Trials@uspto.gov
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` Paper 48
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`Date: October 2, 2017
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`HOLOGIC, INC. and BECTON, DICKINSON AND COMPANY,
`Petitioners,
`
`v.
`
`ENZO LIFE SCIENCES, INC.,
`Patent Owner.
`
`
`Case IPR2016-00822
`Patent 7,064,197 B1
`
`
`
`
`Before MICHAEL J. FITZPATRICK, ZHENYU YANG, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`FITZPATRICK, Administrative Patent Judge.
`
`
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a)
`
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`
`571-272-7822
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` Paper 48
`
`
`Date: October 2, 2017
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`HOLOGIC, INC. and BECTON, DICKINSON AND COMPANY,
`Petitioners,
`
`v.
`
`ENZO LIFE SCIENCES, INC.,
`Patent Owner.
`
`
`Case IPR2016-00822
`Patent 7,064,197 B1
`
`
`
`
`Before MICHAEL J. FITZPATRICK, ZHENYU YANG, and
`CHRISTOPHER G. PAULRAJ, Administrative Patent Judges.
`
`FITZPATRICK, Administrative Patent Judge.
`
`
`
`
`
`
`FINAL WRITTEN DECISION
`35 U.S.C. § 318(a)
`
`
`
`
`
`IPR2016-00822
`Patent 7,064,197 B1
`
`INTRODUCTION
`
`I.
`The original sole Petitioner in this inter partes review, Hologic, Inc.
`(“Hologic”), filed a Petition to institute an inter partes review of claims 17,
`19, 25, 105, 106, 113, 114, 116, 119, 120, 128–131, 150–152, 154, 178, 180,
`185–187, and 189 (“the challenged claims”) of U.S. Patent No. 7,064,197
`B1 (Ex. 1001, “the ’197 patent”) pursuant to 35 U.S.C. § 311(a). Paper 3
`(“Pet.”). Patent Owner, Enzo Life Sciences, Inc., filed a Preliminary
`Response pursuant to 35 U.S.C. § 313. Paper 7 (“Prelim. Resp.”). In an
`October 14, 2016, Decision, we granted the Petition. Paper 8 (“Inst. Dec.”).
`During trial, Becton, Dickinson and Company (“Becton”) was joined
`as co-petitioner. Paper 31. Hologic and Becton are hereafter referred to
`collectively as “Petitioners.”
`Patent Owner filed a Patent Owner Response (Paper 19, “PO Resp.”)
`to which Petitioners filed a Reply (Paper 33, “Reply”). Both sides filed
`Motions to Exclude. See Papers 39, 41. Both sides requested a hearing for
`oral arguments, and a consolidated hearing for this inter partes review and
`Case IPR2016-00820 was held June 1, 2017. A transcript of the hearing
`appears in the record. See Paper 47 (“Tr.”).
`As discussed below, Petitioners have shown by a preponderance of
`the evidence that all of the challenged claims are unpatentable.
`
`A. Related Matters
`Co-petitioner Hologic successfully petitioned for two inter partes
`reviews of claims of the ’197 patent—the instant proceeding and Case
`IPR2016-00820. Co-petitioner Becton also filed two petitions for inter
`partes reviews of the ’197 patent, along with motions to join the already
`2
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`instituted Hologic-petitioned inter partes reviews. See IPR2017-00172;
`IPR2017-00181. Becton’s petitions were denied, but Becton was joined as
`co-petitioner in this proceeding and as well as in Case IPR2016-00820. See
`Paper 31; IPR2016-00820, Paper 32.
`The parties identify the following lawsuits as involving the ’197
`patent: Enzo Life Sciences, Inc. v. Hologic, Inc., No. 1:15-cv-271 (D. Del.);
`Enzo Life Sciences, Inc. v. Siemens Healthcare Diagnostics, Inc., No. 1:12-
`cv-505 (D. Del.); Enzo Life Sciences, Inc. v. Affymetrix, Inc., No. 1:12-cv-
`433 (D. Del.); Enzo Life Sciences, Inc. v. Agilent Technologies Inc., No.
`1:12-cv-434 (D. Del.); Enzo Life Sciences, Inc. v. Illumina Inc., No. 1:12-cv-
`435 (D. Del.); Enzo Life Sciences, Inc. v. Abbott Laboratories et al., No.
`1:12-cv-274 (D. Del.); Enzo Life Sciences, Inc. v. Becton Dickinson and
`Company et al., No. 1:12-cv-275 (D. Del.); Enzo Life Sciences, Inc. v. Life
`Technologies Corp., No. 1:12-cv-105 (D. Del.); and Enzo Life Sciences, Inc.
`v. Roche Molecular Systems Inc. et al., No. 1:12-cv-106 (D. Del.). Pet. 2–3;
`Paper 22, 1.
`
`B. The ’197 Patent
`
`The ’197 patent relates generally to the detection of genetic material
`by polynucleotide or oligonucleotide probes. Ex. 1001, 1:23–24, 5:43–46.
`The ’197 patent refers to the genetic material to be detected as an “analyte.”
`Id. at 1:37–39. An analyte may be present in a biological sample such as a
`clinical sample of blood, urine, saliva, etc. Id. at 5:47–50. If an analyte of
`interest is present in a biological sample, it is fixed, according to the
`invention of the ’197 patent, “in hybridizable form to a solid support.” Id. at
`5:58–60. In the challenged independent claims, the recited analytes are
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`“single-stranded nucleic acids.” Id. at cls. 17, 19, and 25. “Analytes in a
`biological sample are preferably denatured into single-stranded form, and
`then directly fixed to a suitable solid support.” Id. at 5:61–63. The ’197
`patent states that it is preferred, and all of the challenged claims require, that
`the solid support be non-porous. Id. at 6:2–6; e.g., id. at cl. 17 (reciting a
`“non-porous solid support”). To obtain fixation (or binding) to the non-
`porous solid support, the ’197 patent teaches treating the surface of the
`support with a chemical such as polylysine. Id. at 11:37–39.
`
`Chemically-labeled probes are then brought into contact with the
`fixed single-stranded analytes under hybridizing conditions. The
`probe is characterized by having covalently attached to it a
`chemical label which consists of a signaling moiety capable of
`generating a soluble signal. Desirably, the polynucleotide or
`oligonucleotide probe provides sufficient number of nucleotides
`in its sequence, e.g., at least about 25, to allow stable
`hybridization with the complementary nucleotides of the analyte.
`The hybridization of the probe to the single-stranded analyte with
`the resulting formation of a double-stranded or duplex hybrid is
`then detectable by means of the signalling moiety of the chemical
`label which is attached to the probe portion of the resulting
`hybrid. Generation of the soluble signal provides simple and
`rapid visual detection of the presence of the analyte and also
`provides a quantifiable report of the relative amount of analyte
`present, as measured by a spectrophotometer or the like.
`Id. at 6:15–32.
`
`
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`C. The Challenged Claims
`
`Petitioners challenge claims 17, 19, 25, 105, 106, 113, 114, 116, 119,
`120, 128–131, 150–152, 154, 178, 180, 185–187, and 189. Pet. 1.
`Independent claims 17, 19, and 25 are illustrative and reproduced below.
`17. An array comprising various single-stranded
`nucleic acids fixed or immobilized in hybridizable form to a
`non-porous solid support.
`19. An array comprising single-stranded nucleic acids
`fixed or immobilized in hybridizable form to a non-porous solid
`support.
`25. An array comprising various single-stranded
`nucleic acids fixed or immobilized in hybridizable form to a
`non-porous solid support having wells or depressions.
`All of the remaining challenged claims, several of which are in
`multiple dependent form, depend directly from at least one of independent
`claims 17, 19, and 25.
`
`D. Grounds of Unpatentability Tried
`
`We instituted trial on the following grounds of unpatentability:
`Basis1
`References
`Claims Challenged
`Fish (Ex. 1006)2
`§ 102(b)
`17, 19, 25, 105, 106, 114,
`116, 119, 128, 129, 150,
`152, 178, 180, 186, and
`187
`
`
`1 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29, took
`effect on March 18, 2013. Because the application from which the ’197
`patent issued was filed before that date, our citations to 35 U.S.C. §§ 102
`and 103 are to their pre-AIA version.
`2 Falk Fish, et al., “A Sensitive Solid Phase Microradioimmunoassay For
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`References
`Fish
`Fish, Metzgar (Ex. 1009),3
`and Sato (Ex. 1034)4
`Fish and Gilham
`(Ex. 1019)5
`VPK (Ex. 1008)6 and
`Metzgar
`
`Noyes (Ex. 1007),7 VPK,
`Metzgar, and
`Ramachandran (Ex. 1028)8
`Inst. Dec. 26.
`
`Basis1
`§ 103(a)
`§ 103(a)
`
`Claims Challenged
`130, 131, 151, and 154
`120 and 189
`
`§ 103(a)
`
`113 and 185
`
`§ 103(a)
`
`§ 103(a)
`
`17, 19, 25, 105, 106, 114,
`119, 120, 128, 129, 131,
`150–152, 178, 180, 186,
`and 189
`113, 116, 130, 154, 185,
`and 187
`
`
`Anti-Double Stranded DNA Antibodies,” Arthritis and Rheumatism,
`Vol. 24, No. 3, 534–43 (March 1981).
`3 U.S. Patent No. 3,572,892, issued Mar. 30, 1971.
`4 Sato et al., “Cell Surface Charge and Cell Division in Escherichia coli
`after X irradiation,” Radiation Research 87, 646–56 (1981).
`5 P. T. Gilham, “Immobilized Polynucleotides and Nucleic Acids,”
`Immobilized Biochemicals and Affinity Chromatography, 173–85 (1974).
`
`6 A. C. Van Prooijen-Knegt, et al. “In Situ Hybridization of DNA Sequences
`in Human Metaphase Chromosomes Visualized by an Indirect Fluorescent
`Immunocytochemical Procedure,” Experimental Cell Research, Vol. 141,
`397–407 (Oct. 1982).
`7 Barbara E. Noyes, et al., “Nucleic Acid Hybridization Using DNA
`Covalently Coupled to Cellulose,” Cell, vol. 5, 301–10 (July 1975).
`8 K. B. Ramachandran, et al., “Effects of Immobilization of the Kinetics of
`Enzyme-Catalyzed Reactions. I. Glucose Oxidase in a Recirculation Reactor
`System,” Biotechnology and Bioengineering, Vol. XVIII, 669–84 (1976).
`6
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`Patent 7,064,197 B1
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`II. ANALYSIS
`
`A. Claim Construction
`
`“A claim in an unexpired patent that will not expire before a final
`written decision is issued shall be given its broadest reasonable construction
`in light of the specification of the patent in which it appears.” 37 C.F.R.
`§ 42.100(b). Pursuant to that standard, the claim language should be read in
`light of the specification, as it would be interpreted by one of ordinary skill
`in the art. In re Suitco Surface, Inc., 603 F.3d 1255, 1260 (Fed. Cir. 2010).
`Thus, we generally give claim terms their ordinary and customary meaning.
`See In re Translogic Tech., Inc., 504 F.3d 1249, 1257 (Fed. Cir. 2007) (“The
`ordinary and customary meaning is the meaning that the term would have to
`a person of ordinary skill in the art in question.” (internal quotation marks
`omitted)).
`In our Institution Decision, we expressly construed three terms,
`recited in each of independent claims 17, 19, and 25: “array”; “fixed or
`immobilized”; and “hybridizable form.” First, we construed “array” to mean
`“an orderly grouping or arrangement,” as both sides had proposed. Inst.
`Dec. 8; see also Pet. 14; Prelim. Resp. 22; Ex. 1010, 8. Second, we
`construed “fixed or immobilized” to mean “bound,” as both sides had
`proposed. Inst. Dec. 8; see also Pet. 9; Prelim. Resp. 13 n.2; Ex. 1010, 13–
`15. Third, we construed “hybridizable form” to mean a form “capable of
`binding through Watson-Crick base pairing,” as both sides had proposed.
`Inst. Dec. 9; see also Pet. 13; Prelim. Resp. 11; Ex. 1010, 5.
`The parties now dispute what their stipulated constructions of “array”
`and “hybridizable form” encompass. Accordingly, we provide additional
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`Patent 7,064,197 B1
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`clarification below.
`
`1. “array”
`
`All of the challenged independent claims recite an “array.” For
`example, claim 17 recites: “An array comprising various single-stranded
`nucleic acids fixed or immobilized in hybridizable form to a non-porous
`solid support.” (Emphasis added).9
`Prior to institution, the parties agreed that an “array” is “an orderly
`grouping or arrangement.” Pet. 14; Prelim. Resp. 22. In our Institution
`Decision, we applied that agreed-upon meaning. Inst. Dec. 8. For example,
`we found “Fish explicitly describes rows of wells on the tray, which are
`sufficient to constitute an orderly grouping or arrangement.” Id. at 11–12.
`Although neither side opposes our construction post-institution, a
`dispute remains as to what that construction encompasses. For example, to
`meet this term in the Fish-based grounds, Petitioners cite to Fish’s disclosure
`
`
`9 The term “array” appears in claims 17, 19, and 25 in their preambles only,
`and, thus, is not necessarily a limitation. See, e.g., Pitney Bowes, Inc. v.
`Hewlett-Packard Co., 182 F.3d 1298, 1305–06 (Fed. Cir. 1999) (preamble
`may or may not be limiting). However, Petitioners do not argue that “array”
`is not a limitation and, by mapping the asserted prior art to it, Petitioners
`imply that it is a limitation. See, e.g., Pet. 17–18. Petitioners bear “the
`burden of proving a proposition of unpatentability by a preponderance of the
`evidence.” 35 U.S.C. § 316(e). Also, their Petition must explain “[h]ow the
`challenged claim is to be construed” and “[h]ow the construed claim is
`unpatentable under the statutory grounds identified.” 37 C.F.R.
`§ 42.104(3)–(4). The Petition does not explain how the claims are
`unpatentable having their preambles construed as non-limiting.
`Accordingly, for purposes of this Decision, we treat “array” as a limitation
`of the challenged claims.
`
`8
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`of microtitration trays having a plurality of wells arranged in rows. See, e.g.,
`Pet. 17 (citing Ex. 1006, 536 left col. ¶1).10 Patent Owner responds, citing
`cross-examination testimony of Petitioners’ declarant, that an array requires
`an orderly grouping or arrangement of nucleic acids, such that the
`whereabouts of each nucleic acid is known. See PO Resp. 20 (“Dr. Nelson
`explained that in the context of nucleic acid analysis in the early 1980s, an
`‘array’ would comprise an ‘orderly arrangement of nucleic acids,’ meaning
`a ‘pattern’ in which ‘the whereabouts of each nucleic acid is known.’”)
`(citing Ex. 2117, 43:3–13, 44:17–45:12, 46:7–14).
`Thus, Petitioners apply the term “array” as satisfied by, for example,
`an orderly arrangement of wells, whereas Patent Owner applies the term
`“array” as requiring an orderly arrangement of nucleic acids (and further
`such that the whereabouts of each nucleic acid is known). The ’197 patent
`uses the term consistent with Petitioners’ application and inconsistent with
`Patent Owner’s application. See Ex. 1001, 8:66–67 (referring to “an array of
`wells or depressions,” not an array of nucleic acids) (emphasis added); see
`also id. at Abstract (“Nucleic acids are fixed or immobilized to non-porous
`solid supports (substrates), and include systems containing such supports
`and arrays with fixed or immobilized nucleic acids.”). The cross-
`examination testimony on which Patent Owner relies (i.e., Ex. 2117, 43:3–
`13, 44:17–45:12, 46:7–14) does not appear to account for this intrinsic
`evidence.
`
`
`10 Unless otherwise noted, our citations to paragraphs of non-patent
`references are numbered starting with the first full paragraph of a respective
`page or column.
`
`9
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`Patent 7,064,197 B1
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`Accordingly, we reject Patent Owner’s application of the term “array”
`as requiring an orderly grouping or arrangement of nucleic acids, such that
`the whereabouts of each nucleic acid is known. The term “array” as used in
`the challenged claims includes an orderly grouping or arrangement of wells
`or depressions. Other language in the challenged claims ultimately requires
`the array to comprise single-stranded nucleic acids. See, e.g. Ex. 1007,
`cl. 19 (“An array comprising single-stranded nucleic acids fixed or
`immobilized in hybridizable form to a non-porous solid support.”). But, the
`term “array” itself does not require an orderly grouping or arrangement of
`nucleic acids.
`
`2. “hybridizable form”
`
`All of the challenged independent claims recite “hybridizable form.”
`For example, claim 17 recites: “An array comprising various single-
`stranded nucleic acids fixed or immobilized in hybridizable form to a non-
`porous solid support.” (Emphasis added).
`Prior to institution, the parties agreed that “hybridizable form” means
`“capable of binding through Watson-Crick base pairing.” Pet. 13 (citing
`Ex. 1001, 2:22–34); Prelim. Resp. 1111; see also Ex. 1010, 5 (Markman
`order applying same construction). In our Institution Decision, we gave it
`the agreed-upon meaning. Inst. Dec. 8–9. Although neither side opposes
`
`
`11 Patent Owner’s proffered construction additionally added that the
`Watson-Crick base pairing would be “to a complementary nucleic acid
`sequence.” Prelim. Resp. 11. This additional language, however, is
`superfluous, as it merely describes what Watson-Crick base pairing
`inherently requires. See Ex. 1001, 2:22–29.
`10
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`that construction post-institution, a dispute remains as to the meaning of the
`construction to which the parties agreed and we adopted. See, e.g., Pet. 23
`(mapping Fish’s ssDNA bound to poly-L-lysine (“PLL”)-treated plastic to
`the hybridizable form limitation); PO Resp. 10 (“Fish fails to disclose
`sufficient information regarding the various factors and conditions that affect
`hybridization to allow a POSITA to determine whether any bound ssDNA
`would be capable of hybridizing with other nucleic acids.”); Reply 8 (“Enzo
`also focuses on hybridization conditions, even though its claims lack such a
`requirement.”).
`We maintain our construction that “hybridizable form” means
`“capable of binding through Watson-Crick base pairing.” However, in
`response to Patent Owner’s post-institution arguments for patentability over
`the Fish-based grounds, we provide some clarifications.
`The Limitation “hybridizable form” is not Synonymous
`a)
`with the Limitation “single-stranded”
`The limitation “hybridizable form” pertains to the form of the “single-
`stranded nucleic acids” as fixed or immobilized to the non-porous solid
`support. This means that single-stranded nucleic acids must be bound to the
`solid support in a manner that renders them capable of binding to
`complementary sequences through Watson-Crick base pairing. To be so
`capable, single-stranded nucleic acids must be single-stranded and have
`bases available for base-pairing.
`Patent Owner argues that something more must be required of
`“hybridizable form” because otherwise “every ‘single-stranded’ nucleic acid
`necessarily exists in ‘hybridizable form.’” PO Resp. 12. Patent Owner
`elaborates as follows:
`
`11
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`[Petitioners’ declarant, Norman Nelson, Ph.D.,]
`simply assumes that any single-stranded nucleic
`acid is capable of Watson-Crick base pairing—and
`therefore hybridization—regardless of existing
`conditions. In fact, Dr. Nelson testified that he
`could not think of a single example of a single-
`stranded nucleic acid bound to a solid support that
`would not be capable of Watson-Crick base pairing.
`(Nelson Tr. [Ex. 2117] 39:15–41:1.) Petitioner’s
`inherency argument reads out the language “in
`hybridizable form,” contravening even the broadest
`reasonable construction which must attribute some
`meaning to that claim language. Thus, Dr. Nelson’s
`opinions not only lack any supporting analysis or
`facts, they erroneously render the claim limitation
`“hybridizable form” meaningless. Haemonetics
`Corp. v. Baxter Healthcare Corp., 607 F.3d 776,
`781 (Fed. Cir. 2010).
`PO Resp. 12. Patent Owner’s argument is not persuasive.
`We are not applying our construction of “hybridizable form” in a
`manner that would render meaningless “single-stranded.” Patent Owner’s
`own declarant, Dr. Buck, testified that whether a single-stranded nucleic acid
`bound to a solid support is in hybridizable form depends on its “attachment
`methodology and chemistry.” Ex. 2142 ¶94. Dr. Buck elaborated as
`follows:
`
`For example, the way in which a single-stranded
`nucleic acid is bound to a solid support will have a
`large impact on whether or not that nucleic acid is
`capable of hybridizing with a complementary
`sequence. A single-stranded nucleic acid may be
`bound to a support in a way that renders it incapable
`of hybridizing with a complementary nucleic acid
`strand.
`Id. at ¶95; also compare id. at ¶238, with id. at ¶239.
`12
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`In other words, if, for example, a single-stranded nucleic acid were
`bound to a solid support via all of its bases, the bases would not be available
`to pair with a complimentary sequence of bases on a probe. Thus, despite
`being single-stranded, the nucleic acid, with its bases bound to the solid
`support, would not be in a form that renders it capable of further binding
`through Watson-Crick base pairing. Hence, the nucleic acid would not be
`fixed or immobilized in “hybridizable form” despite being single-stranded.12
`Accordingly, our construction of “hybridizable form” as “capable of
`binding through Watson-Crick base pairing” does not render meaningless
`the term “single-stranded.”
`The Limitation “hybridizable form” Modifies Single-
`b)
`Stranded Nucleic Acids, Not Unclaimed Aspects of the
`Surrounding Environment
`Whether single-stranded nucleic acids are fixed or immobilized in
`“hybridizable form” depends on the form of the single-stranded nucleic
`acids when bound to the support, but not on unclaimed aspects of the
`surrounding environment (e.g., temperature, pH, concentration, etc.)—
`termed “factors and conditions” by Patent Owner. See PO Resp. 9–12.
`Patent Owner argues that the challenged claims require the presence
`of certain “factors and conditions affecting hybridization” to satisfy the
`“hybridizable form” limitation. See, e.g., PO Resp. 9 (“Fish does not
`disclose sufficient information about the various factors and conditions
`
`
`12 Although Petitioners’ declarant, Dr. Nelson, could not identify a way to
`bind a single-stranded nucleic acid to a solid support in a form that would
`not be capable of Watson-Crick base pairing (Ex. 2117, 40:8–41:1), Patent
`Owner’s declarant, Dr. Buck, testified that such a form could exist.
`Ex. 2142 ¶¶94–95, 239.
`
`13
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`affecting hybridization for a POSITA to determine whether the ssDNA in
`the Fish experiments would hybridize if complementary DNA were
`present.”). But, the challenged claims do not require actual hybridization;
`they require only the capability to hybridize. And that capability, per the
`claim language, is met by the “form” of the single-stranded nucleic acids
`when bound to the support, and not by extraneous factors and conditions
`such as a solution in which the single-stranded nucleic acids may be present.
`This is not to say that a solution’s temperature, pH, solute, solvent,
`etc. cannot affect whether single-stranded nucleic acids will ultimately
`hybridize through Watson-Crick base pairing. It is merely to say that we
`look to the form of single-stranded nucleic acids, rather than other
`unspecified factors or conditions of the surrounding environment, in
`determining whether those single-stranded nucleic acids are hybridizable.
`As such, the challenged claims are not limited by any particular
`hybridization factors or conditions. For example, the concentration of
`complimentary probes within a solution surrounding single-stranded nucleic
`acids may affect whether or how quickly the single-stranded nucleic acids
`hybridize with complimentary probes, but the concentration of
`complimentary probes does not affect the status of whether the single-
`stranded nucleic acids are in “hybridizable form.”
`In light of the specification and the parties’ stipulation (see Pet. 13;
`Prelim. Resp. 11), we construe “hybridizable form” as meaning that the
`single-stranded nucleic acids are bound to the non-porous solid support in a
`form that renders them capable of binding through Watson-Crick base
`pairing, which, in turn, means that they have bases available for base-
`pairing.
`
`14
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`B. Ground 1: Anticipation by Fish
`
`Petitioners contend that claims 17, 19, 25, 105, 106, 114, 116, 119,
`128, 129, 150, 152, 178, 180, 186, and 187 are anticipated by Fish.
`Anticipation requires that “each and every element as set forth in the
`claim is found, either expressly or inherently described, in a single prior art
`reference.” Verdegaal Bros., Inc. v. Union Oil Co. of Cal., 814 F.2d 628,
`631 (Fed. Cir. 1987).
`
`1. Disclosure of Fish
`
`Fish describes a “sensitive solid phase microradioimmunoassay . . .
`for measurement of antidouble stranded DNA (dsDNA) antibodies.”
`Ex. 1006, Abstract. Fish notes “the capacity of poly-L-lysine (PLL) to
`facilitate the binding of pure dsDNA to plastic surfaces.” Id. Fish describes
`an experiment in which “[t]wenty-five microliter aliquots of the PLL
`solution were introduced into each well of a V-shaped polyvinyl
`microtitration tray.” Id. at 536, left col. ¶1. Synthetic double-stranded DNA
`(“dsDNA”) in the form of a double-stranded copolymer of deoxyadenosine
`and deoxythymidine (“poly dA–dT”) was introduced into the wells of
`alternating rows, and certain washing and incubation steps were performed.
`Id.
`
`Fish next describes the same procedure but using single-stranded
`DNA (“ssDNA”) either in the form of: (1) a mixture of synthetic
`homopolymers of deoxyadenosine (“poly-dA”) and deoxycytidine (“poly-
`dC”) or (2) denatured calf thymus DNA. Id. at 536, left col. ¶2; id. at 539,
`Fig. 1 (caption: “PLL treated microtitration wells were coated with various
`preparations of double-stranded and single-stranded DNA.”).
`15
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`IPR2016-00822
`Patent 7,064,197 B1
`
`“Half of the nucleic acid coated wells were subjected to nuclease S1
`digestion.” Id. at 538, right col. ¶1; see also id. at 539, Fig. 1. S1 nuclease
`digests ssDNA but not dsDNA. Id. at 538, right col. ¶1. The measured
`attachment/activity of the anti-DNA antibody in the wells is shown in the
`right-hand column of Figure 1 of Fish. Id. at 539, Fig. 1. According to Fish,
`the results demonstrated the following:
`
`[N]uclease S1 treatment had no effect on the binding of SLE Ig[13]
`to poly dA–dT coated wells, thus indicating that this DNA
`preparation was indeed wholly double-stranded. On the other
`hand, the binding of [SLE] Ig to heat-denatured DNA was almost
`completely abolished by the enzymatic digestion. This positive
`control for the nuclease S1 activity suggests that single-stranded
`nucleic acid, bound to PLL treated plastic, remains susceptible to
`the hydrolytic activity of the enzyme.
`Id. at 538, right col. ¶1.
`
`2. Application of Fish to the Challenged Independent Claims
`
`Independent claims 17 and 25 recite “[a]n array comprising various
`single-stranded nucleic acids.” Independent claim 19 recites the same
`language except that it omits the word “various.” Fish discloses the same
`because it discloses microtitration trays having wells of ssDNA (i.e., the
`mixture of poly-dA and poly-dC and also the denatured calf thymus DNA)
`arranged in rows. Ex. 1006, 536, left col. ¶¶1–2. Patent Owner argues that
`“a container by itself cannot meet the ‘array’ limitation of the challenged
`claims.” PO Resp. 20. This argument is not persuasive. The containers of
`
`
`13 The anti-DNA antibody employed was plastic systemic lupus
`erythematosus patient serum Immunoglobulin, or SLE Ig. Ex. 1006, 534,
`Abstract.
`
`16
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`IPR2016-00822
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`Fish to which Petitioners cite have “rows” of “wells,” and, thus, an orderly
`grouping or arrangement of wells. Ex. 1006, 536, left col. ¶¶1–2.
`Claims 17 and 19 recite a “non-porous solid support,” and claim 25
`recites “a non-porous solid support having wells or depressions.” Fish meets
`these limitations because its microtitration trays are polyvinvyl (Ex. 1006,
`536, left col. ¶1), which material is plastic and non-porous according to
`unrebutted testimony of Norman Nelson, Ph.D. Ex. 1002 ¶¶38, 40–42.
`Claims 17, 19, and 25 recite “single-stranded nucleic acids fixed or
`immobilized . . . to a non-porous solid support.” (Emphasis added). Fish
`discloses ssDNA (i.e., the mixture of poly-dA and poly-dC as well as the
`denatured calf thymus DNA) bound to the PLL-coated wells of the
`microtitration tray. Ex. 1006, 536, left col. ¶¶1–2, 539, Fig. 1; see also
`Ex. 1002 ¶55 (Dr. Nelson: “[T]he amine groups of PLL form non-covalent
`bonds with nucleic acids via ionic interactions between the positive charges
`of the amine groups and the negative charges of the phosphate groups in the
`DNA.”). In fact, Fish explicitly refers to “[s]ingle stranded DNA coated
`trays” and “single-stranded nucleic acids, bound to the PLL treated plastic.”
`Ex. 1006, 536, left col. ¶2, 538, right col. ¶1. Fish meets this limitation.
`Patent Owner argues that Fish does not meet this limitation because
`“Fish does not describe any experiments that tested, let alone confirmed,
`whether single-stranded nucleic acids actually bound to the disclosed PLL-
`coated wells.” PO Resp. 4 (citing Ex. 2142 ¶¶ 68–91). But that is a straw
`man argument. The fact that the Fish researchers may not have performed
`testing to confirm that ssDNA was bound to the PLL-coated wells does not
`negate that they nonetheless described ssDNA bound to PLL-coated wells.
`See 35 U.S.C. § 102(a)–(b) (“A person shall be entitled to a patent unless —
`17
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`IPR2016-00822
`Patent 7,064,197 B1
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`(a) the invention was known or used by others in this country, or patented or
`described in a printed publication in this or a foreign country, before the
`invention thereof by the applicant for patent, or (b) the invention was
`patented or described in a printed publication in this or a foreign country or
`in public use or on sale in this country, more than one year prior to the date
`of the application for patent in the United States.”) (emphasis added).
`Further, and as we stated in the Institution Decision:
`[I]t appears that the Fish researchers had no need to
`make such a determination because they already
`knew that ssDNA would bind to the PLL-coated
`wells, as they were relying on such binding to carry
`out their experiment. See Ex. 1006, 536, left col. ¶2
`(“Single stranded DNA coated trays. A mixture
`of poly-dA (5 μg/ml) and poly-dC (5 μg/ml) in Tris
`buffer was
`introduced
`into
`PLL-coated
`microtitration trays as described previously [with
`respect to the synthetic dsDNA].”), 538, right col.
`¶1 (“This positive control for the nuclease S1
`activity suggests that single-stranded nucleic acid,
`bound to PLL treated plastic, remains susceptible to
`the hydrolytic activity of the enzyme.”).
`Inst. Dec. 12–13. Patent Owners have not presented any argument or
`evidence post-institution that would change our reading of Fish.
`Petitioners have persuaded us that Fish teaches the limitation of
`claims 17, 19, and 25 of “single-stranded nucleic acids fixed or immobilized
`. . . to a non-porous solid support.”
`Claims 17, 19, and 25 recite “single-stranded nucleic acids fixed or
`immobilized in hybridizable form to a non-porous solid support.”
`(Emphasis added). Petitioners argue that the bound ssDNA in Fish is in
`“hybridizable form” because it “necessarily was capable of binding through
`
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`Watson-Crick base pairing.” Pet. 22 (citing Ex. 1002 ¶66).
`In addition to the cited testimony, Petitioners also rely on certain
`“admissions made by the Patent Owner.” Id. at 23 (citing Ex. 1002 ¶¶62,
`64). Dr. Nelson, Petitioners’ declarant, explains the alleged admissions,
`with citations to the prosecution history of the ’197 patent, as follows:
`[T]he Patent Owner asserted that its single sentence
`disclosure of PLL coating as “the lynchpin[] of
`DNA microarray technology” that uses PLL to
`immobilize single-stranded DNA to solid supports
`in such arrays. Ex. 1003, pp. 96–97[.] The Patent
`Owner further asserted that its one sentence
`disclosure of coating a solid support with PLL,
`which
`included no specific concentration or
`conditions, “allows for hybridization and detection
`of different nucleic acids under the same or similar
`hybridization and detection conditions.” Id. at 98.
`Thus, the Patent Owner admits that attaching a
`single-stranded DNA using a PLL coated non-
`porous solid support results in an immobilized
`single-stranded DNA that necessarily will hybridize
`under appropriate hybridization conditions. Thus,
`the immobilized single-stranded DNA in Fish
`necessarily will be in hybridizable form according
`to the Patent Owner’s own assertions.
`Ex. 1002 ¶64.
`It is true that the ’197 patent describes, via a single sentence, PLL as
`an acceptable surface treatment for its invention. Ex. 1001, 11:37–39. It is
`also true that, during the prosecution of the ’197 patent, Patent Owner touted
`that it invented the use of PLL to coat non-porous solid supports with
`ssDNA. Ex. 1003, 96–98. For example, Patent Owner argued to the
`Examiner the following:
`
`19
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`IPR2016-00822
`Patent 7,064,197 B1
`
`To recap, prior efforts to bind nucleic acids to non-
`porous materials were plagued by: 1) poor binding
`capacity and
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