Trials@uspto.gov
`571-272-7822
`
`Paper 50
`Date: June 12, 2024
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`FORESIGHT DIAGNOSTICS, INC.,
`Petitioner,
`
`V.
`
`PERSONALITS, INC.,
`Patent Owner.
`
`IPR2023-00317
`Patent 11,408,033 B2
`
`Before ULRIKE W. JENKS, ROBERT A. POLLOCK,and
`TIMOTHY G. MAJORS, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`JUDGMENT
`
`Final Written Decision
`Determining All Challenged Claims Unpatentable
`
`35 U.S.C. § 318(a)
`
`
`571-272-7822
`
`Paper 50
`Date: June 12, 2024
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`FORESIGHT DIAGNOSTICS, INC.,
`Petitioner,
`
`V.
`
`PERSONALITS, INC.,
`Patent Owner.
`
`IPR2023-00317
`Patent 11,408,033 B2
`
`Before ULRIKE W. JENKS, ROBERT A. POLLOCK,and
`TIMOTHY G. MAJORS, Administrative Patent Judges.
`
`POLLOCK, Administrative Patent Judge.
`
`JUDGMENT
`
`Final Written Decision
`Determining All Challenged Claims Unpatentable
`
`35 U.S.C. § 318(a)
`
`
`
`IPR2023-00317
`Patent 11,408,033 B2
`
`I.
`
`INTRODUCTION
`
`This is a Final Written Decision in an inter partes review challenging
`
`the patentability of claims 1—23 of U.S. Patent No. 11,408,033 B2 (“the °033
`
`patent,” Ex. 1001). We have jurisdiction under 35 U.S.C. § 6.
`
`Petitioner has the burden of proving unpatentability of the challenged
`
`claims by a preponderanceof the evidence. 35 U.S.C. § 316(e) (2018).
`
`Having reviewed the parties’ arguments and cited evidence, for the reasons
`
`discussed below,wefind that Petitioner has demonstrated by a
`
`preponderance of the evidence that claims 1—23 are unpatentable for the
`
`reasons set forth in the Petition.
`
`A. Procedural History
`
`Foresight Diagnostics Inc. (“Petitioner” or “Foresight’’) filed a
`
`Petition for an inter partes review of claims 1—23 of the °394 patent. Paper 1
`
`(“Pet.”). Personalis, Inc. (“Patent Owner”or “Personalis”’) timely filed a
`
`Preliminary Response. Paper 7. With our authorization (see Ex. 3001),
`
`Petitioner filed a Reply to the Preliminary Response (Paper 8); Patent Owner
`
`filed a corresponding Sur-reply (Paper 10). In view of the then-available
`
`preliminary record, weinstituted an inter partes review. Paper 11
`
`(“Institution Decision” or “DI”).
`
`After institution, Patent Ownerfiled a Response. Paper 18 (“POR”).
`
`Petitioner filed a Reply. Paper 41 (“Reply”). Patent Ownerfiled a Sur-reply.
`
`Paper 38 (“Sur-reply”’). With our authorization, Petitioner further filed a
`
`Response to Patent Owner’s Sur-reply. Paper 42 (“Resp.”’).
`
`On March 19, 2024, weheld an oral hearing, the transcript of whichis
`
`of record. Paper 46 (“Tr.”).
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`Patent 11,408,033 B2
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`B. Real Parties-in-Interest
`
`Petitioner identifies itself, Foresight Diagnostics Inc., as the real
`
`party-in-interest. Paper 32, 1. Patent Owneralso identifies onlyitself,
`
`Personalis, Inc., as the real party-in-interest in this proceeding. Paper6, 1.
`
`C. Related Matters
`
`In addition to the 033 patent at issue here, Petitioner concurrently
`
`challenges claims of related U.S. Patent No. 11, 384,394 B2 (“the °394
`
`patent”) in IPR2023-00224. The ’033 and °394 patents share substantially
`
`the same disclosure.
`
`The parties further identify as “related proceedings,” Petitioner’s
`
`challenge of Personalis’s U.S. Patent Nos. 11,299,783 (“the ’783 patent”)
`
`and 10,450,611 (“the °611 patent”) in IPR2023-00545 and IPR2023-00546,
`
`respectively. Paper 6, 1; Paper 33, 2. IPR2024-00170 involving U.S. Patent
`
`No. 11,584,968 (“the ’968 patent”) is also before us. See Paper 33, 2
`
`The °394, ’033, ’738, and ’611 patents are at issue in Personalis, Inc.
`
`v. Foresight Diagnostics, Inc., C.A. No. 1:22-cv-01913 (D. Colo.) (“the
`
`01913 litigation’’). See Pet. 3; Paper 6, 1; Ex. 1010, 1, 3-6; Exhibit 1010, 1
`
`(First Amended Complaint adding ’033 patent). Petitioner further identifies
`
`as a “related matter[],” Personalis, Inc. v. Foresight Inc., 1:23-cv-01623 (D.
`
`Colo.), which further involves the ’968 patent. Paper 33, 2; Ex. 1010, 1;
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`IPR2024-00170, Paper 1, 1, 3 (stating that Foresight has moved to
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`consolidate the two district court proceedings).
`
`D. Asserted Challenges to Patentability
`
`Petitioner challenges the patentability of claims 1—23 on the following
`
`bases: (Pet. 16):
`
`
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`IPR2023-00317
`Patent 11,408,033 B2
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`Claims
`Challenged
`
`35 U.S.C. §
`
`Reference(s)/Basis
`
`
`
`1-23
`
`1-9, 11-23
`
`§ 103
`
`§ 103
`
`Forshew, Wagle*
`
`Wagle, Chan?
`
`In support of its patentability challenge, Petitioner relies on, inter alia,
`
`the First and Second Declarations of John Quackenbush, Ph.D.,
`
`Exhibits 1020 and 1225, respectively. Patent Ownerrelies on, inter alia, the
`
`Declaration of Henry Morrice Furneaux, Ph.D., Exhibit 2031. Patent Owner
`
`further relies on the Declarations of Jonathan MacQuitty (Ex. 2033), Doug
`
`Zeman(Ex. 2034), Dan Norton (Ex. 2035), and John West (Ex. 2032).4
`
`E. The 033 Patent and Related Background
`
`1. Priority
`
`The °033 patent, titled Methods and Systems for Genetic Analysis,
`
`issued to Barthaet al., from U.S. Application 17/078,857, filed October 23,
`
`' Tim Forshew,et al., “Noninvasive Identification and Monitoring of Cancer
`Mutations by Targeted Deep Sequencing of Plasma DNA,” 4 Science
`Translational Medicine 136ra68 (2012). Ex. 1030, Ex. 1032 (Supplementary
`Materials).
`? Nikhil Wagle etal., “High-Throughput Detection of Actionable Genomic
`Alterations in Clinical Tumor Samples by Targeted, Massively Parallel
`Sequencing,” Jan. 2012 Cancer Discovery 83-93. Ex. 1033.
`>K.C. Allen Chan ef al., “Cancer Genome Scanning in Plasma: Detection of
`Tumor-Associated Copy Number Aberrations, Single-Nucleotide Variants,
`and Tumoral Heterogeneity by Massively Parallel Sequencing,” 59(1) Clin.
`Chem. 211-224 (2013). Ex. 1008.
`4 Mr. West is a named inventor of the challenged patent. Ex. 1001, code
`(72). Mr. West co-founded Personalis and served as its Chief Executive
`Officer from August 2011 through December 2022. Ex. 2023 4 3.
`
`
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`IPR2023-00317
`Patent 11,408,033 B2
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`2020, via a series of continuation and divisional applicationsfirst filed on
`
`December 27, 2013, and further claims benefit of priority to U.S. Provisional
`
`Application No. 61/753,828, filed on January 17, 2013 (“the °828
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`Provisional Application’). Ex. 1001, code (12), (21), (22), (54), and (60).°
`
`The parties dispute whether the 033 patent1s entitled to the benefit of the
`
`provisional filing date. See, e.g., Reply 12-13; POR 2, 6.
`
`2. Abstract and Specification
`
`The Abstract of the °033 patent broadly describes “systems and
`
`methods for sample processing and data analysis,” which can include
`
`“nucleic acid sample processing and subsequent sequencing.” Ex. 1001,
`
`code (57). According to the Abstract, the resultant “sequence information
`
`may be analyzed with the aid of a computer processor, and the analyzed
`
`sequence information may bestored in an electronic storage location that
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`may include a poolor collection of sequence information and analyzed
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`sequence information generated from the nucleic acid sample.”/d.
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`The °033 Specification more specifically discloses methods for
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`“predicting, diagnosing, and/or prognosing a status or outcome ofa disease
`
`or condition in a subject.” /d. at 55:38—50. In some embodiments,this
`
`involves the collection and analysis of sequence information derived from
`
`body fluid or tissue, including “from a subject suffering from a cancer.” /d.
`
`at 38:57—-67, 55:51-57:8.
`
`> The ’394 patent likewise issued from a series of continuation and division
`applicationsfirst filed on December 27, 2013, and claims benefit of priority
`to the ’828 Provisional Application such that the ’033 and ’394 patents share
`the same disclosure. As such, the parties’ declarants generally cite only one
`of the two substantially identical disclosures. See, e.g., Ex. 2031 957 n.3;
`Ex. 1225 4 39.
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`
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`IPR2023-00317
`Patent 11,408,033 B2
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`3. Challenged Claims
`
`Petitioner challenges claims 1—23, of which only claim 1 is
`
`independent andrecites:
`
`1. A method for analyzing a nucleic acid sample obtained
`from an individual, comprising:
`
`(a) producing, with the aid of a computer processor, a
`plurality of capture probes, wherein said plurality of capture
`probes hybridize to a plurality of polymorphisms, wherein said
`plurality of polymorphisms are in sequences encoding genes
`with known biomedically interpretable variants, and wherein
`said plurality of polymorphisms are based on or extracted from
`one or more databases of polymorphisms andare observedin a
`population of one or more samples;
`
`(b) contacting said nucleic acid sample with said plurality of
`capture probes produced in(a);
`
`(c) conducting a sequencing assay on a subset of nucleic
`acid molecules generated from said nucleic acid samplein step
`(b) to yield a result comprising a nucleic acid sequence, thereby
`analyzing said nucleic acid sample; and
`
`(d) repeating steps (b)-(c) on a subsequently obtained
`biological sample from said individual.
`
`Ex. 1001, 79:46—-65. Depending from claim 1, claim 2 entails
`
`“generating a biomedical report that includes biomedical
`
`information”referenced in claim step 1(a), whereas dependent
`
`claim 3 recites that this biomedical information
`
`is predictive, prognostic, or diagnostic of one or more
`biomedical features selected from the group consisting of
`diseasestate, efficacy of a drug therapy, prediction of optimal
`drug dosage, recommendation of one or more therapies, and
`recommendation of a course of treatment of a disease.
`
`Id. at 79:66—80:32. Also depending from claim 1, claim 10 specifies that the
`
`“capture probes further comprise barcodes.”/d. at 80:50—51.
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`
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`IPR2023-00317
`Patent 11,408,033 B2
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`A. Legal Standards
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`Il.
`
`ANALYSIS
`
`“In an IPR, the petitioner has the burden from the onset to show with
`
`particularity why the patent it challenges is unpatentable.” Harmonic Inc.v.
`
`Avid Tech., Inc., 815 F.3d 1356, 1363 (Fed. Cir. 2016) (citing 35 U.S.C.
`
`§ 312(a)(3) (requiring inter partes review petitions to identify “with
`
`particularity ... the evidence that supports the grounds for the challenge to
`
`each claim’’)). This burden of persuasion never shifts to Patent Owner. See
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`Dynamic Drinkware, LLC vy. Nat’l Graphics, Inc., 800 F.3d 1375, 1378
`
`(Fed. Cir. 2015) (discussing the burden of proof in inter partes review).
`
`Petitioner contends that claims 1—7 and 10—23 are anticipated by the
`
`prior art. Pet. 11. To show anticipation under 35 U.S.C. § 102, each and
`
`every claim element, arranged as in the claim, must be found in a single
`
`prior art reference. Net MoneyIN, Inc. v. VeriSign, Inc., 545 F.3d 1359 (Fed.
`
`Cir. 2008). The prior art need not, however, use the same wordsas the
`
`claims to find anticipation. /n re Gleave, 560 F.3d 1331, 1334 (Fed. Cir.
`
`2009). In evaluating anticipation, it is permissible to take into account not
`
`only the literal teachings of the prior art reference, but also the inferences the
`
`skilled artisan would draw from it. E/i Lilly and Co. v. Los Angeles
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`Biomedical Res. Inst. At Harbor-UCLA Med. Ctr., 849 F.3d 1073, 1074-75
`
`(Fed. Cir. 2017) (holding that the “dispositive question regarding
`
`anticipation is whether one skilled in the art would reasonably understand or
`
`infer from a prior art reference that every claim elementis disclosed in that
`
`reference’’). As such, “a reference can anticipate a claim evenif it does not
`
`expressly spell out all the limitations arranged or combined as in the claim,
`
`if a person of skill in the art, reading the reference, would at once envisage
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`
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`IPR2023-00317
`Patent 11,408,033 B2
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`the claimed arrangement or combination.” Kennametal, Inc. v. Ingersoll
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`Cutting Tool Co., 780 F.3d 1376, 1381 (Fed. Cir. 2015) (internal quotation
`
`and alterations omitted).
`
`Petitioner also contends that each claim of the ’033 patentis
`
`unpatentable as obvious under § 103(a). The Supreme Court in KSR
`
`International Co. v. Teleflex Inc., 550 U.S. 398 (2007), reaffirmed the
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`framework for determining obviousnessset forth in Graham v. John Deere
`
`Co., 383 U.S. 1 (1966). The KSR Court summarized the four factual
`
`inquiries set forth in Graham (383 U.S. at 17—18) that are applied in
`
`determining whethera claim is unpatentable as obvious under 35 U.S.C.
`
`§ 103 as follows: (1) determining the scope and contentof the priorart;
`
`(2) ascertaining the differences between the prior art and the claimsat issue;
`
`(3) resolving the level of ordinary skill in the art; and (4) considering
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`objective evidence indicating obviousness or non-obviousness,if present.
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`KSR, 550 US. at 406.
`
`“TWhen a patent ‘simply arranges old elements with each performing
`
`the same function it had been known to perform’ andyields no more than
`
`one would expect from such an arrangement, the combination is obvious.”
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`Id. at 417 (quoting Sakraida v. Ag Pro, Inc., 425 U.S. 273, 282 (1976)). But
`
`in analyzing the obviousness of a combination ofprior art elements, it can
`
`also be important to identify a reason that would have prompted one of skill
`
`in the art “to combine .
`
`.
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`. known elements in the fashion claimed by the
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`patent at issue.” /d. at 418.
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`“TI|Jn considering the disclosure of a reference,it is proper to take into
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`accountnot only specific teachings of the reference but also the inferences
`
`which one skilled in the art would reasonably be expected to draw
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`IPR2023-00317
`Patent 11,408,033 B2
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`therefrom.” /n re Preda, 401 F.2d 825, 826 (CCPA 1968). Moreover, a
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`precise teaching directed to the specific subject matter of a challenged claim
`
`is not necessary to establish obviousness. KS, 550 U.S. at 418. Rather, “any
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`need or problem knownin the field of endeavorat the time of invention and
`
`addressed by the patent can provide a reason for combining the elements in
`
`the mannerclaimed.” /d. at 420. Accordingly, a party that petitions the
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`Board for a determination of unpatentability based on obviousness must
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`show that “a skilled artisan would have been motivated to combine the
`
`teachings of the prior art references to achieve the claimed invention, and
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`that the skilled artisan would have had a reasonable expectation of success in
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`doing so.” In re Magnum Oil Tools International, Ltd., 829 F.3d 1364, 1381
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`(Fed. Cir. 2016) (quoting /nfelligent Bio —Sys., inc. v. lumina Cambridge,
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`Lid., 821 F.3d 1359, 1367-68 (Fed. Cir. 2016)).
`
`B. Level of Ordinary Skill in the Art
`
`In our Institution Decision, we provisionally adopted Petitioner’s
`
`definition of a person of ordinary skill in the art (“POSA”) as having:
`
`1) an advanced degree (such as an M.D. or the equivalent of a
`Ph.D. inalife or physical sciences, engineering, or mathematics
`discipline)...
`
`2) an understanding of various sequencing and next generation
`sequencing methods, sample preparation methods, targeted
`enrichment methods, bioinformatics methodsfor interpreting
`sequencing data, and methodsfor identifying genetic variants in
`asample....
`
`3 Nowe” an understanding of clinical applications of sequencing
`technology to conditions associated with nucleic acid variation,
`such as cancer, non-invasive prenatal testing, and transplant
`rejection .. . [and]
`
`4Nowe” an understanding of cancer biology asit relates to mutations
`associated with tumor diagnosis, progression, and treatment, as
`
`
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`IPR2023-00317
`Patent 11,408,033 B2
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`well as awarenessof the various types of mutations that can
`occur in and influence the course of a patient’s cancer.
`
`DI, 13-14 (citing, e.g., Pet. 6; Ex. 1020 4] 25-38).
`
`Patent Ownerhas not subsequently challenged the above definition.
`
`See Ex. 2031 § 48 (Dr. Furneaux applying the above definition). For the
`
`reasonsset forth in our Institution Decision, and because Petitioner’s
`
`proposedlevel is commensurate with the level of skill reflected in the prior
`
`art of record, we apply the same definition here. See Okajima v. Bourdeau,
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`261 F.3d 1350, 1355 (Fed. Cir. 2001); Jn re GPAC Inc., 57 F.3d 1573, 1579
`
`(Fed. Cir. 1995); In re Oelrich, 579 F.2d 86, 91 (CCPA 1978).
`
`C. Claim Construction
`
`“Only when a claim is properly understood can a determination be
`
`made... whether the prior art anticipates and/or renders obvious the
`
`claimed invention.” Amazon.com, Inc. v. Barnesandnoble.com, Inc., 239
`
`F.3d 1343, 1351 (Fed. Cir. 2001). In this proceeding, we interpret a claim
`
`“using the same claim construction standard that would be used to construe
`
`the claim in a civil action under 35 U.S.C. 282(b).” 37 C.F.R. § 42.100(b)
`
`(2020). Under this standard, we construe the claim “in accordance with the
`
`ordinary and customary meaning of such claim as understood by one of
`
`ordinary skill in the art and the prosecution history pertaining to the patent.”
`
`Id. Furthermore, we need only construe claim languagethat is in
`
`controversy, and only to the extent necessary to resolve the controversy.
`
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795, 803 (Fed. Cir.
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`1999); see also Nidec Motor Corp. v. Zhongshan Broad Ocean Motor Co.,
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`868 F.3d 1013, 1017 (Fed. Cir. 2017) (applying Vivid Techs. in the context
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`of an AIAtrial proceeding).
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`10
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`Patent 11,408,033 B2
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`In this respect, Petitioner raises the issue of whether the preamble to
`
`claim | is limiting, proposes a construction for the term “polymorphism,” as
`
`used in claim step l(a), and argues that the “biomedical report” of claim 2 is
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`directed to printed matter not entitled to patentable weight. See Pet. 18-19,
`
`29, 53-54. Because these termsare not in dispute, we decline to address
`
`them here. We address below the sole disputed claim term in this IPR—
`
`“capture probes.”
`
`Claim step 1(b) involves “generating a second subset of nucleic acid
`
`molecules... by contacting said second nucleic acid sample with a plurality
`
`of capture probes, wherein said plurality of capture probes hybridize to one
`
`or more polymorphisms.” According to Patent Owner, “Foresight’s entire
`
`challenge to the °033 patent hinges on a POSA conflating Forshew’s PCR
`
`primers with the claimed capture probes.’” POR 66; see also Tr. 19:19 (“[a]
`
`central dispute is the construction of capture probes’’).
`
`Patent Ownerarguesthat one of ordinary skill in the art would have
`
`understood “capture probes” to mean “a nucleic acid sequence that
`
`hybridizes to target DNA,either in solution or on a solid support, so that one
`
`can physically capture and isolate the target DNA.” See generally POR 54—
`
`66; Sur-reply 10-16. Applyingits preferred construction, Patent Owner
`
`argues that “A POSA would not have considered Forshew’s PCR primersto
`
`be ‘capture probes’ because Forshew’s PCR primers do not hybridize to
`
`target DNA so that one can physically capture the target DNA.” POR 66.
`
`For the purpose ofinstitution, we foundit sufficient to provisionally
`
`adopt Petitioner’s proposed definition of “capture probes” as encompassing
`
`at least, “PCR primer capture probes and solution-based hybridization
`
`capture probes(e.g., biotinylated oligonucleotide baits).” See DI 18-24. For
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`11
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`the reasonsset forth in our Institution Decision, and as further addressed
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`below, weapply that definition here—albeit with a minor modification in
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`wording. In particular, we credit Patent Owner’s argumentthat the phrase
`
`“PCR primer capture probe”is not a recognized term of art and its use in our
`
`construction “would improperly inject ambiguity into the claim.” POR 58—
`
`59 (citing, e.g., Ex. 2018, 166:10—169:1, 171:16—175:2; Liquid Dynamics
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`Corp. v. Vaughan Co., 355 F.3d 1361, 1367 (Fed. Cir. 2004)). Although we
`
`recognize Petitioner’s use of “PCR primer capture probe”as a shorthand for
`
`its position that, as read in light of the Specification, PCR primers are a
`
`species of, and/or indistinguishable from, the genus of capture probes, Patent
`
`Owner’s point is well taken. Accordingly, weclarify the meaning of
`
`“capture probes,” as used in the instant Specification, to encompass PCR
`
`primers and solution-based hybridization capture probes(e.g., biotinylated
`
`oligonucleotide baits). We do not view this modification as altering the
`
`substance of our provisional construction or the analysis in our Institution
`
`Decision.
`
`In considering how oneofordinary skill in the art would have
`
`understood “capture probes”in the context of the 033 patent, we look first
`
`to the Specification—‘the single best guide to the meaningof a disputed
`
`term.” Jn re Abbott Diabetes Care Inc., 696 F.3d 1142, 1149 (Fed. Cir.
`
`2012) (quoting Phillips v. AWH Corp., 415 F.3d 1303, 1315 (Fed. Cir. 2005)
`
`(en banc)). The ’033 patent’s Specification provides no express definition of
`
`“capture probes,” but does, as Patent Ownerpoints out, “describe[] several
`
`features of capture probes.” See POR, 56; see also, Tr. 20:1—21:19, 28:3-9
`
`(“[O]Jur specification does not provide a definition. It provides some
`
`description, but not a complete description”).
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`12
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`First, with respect to structure, the ’033 patent teachesthat, “capture
`
`probes may comprise one or more nucleotides .. . or 1000 or more
`
`nucleotides.” Ex. 1001, 31:35—43 (emphasis added); id. at 41:33-34 (“The
`
`capture probes... may comprise one or more nucleotides.”) In other words,
`
`capture probes within the scope of the ’033 patent encompassesa nucleic
`
`acid range from a single nucleic acid to one of arguably infinite length.®
`
`The Specification further discloses that a capture probe may
`
`optionally comprise one or more linkers and/or one or more labels. Ex. 1001,
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`31:4—-12 (“The capture probe may further comprise one or more linkers. The
`
`capture probes may further comprise one or more labels. The one or more
`
`linkers may attach the one or morelabels to the nucleic acid bindingsite.”’).
`
`According to the Specification, the optional linker and/or label component of
`
`a capture probe encompasses a wide range of suitable materials:
`
`Examples of linkers include, but are not limitedto,
`hydrazone, disulfide, thioether, and peptide linkers. The linker
`may be a peptide linker. The peptide linker may comprise a
`proline residue. The peptide linker may comprise an arginine,
`phenylal[a]nine, threonine, glutamine, glutamate, or any
`combination thereof. The linker may be a heterobifunctional
`crosslinker.
`
`Id. at 43:5-11; see also id. at 42:49-51 (“Suitable linkers comprise
`
`any chemical or biological compoundcapable of attaching to a label,
`
`primer, and/or capture probe disclosed herein.)”
`
`With respect to “label” (interchangeable with “detectable
`
`label”), the Specification further teaches that these term’s “generally
`
`© Patent Owneragreesthat the Specification encompasses capture probes
`having a length of one nucleotide. POR 62 (citing Ex. 2031 4 69; Ex. 2027
`(Gellert et al., “Helix Formation by Guanylic Acid,” 48 Proc. Nat. Acad. Sci.
`2013-2018 (1962)).
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`13
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`Patent 11,408,033 B2
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`refer() to any chemical moiety attached to a nucleotide.” /d. at 14:22-
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`29. More particularly,
`
`labels include, but are not limited to, detectable labels, such as
`radioisotopes, fluorophores, chemiluminophores, chromophore,
`lumiphore, enzymes, colloidal particles, and fluorescent
`microparticles, quantum dots, as well as antigens, antibodies,
`haptens, avidin/streptavidin, biotin, haptens, enzymes
`cofactors/substrates, one or more membersof a quenching
`system, a chromogens, haptens, a magnetic particles, materials
`exhibiting nonlinear optics, semiconductor nanocrystals, metal
`nanoparticles, enzymes, aptamers, and one or more members of
`a bindingpair.
`
`Id. at 23:23—36. The Specification further discloses that at least some linker
`
`molecules may also be labels. See also id. at 14:29-42 (further exemplifying
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`labels as including “linker molecules” such as “biotin, avidin, streptavidin,
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`HRP,protein A, protein G, antibodies or fragments thereof’). Illustrating the
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`breadth of this term, the Specification “envision[s] that a change in mass
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`may be considered a detectable label.” /d. at 14:42—47.
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`The Specification also refers to bead-boundnucleic acid molecules
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`“associated with a nucleic acid molecule.” /d. at 14:18—-19; 56-58.
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`Relatedly, the Specification teaches that “one or more subsets of nucleic acid
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`molecules may be produced by contacting a nucleic acid sample with one or
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`more beads, capture probes, labels, or a combination thereof.” /d. at 32:12-
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`15. “The capture probes, primers, labels, and/or beads may comprise one or
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`more nucleotides. The one or more nucleotides may comprise RNA, DNA, a
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`mix of DNA and RNAresiduesor their modified analogs such as 2'-OMe,or
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`2'-fluoro (2'-F), locked nucleic acid (LNA), or abasic sites.” /d. at 41:32—37
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`(emphasis added). As such, the Specification instructs that the structure of
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`capture probes(as well as primers, labels, and/or beads) encompasses a
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`nucleic acid of any length, with or without the addition of other adducts—
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`which, themselves, may comprise a single nucleotide and/or a vast array of
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`other entities.
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`Second, the Specification teaches that capture probes may also
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`possess the functional attributes of binding or hybridization. Consistent with
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`the plain language of step 1(a), “wherein said plurality of capture probes
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`hybridize to a plurality of polymorphisms,” the Specification teaches that
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`“It]ypically, the capture probe comprises a nucleic acid binding site” and
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`“may comprise a nucleic acid binding site that hybridizes to at least a portion
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`of the one or more nucleic acid molecules or variant or derivative thereof in
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`the sample or subset of nucleic acid molecules.” /d. at 31:7—8, 24-27.
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`According to the Specification, “a capture probe hybridized nucleic acid
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`refers [to] a capture probe associated with a nucleic acid molecule. The
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`capture probe and the nucleic acid are in contact with each other.” /d. at
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`7:57-64, 14:48—59; see also id. at 22:65—23:9 (discussing genomic
`
`features/regions that may be hybridized by capture probes).
`
`The Specification discloses that, “[c]lapture probes may hybridize to
`
`one or more genomicregions”(id. at 22:65—23:1 (emphasis added)), but
`
`does not expressly define the size of a nucleic acid bindingsite, nor the size
`
`of a genomic region that needs to hybridize with the capture probe, nor
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`binding conditions, nor any particular binding affinity for the capture probe.’
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`All that is required functionally, is that the capture probe “hybridizesto at
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`7 Given that the Specification teaches that a capture probe maybeas short as
`one nucleotide, we might infer that the minimum size of its binding site and
`hybridized genomic region is also one nucleotide. See Ex. 1001, 31:35-43,
`41:33-34; see also POR 62 (Patent Owner’s argumentthat “[t]he
`specification correctly includes capture probes having a length of one
`nucleotide because there are instances where a single nucleotide can
`function as a capture probe’).
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`15
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`least a portion of the one or more nucleic acid moleculesor variant or
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`derivative thereof in the sample or subset of nucleic acid molecules.” /d. at
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`31:25-27.
`
`In short, all the Specification requires of capture probe function is that
`
`it hybridize to one or more nucleic acids. Andasarticulated at the institution
`
`stage, “[u]nder some (unspecified) conditions, and at some (unspecified)
`
`binding affinity, a single nucleic acid would be expected to hybridize with
`
`its complement and thereby meet the “capture probe” limitation as set out in
`
`the °033 patent Specification.” DI, 44 (Jenks J., concurring).
`
`In provisionally adopting Petitioner’s proposed definition in our
`
`Institution Decision, we first addressed Patent Owner’s contention that the
`
`°033 patent “refers to capture probes and primers as separate and
`
`distinguishable from one another.” See DI 21—22; Prelim. Resp. 20-21
`
`(citing, e.g., Ex. 1001, 23:23—36; 32:56—60, 41:33-36). Considering the
`
`cited passages and, moreover, the entirety of the Specification, we were
`
`unable to discern any teaching as to how capture probes and primers might
`
`be “separate and distinguishable from one another,” as Patent Owner
`
`contends. /d. at 22. We noted,in particular, that
`
`the Specification evinces no physical characteristics
`differentiating capture probes from primers. Both comprise
`from as few as “one or more nucleotides” to “1000 or more
`nucleotides” (Ex. 1001, 31:35-53, 40:28-54); both include
`nucleotides “compris[ing] RNA, DNA, a mix of DNA and
`RNA ... modified analogs. .
`. locked nucleic acid (LNA), or
`abasic sites” (41:32—36); both may—or may not—comprise a
`detectable label (id. at 14:22—47, 23:23-36, 31:54—32:5, 40:29-
`35, 41:38—42:3); and both may—or may not—comprise a linker
`(id. at 31:8—-9, 31:54-67, 40:29-31, 41:15—26, 42:49-43:11),
`wherein said linker can also be a detectable label (id. at 14:36-
`42),
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`16
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`DI 21-22.
`
`With respect to function, we reasoned that because the Specification
`
`provides no physical difference between capture probes and primers“it
`
`would appear that the same polynucleotide could be employed as an
`
`amplification primer and a capture probe.” /d. at 22 (citing Prelim. Resp.
`
`21). We likewise agreed with Petitioner that “none of the cited passages [by
`
`Patent Owner] describe ‘primers’ and ‘capture probes’ as mutually exclusive
`
`or precludes a similarly structured nucleic acid from performing each
`
`function.” /d. at 19; see also Reply 14 (citing POR 58, Ex. 1001, 23:23-26;
`
`Ex. 1225 4 40).
`
`Wealso noted Dr. Quackenbush’s testimony that dependent claim
`
`10’s requirement that “capture probes further comprise barcodes,” typically
`
`indicated the use of PCR primers, but not hybrid capture baits. DI 19-20
`
`(citing Ex. 1020 §§] 102-103). And although Patent Owner respondsthat
`
`“barcodes can also be used on capture probes” (POR 63 (citing Ex. 2031
`
`4] 70; Ex. 2028, 251)), this is not quite on point as Dr. Quackenbush and
`
`Mr. West subsequently confirmed that, while the use of barcoded PCR
`
`primers are well known, where bar codesare used in the context of
`
`biotinylated oligonucleotide bait systems, the barcodes are not part of the
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`capture probes, rather, the barcodes are “part of the [captured DNA]
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`molecule that’s being sequenced.” Ex. 1222, 167:20—170:4; Ex. 1225 4 41.
`
`As noted above, Patent Owner contendsthat its proffered definition of
`
`“capture probes” as meaning “a nucleic acid sequence that hybridizes to
`
`target DNA,either in solution or on a Solid support, so that one can
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`Physically capture and isolate the target DNA,” excludes PCR primers, such
`
`as those employed by Forshew. See generally POR 55-67; Sur-reply 10-16.
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`17
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`In support of its construction, Patent Ownerpointsfirst to the intrinsic
`
`record. Patent Owner arguesthat the Specification “treats capture probes and
`
`PCR primersas different types of nucleic acids,”that it separately describes
`
`the two terms, and, for some embodiments,“describe[s] the use of capture
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`probes as a separate and distinct step from using PCR primers.” POR 58
`
`(citing Ex. 1001, 31:4—32:5, 40:29-41:36, 23:23—26, 32:56-60, 64:29-43,
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`65:38—50, 66:53-67). Patent Owner made much the same argumentprior to
`
`institution, but again, does not adequately describe any physical difference
`
`between the capture probes and PCRprimersin its citations, nor persuade us
`
`that these entities, so defined in the Specification, are not functionally
`
`interchangeable. See DI 22 (concluding that “reading the Specification, it
`
`would appear that the same polynucleotide could be employed as an
`
`amplification primer and a capture probe in Patent Owner’s referenced
`
`embodiment(s)’).
`
`Patent Ownerfurther argues that during the prosecution history of the
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`°033 and °394 patents, the Examiner® agreed “that ‘pulldown probes’ are not
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`PCR primers” and, in conducting prior art searches, the Examiner used the
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`terms “capture” and “pull-down” synonymously, without including
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`“primers” or “PCR”as search terms. POR 59 (citing Ex. 2004, 14, 17, 25;
`
`Ex. 2005, 19, 24, 31; Ex. 2024, 3-8, Ex. 2025, 3-25). But as previously
`
`noted, when the Examineragreed that “pulldown probes” are not PCR
`
`primers, “the cited applications involved the claim limitation ‘pulldown
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`probe,’ and claims reciting ‘capture probe’ were not before the Office.” DI
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`22-23 (“Although the cited interchange does not involve the claim term
`
`8’ Primary Examiner Kaijiang Zhang was the examinerof record in both the
`°033 and °394 patents.
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`“capture probe,” it shows the Examiner understood that ‘probes’
`
`encompassed ‘amplification primers’.”’). As such, Patent Owner’s argument
`
`remains unavailing.
`
`Asto Patent Owner’s assertion that the Examiner did not include
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`“PCR”or “primers” in conducting prior art searches—butdid apply
`
`“capture” and “pull-down”as synonyms—wenote that the Examiner’s
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`arguably synonymous search terms further encompassed “enrichment.” See
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`Ex. 2024, 3-8 (“(enrich$5 captur$5 pull-down pulldown)”); Ex. 2025, 3-25
`
`(same). As Patent Owner admits, the prior art recognized PCRas an
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`enrichment technique. See, e.g., POR 61 (citing Ex. 1006, 375), 63-64
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`(citing Ex. 1006, 378-80), 65—66 (“[A] POSA would understand that capture
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`probes and PCRprimers are different enrichment techniques’). As such,it
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`would be reasonable to infer that the Examiner understood the search
`
`parameters to encompass PCR and PCR primers. Moreover, even if the
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`Examiner had
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