UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`
`TWINSTRAND BIOSCIENCES, INC.
`Petitioner,
`v.
`GUARDANT HEALTH, INC.
`Patent Owner.
`
`___________________
`
`Case IPR2022-01152
`U.S. Patent No. 11,118,221
`___________________
`
`PETITION FOR INTER PARTES REVIEW
`OF U.S. PATENT NO. 11,118,221
`
`
`
`
`
`
`
`
`
`
`
`Mail Stop "PATENT BOARD"
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`

`

`TABLE OF CONTENTS
`
`Case IPR2022-01152
`Patent 11,118,221
`
`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. ........................................................................................... 3
`Cell-free DNA isolated from blood was widely used in NGS
`platforms. ............................................................................................... 5
`1.
`The presence of cell-free tumor DNA in human blood
`was well known. ......................................................................... 6
`Isolating cfDNA from blood was routine with off-the-
`shelf kits. .................................................................................... 7
`The prior art taught that Duplex Sequencing dramatically
`lowers NGS error rate. .......................................................................... 7
`The prior art taught applying Duplex Sequencing to cfDNA. ............ 14
`D.
`IV. The '221 patent and its prosecution history .................................................. 15
`V.
`Person of ordinary skill in art ....................................................................... 19
`VI. Claim construction ........................................................................................ 19
`VII.
`Identification of the challenge (37 C.F.R. §42.104(b)) ................................ 20
`VIII. The facts and law weigh against discretionary denial of institution. ........... 22
`A.
`This Petition satisfies 35 U.S.C. §325(d). ........................................... 22
`B.
`The Fintiv factors do not support discretionary denial. ...................... 26
`IX. Ground 1: claims 1-4, 6-7, 9-15, 18-22, and 24-28 would have been obvious
`over Narayan and Schmitt ............................................................................ 27
`A.
`Claim 1 ................................................................................................ 28
`1.
`“A method, comprising: (a) providing a population of
`cell-free deoxyribonucleic acid (cfDNA) molecules
`having first and second complementary strands…” ................ 28
`“(b) tagging a plurality of the cfDNA molecules of the
`population with a set of duplex tags comprising
`molecular barcodes from a set of molecular barcodes to
`produce tagged parent polynucleotides, wherein duplex
`tags from the set of duplex tags are attached at both
`
`2.
`
`2.
`
`- i -
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`

`

`4.
`
`5.
`
`3.
`
`Case IPR2022-01152
`Patent 11,118,221
`ends of a molecule of the plurality of the cfDNA
`molecules…” ............................................................................ 28
`“(c) amplifying a plurality of the tagged parent
`polynucleotides
`to produce amplified progeny
`polynucleotides...”.................................................................... 30
`“(d) sequencing at least a subset of the amplified
`progeny polynucleotides to produce a set of sequence
`reads…” ................................................................................... 30
`“(e) reducing or tracking redundancy in the set of
`sequence reads using at least sequence information
`from the molecular barcodes to generate a plurality of
`consensus sequences representative of original cfDNA
`molecules
`from
`among
`the
`tagged
`parent
`polynucleotides, wherein the plurality of consensus
`sequences
`is generated
`from
`(i) paired
`reads
`corresponding to sequence reads generated from a first
`tagged strand and a second tagged complementary
`strand derived from a cfDNA molecule from among the
`tagged parent polynucleotides, and (ii) unpaired reads
`corresponding to sequence reads generated from a first
`tagged strand having no second tagged complementary
`strand derived from a cfDNA molecule from among the
`tagged parent polynucleotides.” ............................................... 30
`A POSA would have had a reason to combine Narayan
`and Schmitt. ............................................................................. 33
`A POSA would have had a reasonable expectation of
`success. ..................................................................................... 37
`Claim 18 .............................................................................................. 38
`1.
`“A method, comprising: (a) providing a population of
`double-stranded
`cell-free deoxyribonucleic
`acid
`(cfDNA) molecules having
`first and
`second
`complementary strands…” ....................................................... 39
`“(b) non-uniquely tagging a plurality of the double-
`stranded cfDNA molecules of the population with a set
`of duplex tags comprising molecular barcodes from a
`set of molecular barcodes to produce non-uniquely
`tagged parent polynucleotides, wherein the doule-
`stranded cfDNA molecules that map to a mappable
`base position of a reference sequence are tagged with a
`number of different molecular barcodes ranging from
`
`6.
`
`7.
`
`2.
`
`- ii -
`
`B.
`
`

`

`6.
`
`7.
`
`4.
`
`5.
`
`3.
`
`Case IPR2022-01152
`Patent 11,118,221
`at least 2 to fewer than a number of the double-stranded
`cfDNA molecules that map to the mappable base
`position...” ................................................................................ 39
`“(c) amplifying a plurality of the non-uniquely tagged
`parent polynucleotides to produce amplified progeny
`polynucleotides...”.................................................................... 42
`“(d) sequencing at least a subset of the amplified
`progeny polynucleotides to produce a set of sequence
`reads…” ................................................................................... 43
`“(e) reducing or tracking redundancy in the set of
`sequence reads using at least sequence information
`from the molecular barcodes…” .............................................. 43
`“(f) sorting the set of sequence reads into paired reads
`and unpaired reads, wherein (i) a paired read
`corresponds to sequence reads generated from a first
`tagged strand and a second tagged complementary
`strand derived
`from a double-stranded cfDNA
`molecule from among the non-uniquely tagged parent
`polynucleotides, and (ii) an unpaired read corresponds
`to sequence reads generated from a first tagged strand
`having no second
`tagged complementary strand
`derived from a double-stranded cfDNA molecule from
`among
`the
`non-uniquely
`tagged
`parent
`polynucleotides…”................................................................... 43
`“(g) determining, at one or more loci of a reference
`sequence, quantitative measures of at least two of (i)
`the paired reads, (ii) the unpaired reads, (iii) read depth
`of the paired reads, and (iv) read depth of the unpaired
`reads.”....................................................................................... 46
`Claims 2 and 19 ................................................................................... 49
`C.
`Claims 3 and 20 ................................................................................... 50
`D.
`Claims 4 and 21 ................................................................................... 51
`E.
`Claim 6 ................................................................................................ 52
`F.
`Claim 7 ................................................................................................ 53
`G.
`Claim 22 .............................................................................................. 53
`H.
`Claims 9-10 and 24-25 ........................................................................ 54
`I.
`Claims 11 and 26 ................................................................................. 55
`J.
`Claims 12 and 13 ................................................................................. 57
`K.
`Claim 14 .............................................................................................. 58
`L.
`M. Claim 15 .............................................................................................. 59
`
`- iii -
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`

`

`Case IPR2022-01152
`Patent 11,118,221
`N.
`Claims 27 and 28 ................................................................................. 60
`X. Ground 2: claim 5 would have been obvious over Narayan, Schmitt, and
`Meyer ............................................................................................................ 61
`XI. Ground 3: claims 8 and 23 would have been obvious over Narayan, Schmitt,
`and Craig ....................................................................................................... 63
`XII. Ground 4: claims 16-17 and 29-30 would have been obvious over Narayan,
`Schmitt, and Kivioja. .................................................................................... 65
`XIII. Objective indicia do not support patentability. ............................................. 70
`XIV. Certification of standing and Patent IPR eligibility (37 C.F.R. §42.104(a)) 70
`XV. Mandatory Notices (37 C.F.R. §42.8(a)(1)) ................................................. 70
`XVI. Conclusion. ................................................................................................... 72
`
`
`
`
`
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`- iv -
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`

`TABLE OF AUTHORITIES
`
`Case IPR2022-01152
`Patent 11,118,221
`
` Page(s)
`
`Cases
`Abbott Labs. v. Sandoz, Inc.,
`544 F.3d 1341 (Fed. Cir. 2008) .................................................................... 63, 64
`
`Advanced Bionics, LLC v. MED-EL Elektromedizinische Geräte
`GmbH,
`IPR2019-01469 (P.T.A.B., Feb, 13, 2020) ......................................................... 22
`Apple Inc. v. Fintiv, Inc.,
`IPR2020-0019 (P.T.A.B., March 20, 2020) ................................................. 26, 27
`Bayer Healthcare Pharms., Inc. v. Watson Pharms., Inc.,
`713 F.3d 1369 (Fed. Cir. 2013) .......................................................................... 69
`Bristol-Myers Squibb Co. v. Teva Pharms. USA, Inc.,
`752 F.3d 967 (Fed. Cir. 2014) ............................................................................ 23
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) ...................................................................... 4, 21
`Hanwha Sols. Corp. v. Rec Solar PTE. Ltd.,
`IPR2021-00988 (P.T.A.B., Dec. 13, 2021) ........................................................ 26
`
`Illumina, Inc. v. Guardant Health, Inc.; Helmy Eltoukhy; and Amirali
`Talasaz,
`1-21-cv-00334 (D. Del. March 17, 2022) ........................................................... 71
`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.) ..................................................................................... 71
`Statutes
`35 U.S.C. §102(a)(1) ................................................................................................ 21
`
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`

`

`Case IPR2022-01152
`Patent 11,118,221
`35 U.S.C. §102(a)(2) ...................................................................................... 4, 21, 22
`35 U.S.C. §314(a) .................................................................................................... 26
`35 U.S.C. §325(d) .............................................................................................. 22, 26
`Other Authorities
`37 C.F.R. §42.8(A)(1) .............................................................................................. 70
`37 C.F.R. §42.8(b)(1) ............................................................................................... 70
`37 C.F.R. §42.8(b)(2) ............................................................................................... 71
`37 C.F.R. §42.8(b)(3) ............................................................................................... 71
`37 C.F.R. §42.8(b)(4) ............................................................................................... 72
`37 C.F.R. §42.10(b) ................................................................................................. 72
`37 C.F.R. §42.22(A)................................................................................................... 2
`37 C.F.R. §42.63(e) .................................................................................................. 72
`37 C.F.R. §42.100(b) ............................................................................................... 19
`37 C.F.R. §42.104(A) .............................................................................................. 70
`37 C.F.R. §42.104(B) ............................................................................................... 20
`37 C.F.R. §42.106(a) ................................................................................................ 72
`
`
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`- vi -
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`

`EXHIBIT LIST
`
`Case IPR2022-01152
`Patent 11,118,221
`
`Exhibit #
`1001
`
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`
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`- vii -
`
`

`

`Case IPR2022-01152
`Patent 11,118,221
`
`Description
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`- viii -
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`

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`- ix -
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`

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`- x -
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`

`

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`

`Case IPR2022-01152
`Patent 11,118,221
`
`Description
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`Dr. Spellman’s Calculations for prior art disclosures of molar ratios of
`adapters relative to DNA fragments
`Kitzman, J.O., et al., “Non-invasive whole genome sequencing of a
`human fetus,” Sci Transl Med. 4(137): 137ra76 (2012)
`ThruPLEX™ DNA-seq Kit Instruction Manual, Rubicon Genomics
` Complaint, Twinstrand Biosciences, Inc. & The University of
`Washington v. Guardant Health, Inc., 1-21-cv-01126 (D. Del.)
`(August 3, 2021)
`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 (2008)
`Semsarian, C. and Seidman, C.E., “Molecular medicine in the 21st
`century,” Internal Medicine Journal 31: 53–59 (2001)
`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 #
`
`1068
`
`1069
`
`1070
`
`1071
`
`1072
`
`1073
`
`1074
`
`1075
`
`1076
`1077
`
`1078
`
`1079
`
`1080
`
`1081
`
`1082
`
`1083
`
`- xii -
`
`

`

`Exhibit #
`1084
`
`Description
`File History for U.S. Patent No. 10,801,063
`
`Case IPR2022-01152
`Patent 11,118,221
`
`- xiii -
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`

`

`Case IPR2022-01152
`Patent 11,118,221
`
`I.
`
`INTRODUCTION
`Guardant’s claimed methods were already known in the prior art. As
`
`detailed below, Guardant’s claimed steps of tagging, amplifying, sequencing, and
`
`reducing or tracking redundancy in the set of sequence reads based on paired and
`
`unpaired reads, are all straight out of Schmitt, with only trivial additions.
`
`Further, Guardant mischaracterized the state of the art in its arguments to the
`
`Office during prosecution of the ’221 patent and its family members (which were
`
`examined by the same Examiner) in significant ways. First, Guardant
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`misrepresented the quantity of cell-free DNA (cfDNA) in a human blood sample,
`
`arguing that a skilled artisan would not have expected Schmitt’s methods to be
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`applicable to cfDNA because human blood (according to Guardant) contained
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`insufficient quantities of cfDNA. Tellingly, Guardant never provided the Examiner
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`with any prior art evidence to support its argument. It’s no wonder. The prior art
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`flatly contradicts Guardant’s argument, showing that ample quantities of cfDNA
`
`are present in human blood. In fact, the prior art expressly suggested benefits of
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`using Schmitt’s Duplex Sequencing (also called “Duplex Consensus Sequencing”
`
`or “DCS”) with cfDNA. EX1008, 7.
`
`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
`
`art in 2013 would not have expected Schmitt’s methods to work with cfDNA. But,
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`

`

`Case IPR2022-01152
`Patent 11,118,221
`as explained above, Guardant’s position is contradicted by contemporaneous
`
`evidence—including Schmitt itself—that taught applying DCS methods to cfDNA.
`
`Third, Guardant failed to correct the Examiner’s misinterpretation of a Final
`
`Written Decision in an IPR of Guardant’s related ’822 patent. The Examiner
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`erroneously stated that the PTAB found that the Schmitt ’188 patent does not
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`disclose non-uniquely tagging cfDNA molecules with a number of different
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`molecular barcodes ranging from at least 2 to fewer than a number the cfDNA
`
`molecules that map to the mappable base position. The PTAB made no such
`
`finding, and Guardant failed to notify the Examiner of his error.
`
`The Board should institute trial and cancel the claims of the ’221 patent.
`
`II.
`
`STATEMENT OF PRECISE RELIEF REQUESTED AND REASONS
`THEREFOR (37 C.F.R. §42.22(A))
`TwinStrand Biosciences, Inc. (“TwinStrand”) petitions for IPR, requesting
`
`cancellation of claims 1-30 of U.S. Patent No. 11,118,221 (“the ’221 patent”;
`
`EX1001), assigned to Guardant Health, Inc. This Petition is supported by the
`
`declaration of Paul Spellman, Ph.D. (EX1002), Professor of Molecular and
`
`Medical Genetics and an expert in genetics and genomics approaches to detecting
`
`and monitoring human diseases. This Petition demonstrates that claims 1-30 are
`
`unpatentable as obvious.
`
`III. STATE OF THE ART BEFORE DECEMBER 2013
`Before the ’221 patent’s earliest possible priority date (December 28,
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`Case IPR2022-01152
`Patent 11,118,221
`2013)1, next-generation sequencing (“NGS”) methods were well known. EX1011,
`
`32-41; EX1002, ¶¶31-63.
`
`A. Optimization techniques for DNA library preparation were well
`known.
`Before December 2013, most NGS methods began with the preparation of a
`
`library of template DNA fragments. This was accomplished by fragmenting DNA
`
`or by using previously fragmented DNA, such as cfDNA (discussed below).
`
`EX1012, 291; EX1011, 32. Library preparation commonly involved “tagging” the
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`DNA with “adapters” having an identifier sequence, which were added to the DNA
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`fragment ends. Id. Adapters often contained “molecular barcodes” or “identifiers,”
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`which are nucleotide sequences that help to further identify and distinguish the
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`sequenced DNA fragments from one another. EX1083, ¶¶[0005], [0008]-[0009],
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`[0030]; EX1005, Fig. 1; EX1002, ¶¶39-41. A common technique for tagging was
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`ligation. EX1083, ¶[0020]; EX1005, Fig. 1; EX1015, 4-5; EX1031, 11-12, Fig. 4;
`
`EX1002, ¶39.
`
`Guardant’s claims recite open-ended ranges of “more than a 10×” excess of
`
`adapters relative to cfDNA molecules, and ligation efficiencies of “at least 20%.”
`
`But long before December 2013, artisans already knew to use significant molar
`
`excesses of adapters to achieve high efficiency ligations. EX1020, 18.4.15;
`
`
`1 TwinStrand does not concede the ’221 patent is entitled to this priority date.
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`Case IPR2022-01152
`Patent 11,118,221
`EX1031, 2. EX1083, ¶[0005]; EX1002, ¶¶42-56; EX1021, 5, Fig. 2; EX10262,
`
`¶¶[0130], [0143], [0159]; EX1025, ¶¶[0106], [0119], [0135].
`
`For example, So 2004 taught that “[t]he yield of the desired [adapter-ligated
`
`DNA] was found to depend on the amount of SAGE adaptor introduced into the
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`ligation mixture, and increased with increasing adaptor concentration.” EX1021,
`
`5, Fig. 2; EX1002, ¶44. Diehn also disclosed that “[i]ncreasing adapter
`
`concentration during ligation increases ligation efficiency and reporter recovery”
`
`and used adapter concentrations that were in “100-fold molar excess” compared to
`
`the DNA targets. EX1026, ¶¶[0130], [0143], [0159]; EX