Paper No. ___
`Filed: July 19, 2019
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
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`FOUNDATION MEDICINE, INC.,
`Petitioner,
`
`v.
`
`GUARDANT HEALTH, INC.,
`Patent Owner.
`_____________________________
`
`Case IPR2019-00636
`Patent No. 9,902,992
`_____________________________
`
`CORRECTED PATENT OWNER’S PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
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`

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`TABLE OF CONTENTS
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`I.INTRODUCTION ................................................................................................... 1 
`II.THE CHALLENGED CLAIMS ............................................................................ 2 
`III.CLAIM CONSTRUCTION .................................................................................. 4 
`A. 
`Petitioner proposes constructions for claim terms not in dispute ......... 4 
`B. 
`The proposed constructions contradict claim interpretations
`adopted by Petitioner in related proceedings ........................................ 5 
`IV.THE GROUNDS REFERENCES ........................................................................ 6 
`A. 
`Schmitt ................................................................................................... 6 
`B. 
`Fan ......................................................................................................... 6 
`C. 
`Forshew ................................................................................................. 7 
`V.THE PETITION FAILS TO ESTABLISH OBVIOUSNESS OF CLAIMS
`1-11, 13, 15-26 ................................................................................................. 8 
`A. 
`Schmitt does not disclose tagging any DNA with “at least 20%”
`tagging efficiency, much less cell-free DNA ........................................ 9 
`Petitioner fails to establish that Schmitt discloses detecting
`“two or more different members selected from the group of
`members consisting of a single base substitution, a copy
`number variation (CNV), an insertion or deletion (indel), or a
`gene fusion” ......................................................................................... 13 
`(i)
`Schmitt’s disclosure of detecting a “single base substitution” is
` 
`not prior art ................................................................................... 14 
`  Schmitt does not disclose detection of copy number variation .... 15 (ii)
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`  Petitioner’s remaining arguments are insufficient ........................ 17 (iii)
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`Petitioner fails to establish that Schmitt would be applicable to
`cell-free DNA ...................................................................................... 18 
`(i)
`The petition materials fail to establish motivation to apply the
` 
`Schmitt method to cell-free DNA ................................................. 19 
`
`a reasonable expectation of success in applying Schmitt to cell-
`free DNA ....................................................................................... 21 
`VI.CONCLUSION ................................................................................................... 27 
`VII.APPENDIX ....................................................................................................... 29
`
`
`  The petition materials fail to establish that there would have been (ii)
`
`B. 
`
`C. 
`
`-i-
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`I.
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`INTRODUCTION
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`The Board should not institute inter partes review of claims 1-11, 13, 15-26
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`of U.S. Patent No. 9,902,992 (“the ’992 patent”) because Foundation Medicine,
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`Inc. (“Petitioner”) fails to show that it has a reasonable likelihood of prevailing.
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`The ’992 patent is directed to and claims methods for detecting genetic
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`aberrations in cell-free DNA (“cfDNA”). E.g., EX1001, 1:61-2:40, claim 1.
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`Detecting and analyzing cell-free DNA was known to be challenging for a number
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`of reasons, including that it is highly fragmented and present in minute quantities
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`in clinical samples. The ’992 patent filled the “need in the art for improved
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`methods and systems for using cell-free DNA to detect and monitor disease” by
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`disclosing methods for high efficiency conversion of cell-free DNA into non-
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`uniquely tagged parent polynucleotides. E.g., id., 1:55-57.
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`Despite the specific focus of the ’992 patent and challenged claims on cell-
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`free DNA, each of the petition’s grounds of challenge rely on Schmitt as the
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`primary reference. Schmitt has no applicable teachings for detecting rare mutation
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`in cell-free DNA. Indeed, the petition concedes as much. Pet. 28 (“Schmitt focused
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`on using well-characterized DNA instead of cfDNA from clinical samples.”). This
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`defect in Petitioner’s primary reference is inescapable. Schmitt does not disclose
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`any of the recited steps directed to cell-free DNA.
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`-1-
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`The petition is replete with additional defects. For example, the petition
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`repeatedly points to disclosure that simply is not prior art. Furthermore, the petition
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`fails to establish that multiple elements of claim 1 are found in the prior art such as
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`“attaching tags comprising barcodes...to the cfDNA molecules to tag at least 20%
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`of the cfDNA molecules,” and detecting “two or more different members selected
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`from the group of members consisting of a single base substitution, a copy number
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`variation (CNV), an insertion or deletion (indel), or a gene fusion.” Also lacking
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`from Petitioner’s obviousness challenge is any substantiated assertion that a skilled
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`artisan would have been motivated to apply the steps of Schmitt to cell-free DNA
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`or would have had any expectation of success in doing so.
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`Accordingly, institution of inter partes review should be denied.
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`II. THE CHALLENGED CLAIMS
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`The petition challenges claims 1-11, 13, and 15-26 as allegedly obvious over
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`Schmitt in view of either Fan or Forshew. Claim 1 is representative and claims a
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`method for detecting two or more genetic aberrations (e.g., single base substitution,
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`a copy number variation, an insertion or deletion (indel), gene fusion) in cell-free
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`DNA obtained from a subject.
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` 1. A method for detecting genetic aberrations in cell-free DNA
`(“cfDNA”) molecules from a subject, comprising:
`a) providing cfDNA molecules obtained from a bodily sample of
`the subject;
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`-2-
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`b) attaching tags comprising barcodes having a plurality of
`different barcode sequences to the cfDNA molecules to tag at least 20%
`of the cfDNA molecules, which attaching comprises ligating adaptors
`comprising the barcodes to both ends of the cfDNA molecules, wherein
`ligating comprises using more than 10× molar excess of the adaptors as
`compared to the cfDNA molecules, thereby generating tagged parent
`polynucleotides;
`c) amplifying the tagged parent polynucleotides to produce
`amplified tagged progeny polynucleotides;
`d) sequencing the amplified tagged progeny polynucleotides to
`produce a plurality of sequence reads from each of the tagged parent
`polynucleotides, wherein each sequence read of the plurality of sequence
`reads comprises a barcode sequence and a sequence derived from a
`cfDNA molecule of the cfDNA molecules;
`e) mapping sequence reads of the plurality of sequence reads to
`one or more reference sequences from a human genome;
`f) grouping the sequence reads mapped in e) into families based at
`least on barcode sequences of the sequence reads, each of the families
`comprising sequence reads comprising the same barcode sequence,
`whereby each of the families comprises sequence reads amplified from
`the same tagged parent polynucleotide;
`g) at each of a plurality of genetic loci in the one or more reference
`sequences, collapsing sequence reads in each family to yield a base call
`for each family at the genetic locus; and
`h) detecting, at one or more genetic loci, a plurality of genetic
`aberrations, wherein the plurality of genetic aberrations comprises two or
`more different members selected from the group of members consisting
`-3-
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`of a single base substitution, a copy number variation (CNV), an
`insertion or deletion (indel), and a gene fusion.
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`III. CLAIM CONSTRUCTION
`
`The claim terms should be given their ordinary and customary meaning,
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`consistent with the specification, as a person of ordinary skill in the art (“POSA”)
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`understood them. 37 C.F.R. § 42.100(b); Phillips v. AWH Corp., 415 F.3d 1303,
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`1313 (Fed. Cir. 2005) (en banc) (“[T]he person of ordinary skill in the art is
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`deemed to read the claim term not only in the context of the particular claim in
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`which the disputed term appears, but in the context of the entire patent, including
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`the specification.”).
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`A.
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`Petitioner proposes constructions for claim terms not in
`dispute
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`Claim construction “is not an obligatory exercise in redundancy.” U.S.
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`Surgical Corp. v. Ethicon, Inc., 103 F.3d 1554, 1568 (Fed. Cir. 1997). Petitioner
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`provides a laundry list of proposed constructions for various terms. Pet. 18-19. Yet,
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`not once does Petitioner explain why any of these terms need to be construed for
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`the Board to resolve the scope of the claims. U.S. Surgical, 103 F.3d at 1568. For
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`example, Petitioner proposes a construction for the term “non-uniquely tagged.”
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`Pet. 19. This term is not recited in the challenged claims. Petitioner’s constructions
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`should be rejected as the Board is not obligated to construe terms where the
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`construction is not material to the dispute. E.g., Vivid Techs., Inc. v. Am. Sci. &
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`-4-
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`Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (“[O]nly those terms which are in
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`controversy need to be construed and only to the extent necessary to resolve the
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`controversy.”).1
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`B.
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`The proposed constructions contradict claim interpretations
`adopted by Petitioner in related proceedings
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` Next, Petitioner’s penchant for offering differing and contradictory
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`constructions, which it perpetuates here, provides another reason why the Board
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`should decline to adopt the proposed constructions. Petitioner has now advanced at
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`least five different constructions before the Board for the term “parent
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`polynucleotide.” Here, Petitioner proposes construing the term “parent
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`polynucleotide” as “the starting DNA fragment that is tagged, amplified to
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`generate copies, sequenced, and analyzed for the presence of mutations,” Pet. 19;
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`see also id., 38 (citing EX1001, Figure 9). Yet, Petitioner proposed construing the
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`same term in the context of a similar specification in U.S. Pat. No. 9,598,731 (“the
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`’731 patent”) in IPR2019-00130. In IPR2019-00130, Petitioner offered at least
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`four different constructions of “parent polynucleotide” all of which are different
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`from that proposed here. See EX2004 at 5, 19, 35, 63 (citing EX1001, Figure 9);
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`1 Should the Board find construction of any claim terms necessary, these terms
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`should be construed consistent with Patent Owner’s construction offered in district
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`court. See EX2001.
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`-5-
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`IPR2019-00130, Paper 6 at 9-11. Petitioner offers no explanation for its ever
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`evolving views on the meaning of “parent polynucleotide.”
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`IV. THE GROUNDS REFERENCES
`A.
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`Schmitt
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`Schmitt (EX1011) discloses “Duplex Consensus Sequencing” or “DCS”
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`which purports to reduce sequence errors in high throughput sequencing reads.
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`EX1011, 3:10-20. Schmitt accomplishes error correction using single molecule
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`identifiers (“SMIs”) which are attached to either end of the DNA fragment to be
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`sequenced. Id., 3:1-6. Every SMI adaptor “contains a unique, double-stranded,
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`complementary n-mer random tag on each end.” EX1011, 3:48-51. After SMI
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`adaptors are attached to the sample DNA fragments, the fragments are amplified
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`and then sequenced. Id., 3:54-62, Figure 1. According to Schmitt, the error
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`correction method depends on grouping together families of PCR duplicates which
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`are identified by virtue of their unique random SMI tag. Id., 21:55-61.
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`B.
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`Fan
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`Fan does not disclose a method for detecting rare mutation, rather it
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`describes a method for detecting of fetal aneuploidy. E.g., EX1048 at 16266
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`(“Shotgun Sequencing of Cell-free Plasma DNA”). According to Fan, aneuploidy
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`is detected by shotgun sequencing cell-free DNA from maternal plasma, mapping
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`the resulting reads to a reference sequence, and then obtaining a measure of the
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`-6-
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`

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`number of sequence reads that map to each chromosome. Id., 16266-67 (“Shotgun
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`Sequencing of Cell-Free Plasma DNA”), (“Detection of Fetal Aneuploidy”). Fan
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`does not require highly accurate sequencing methods because the method is
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`“polymorphism-independent” and can tolerate sequencing errors. EX1048, 16266,
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`16271. Additionally, because Fan does not require highly accurate sequencing of
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`sample DNA, it uses low depth sequencing. Id., 16269 (“Because those 5 million
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`reads2 represent only a portion of one human genome, in principle less than one
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`genomic equivalent of DNA is sufficient for the detection of aneuploidy…”). Fan
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`does not disclose the use of molecular barcodes, or any other form of error
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`correction.
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`C.
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`Forshew
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`Forshew discloses detection of mutation in plasma samples using targeted
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`deep sequencing. E.g., EX1004 at Table 1, 3 (“Quantitative limitations of mutation
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`detection”). Forshew discloses a mutation detection method that amplifies regions
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`of interest (e.g., genes commonly mutated in cancer) and then uses a combination
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`of deep sequencing and replicate analysis to avoid false positives resulting from
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`sequencing errors. EX1004, 9 (“Duplicate sequencing of each sample is used to
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`avoid false positives stemming from PCR errors.”), 10 (“Higher read depth or
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`2 The human genome is approximately 3 billion base pairs.
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`https://en.wikipedia.org/wiki/Human_genome (last accessed May 23, 1019).
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`-7-
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`fidelity, additional replicates, or improved algorithms could allow for enhanced
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`mutation detection without change to protocols.”). Forshew does not disclose using
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`molecular barcodes to correct sequencing errors. To the extent Forshew teaches
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`use of barcodes, it is to facilitate multiplex analysis of patient samples. E.g.,
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`EX1004, 9 (“Sample barcodes and high throughput PCR reduce the per sample
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`costs to a range where this may be widely applicable.”).
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`V. THE PETITION FAILS TO ESTABLISH OBVIOUSNESS OF
`CLAIMS 1-11, 13, 15-26
`
`The petition materials allege that claims 1-11, 13, 15-26 are unpatentable
`
`over Schmitt in view Fan or Forshew. Ground 1, the only ground of challenge, has
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`numerous fatal flaws including failure to demonstrate the cited references disclose
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`all elements of the challenged claims. For example, Schmitt fails to teach at least
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`two claim elements including “attaching tags … [to] at least 20% of the cfDNA
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`molecules” (step (b)) and “two or more different members selected from the group
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`of members consisting of a single base substitution, a copy number variation
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`(CNV), an insertion or deletion (indel), or a gene fusion,” (step (h)) as required by
`
`claim 1. Furthermore, none of Schmitt, Fan, and Forshew teaches tagging of cell-
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`free DNA molecules as recited in at least the preamble and steps (a), (b), and (d) of
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`claim 1.
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`-8-
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`A.
`
`Schmitt does not disclose tagging any DNA with “at least 20%”
`tagging efficiency, much less cell-free DNA
`
`The petition materials fail to establish that the cited references teach or
`
`suggest “attaching tags comprising barcodes...to the cfDNA molecules to tag at
`
`least 20% of the cfDNA molecules,” as specifically recited in claim 1. This aspect
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`of claim 1 is addressed at pages 39-41 of the petition, where Petitioner relies on the
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`Schmitt reference.
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`Petitioner concedes that “Schmitt does not explicitly recite tagging ‘at least
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`20%’ of the cfDNA molecules by ligation.” Pet. 39. Instead, the petition asserts
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`that “a POSA would have understood [Schmitt] to result in at least a 10-20% yield
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`of tagged DNA fragments.” But the petition materials fail to establish this aspect of
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`claim 1 is necessarily present in Schmitt. See Akamai Techs. v. Cable & Wireless
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`Internet Servs., 344 F.3d 1186, 1192 (Fed. Cir. 2003) (“A claim limitation is
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`inherent in the prior art if it is necessarily present in the prior art, not merely
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`probably or possibly present.”); MEHL/Biophile Int’l Corp. v. Milgraum, 192 F.3d
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`1362, 1365 (Fed. Cir. 1999) (“Inherency … may not be established by probabilities
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`or possibilities.”) (internal quotes omitted).
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`As an initial matter, the petition materials ignore the cfDNA requirement of
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`the claims when discussing tagging efficiency. Claim 1 requires “attaching tags
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`comprising barcodes …to the cfDNA molecules to tag at least 20% of the cfDNA
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`molecules.” Schmitt applies its method exclusively to genomic DNA. See also
`-9-
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`Section V.C. Moreover, Meyer, Quail, and the NEB Publication (i.e., EX1061-
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`1063) discussed at pages 39-41 of the petition do not describe their methods as
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`being applicable to cell-free DNA—nor does Petitioner allege that they do.
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`Similarly, the arguments for motivation and reasonable expectation of success at
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`pages 29-36 of the petition ignore the tagging efficiency requirement. As such,
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`Petitioner cannot establish that Schmitt, alone or in combination with any other
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`reference, teaches “attaching tags … [to] at least 20% of the cfDNA molecules”
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`when tagging efficiency of cfDNA is discussed nowhere in the petition materials.
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`The petition may be rejected on this basis alone.
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`Beyond lacking disclosure regarding cfDNA, Schmitt does not teach tagging
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`any DNA with “at least 20%” tagging efficiency as recited in claim 1. Petitioner’s
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`assertion that “a POSA would have understood [Schmitt] to result in at least 10-
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`20% yield of tagged DNA fragments” fails for several reasons.
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`First, the petition (page 39 (citing EX1011, 7:58-62, 15:5-20)) points to
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`Schmitt’s mention of ligating adaptors to “a blunt end,” but these citations
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`certainly do not show that Schmitt uses blunt-end ligation “to tag at least 20%” of
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`any DNA molecules. Petitioner points to a different reference of Meyer as
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`exemplifying a blunt-end ligation that “was capable of generating a 10-20% final
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`library yield.” Pet. 39 (citing EX1061, 2, 7). But Meyer, not a grounds reference,
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`does not establish the ligation efficiency of Schmitt’s method at least because it
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`-10-
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`does not describe the use of Schmitt’s method—nor does Petitioner allege that it
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`does. Nor does the petition assert, let alone establish, that Schmitt and Meyer use
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`the same blunt-end ligation method.3
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`Petitioner then turns to another non-grounds reference, Quail, for the
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`argument that yet a different ligation strategy “was likely to result in a higher yield
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`of tagged fragments.” Id. (citing EX1062, 1006). As with Meyer, Petitioner does
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`not even allege that Quail uses Schmitt’s method (it does not), that Quail and
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`Schmitt use the same TA ligation method, or that the Quail TA ligation method
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`would even be suitable for use in the methods of Schmitt. Neither Meyer nor Quail
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`demonstrates that Schmitt necessarily discloses 20% tagging efficiency.
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`The petition (pages 40-41) then pivots from assertions of inherent disclosure
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`to a theory of obviousness. In particular, the petition asserts that “a POSA would
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`have understood that ligation efficiency could be improved using a variety of
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`techniques known in the art...” Pet. 40; see also id. (“Quail taught that ligation
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`efficiency can be improved using ultrapure commercial ligases.”) (emphasis
`
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`3 The petition does not assert that it would have been obvious to use the sample
`
`preparation methods of Meyer in Schmitt, motivation to do so, or whether success
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`would reasonably be expected—or that such methods would be suitable for such
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`use.
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`-11-
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`added). But such assertions have never been sufficient to establish obviousness.
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`InTouch Techs., Inc. v. VGo Communs., Inc., 751 F.3d 1327, 1352 (Fed. Cir. 2014)
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`(obviousness analysis failed for stating “that one of ordinary skill in the art could
`
`combine these references, not that they would have been motivated to do so.”)
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`(original emphasis); PersonalWeb Techs., LLC v. Apple, Inc., 848 F.3d 987, 993-
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`994 (Fed. Cir. 2017) (same); Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064, 1073
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`(Fed. Cir. 2015) (same). Here, Petitioner does not explain why a POSA would have
`
`been motivated to pursue improvements to Schmitt’s method in this regard, how
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`this modification would have been carried out, or whether success would have
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`been reasonably expected. These critical aspects of an obviousness assertion are
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`missing entirely.
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`The petition (pages 40-41) additionally relies on the NEB Publication
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`(EX1063), but fails to establish the NEB Publication even qualifies as prior art to
`
`the ’992 patent. There is no publication date provided in the petition materials or
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`listed in the NEB document itself. However, the NEB Publication includes a
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`citation to “Greenough et. al. (2016),” indicating the NEB Publication could not
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`have been published prior to 2016. EX1063, 4. The petition includes a footnote
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`(page 41) arguing that the NEB Quick Ligation Kit (“Kit”) was used in 2012. But
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`inter partes review is limited to patents and printed publications. 35 U.S.C.
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`§ 311(b). Even assuming arguendo that the Kit was used does not establish that the
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`-12-
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`

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`NEB Publication cited and relied upon in the petition qualifies as prior art. Clearly
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`it does not.
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`Accordingly, Petitioner fails to establish that the cited references teach or
`
`suggest “attaching tags comprising barcodes...to the cfDNA molecules to tag at
`
`least 20% of the cfDNA molecules,” as specifically recited in claim 1.
`
`B.
`
`Petitioner fails to establish that Schmitt discloses detecting
`“two or more different members selected from the group of
`members consisting of a single base substitution, a copy
`number variation (CNV), an insertion or deletion (indel), or a
`gene fusion”
`
`Petitioner alleges that “Schmitt explicitly teaches DCS can detect ‘single
`
`base substitution’ and ‘CNV.’” Pet. 49. No such “explicit” teaching can be found
`
`in Schmitt. The disclosure that Petitioner relies on for “single base substitution” is
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`not present in Schmitt’s priority document and therefore is not prior art.
`
`Furthermore, Schmitt cannot “explicitly” disclose detection of copy number
`
`variation because it does not describe doing so anywhere in the reference. Finally,
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`Petitioner tacitly concedes that Schmitt does not disclose detection of “an insertion
`
`or deletion (indel), or a gene fusion.” Instead, Petitioner argues that Schmitt “can
`
`detect” other mutations—but this argument is both factually and legally deficient.
`
`-13-
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` Schmitt’s disclosure of detecting a “single base
`(i)
`substitution” is not prior art
`The Petition alleges the Schmitt patent is prior art because it “claims the
`
`benefit of U.S. Provisional Application 61/613,413 filed on March 20, 2012
`
`(EX1012) (“’413 Provisional”).” Pet. 20.
`
`But the petition materials fail to show that the material in the Schmitt patent
`
`that is relied upon in the petition was disclosed in and carried through from the
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`’413 Provisional. See, e.g., Cox Communications, Inc. v. AT&T Intellectual
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`Property I, L.P., IPR2015-01227, Paper 70 at 40 (“[T]he material relied upon as
`
`teaching the subject matter of the challenged claims must be carried through from
`
`that earlier filed application to the reference patent being used against the claim.”)
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`(citing In re Giacomini, 612 F.3d 1380, 1383 (Fed. Cir. 2010)); see also Ariosa
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`Diagnostics, Inc. v. Illumina, Inc., IPR2014-01093, Paper 69 at 11 (same).
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`Here, the petition includes only a single conclusory statement that “the
`
`teachings that Petitioner relies upon were carried forward from the ’413
`
`Provisional to Schmitt.” Pet. 20. But this conclusory assertion is unsubstantiated
`
`and incorrect.
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`For instance, Petitioner critically relies on disclosure within Example 4 of
`
`the Schmitt patent as teaching “single base substitutions” of the challenged claims.
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`Pet. 49 (“Consensus Sequencing Accurately Recovers Spiked-in Control
`
`Mutations. A series of M13mp2 variants were constructed which contain known
`-14-
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`single base substitutions. EX1011, 29:57-60 (emphasis added).”). But Example 4
`
`of the Schmitt patent is not found in the ’413 Provisional. The ’413 Provisional
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`includes only Examples 1 and 2 which appear to correspond to Examples 1 and 3
`
`of the Schmitt patent. There is no Example 4 in the ’413 Provisional.
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`As such, the petition fails to establish that the subject matter relied on in the
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`Schmitt patent is in the ’413 provisional and that the Schmitt patent is prior art to
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`the challenged patent. The petition may be denied for this reason alone.
`
` Schmitt does not disclose detection of copy number
`(ii)
`variation
`The petition hinges on the notion that Schmitt “explicitly” discloses
`
`detection of copy number variation. Pet. 49. Yet, Petitioner does not and cannot
`
`point to any such disclosure in Schmitt because there is none. Instead, Petitioner
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`asserts only that “Schmitt states that SMI tags allow for ‘single-molecule counting
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`for accurate determination of DNA or RNA copy number’ that is applicable for
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`‘accurate detection of altered genomic copy number … such as trisomy 21.’” Pet.
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`49 (citing EX1011, 18:3-21; EX1012, [0048]; EX1002, ¶163).
`
`Petitioner fails to acknowledge that “copy number variation” and
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`“aneuploidy” (e.g., trisomy 21) are discussed in the ’992 patent specification as
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`distinct genetic aberrations. E.g., EX1001, 53:32-37 (“These system and methods
`
`may be used to detect any number of genetic aberrations that may cause or result
`
`from cancers. These may include but are not limited to …, copy number
`-15-
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`variations, transversions, translocations, inversion, deletions, aneuploidy, …”).
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`The ’992 patent further describes copy number variations as sub-chromosomal
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`aberrations. Id., 7:52-54 (“[T]he genetic variation is copy number/heterozygosity
`
`variation and detecting is performed with sub-chromosomal resolution.”).
`
`Aneuploidies, in contrast, are genetic aberrations in the number of
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`chromosomes—as opposed to aberrations in the copy number of sub-chromosomal
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`regions. Notably, the Japanese Patent Office (JPO) came to this same conclusion in
`
`an Opposition Proceeding where prior art aneuploidy methods were asserted
`
`against the patentability of claims reciting detection of copy number variation.
`
`EX2005, 2-5. Upon review, the JPO made the factual determination that
`
`aneuploidies are distinct from copy number variations.
`
`“[F]etal trisomy 21” in the subject matter of [Chiu 2011, EX1050] is a
`genome level abnormality, but should be considered in view of common
`general knowledge as of the priority dates as “aneuploidy”, which does
`not correspond to “copy number variation”. This is also consistent with
`the instant specification describing “copy number variation” separately
`from “aneuploidy”…
`
`EX2005, 15.
`
`Petitioner provides no explanation why Schmitt’s disclosure of detecting
`
`trisomy 21 should be considered an explicit disclosure of detecting copy number
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`variation. This is insufficient to justify a determination at odds with the
`
`specification of the ’992 patent and the conclusions of the JPO.
`
` Petitioner’s remaining arguments are insufficient
`(iii)
`Perhaps sensing the deficiencies in Schmitt’s disclosure, Petitioner also
`
`argues that a “POSA would have understood that Schmitt’s methods can detect
`
`more than one type of genetic aberration in the same experiment.” Pet. 49. This
`
`unsupported assertion is factually and legally deficient. The only objective
`
`evidence Petitioner points to is that other prior art methods could detect more than
`
`one type of genetic aberration. Pet. 49 (citing EX1005, Figure 3; EX1067, 3;
`
`EX1068, Abstract). But the petition materials provide no discussion of what these
`
`methods entail and how they might differ from Schmitt. Even if Petitioner’s
`
`assertion is accepted, Petitioner does not explain why a POSA would have been
`
`motivated to detect other genetic aberration using Schmitt’s method, how Schmitt
`
`would have been modified to do so, or whether success would have been
`
`reasonably expected. That is, Petitioner fails to establish even a reasonable
`
`likelihood of proving obviousness.
`
`Petitioner also argues that a “POSA would need only to compare differences
`
`between the consensus sequences and reference sequences to determine the nature
`
`of the genetic aberration.” Pet. 50 (citing EX1002, ¶¶164-165, ¶38). This argument
`
`does not rely on any objective evidence. A review of Dr. Gabriel’s declaration
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`finds no citation to Schmitt or references describing use of the Schmitt technique.
`
`Paragraphs 164 and 165 discuss references other than Schmitt and paragraph 38
`
`purports to demonstrate genetic mutation detection “in the context of single-strand
`
`consensus sequencing (“SSCS”) and double-strand consensus sequencing
`
`(“DCS”)”—i.e., the Schmitt method. The figure appears to have been assembled
`
`by Dr. Gabriel. There is no citation to any reference and, despite purporting to
`
`describe the DCS method, this figure does not appear in Schmitt. That is, this
`
`figure is not prior art, but rather speculation made in attempting to provide support
`
`for the petition.
`
`Beyond lacking a shred of evidentiary support, Petitioner’s argument that
`
`Schmitt’s methods allegedly can detect more than one type of genetic aberration is
`
`insufficient to prove obviousness. InTouch, 751 F.3d at 1352; PersonalWeb, 848
`
`F.3d at 993-4; Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064, 1073 (Fed. Cir. 2015).
`
`
`
`C.
`
`Petitioner fails to establish that Schmitt would be applicable to
`cell-free DNA
`
`The petition relies entirely on the Schmitt references as allegedly providing
`
`all aspects of claim 1, except step (a). Fan and Forshew are cited only for providing
`
`a cell-free DNA sample as in claim 1(a). Pet. 29 (“Ground 1 relies upon Fan or
`
`Forshew only for disclosure relating to testing DNA from cfDNA samples.”). But
`
`Petitioner concedes that Schmitt does not disclose applying the DCS method to
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`cell-free DNA. Pet. 28 (“Because this experiment and other working examples
`
`were proof-of-concept, Schmitt focused on using well-characterized DNA instead
`
`of cfDNA from clinical samples.”). Thus, the only disputed issues with respect to
`
`the cell-free DNA limitations are whether a POSA would have been motivated to
`
`apply Schmitt to cell-free DNA and whether a POSA would have reasonably
`
`expected success in doing so. As explained below, Petitioner has failed to establish
`
`motivation or a reasonable expectation of success.
`
` The petition materials fail to establish motivation to
`(i)
`apply the Schmitt method to cell-free DNA
` Despite having a section labeled “motivation to combine” the petition has
`
`very little to say about why, specifically, a POSA would have been motivated to
`
`apply Schmitt to the cell-free DNA samples of Fan or Forshew. Much of
`
`Petitioner’s argument rests on mischaracterizing Schmitt as “explicitly” disclosing
`
`a motivation.
`
`For example, Petitioner incorrectly asserts that “Schmitt provides explicit
`
`motivation to combine its methods with the disclosures in Fan.” Pet. 29. The only
`
`alleged support for this dubious assertion is that “Schmitt specifically cites Fan,
`
`along with one other paper, that discuss sequencing cell-free DNA to detect genetic
`
`aberrations.” Pet. 29 (citing EX1011, 1:28-55). This portion of Schmitt reveals
`
`nothing beyond a benign and general introductory remark that high throughput
`
`sequencing methods are being developed for various applications.
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`Clinical applications, such [as] prenatal screening for fetal aneuploidy
`[citing Fan and Chiu], early detection of cancer [11] and monitoring its
`response to therapy [12, 13] with nucleic acid-based serum biomarkers,
`are rapidly being developed.
`
`EX1011, 1:38-45.
`
`Petitioner further asserts that “[b]ecause Schmitt’s DCS approach is a
`
`workflow that can have a ‘general role in next generation DNA sequencing,’
`
`Schmitt provides explicit motivation to apply the DCS approach for sequencing
`
`cell-free DNA as taught by Fan.” Pet. 29 (citing EX1002, ¶97). Although
`
`unattributed, the quoted material at p. 29 is from Schmitt.
`
`The compatibility of DCS with existing sequencing workflows, the
`potential for