Paper No. ___
`Filed: July 19, 2019
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________________
`
`FOUNDATION MEDICINE, INC.,
`Petitioner,
`
`v.
`
`GUARDANT HEALTH, INC.,
`Patent Owner.
`_____________________________
`
`Case IPR2019-00637
`Patent No. 9,902,992
`_____________________________
`
`CORRECTED PATENT OWNER’S PRELIMINARY RESPONSE
`PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`

`

`TABLE OF CONTENTS
`
`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 ......................................................................................................... 7 
`C. 
`Forshew ................................................................................................. 8 
`D.  Kucera.................................................................................................... 8 
`E. 
`Schwarzenbach ...................................................................................... 9 
`V.THE PETITION FAILS TO DEMONSTRATE THAT CLAIM 1 IS
`OBVIOUS ........................................................................................................ 9 
`A. 
`Schmitt does not disclose tagging any DNA with “at least 20%”
`tagging efficiency, much less cell-free DNA ...................................... 10 
`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” ......................................................................................... 15 
`(i) 
`Schmitt’s disclosure of detecting a “single base substitution” is
`not prior art ...................................................................................................... 15 
`(ii) 
`Schmitt does not disclose detection of copy number variation .... 17 
`(iii)  Petitioner’s remaining arguments are insufficient ....................... 18 
`Petitioner fails to establish that Schmitt would be applicable to
`cell-free DNA ...................................................................................... 20 
`(i) 
`The petition materials fail to establish motivation to apply the
`Schmitt method to cell-free DNA ..................................................................... 21 
`(ii)  The petition materials fail to establish that there would have been
`a reasonable expectation of success in applying Schmitt to cell-free DNA ..... 23 
`VI.GROUND 1 FAILS ............................................................................................ 29 
`VII.GROUND 2 FAILS ........................................................................................... 30 
`VIII.GROUND 3 FAILS ......................................................................................... 31 
`
`B. 
`
`C. 
`
`-i-
`
`

`

`IX.CONCLUSION ................................................................................................... 33
`
`IX.CONCLUSION ................................................................................................... 33 
`X.APPENDIX .......................................................................................................... 35 
`
`
`X.APPENDIX .......................................................................................................... 35
`
`
`
`
`
`
`-i-
`
`

`

`I.
`
`INTRODUCTION
`
`The Board should not institute inter partes review of claims 11, 12, 14, and
`
`27-33 of U.S. Patent No. 9,902,992 (“the ’992 patent”) because Foundation
`
`Medicine, Inc. (“Petitioner”) fails to show that it has a reasonable likelihood of
`
`prevailing.
`
`The ’992 patent is directed to and claims methods for detecting genetic
`
`aberrations in cell-free DNA (“cfDNA”). E.g., EX1001, 1:61-2:40, claim 1.
`
`Detecting and analyzing cell-free DNA was known to be challenging for a number
`
`of reasons, including that it is highly fragmented and present in minute quantities
`
`in clinical samples. The ’992 patent filled the “need in the art for improved
`
`methods and systems for using cell-free DNA to detect and monitor disease” by
`
`disclosing methods for high efficiency conversion of cell-free DNA into non-
`
`uniquely tagged parent polynucleotides. E.g., id., 1:55-57.
`
`Despite the specific focus of the ’992 patent and challenged claims on cell-
`
`free DNA, each of the petition’s grounds of challenge rely on Schmitt as the
`
`primary reference. Schmitt has no applicable teachings for detecting rare mutation
`
`in cell-free DNA. Indeed, the petition concedes as much. Pet. 30 (“Schmitt focused
`
`on using well-characterized DNA instead of cfDNA from clinical samples.”). This
`
`defect in Petitioner’s primary reference is inescapable. Schmitt does not disclose
`
`any of the recited steps directed to cell-free DNA.
`
`-1-
`
`
`

`

`The petition is replete with additional defects. For example, the petition
`
`repeatedly points to disclosure that simply is not prior art. Furthermore, the petition
`
`fails to establish that multiple elements of claim 1 are found in the prior art such as
`
`“attaching tags comprising barcodes...to the cfDNA molecules to tag at least 20%
`
`of the cfDNA molecules,” and 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.” Also lacking
`
`from Petitioner’s obviousness challenge is any substantiated assertion that a skilled
`
`artisan would have been motivated to apply the steps of Schmitt to cell-free DNA
`
`or would have had any expectation of success in doing so.
`
`Petitioner fails to demonstrate that all elements of claim 1 are found in the
`
`prior art. While Petitioner does not challenge claim 1, the petition may be denied
`
`because all challenged claims depend from claim 1 and Grounds 1-3 fail to remedy
`
`any of the deficiencies associated with claim 1.
`
`Accordingly, institution of inter partes review should be denied.
`
`II. THE CHALLENGED CLAIMS
`
`The petition challenges claims 27-33 as allegedly obvious over Schmitt in
`
`view of either Fan or Forshew, claims 11 and 12 over Schmitt in view of either Fan
`
`or Forshew, and further in view of Kucera, and claim 14 over Schmitt in view of
`
`either Fan or Forshew, and further in view of Schwarzenbach. Claims 11, 12, 14,
`
`-2-
`
`
`

`

`and 27-33 depend either directly or indirectly from claim 1. Claim 1 is
`
`representative and claims a method for detecting two or more genetic aberrations
`
`(e.g., single base substitution, a copy number variation, an insertion or deletion
`
`(indel), gene fusion) in cell-free DNA obtained from a subject.
`
` 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;
`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;
`
`-3-
`
`
`

`

`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
`of a single base substitution, a copy number variation (CNV), an
`insertion or deletion (indel), and a gene fusion.
`
`III. CLAIM CONSTRUCTION
`
`The claim terms should be given their ordinary and customary meaning,
`
`consistent with the specification, as a person of ordinary skill in the art (“POSA”)
`
`understood them. 37 C.F.R. § 42.100(b); Phillips v. AWH Corp., 415 F.3d 1303,
`
`1313 (Fed. Cir. 2005) (en banc) (“[T]he person of ordinary skill in the art is
`
`deemed to read the claim term not only in the context of the particular claim in
`
`which the disputed term appears, but in the context of the entire patent, including
`
`the specification.”).
`
`A.
`
`Petitioner proposes constructions for claim terms not in
`dispute
`
`Claim construction “is not an obligatory exercise in redundancy.” U.S.
`-4-
`
`
`

`

`Surgical Corp. v. Ethicon, Inc., 103 F.3d 1554, 1568 (Fed. Cir. 1997). Petitioner
`
`provides a laundry list of proposed constructions for various terms. Pet. 18-19. Yet,
`
`not once does Petitioner explain why any of these terms need to be construed for
`
`the Board to resolve the scope of the claims. U.S. Surgical, 103 F.3d at 1568. For
`
`example, Petitioner proposes constructions for the terms “non-uniquely tagging”
`
`and “uniquely tagging.” Pet. 19. Neither term is recited in the challenged claims.
`
`Petitioner’s constructions should be rejected as the Board is not obligated to
`
`construe terms where the construction is not material to the dispute. E.g., Vivid
`
`Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir. 1999) (“[O]nly
`
`those terms which are in controversy need to be construed and only to the extent
`
`necessary to resolve the controversy.”).1
`
`B.
`
`The proposed constructions contradict claim interpretations
`adopted by Petitioner in related proceedings
`
`Next, Petitioner’s penchant for offering differing and contradictory
`
`constructions, which it perpetuates here, provides another reason why the Board
`
`should decline to adopt the proposed constructions. Petitioner has now advanced at
`
`least five different constructions before the Board for the term “parent
`
`1 If construction of any claim term is necessary, these terms should be construed
`
`consistent with Patent Owner’s construction offered in district court. See EX2001.
`
`
`
`-5-
`
`
`

`

`polynucleotide.” Here, Petitioner proposes construing the term “parent
`
`polynucleotide” as “the starting DNA fragment that is tagged, amplified to
`
`generate copies, sequenced, and analyzed for the presence of mutations,” Pet. 19;
`
`see also id., 41 (citing EX1001, Figure 9). Yet, Petitioner proposed construing the
`
`same term in the context of a substantially similar specification in U.S. Pat. No.
`
`9,598,731 (“the ’731 patent”) in IPR2019-00130. In IPR2019-00130, Petitioner
`
`offered at least four different constructions of “parent polynucleotide” all of which
`
`are different from that proposed here. See EX2004 at 5, 19, 35, 63 (citing EX1001,
`
`Figure 9); IPR2019-00130, Paper 6 at 9-11. Petitioner offers no explanation for its
`
`ever evolving views on the meaning of “parent polynucleotide.”
`
`IV. THE GROUNDS REFERENCES
`A.
`
`Schmitt
`
`Schmitt (EX1011) discloses “Duplex Consensus Sequencing” or “DCS”
`
`which purports to reduce sequence errors in high throughput sequencing reads.
`
`EX1011, 3:10-20. Schmitt accomplishes error correction using single molecule
`
`identifiers (“SMIs”) which are attached to either end of the DNA fragment to be
`
`sequenced. Id., 3:1-6. Every SMI adaptor “contains a unique, double-stranded,
`
`complementary n-mer random tag on each end.” EX1011, 3:48-51. After SMI
`
`adaptors are attached to the sample DNA fragments, the fragments are amplified
`
`and then sequenced. Id., 3:54-62, Figure 1. According to Schmitt, the error
`
`-6-
`
`
`

`

`correction method depends on grouping together families of PCR duplicates which
`
`are identified by virtue of their unique random SMI tag. Id., 21:55-61.
`
`B.
`
`Fan
`
`Fan does not disclose a method for detecting rare mutation, rather it
`
`describes a method for detecting of fetal aneuploidy. E.g., EX1048 at 16266
`
`(“Shotgun Sequencing of Cell-free Plasma DNA”). According to Fan, aneuploidy
`
`is detected by shotgun sequencing cell-free DNA from maternal plasma, mapping
`
`the resulting reads to a reference sequence, and then obtaining a measure of the
`
`number of sequence reads that map to each chromosome. Id., 16266-67 (“Shotgun
`
`Sequencing of Cell-Free Plasma DNA”), (“Detection of Fetal Aneuploidy”). Fan
`
`does not require highly accurate sequencing methods because the method is
`
`“polymorphism-independent” and can tolerate sequencing errors. EX1048, 16266,
`
`16271. Additionally, because Fan does not require highly accurate sequencing of
`
`sample DNA, it uses low depth sequencing. Id., 16269 (“Because those 5 million
`
`reads2 represent only a portion of one human genome, in principle less than one
`
`genomic equivalent of DNA is sufficient for the detection of aneuploidy…”). Fan
`
`does not disclose the use of molecular barcodes, or any other form of error
`
`correction.
`
`2 The human genome is approximately 3 billion base pairs.
`
`https://en.wikipedia.org/wiki/Human_genome (last accessed May 23, 1019).
`
`-7-
`
`
`

`

`C.
`
`Forshew
`
`Forshew discloses detection of mutation in plasma samples using targeted
`
`deep sequencing. E.g., EX1004 at Table 1, 3 (“Quantitative limitations of mutation
`
`detection”). Forshew discloses a mutation detection method that amplifies regions
`
`of interest (e.g., genes commonly mutated in cancer) and then uses a combination
`
`of deep sequencing and replicate analysis to avoid false positives resulting from
`
`sequencing errors. EX1004, 9 (“Duplicate sequencing of each sample is used to
`
`avoid false positives stemming from PCR errors.”), 10 (“Higher read depth or
`
`fidelity, additional replicates, or improved algorithms could allow for enhanced
`
`mutation detection without change to protocols.”). Forshew does not disclose using
`
`molecular barcodes to correct sequencing errors. To the extent Forshew teaches
`
`use of barcodes, it is to facilitate multiplex analysis of patient samples. E.g.,
`
`EX1004, 9 (“Sample barcodes and high throughput PCR reduce the per sample
`
`costs to a range where this may be widely applicable.”).
`
`D. Kucera
`
`Kucera discloses small molecules that may be used to enhance ligation of
`
`DNA fragments. E.g., EX1071, 5:17-20. Kucera does not describe methods for
`
`detecting genetic aberration in cell-free DNA, much less attaching tags comprising
`
`barcodes to cell-free DNA.
`
`-8-
`
`
`

`

`E.
`
`Schwarzenbach
`
`Schwarzenbach describes the biology and potential clinical utility of cell-
`
`free DNA. E.g., EX1054, Abstract. Schwarzenbach does not describe sample
`
`preparation methods for cell-free DNA. Id., 433 (“A major technical issue that
`
`hampers consistency in all the cfDNA assays is the efficacy of the extraction
`
`procedures, with only small amounts of DNA obtained from plasma and serum.”).
`
`V. THE PETITION FAILS TO DEMONSTRATE THAT CLAIM 1 IS
`OBVIOUS
`
`The petition materials allege that claim 1 is unpatentable over Schmitt in
`
`view Fan or Forshew. This allegation has numerous fatal flaws including failure to
`
`demonstrate the cited references disclose all elements of the challenged claims. For
`
`example, Schmitt fails to teach at least two claim elements including “attaching
`
`tags … [to] at least 20% of the cfDNA molecules” (step (b)) and “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,” (step (h)) as required by claim 1. Furthermore, none of Schmitt, Fan,
`
`and Forshew teaches tagging of cell-free DNA molecules as recited in at least the
`
`preamble and steps (a), (b), and (d) of claim 1.
`
`Grounds 1-3 challenge only claims depending from claim 1. None of the
`
`deficiencies associated with Petitioner’s allegations against claim 1 are remedied in
`
`the grounds of challenge.
`
`-9-
`
`
`

`

`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
`
`of claim 1 is addressed at pages 42-44 of the petition, where Petitioner relies on the
`
`Schmitt reference. Schmitt fails to disclose this aspect of the claim because (1)
`
`Schmitt does not tag cell-free DNA at all, and (2) Schmitt is entirely silent as to the
`
`efficiency at which its cellular DNA is tagged.
`
`Petitioner concedes that Schmitt is silent on tagging efficiency, stating
`
`“Schmitt does not explicitly recite tagging ‘at least 20%’ of the cfDNA molecules
`
`by ligation.” Pet. 42. Instead, the petition asserts that “a POSA would have
`
`understood [Schmitt] to result in at least a 10-20% yield of tagged DNA fragments.”
`
`But the petition materials fail to establish this aspect of claim 1 is necessarily
`
`present in Schmitt. See Akamai Techs. v. Cable & Wireless Internet Servs., 344
`
`F.3d 1186, 1192 (Fed. Cir. 2003) (“A claim limitation is inherent in the prior art if
`
`it is necessarily present in the prior art, not merely probably or possibly present.”);
`
`MEHL/Biophile Int’l Corp. v. Milgraum, 192 F.3d 1362, 1365 (Fed. Cir. 1999)
`
`(“Inherency … may not be established by probabilities or possibilities.”) (internal
`
`quotes omitted).
`
`-10-
`
`
`

`

`As an initial matter, the petition materials ignore the cfDNA requirement of
`
`the claims when discussing tagging efficiency. Claim 1 requires “attaching tags
`
`comprising barcodes …to the cfDNA molecules to tag at least 20% of the cfDNA
`
`molecules.” Schmitt applies its method exclusively to genomic DNA. See also
`
`Section V.C. Moreover, Meyer, Quail, and the NEB Publication (i.e., EX1061-
`
`1063) discussed at pages 42-44 of the petition do not describe their methods as
`
`being applicable to cell-free DNA—nor does Petitioner allege that they do.
`
`Similarly, the arguments for motivation and reasonable expectation of success at
`
`pages 31-38 of the petition ignore the tagging efficiency requirement altogether.
`
`As such, Petitioner cannot establish that Schmitt, alone or in combination with any
`
`other reference, teaches “attaching tags … [to] at least 20% of the cfDNA
`
`molecules” when tagging efficiency of cfDNA is discussed nowhere in the petition
`
`materials. In other words, even assuming arguendo that Schmitt inherently
`
`discloses attaching tags to at least 20% of the cellular DNA analyzed as asserted,
`
`the petition materials give no reason to assume that the same tagging efficiency
`
`would be observed when working with the different substrate of cell-free DNA.
`
`Cell-free DNA is simply unaddressed entirely in this regard. The petition may be
`
`rejected on this basis alone.
`
`In any event, the petition fails to establish that Schmitt discloses tagging any
`
`DNA samples with “at least 20%” tagging efficiency. Beyond lacking disclosure
`
`-11-
`
`
`

`

`regarding cfDNA, Schmitt does not teach tagging genomic DNA samples, or
`
`anything else, with “at least 20%” tagging efficiency as recited in claim 1.
`
`Petitioner’s assertion that “a POSA would have understood [Schmitt] to result in at
`
`least 10-20% yield of tagged DNA fragments” fails for several reasons.
`
`First, the petition (page 42 (citing EX1011, 7:58-62, 15:5-20)) points to
`
`Schmitt’s mention of ligating adaptors to “a blunt end,” but these citations do not
`
`show that Schmitt uses blunt-end ligation “to tag at least 20%” of any DNA
`
`molecules. Petitioner points to a different reference of Meyer as exemplifying a
`
`blunt-end ligation that “was capable of generating a 10-20% final library yield.”
`
`Pet. 42 (citing EX1061, 2, 7). But Meyer, not a grounds reference, does not
`
`establish the ligation efficiency of Schmitt’s method at least because it does not
`
`describe the use of Schmitt’s method—nor does Petitioner allege that it does. Nor
`
`does the petition assert, let alone establish, that Schmitt and Meyer use the same
`
`blunt-end ligation method.3
`
`
`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
`
`would reasonably be expected—or that such methods would be suitable for such
`
`use.
`
`-12-
`
`
`

`

`Petitioner then turns to another non-grounds reference, Quail, for the
`
`argument that yet a different ligation strategy “was likely to result in a higher yield
`
`of tagged fragments.” Id. (citing EX1062, 1006). As with Meyer, Petitioner does
`
`not even allege that Quail uses Schmitt’s method (it does not), that Quail and
`
`Schmitt use the same TA ligation method, or that the Quail TA ligation method
`
`would even be suitable for use in the methods of Schmitt. Neither Meyer nor Quail
`
`demonstrates that Schmitt necessarily discloses 20% tagging efficiency.
`
`The petition (pages 43-44) then pivots from assertions of inherent disclosure
`
`to a theory of obviousness. In particular, the petition asserts that “a POSA would
`
`have understood that ligation efficiency could be improved using a variety of
`
`techniques known in the art...” Pet. 43; see also id. (“Quail taught that ligation
`
`efficiency can be improved using ultrapure commercial ligases.”) (emphasis
`
`added). But such assertions have never been sufficient to establish obviousness.
`
`InTouch Techs., Inc. v. VGo Communs., Inc., 751 F.3d 1327, 1352 (Fed. Cir. 2014)
`
`(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.”)
`
`(original emphasis); PersonalWeb Techs., LLC v. Apple, Inc., 848 F.3d 987, 993-
`
`994 (Fed. Cir. 2017) (same); Belden Inc. v. Berk-Tek LLC, 805 F.3d 1064, 1073
`
`(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
`
`-13-
`
`
`

`

`this modification would have been carried out, or whether success would have
`
`been reasonably expected. These critical aspects of an obviousness assertion are
`
`missing entirely.
`
`The petition (pages 43-44) additionally relies on the NEB Publication
`
`(EX1063), but fails to establish the NEB Publication even qualifies as prior art to
`
`the ’992 patent in the first place. There is no publication date provided in the
`
`petition materials or listed in the NEB Publication itself. In fact, the NEB
`
`Publication includes a citation to “Greenough et. al. (2016),” indicating the NEB
`
`Publication could not have been published prior to 2016. EX1063, 4. The petition
`
`includes a footnote (page 44) arguing that the NEB Quick Ligation Kit (“Kit”) was
`
`used in 2012. But the “Kit” is not a “printed publication”—and certainly not the
`
`NEB Publication being relied upon. This, of course, is a critical distinction since
`
`inter partes review is limited to patents and printed publications. 35 U.S.C.
`
`§ 311(b). Moreover, even assuming arguendo that the Kit was used does not
`
`establish that the NEB Publication cited and relied upon in the petition qualifies as
`
`prior art. Clearly it does not.
`
`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.
`
`-14-
`
`
`

`

`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. 52 (emphasis added). No such “explicit”
`
`teaching can be found in Schmitt.
`
`First, the disclosure that Petitioner relies on for “single base substitution” is
`
`not present in Schmitt’s priority document and therefore Schmitt does not qualify
`
`as prior art to the challenged patent in this regard. Second, Schmitt does not
`
`“explicitly” disclose detection of copy number variation as asserted—Schmitt does
`
`not describe doing so anywhere in the reference. Finally, as to the recited
`
`insertion/deletion or gene fusion recited in claim 1, 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.
`
`(i) Schmitt’s disclosure of detecting a “single base
`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.
`
`-15-
`
`
`

`

`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
`
`’413 Provisional. See, e.g., Cox Communications, Inc. v. AT&T Intellectual
`
`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.”)
`
`(citing In re Giacomini, 612 F.3d 1380, 1383 (Fed. Cir. 2010)); see also Ariosa
`
`Diagnostics, Inc. v. Illumina, Inc., IPR2014-01093, Paper 69 at 11 (same).
`
`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.
`
`For instance, Petitioner critically relies on disclosure within Example 4 of
`
`the Schmitt patent as teaching “single base substitutions” of the challenged claims.
`
`Pet. 49 (“Consensus Sequencing Accurately Recovers Spiked-in Control
`
`Mutations. A series of M13mp2 variants were constructed which contain known
`
`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
`
`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.
`
`-16-
`
`
`

`

`As such, the petition fails to establish that the subject matter relied on in the
`
`Schmitt patent is in the ’413 provisional and that the Schmitt patent is prior art to
`
`the challenged patent. The petition may be denied for this reason alone.
`
`(ii) Schmitt does not disclose detection of copy number
`variation
`The petition is based on the assertion that Schmitt “explicitly” discloses
`
`detection of copy number variation. Pet. 52. Yet, Petitioner does not and cannot
`
`point to any such disclosure in Schmitt because there is none. Instead, Petitioner
`
`asserts only that “Schmitt states that SMI tags allow for ‘single-molecule counting
`
`for accurate determination of DNA or RNA copy number’ that is applicable for
`
`‘accurate detection of altered genomic copy number … such as trisomy 21.’” Pet.
`
`52 (citing EX1011, 18:3-21; EX1012, [0048]; EX1002, ¶168).
`
`Petitioner fails to acknowledge that “copy number variation” and
`
`“aneuploidy” (e.g., trisomy 21) are discussed in the ’992 patent specification as
`
`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
`
`variations, transversions, translocations, inversion, deletions, aneuploidy, …”).
`
`The ’992 patent further describes copy number variations as sub-chromosomal
`
`aberrations. Id., 7:52-54 (“[T]he genetic variation is copy number/heterozygosity
`
`variation and detecting is performed with sub-chromosomal resolution.”).
`-17-
`
`
`

`

`Aneuploidies, in contrast, are genetic aberrations in the number of
`
`chromosomes—as opposed to aberrations in the copy number of sub-chromosomal
`
`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
`
`variation. This is insufficient to justify a determination at odds with the
`
`specification of the ’992 patent and the conclusions of the JPO.
`
`(iii) Petitioner’s remaining arguments are insufficient
`Perhaps sensing the deficiencies in Schmitt’s disclosure, Petitioner also
`
`argues that a “POSA would have understood that Schmitt’s methods can detect
`
`-18-
`
`
`

`

`more than one type of genetic aberration in the same experiment.” Pet. 52. 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. 52 (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, it does not establish that Schmitt’s method (rather than other
`
`methods) could detect more than one genetic aberration, including those recited in
`
`claim 1. And, Petitioner does not explain why a POSA would have been motivated
`
`to detect other genetic aberrations 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. 53 (citing EX1002, ¶¶169-170, ¶38). This argument
`
`is entirely conclusory and lacks the support of any objective evidence. A review of
`
`Dr. Gabriel’s declaration finds no citation to Schmitt or references describing use
`
`of the Schmitt technique. Paragraphs 169 and 170 discuss references other than
`
`Schmitt and paragraph 38 purports to demonstrate genetic mutation detection “in
`
`-19