UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`TWINSTRAND BIOSCIENCES, INC.
`Petitioner,
`v.
`GUARDANT HEALTH, INC.
`Patent Owner.
`
`___________________
`
`Case IPR2022-01116
`U.S. Patent No. 10,889,858
`___________________
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 10,889,858
`
`
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`Case IPR2022-01116
`Patent 10,889,858
`
`
`TABLE OF CONTENTS
`
`I.
`II.
`
`III.
`
`B.
`
`C.
`
`Introduction ..................................................................................................... 1
`Statement of Precise Relief Requested and Reasons Therefor (37 C.F.R.
`§42.22(A)) ...................................................................................................... 2
`State of the art before December 2013 ........................................................... 2
`A. Optimization techniques for DNA library preparation were
`well known. ........................................................................................... 2
`Cell-free DNA isolated from blood was widely used in next-
`generation sequencing platforms. .......................................................... 5
`1.
`The presence of cell-free tumor DNA in human blood
`was well known. ......................................................................... 5
`Isolating cfDNA from blood was routine with
`commercially available kits. ...................................................... 6
`The prior art
`taught
`that Duplex Sequencing could
`dramatically lower the error rate of NGS. ............................................. 7
`The prior art taught applying Duplex Sequencing to cfDNA. ............ 13
`D.
`IV. The ’858 patent and its prosecution history ................................................. 15
`V.
`Person of ordinary skill in art ....................................................................... 18
`VI. Claim construction ........................................................................................ 18
`VII.
`Identification of the challenge (37 C.F.R. §42.104(b)) ................................ 19
`VIII. The facts and law weigh against discretionary denial of institution. ........... 21
`A.
`This Petition satisfies 35 U.S.C. §325(d). ........................................... 21
`B.
`Fintiv does not support discretionary denial. ...................................... 25
`IX. Ground 1: claims 1-7 and 10-27 would have been obvious over Narayan,
`Schmitt, and Meyer ....................................................................................... 26
`A.
`Claim 1 ................................................................................................ 26
`1.
`“A method for analyzing sequencing reads of double-
`stranded cell-free deoxyribonucleic acid (cfDNA)
`molecules from a sample of a subject…” ................................ 26
`“(a) tagging a plurality of double-stranded cfDNA
`molecules from a population of double-stranded
`cfDNA molecules from the sample with a set of library
`adaptors comprising a plurality of molecular barcodes
`to generate tagged parent polynucleotides, wherein the
`
`2.
`
`2.
`
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`Case IPR2022-01116
`Patent 10,889,858
`
`
`3.
`
`4.
`
`tagging comprises ligating a plurality of library
`adaptors from the set of library adaptors to the plurality
`of double-stranded cfDNA molecules from
`the
`population using more than a 10× molar excess of
`library adaptors as compared to the double-stranded
`cfDNA molecules of the population…” .................................. 27
`“wherein the tagging produces at least 20% of the
`double-stranded cfDNA molecules of the populations
`having library adaptors ligated to both ends of a
`molecule of the double-stranded cfDNA molecules…” .......... 29
`“(b) amplifying a plurality of the tagged parent
`polynucleotides
`to
`produce
`progeny
`polynucleotides…”................................................................... 30
`“(c)
`sequencing a plurality of
`the progeny
`polynucleotides to produce a set of sequencing
`reads…” ................................................................................... 30
`“and (d) determining, based at least on sequence
`information from the molecular barcodes, individual
`double-stranded cfDNA molecules from among the
`tagged parent polynucleotides for which either (1) both
`a Watson strand and a Crick strand of the individual
`double-stranded cfDNA molecule are detected or (2)
`only one of a Watson strand or a Crick strand of the
`individual double-stranded cfDNA molecule
`is
`detected from a plurality of sequencing reads from the
`set of sequencing reads.” .......................................................... 30
`A POSA would have had a reason to combine Narayan,
`Schmitt, and Meyer. ................................................................. 32
`A POSA would have had a reasonable expectation of
`success. ..................................................................................... 36
`Claim 16 .............................................................................................. 39
`1.
`“A method for analyzing double-stranded cell-free
`deoxyribonucleic acid (cfDNA) molecules from a
`sample of a subject…” ............................................................. 39
`“(a) tagging a plurality of double-stranded cfDNA
`molecules from a population of double-stranded
`cfDNA molecules from the sample with a set of library
`adaptors comprising a plurality of molecular barcodes
`to generate tagged parent polynucleotides, wherein the
`
`2.
`
`5.
`
`6.
`
`7.
`
`8.
`
`B.
`
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`Case IPR2022-01116
`Patent 10,889,858
`
`
`4.
`
`5.
`
`6.
`
`3.
`
`tagging comprises ligating a plurality of library
`adaptors from the set of library adaptors to the plurality
`of double-stranded cfDNA molecules from
`the
`population using more than a 10× molar excess of
`library adaptors as compared to the double-stranded
`cfDNA molecules of the population…” .................................. 40
`“wherein the tagging produces at least 20% of the
`double-stranded cfDNA molecules of the population
`having library adaptors ligated to both ends of a
`molecule of the double-stranded cfDNA molecules…” .......... 40
`“(b) amplifying a plurality of the tagged parent
`polynucleotides
`to
`produce
`progeny
`polynucleotides…”................................................................... 41
`“(c) determining nucleotide sequences of a plurality of
`the progeny polynucleotides…” .............................................. 41
`“(d) analyzing a plurality of the nucleotide sequences
`with a programmed computer processor the analyzing
`comprising mapping a plurality of the nucleotide
`sequences to a reference sequence to produce mapped
`sequences …” ........................................................................... 41
`“grouping a plurality of the mapped sequences into
`families based on a combination of sequence
`information from the molecular barcodes and start and
`stop positions of the mapped sequences, wherein a
`family of the families is representative of an individual
`double-stranded cfDNA molecule from among the
`tagged parent polynucleotides…” ............................................ 42
`“and identifying a plurality of the families as having
`nucleotide sequences representing either (1) both a
`Watson strand and a Crick strand of an individual
`double-stranded cfDNA molecule from among the
`tagged parent polynucleotides or (2) only one of a
`Watson strand or a Crick strand of an individual
`double-stranded cfDNA molecule from among the
`tagged parent polynucleotides.” ............................................... 44
`Claims 2 and 17 ................................................................................... 46
`Claims 3 and 18 ................................................................................... 47
`Claims 4 and 19 ................................................................................... 48
`Claims 5 and 20 ................................................................................... 49
`
`7.
`
`8.
`
`C.
`D.
`E.
`F.
`
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`

`Case IPR2022-01116
`Patent 10,889,858
`
`G.
`Claims 6 and 7 ..................................................................................... 50
`Claim 10 .............................................................................................. 51
`H.
`Claims 11-14 and 21 ........................................................................... 52
`I.
`Claim 15 .............................................................................................. 54
`J.
`Claims 22 and 24 ................................................................................. 56
`K.
`Claims 23 and 25 ................................................................................. 59
`L.
`M. Claim 26 .............................................................................................. 60
`N.
`Claim 27 .............................................................................................. 61
`X. Ground 2: claims 8-9 would have been obvious over Narayan, Schmitt,
`Meyer, and Craig .......................................................................................... 62
`XI. Ground 3: claims 28 and 29 would have been obvious over Narayan, Schmitt,
`Meyer, and Kivioja ....................................................................................... 66
`XII. Objective indicia do not support patentability. ............................................. 71
`XIII. Certification of standing and Patent IPR eligibility (37 C.F.R. §42.104(a)) 71
`XIV. Mandatory Notices (37 C.F.R. §42.8(a)(1)) ................................................. 71
`XV. Conclusion. ................................................................................................... 73
`
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`

`TABLE OF AUTHORITIES
`
`Case IPR2022-01116
`Patent 10,889,858
`
`
` Page(s)
`
`Cases
`Abbott Labs. v. Sandoz, Inc.,
`544 F.3d 1341 (Fed. Cir. 2008) .................................................................... 38, 50
`
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte
`GmbH,
`IPR2019-01469 (P.T.A.B., Feb, 13, 2020) ......................................................... 21
`Apple Inc. v. Fintiv, Inc.,
`IPR2020-0019 (P.T.A.B., March 20, 2020) ..................................... 25, 26, 27, 29
`Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .......................................................................... 70
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ............................................................................ 24
`Guardant Health, Inc. v. Foundation Medicine, Inc.,
`1-20-cv-01580 (D. Del.) ..................................................................................... 72
`Medtronic, Inc. v. Niazi Licensing Corp.,
`IPR2018-00609 (P.T.A.B. Aug. 20, 2018) ......................................................... 21
`Ormco Corp. v. Align Technology, Inc.,
`463 F. 3d 1299 (Fed. Cir. 2006) ..................................................................passim
`TwinStrand Biosciences, Inc. et al v. Guardant Health, Inc.,
`1-21-cv-01126 (D. Del.) ..................................................................................... 72
`Statutes
`35 U.S.C. §102(a)(1) ................................................................................................ 20
`35 U.S.C. §102(a)(2) ................................................................................................ 20
`35 U.S.C. §314(a) .................................................................................................... 25
`35 U.S.C. §325(d) .............................................................................................. 21, 24
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`Case IPR2022-01116
`Patent 10,889,858
`
`
`Other Authorities
`37 C.F.R. §42.8(A)(1) .............................................................................................. 71
`37 C.F.R. §42.8(b)(1) ............................................................................................... 71
`37 C.F.R. §42.8(b)(2) ............................................................................................... 72
`37 C.F.R. §42.8(b)(3) ............................................................................................... 72
`37 C.F.R. §42.10(b) ................................................................................................. 73
`37 C.F.R. §42.63(e) .................................................................................................. 73
`37 C.F.R. §42.100(b) ............................................................................................... 18
`37 C.F.R. §42.104(A) .............................................................................................. 71
`37 C.F.R. §42.104(B) ............................................................................................... 19
`37 C.F.R. §42.106(a) ................................................................................................ 73
`
`
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`Case IPR2022-01116
`Patent 10,889,858
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`
`EXHIBIT LIST
`
`Exhibit #
`1001
`
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`
`1004
`
`1006
`
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`Description
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`

`Case IPR2022-01116
`Patent 10,889,858
`
`
`Description
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`Case IPR2022-01116
`Patent 10,889,858
`
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`Case IPR2022-01116
`Patent 10,889,858
`
`
`Description
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`Case IPR2022-01116
`Patent 10,889,858
`
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`Case IPR2022-01116
`Patent 10,889,858
`
`
`Description
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`Decision Denying Institution for Inter Partes Review, Foundation
`Medicine, Inc. v. Guardant Health, Inc., IPR2019-00636 and
`IPR2019-00637, Paper 10 (August 20, 2019)
`Pray, L.A., “Eukaryotic Genome Complexity,” Nature Education
`1(1):96 (2013)
`Semsarian, C. and Seidman, C.E., “Molecular medicine in the 21st
`century,” Internal Medicine Journal 31: 53–59 (2001)
`
`Exhibit #
`1067
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`1068
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`1069
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`1070
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`1071
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`1072
`
`1073
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`1074
`
`1075
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`1076
`1077
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`1078
`
`1079
`
`1080
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`1081
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`- viii -
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`

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`Case IPR2022-01116
`Patent 10,889,858
`
`
`Description
`Narayan et al., “Ultrasensitive Measurement of Hotspot Mutations in
`Tumor DNA in Blood Using Error-Suppressed Multiplexed Deep
`Sequencing,” Cancer Research, 72(14):3492-3498 (2012)
`U.S. Provisional Application No. 61/625,623, filed on April 17, 2012
`
`Exhibit #
`
`1082
`
`1083
`
`
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`- ix -
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`

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`INTRODUCTION
`Guardant’s patent claims methods that were already known in the art. As
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`Case IPR2022-01116
`Patent 10,889,858
`
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`I.
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`detailed below, Guardant’s claimed steps of tagging, amplifying, sequencing, and
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`determining sequences as paired or unpaired, are all straight from Schmitt’s
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`Duplex Sequencing, with only trivial additions.
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`Guardant misled the Office during prosecution, causing the Examiner to
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`make two main errors in allowing the claims. First, Guardant misrepresented the
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`amount of cell-free DNA (cfDNA) in a human blood sample, arguing that a skilled
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`artisan would not have expected Schmitt’s methods to be applicable to cfDNA
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`because human blood (according to Guardant) contained insufficient quantities of
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`cfDNA. Tellingly, Guardant never provided the Examiner with any prior art
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`evidence to support its argument. It’s no wonder. The prior art flatly contradicts
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`Guardant’s argument, showing that ample quantities of cfDNA are present in
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`human blood for use in Duplex Sequencing. In fact, the prior art expressly taught
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`the benefits of using Duplex Sequencing with cfDNA. EX1008, 7.
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`Second¸ Guardant misled the Examiner by relying on a statement from a
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`2017 publication—not prior art—as alleged evidence that a person of skill in the
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`art in 2013 would not have expected Schmitt’s methods to work with cfDNA. But,
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`as explained above, Guardant’s position is contradicted by contemporaneous
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`evidence
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`—including Schmitt itself— that taught applying Duplex Sequencing methods to
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`Case IPR2022-01116
`Patent 10,889,858
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`cfDNA.
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`The Board should institute trial and cancel the claims of the ’858 patent.
`
`II.
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`STATEMENT OF PRECISE RELIEF REQUESTED AND REASONS
`THEREFOR (37 C.F.R. §42.22(A))
`TwinStrand Biosciences, Inc. (“TwinStrand”) petitions for inter partes
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`review, requesting cancellation of claims 1-29 of U.S. Patent No 10,889,858 (“the
`
`’858 patent”; EX1001), assigned to Guardant Health, Inc. This Petition is
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`supported by the declaration of Paul Spellman, Ph.D. (EX1002), Professor of
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`Molecular and Medical Genetics and an expert in genetics and genomics
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`approaches to detecting and monitoring human diseases. This Petition
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`demonstrates that claims 1-29 are unpatentable as obvious.
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`III. STATE OF THE ART BEFORE DECEMBER 2013
`Before the ’858 patent’s earliest possible priority date (December 28,
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`2013)1, next-generation sequencing (“NGS”) methods were well known. EX1011,
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`32-41; EX1002, ¶¶30-62.
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`A. Optimization techniques for DNA library preparation were well
`known.
`Before December 2013, most NGS methods began with preparing a library
`
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`1 TwinStrand does not concede the ’858 patent is entitled to this priority date.
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`of template DNA fragments to be sequenced. This was accomplished by shearing
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`Case IPR2022-01116
`Patent 10,889,858
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`DNA into suitably sized fragments or by using DNA that is already fragmented,
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`such as cfDNA (discussed below). EX1012, 291; EX1011, 32. Library preparation
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`commonly involved “tagging” the DNA with “adapters,” which were added to the
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`ends of each DNA fragment. Id. Adapters often contained “molecular barcodes” or
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`“identifiers,” which are nucleotide sequences that help to further identify and
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`distinguish the sequenced DNA fragments from one another. EX1083, ¶¶[0005],
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`[0008]-[0009], [0030] EX1005, Fig. 1; EX1002, ¶40. A common technique for
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`tagging was ligation. EX1083, ¶[0020]; EX1005, Fig. 1; EX1015, 4-5; EX1031,
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`11-12, Fig. 4; EX1002, ¶38.
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`Guardant’s claims recite open ended ranges of “more than a 10×” and “more
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`than a 100×” molar excesses of adapters relative to cfDNA molecules, and ligation
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`efficiencies of “at least 20%” and “at least 40%.” But long before December 2013,
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`artisans already knew to use significant molar excesses of adapters to achieve high
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`efficiency ligations. EX1020, 18.4.15; EX1031, 2. EX1083, ¶[0005]; EX1002,
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`¶¶43-55; EX1021, 5, Fig. 2; EX10262, ¶¶[0130], [0143], [0159]; EX1025,
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`2 EX1026 (“Diehn ’807”) is the publication of 14/209,807 (filed March 13,
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`2014), which claims priority to 61/798,925 (filed March 15, 2013) (EX1025,
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`“Diehn ’925”). Diehn ’925’s specification is substantially similar to Diehn ’807’s,
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`¶¶[0106], [0119], [0135].
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`Case IPR2022-01116
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`For example, So 2004 (EX1021) taught that “[t]he yield of the desired
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`[adapter-ligated DNA] was found to depend on the amount of SAGE adaptor
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`introduced into the ligation mixture, and increased with increasing adaptor
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`concentration.” EX1021, 5, Fig. 2; EX1002, ¶43. Diehn also disclosed that
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`“[i]ncreasing adapter concentration during ligation increases ligation efficiency
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`and reporter recovery” and further demonstrated using adapter concentrations that
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`were “100-fold molar excess” compared to the DNA molecules. EX1026,
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`¶¶[0130], [0143], [0159]; EX1025, ¶¶[0106], [0119], [0135]; EX1024, 4-14
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`(adapter:DNA molar ratio of 90:1); EX1005, 272-273 (adapter:DNA ratios from
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`790:1 and 7,509:1); EX1022, 1-2, S7-S8 (adapter:DNA molar ratios from 230:1 to
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`315:1); EX1023, 32; EX1080, 2-3; EX1081, Abstract; EX1002, ¶¶43-51. Ligation
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`byproducts such as adapter-dimers were easily removed through standard
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`techniques. Id.; EX1002, ¶51.
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`A high molar excess of adapters was known to be useful to obtain increased
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`ligation efficiency, and yield a more complex library to sequence deeply. EX1019,
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`including identical claim sets. EX1025; EX1026. Thus, Diehn ’807 is prior art to
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`the ’858 patent under §102(a)(2) because Diehn ’925 provides §112 support for at
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`least one claim in Diehn ’807. EX1002, ¶50.
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`1; EX1020, 18.4.15; EX1031, 2; EX1083, ¶[0005]; EX1002, ¶¶41-55. The art
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`Case IPR2022-01116
`Patent 10,889,858
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`reported that 40% or more of input D