Trials@uspto.gov
`571-272-7822
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`Paper No. 52
`Date: September 28, 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 IPR2016-00820
`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)
`
`
`
`
`571-272-7822
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`Paper No. 52
`Date: September 28, 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 IPR2016-00820
`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)
`
`
`
`
`
`IPR2016-00820
`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 1, 6,
`8, 9, 12–16, 27, 31–34, 38, 41, 61–64, 68–70, 72–74, 78, 79, 100, 101, 191–
`195, 212, 213, 218, 219, 222, 225–227, 230, 233, and 236 (“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 1 (“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 4, 2016, Decision, we granted the
`Petition. Paper 8 (“Inst. Dec.”).
`During trial, Becton, Dickinson and Company (“Becton”) was joined
`as co-petitioner. Paper 32. Hologic and Becton are hereafter referred to
`collectively as “Petitioners.”
`Patent Owner filed a Patent Owner Response (Paper 24, “PO Resp.”),
`to which Petitioners filed a Reply (Paper 38, “Reply”). Both sides filed
`Motions to Exclude. See Papers 43, 45. Both sides requested a hearing for
`oral arguments, and a consolidated hearing for this inter partes review and
`Case IPR2016-00822 was held June 1, 2017. A transcript of the hearing
`appears in the record. See Paper 51 (“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
`IPR2016-00822. Co-petitioner Becton also filed two petitions for inter
`2
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`IPR2016-00820
`Patent 7,064,197 B1
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`partes reviews of the ’197 patent, along with motions to join the already
`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 IPR2016-00822. See
`Paper 32; IPR2016-00822, Paper 31.
`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 23, 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
`
`3
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`5:58–60. In the challenged claims, the analyte is either “single-stranded
`nucleic acid” (claims 1, 6, 12, 13, 27), “DNA or RNA” (claims 8, 15), or
`“nucleic acid” (claims 9, 14). “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 15:51–53 (claim 1 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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`4
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`C. The Challenged Claims
`
`Petitioners challenge claims 1, 6, 8, 9, 12–16, 27, 31–34, 38, 41, 61–
`64, 68–70, 72–74, 78, 79, 100, 101, 191–195, 212, 213, 218, 219, 222, 225–
`227, 230, 233, and 236 of the ’197 patent. Pet. 1. Of the challenged claims,
`claims 1, 6, 8, 9, 12–15, and 27 are independent. The remainder of the
`challenged claims all depend directly from at least one of the challenged
`independent claims, with several of them in multiple dependent form.
`Claim 1 is illustrative and reproduced below.
`1.
`A non-porous solid support comprising one or
`more amine(s), hydroxyl(s) or epoxide(s) thereon, wherein at
`least one single-stranded nucleic acid is fixed or immobilized in
`hybridizable form to said non-porous solid support via said one
`or more amine(s), hydroxyl(s) or epoxide(s).
`
`
`D. Grounds of Unpatentability Tried
`
`We instituted trial on the following grounds of unpatentability:
`Basis1
`References
`Claims Challenged
`Fish (Ex. 1006)2
`§ 102(b)
`1, 6, 8, 9, 12–16, 27, 32–
`34, 41, 61–63, 69, 70, 72–
`74, 79, 100, 191, 193, 194,
`212, 213, 219, 222, 225–
`227, 230, 233, and 236
`
`
`1 The Leahy-Smith America Invents Act (“AIA”), Pub. L. No. 112-29,
`enacted September 16, 2011, amended 35 U.S.C. §§ 102 and 103. AIA
`§ 3(b)–(c). Their amendment became effective eighteen months later on
`March 16, 2013. Id. at § 3(n). Because the application from which the ’197
`patent issued was filed before March 16, 2013, any citations herein to 35
`U.S.C. §§ 102 and 103 are to their pre-AIA versions.
`2 Falk Fish, et al., “A Sensitive Solid Phase Microradioimmunoassay For
`
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`References
`Fish
`
`Fish and Gilham
`(Ex. 1019)3
`VPK (Ex. 1008)4
`
`Basis1
`§ 103(a)
`
`§ 103(a)
`
`§ 102(a)
`and (b)
`
`Claims Challenged
`31, 64, 68, 101, 192, and
`195
`38, 78, and 218
`
`1, 6, 8, 9, 12–15, 27, 31,
`32, 34, 61–63, 68–70, 72,
`74, 79, 100, 191–193, 194,
`213, 219, 226, 227, and
`236
`33, 41, 73, 212, 225, and
`233
`16, 38, 64, 78, 101, 195,
`218, 222, and 230
`
`VPK and Metzgar
`(Ex. 1009)5
`Noyes (Ex. 1007),6 VPK,
`and Ramachandran
`(Ex. 1028)7
`Inst. Dec. 26; see also Paper 10 (errata to Institution Decision).
`
`§ 103(a)
`
`§ 103(a)
`
`
`Anti-Double Stranded DNA Antibodies,” Arthritis and Rheumatism,
`Vol. 24, No. 3, 534–43 (March 1981).
`3 P. T. Gilham, “Immobilized Polynucleotides and Nucleic Acids,”
`Immobilized Biochemicals and Affinity Chromatography, 173–85 (1974).
`
`4 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).
`5 U.S. Patent No. 3,572,892, issued Mar. 30, 1971.
`6 Barbara E. Noyes, et al., “Nucleic Acid Hybridization Using DNA
`Covalently Coupled to Cellulose,” Cell, vol. 5, 301–10 (July 1975).
`7 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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`IPR2016-00820
`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)).
`There are two major claim construction disputes in this case. They
`regard the meaning of “fixed or immobilized” and “hybridizable form.”
`These limitations are recited by all challenged independent claims. At
`institution, we adopted express constructions that the parties had stipulated
`to for both limitations, but that was not the end of the matter. Inst. Dec. 8–9.
`The parties now dispute what their stipulated constructions encompass.
`
`1. “fixed or immobilized”
`
`All of the challenged independent claims recite “fixed or
`immobilized.” For example, claim 1 recites “at least one single-stranded
`nucleic acid is fixed or immobilized in hybridizable form to said non-porous
`solid support via said one or more amine(s), hydroxyl(s) or epoxide(s).”
`(Emphasis added).
`
`7
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`Prior to institution, the parties agreed that “fixed or immobilized”
`means “bound.” Pet. 11; Prelim. Resp. 13 n.3; see also Ex. 1010, 13–15
`(Markman order applying same construction). In our Institution Decision,
`we applied that agreed-upon meaning. Inst. Dec. 8. Although neither side
`opposes that construction post-institution, a dispute remains as to whether
`“fixed or immobilized” encompasses only that which is directly bound or
`additionally that which is indirectly bound. See, e.g., Pet. 48 (mapping
`VPK’s disclosure of indirect binding to the “fixed or immobilized”
`limitation); PO Resp. 55–57 (Patent Owner arguing that VPK’s indirect
`binding does not meet the “fixed or immobilized” limitation); Reply 20–21
`(Petitioners arguing the opposite).
`This remaining dispute can be resolved by resorting to the
`specification, in light of which the limitation must be read. The
`specification states:
`
`Analytes in a biological sample are preferably denatured
`into single-stranded form, and then directly fixed to a suitable
`solid support. Alternatively, the analyte may be directly fixed to
`the support in double-stranded form, and then denatured. The
`present invention also encompasses indirect fixation of the
`analyte, such as in in situ techniques where the cell is fixed to the
`support and sandwich hybridization techniques where the analyte
`is hybridized to a polynucleotide sequence that is fixed to the
`solid support.
`Ex. 1001, 5:61–6:2 (emphasis added). This excerpt unequivocally
`demonstrates two things. First, the applicants considered indirect fixation to
`be within the scope of their invention, and they so informed the public.
`Second, the applicants considered the term “fixation” to include both direct
`fixation and indirect fixation in the absence of an explicit reference to the
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`former or latter. Critically, the independent claims recite an analyte that
`merely “is fixed or immobilized” without specifying that the fixation or
`immobilization must be direct or indirect. See, e.g., id. at 13:63–67
`(claim 1). Accordingly, we construe “fixed or immobilized” as meaning
`bound, whether directly or indirectly.
`Further intrinsic evidence supports our construction via the doctrine of
`claim differentiation and application of 35 U.S.C. § 112 ¶5 (now § 112(e)).
`Claim 16, which is in multiple dependent form, is reproduced below:
`16. The non-porous solid support of
`claims 1, 2, 12, 13, 14, 15 or 4, wherein said
`fixation or immobilization is not to a cell fixed in
`situ to said non-porous solid support.
`Each of the claims from which claim 16 depends is an independent claim
`that recites “fixed or immobilized.” By statute, claim 16 must specify a
`further limitation beyond each claim from which it depends. See 35 U.S.C.
`§ 112 ¶5 (“A claim in multiple dependent form shall contain a reference, in
`the alternative only, to more than one claim previously set forth and then
`specify a further limitation of the subject matter claimed.”). The only
`limitation specified by claim 16 is that “said fixation or immobilization is
`not to a cell fixed in situ to said non-porous solid support.” Hence, for claim
`16 to comply with 35 U.S.C. § 112 ¶5, the further limitation that it specifies
`(i.e., “said fixation or immobilization is not to a cell fixed in situ to said non-
`porous solid support”) must not be a limitation of the claims from which it
`alternatively depends. In other words, the “fixed or immobilization”
`limitation of each of claims 1, 2, 12, 13, 14, 15 and 4 must encompass
`fixation or immobilization that is to a cell fixed in situ to said non-porous
`solid support. This type of claim differentiation is the strongest type to
`9
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`Patent 7,064,197 B1
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`which the doctrine applies.
`In the most specific sense, “claim differentiation”
`refers to the presumption that an independent claim
`should not be construed as requiring a limitation
`added by a dependent claim. Thus, the claim
`differentiation tool works best in the relationship
`between independent and dependent claims.
`Curtiss-Wright Flow Control Corp. v. Velan, Inc., 438 F.3d 1374, 1380
`(Fed. Cir. 2006) (citations omitted).
`Thus, in light of the specification and claim differentiation, we
`construe “fixed or immobilized” to mean bound, whether directly or
`indirectly.
`
`2. “hybridizable form”
`
`All of the independent claims that are challenged recite “hybridizable
`form.” For example, claim 1 recites “at least one single-stranded nucleic
`acid is fixed or immobilized in hybridizable form to said non-porous solid
`support via said one or more amine(s), hydroxyl(s) or epoxide(s).”
`(Emphasis added).
`Prior to institution, the parties agreed that “hybridizable form” means
`“capable of binding through Watson-Crick base pairing.” Pet. 14 (citing
`Ex. 1001, 2:22–34); Prelim. Resp. 128; see also Ex. 1010, 5 (Markman order
`applying same construction). In our Institution Decision, we gave it the
`
`
`8 Patent Owner’s proffered construction additionally added that the Watson-
`Crick base pairing would be “to a complementary nucleic acid sequence.”
`Prelim. Resp. 12. 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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`Patent 7,064,197 B1
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`agreed-upon meaning. Inst. Dec. 8–9. Although neither side opposes 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. 25
`(mapping Fish’s ssDNA bound to poly-L-lysine (“PLL”)-treated plastic to
`the hybridizable form limitation); PO Resp. 11 (“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
`argues Fish discloses no hybridization conditions, although the challenged
`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.
`
`a) The Limitation “hybridizable form” is not Synonymous with the
`Limitation “single-stranded”
`
`The limitation “hybridizable form” pertains to the form of the recited
`analyte (i.e., “single-stranded nucleic acid” in independent claims 1, 6, 12,
`13, and 27; “DNA or RNA” in independent claims 8 and 15; and “nucleic
`acid” in independent claims 9 and 14) when it is fixed or immobilized to the
`non-porous solid support. This means that the analyte must be bound to the
`solid support in a manner that renders it capable of binding to a
`complementary sequence through Watson-Crick base pairing. To be so
`capable, the analyte must be single-stranded and have bases available for
`base-pairing.
`
`11
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`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. 13. Patent Owner
`elaborates as follows:
`[Petitioner’s 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. 2017] 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. 13. 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,” which is an
`additional limitation of some but not all of the challenged claims.9 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
`
`
`9 Independent claims 1, 6, 12, 13, and 27 recite a “single-stranded nucleic
`acid,” but independent claims 8 and 15 merely recite “DNA or RNA” and
`independent claims 9 and 14 merely recite “nucleic acid.”
`12
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`“attachment methodology and chemistry.” Ex. 2042 ¶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. 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.10
`In contrast to this example, in the ’197 patent, the analyte is bound to
`the solid support via its phosphate backbone, thus making the bases
`available for potential base-pairing. Ex. 2042 ¶189. Dr. Buck, Patent
`Owner’s declarant, prepared an illustration of this configuration in his
`declaration, which illustration is reproduced below.
`
`
`10 Although Petitioner’s 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. 2017, 40:8–41:1), Patent
`Owner’s declarant, Dr. Buck, testified that such a form could exist. Ex.
`2042 ¶¶94–95.
`
`13
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`Ex. 2042 ¶189. Dr. Buck’s illustration, reproduced above, depicts the
`“binding interaction [that] occurs between the negatively charged phosphate
`backbone of the nucleic acid strand and the positively charged amines on the
`gamma-aminopropyltriethoxysilane-treated surface” of the solid support. Id.
`(Dr. Buck statement after citing Ex. 1001, 8:48–52; 8:65–9:2).
`Accordingly, our construction of “hybridizable form” as “capable of
`binding through Watson-Crick base pairing” does not render meaningless
`the term “single-stranded.”
`
`b) The Limitation “hybridizable form” Modifies the Recited Analyte, Not
`Unclaimed Aspects of the Surrounding Environment
`
`Whether a recited analyte is fixed or immobilized in “hybridizable
`form” depends on the form of the recited analyte as 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, 11.
`Patent Owner argues that the challenged claims require the presence
`of certain “factors and conditions affecting hybridization” to satisfy the
`
`14
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`“hybridizable form” limitation. See, e.g., PO Resp. 9–10 (“Fish does not
`disclose sufficient information about the various factors and conditions
`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 recited analyte, and not by
`extraneous factors and conditions such as a solution in which the analyte
`may be present.
`This is not to say that a solution’s temperature, pH, solute, solvent,
`etc. cannot affect whether an analyte will ultimately hybridize through
`Watson-Crick base pairing. It is merely to say that we look to the form of
`the recited analyte, rather than other unspecified factors or conditions of the
`surrounding environment, in determining whether that analyte is
`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 an
`analyte may affect whether or how quickly the analyte hybridizes with a
`complimentary probe, but the concentration of complimentary probes does
`not affect the status of whether the analyte is in a “hybridizable form.”
`In light of the specification and the parties’ stipulation (see Pet. 14;
`Prelim. Resp. 12), we construe “hybridizable form” as meaning that the
`recited analyte is bound to the non-porous solid support in a form that
`renders it capable of binding through Watson-Crick base pairing, which, in
`turn, means that it has bases available for base-pairing.
`
`15
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`B. Ground 1: Anticipation by Fish
`
`Petitioners contend that claims 1, 6, 8, 9, 12–16, 27, 32–34, 41, 61–
`63, 69, 70, 72–74, 79, 100, 191, 193, 194, 212, 213, 219, 222, 225–227, 230,
`233, and 236 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. ¶1.11 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
`
`11 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.
`
`16
`
`
`
`IPR2016-00820
`Patent 7,064,197 B1
`
`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.”).
`“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[12]
`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
`
`The challenged independent claims (namely, claims 1, 6, 8, 9, 12–15,
`and 27) are of similar scope, and none of their differences is material in light
`of the Fish teachings on which Petitioners rely. Further, all of Patent
`Owner’s arguments for patentability of the challenged independent claims
`
`
`12 The anti-DNA antibody employed was plastic systemic lupus
`erythematosus patient serum Immunoglobulin, or SLE Ig. Ex. 1006, 534,
`Abstract.
`
`17
`
`
`
`IPR2016-00820
`Patent 7,064,197 B1
`
`are common to all of the challenged independent claims. See PO Resp. 2–
`22. Accordingly, for the challenged independent claims, we address
`explicitly only claim 1.
`Independent claim 1 recites, in both the preamble and the body of the
`claim, a “non-porous solid support.” Fish meets this limitation because Fish
`uses microtitration trays that are polyvinvyl (Ex. 1006, 536, left col. ¶1),
`which material is plastic and non-porous according to unrebutted testimony
`of Dr. Nelson. Ex. 1002 ¶¶38, 40–42.
`Claim 1 recites a “non-porous solid support comprising one or more
`amine(s), hydroxyl(s) or epoxide(s) thereon.” Fish meets this limitation
`because it discloses treating the microtitration tray with poly-L-lysine (PLL)
`(Ex. 1006, 536, left col. ¶¶1–2), which provides amine groups on the surface
`of the tray. Ex. 1002 ¶42; Ex. 1017, 1, right col. ¶2 (“Non-terminated DNA
`has also been spotted onto amine functionalized surfaces such as PLL.”), 2,
`left col. ¶1 (“PLL, APS and PAMAM all present amine functional groups
`suitable for interaction with DNA.”). Indeed, the ’197 patent itself describes
`treating the surface of the non-porous solid support with polylysine to
`facilitate fixation of single-stranded DNA thereto. Ex. 1001, 11:37–39.13
`Claim 1 recites “at least one single-stranded nucleic acid fixed or
`immobilized . . . to said non-porous solid support via said one or more
`
`
`13 The ’197 patent refers to “polylysine” (PPL) generally, without specifying
`poly-L-lysine (PLL). Ex. 1001, 11:37–39. However, the ’197 patent
`applicants touted the use of “poly-L-lysine” specifically during the
`prosecution history. See, e.g., Ex. 1003, 97; see also Tr. 54:10–15 (counsel
`for Patent Owner agreeing that polylysine (per the ’197 patent) and poly-L-
`lysine (per Fish) are both polylysines.).
`18
`
`
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`IPR2016-00820
`Patent 7,064,197 B1
`
`amine(s), hydroxyl(s) or epoxide(s).” (Emphasis added.) Fish discloses
`wells of 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 ¶53 (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 “Single stranded DNA coated
`trays” (Ex. 1006, 536, left col. ¶2) and “single-stranded nucleic acids, bound
`to the PLL treated plastic, . . .” (Ex. 1006, 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. 2042 ¶¶67–71, 76, and 77). But that
`is a straw man argument. The fact that 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 — (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).
`
`19
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`IPR2016-00820
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`
`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. 13. Patent Owners have not presented any argument or evidence
`post-institution that would change our reading of Fish.
`Petit
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