” Reply 8 (quoting
`
`Ex. 1001, 17:9-13). Accordingto Petitioner, the “salient point”is that
`
`Schmittteaches “tagging the double-stranded DNA molecules such that the
`
`tags differently label the complementarystrand(1.e., ‘duplex tags,’ under the
`
`[’]306 patent’s definition.”’). /d. (citing Ex. 1002 4 162; Ex. 1098 44] 38—40;
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`Ex. 1097, 98:16—99:1). Moreover, Petitioner contendsthat the ’306 “patent
`
`admits that tagging can be achieved using the combination ofa DNA
`
`barcode and one or more endogenous sequences ofthe polynucleotide.”
`
`19
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`IPR2022-01400
`Patent 11,149,306 B2
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`Reply 9 (citing Ex. 1001, 21:23—25, 21:39-42, 22:44—51, 34:55-58)
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`(internal quotations omitted).
`
`In sur-reply, Patent Ownerurgesthat the Reply “never addresses the
`
`plain language”of claim 1 stating “that 1) the duplex tags include the
`
`molecular barcodes and 2) those duplex tags are attached to and
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`distin guished from the ‘cfDNA molecules.’” Sur-reply 3. Patent Owner
`
`arguesthat the funct
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