Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`
`
`HOLOGIC, INC.,
`Petitioner
`
`
`
`v.
`
`
`
`ENZO LIFE SCIENCES, INC.,
`Patent Owner
`
`__________________
`
`
`
`Case IPR2016-00820
`
`U.S. Patent No. 7,064,197
`TITLE: SYSTEM, ARRAY AND NON-POROUS SOLID SUPPORT
`COMPRISING FIXED OR IMMOBILIZED NUCLEIC ACIDS
`Issue Date: June 20, 2006
`
`______________
`
`
`
`
`ENZO’S PATENT OWNER RESPONSE
`
`
`Mail Stop Patent Board
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`TABLE OF CONTENTS
`
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`Page
`
`II. OVERVIEW OF THE ’197 PATENT ............................................................ 1
`
`III. FISH DOES NOT ANTICIPATE ANY CLAIMS IN GROUND 1. .............. 2
`
`A.
`
`Independent Claims 1, 6, 8, 9, 12, 13, 14, 15, And 27 .......................... 2
`
`1.
`
`2.
`
`Fish Does Not Disclose Nucleic Acid Strands Fixed Or
`Immobilized To A Non-Porous Solid Support. .......................... 3
`
`Fish Does Not Expressly Or Inherently Disclose Nucleic
`Acid Strands In Hybridizable Form. ........................................... 9
`
`a.
`
`b.
`
`Petitioner’s Reliance on Diehl Does Not Establish
`That Fish
`Inherently Discloses
`ssDNA
`In
`Hybridizable Form. ......................................................... 14
`
`The ’197 Patent Prosecution History Does Not
`Support Petitioner’s Inherency Theory. ......................... 20
`
`B. Dependent Claims 16, 32-34, 41, 61-63, 69, 70, 72-74, 79, 100,
`191, 193, 194, 212, 213, 219, 222, 225- 227, 230, 233, And 236 ...... 22
`
`IV. FISH, STANDING ALONE, DOES NOT RENDER OBVIOUS ANY
`CLAIM IN GROUND 2. ............................................................................... 22
`
`A.
`
`Claims 31, 68, And 192 ....................................................................... 23
`
`B.
`
`Claims 64, 101, And 195 ..................................................................... 26
`
`V.
`
`FISH IN VIEW OF GILHAM DOES NOT RENDER OBVIOUS
`ANY OF CLAIMS 38, 78, OR 218. .............................................................. 28
`
`A.
`
`B.
`
`Petitioner Did Not Establish That Fish In View Of Gilham
`Meets All Of The Limitations Of Claims 38, 78, Or 218. .................. 28
`
`Petitioner Did Not Establish That A POSITA Would Have
`Combined Fish And Gilham Or That A POSITA Would Have
`Had A Reasonable Expectation Of Success. ....................................... 28
`
`
`
`i
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`VI. VPK IS NOT PRIOR ART TO ANY CHALLENGED CLAIM. ................. 32
`
`A.
`
`The Challenged Claims Are Entitled To The Filing Date Of The
`1983 Application. ................................................................................ 33
`
`1.
`
`2.
`
`The 1983 Application’s Examples Of Non-Porous Solid
`Supports Provide Sufficient Written Description For The
`Genus Of “Non-Porous Solid Supports.” ................................. 34
`
`Factually
`On
`Rely
`Arguments
`Petitioner’s
`Distinguishable Cases, Incorrect Statements Of Law, Or
`Both. 37
`
`B.
`
`The Invention of the Challenged Claims Was Conceived and
`Reduced to Practice Before VPK’s Effective Date Of October
`1982. 39
`
`1.
`
`2.
`
`Legal Standards For Antedating An Alleged 35 U.S.C.
`§ 102(a) Reference In An Inter Partes Review. ....................... 39
`
`Enzo’s Inventors Conceived And Reduced to Practice
`The Challenged Claims’ Subject Matter Before October
`1982. ........................................................................................ 40
`
`VII. VPK DOES NOT ANTICIPATE ANY OF CLAIMS 1, 6, 8, 9, 12-15,
`27, 31, 32, 34, 61-63, 68-70, 72, 74, 79, 100, 191-194, 213, 219, 226,
`227, OR 236. .................................................................................................. 54
`
`A.
`
`Independent Claims 1, 6, 8, 9, 12-15, And 27 .................................... 54
`
`B.
`
`Claims 31, 32, 34, 61, 62, 63, 68-70, 72, 74, 79, 100, 191-194,
`213, 219, 226, 227, And 236 ............................................................... 57
`
`VIII. VPK IN VIEW OF NOYES AND RAMACHANDRAN DOES NOT
`RENDER OBVIOUS ANY OF CLAIMS 16, 38, 64, 78, 101, 195,
`218, 222, OR 230. .......................................................................................... 60
`
`A.
`
`B.
`
`Petitioner Did Not Establish That Noyes, VPK, And
`Ramachandran Meet All Of The Limitations Of Any
`Challenged Claim. ............................................................................... 60
`
`Petitioner Did Not Establish That A POSITA Would Combine
`VPK, Noyes, And Ramachandran. ...................................................... 62
`
`
`
`ii
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`IX. VPK IN VIEW OF METZGAR DOES NOT RENDER OBVIOUS
`ANY OF CLAIMS 33, 41, 73, 212, 225, OR 233. ........................................ 65
`
`X.
`
`SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS .............. 67
`
`XI. CONCLUSION .............................................................................................. 68
`
`iii
`
`
`
`
`
`
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`Cases
`
`TABLE OF AUTHORITIES
`
`Page(s)
`
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) ..................................................................... 29, 64
`
`Agilent Techs., Inc. v. Affymetrix, Inc.,
`567 F.3d 1366 (Fed. Cir. 2009) ............................................................................ 10
`
`Bilstad v. Wakalopulos,
`386 F.3d 1116 (Fed. Cir. 2004) ............................................................... 34, 37, 38
`
`Borror v. Herz,
`666 F.2d 569 (CCPA 1981) .................................................................................. 40
`
`CFMT, Inc. v. Yieldup Int’l. Corp.,
`349 F.3d 1333 (Fed. Cir. 2003) ............................................................... 22, 28, 65
`
`Corning, Inc. v. DSM IP Assets B.V.,
`Case IPR2013-00053, Paper 66 (PTAB May 1, 2014) ........................................ 40
`
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) ..................................................................... 33, 40
`
`Haemonetics Corp. v. Baxter Healthcare Corp.,
`607 F.3d 776 (Fed. Cir. 2010) ....................................................................... 13, 58
`
`Hartness Int’l Inc. v. Simplimatic Eng’g Co.,
`819 F. 2d 1100 (Fed. Cir. 1987) .................................................................... 22, 57
`
`Holmwood v. Sugavanam,
`948 F.2d 1236 (Fed. Cir. 1991) ............................................................................ 40
`
`Hybritech Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986) ............................................................................ 39
`
`In re Fine,
`837 F.2d 1071 (Fed. Cir. 1988) ............................................................................ 65
`
`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) ................................................................. 27, 30, 62
`
`
`
`iv
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) .............................................................................. 63
`
`In re Oelrich,
`666 F.2d 578 (CCPA 1981) .................................................................................. 10
`
`In re Rasmussen,
`650 F.2d 1212 (CCPA 1981) ................................................................................ 34
`
`In re Ratti,
`270 F.2d 810 (CCPA 1959) ..................................................................... 28, 30, 62
`
`In re Smythe,
`480 F.2d 1376 (CCPA 1973) ......................................................................... 34, 37
`
`Int’l Bus. Machines Corp. v. Intellectual Ventures II LLC,
`Case IPR2014-00587, Paper 57 (PTAB Nov. 6, 2015) ................................. 33, 39
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) ...................................................................................... 26, 29
`
`Lampi Corp. v. American Power Prods., Inc.,
`228 F.3d 1365 (Fed. Cir. 2000) ..................................................................... 33, 39
`
`LizardTech v. Earth Resource Mapping, Inc.,
`424 F.3d 1336 (Fed. Cir. 2005) ..................................................................... 37, 38
`
`Lockwood v. Am. Airlines, Inc.,
`107 F.3d 1565 (Fed. Cir. 1997) ............................................................................ 33
`
`Mahurkar v. C.R. Bard, Inc.,
`79 F.3d 1572 (Fed. Cir. 1998) .............................................................................. 39
`
`Martek Biosciences Corp. v. Nutrinova, Inc.,
`579 F.3d 1363 (Fed. Cir. 2009) ..................................................................... 33, 37
`
`Par Pharm., Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ............................................................... 22, 28, 65
`
`Price v. Symsek,
`988 F.2d 1187 (Fed. Cir. 1991) ............................................................................ 40
`
`
`
`v
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`Princeton Biochemicals, Inc. v. Beckman Coulter, Inc.,
`411 F.3d 1332 (Fed. Cir. 2005) ............................................................................ 32
`
`Purdue Pharma L.P. v. Faulding Inc.,
`230 F.3d 1320 (Fed. Cir. 2000) ............................................................................ 38
`
`Ralston Purina Co. v. Far-Mar-Co, Inc.,
`777 F.2d 1570 (Fed. Cir. 1985) ............................................................................ 34
`
`Sequenom, Inc. v. Bd. Trs. of Leland Stanford Jr. Univ.,
`Case IPR2013-00390, Paper 45 (PTAB Nov. 25, 2014) ...................................... 40
`
`Tech. Licensing Corp. v. Videotek, Inc.,
`545 F.3d 1316 (Fed. Cir. 2008) ............................................................................ 38
`
`TriVascular, Inc. v. Samuels,
`812 F.3d 1056 (Fed. Cir. 2016) ............................................................................ 62
`
`Tronzo v. Biomet,
`156 F.3d 1154 (Fed. Cir. 1998) ............................................................................ 38
`
`Verdegaal Bros. v. Union Oil Co. of California,
`814 F.2d 628 (Fed. Cir. 1987) ................................................................... 2, 54, 57
`
`Statutes
`
`35 U.S.C. § 102(a) ................................................................................................... 39
`
`35 U.S.C. § 102(b) ................................................................................................... 33
`
`37 C.F.R. § 1.131 ..................................................................................................... 40
`
`Rules
`
`Fed. R. Evid. 803(16) ............................................................................................... 41
`
`Fed. R. Evid. 803(6) ................................................................................................. 41
`
`Fed. R. Evid. 807 ..................................................................................................... 36
`
`
`
`vi
`
`
`
`
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`PATENT OWNER’S EXHIBIT LIST
`
`DESCRIPTION
`
`Enzo
`Exhibit
`No.
`2001
`2002
`
`2003
`2004
`
`Declaration of Gregory Buck, Ph.D.
`Declaration of Dollie M.W. Kirtikar, Ph.D., submitted in U.S. Patent
`App. No. 08/486,070 (Oct. 28, 2003).
`Robberson, D. L. and Davidson, N., Biochemistry 11, 533 (1972).
`Schott, Herbert, “Special Methods for the Immobilization of RNA and
`Polyribonucleotides,” in Affinity Chromatography, Chromatographic
`Science Series, Vol. 27 (allegedly 1984).
`Petitioner’s Petition for Inter Partes Review of U.S. Patent No.
`7,064,197 in Case IPR2016-00822.
`Declaration of Gregory Buck, Ph.D.
`Declaration of Dollie M.W. Kirtikar, Ph.D., submitted in U.S. Patent
`App. No. 08/486,070 (Oct. 28, 2003).
`Robberson, D. L. and Davidson, N., Biochemistry 11, 533 (1972).
`Schott, Herbert, “Special Methods for the Immobilization of RNA and
`Polyribonucleotides,” in Affinity Chromatography, Chromatographic
`Science Series, Vol. 27 (allegedly 1984).
`Petitioner’s Petition for Inter Partes Review of U.S. Patent No.
`7,064,197 in Case IPR2016-00822.
`Anish Desai, Christopher Marando, & Amanda Do Couto, PTAB
`Approaches To Accessibility Of Printed Publication, LAW360 (Oct. 3,
`2016), http://www.law360.com/articles/845934/print?section=ip.
`2007 Michael R. Weiner, APJs Dispute Requirements for a Reference to
`Qualify as a Printed Publication, PTABWATCH (Oct. 15, 2015),
`http://www.ptabwatch.com/2015/10/apjs-dispute-requirements-for-a-
`reference-to-qualify-as-a-printed-publication.
`Affidavit of Michael P. Stadnick.
`Affidavit of Justin P.D. Wilcox.
`[Reserved]
`Herzer, Sibylle and Englert, David, “Nucleic Acid Hybridization,”
`Ch. 14 from Molecular Biology Problem Solver: A Laboratory Guide
`(Gerstein, Alan ed.) (2001).
`
`2005
`
`2001
`2002
`
`2003
`2004
`
`2005
`
`2006
`
`2008
`2009
`2010
`2011
`
`2012
`
`Spiegelman, George et al., “Kinetics of Ribonucleic Acid-
`Deoxyribonucleic Acid Membrane Filter Hybridization,”
`
`
`
`vii
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`DESCRIPTION
`
`Enzo
`Exhibit
`No.
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
`
`Biochemistry, Vol. 12, No. 6, 1234-1242 (1973).
`
`Söderlund, H., “DNA Hybridization: Comparison of Liquid and Solid
`Phase Formats,” Ann. Biol. Clin., 48, 489-491 (1990).
`
`Reed, Ken and Mann, David, “Rapid Transfer of DNA From Agarose
`Gels to Nylon Membranes,” Nucleic Acid Research, Vol. 13, No. 20,
`7207-7221 (1985).
`
`Kahn, Michael, “The Effect of Thymine Dimers on DNA: DNA
`Hybridization,” Biopolymers, Vol. 13, 669-675 (1974).
`
`Smith, G.L.F. et al., “’Reverse’ DNA Hybridization Method for the
`Rapid Identification of Subgingival Microorganisms,” Oral
`Microbiology Immunology, 4: 141-145 (1989).
`
`Deposition Transcript of Norman Nelson, Ph.D., taken in Hologic,
`Inc., v. Enzo Life Sciences, Inc., IPR Case Nos. 2016-00820 and 2016-
`00822 on Dec. 21, 2016.
`
`2018 Meinkoth, Judy and Wahl, Geoffrey, “Review: Hybridization of
`Nucleic Acids Immobilized on Solid Supports,” Analytical
`Biochemistry, 138, 267-284 (1984).
`
`2019
`
`2020
`
`2021
`
`2022
`
`U.S. Patent Application Publication No. US2016/0017392 to Arnold
`et al., published Jan. 21, 2016.
`
`Excerpt from File History for U.S. Patent No. 7,064,197 – June 30,
`2004 Amendment.
`
`Excerpt from File History for U.S. Patent No. 7,064,197 – May 25,
`2005 Amendment.
`
`Diagram of Cell Structure, obtained from:
`http://training.seer.cancer.gov/anatomy/cells_tissues_membranes/cells
`/structure.html.
`
`2023
`
`Excerpt from File History for U.S. Patent No. 7,064,197 – Nov. 26,
`2004 Office Action.
`
`2024
`
`U.S. Patent No. 4,732,847 to Stuart et al., issued Mar. 22, 1988.
`
`2025
`
`Sigma-Aldrich Particle Size Conversion Table, obtained from:
`http://www.sigmaaldrich.com/chemistry/stockroom-reagents/learning-
`
`
`
`viii
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`Enzo
`Exhibit
`No.
`
`
`
`DESCRIPTION
`
`center/technical-library/particle-size-conversion.html.
`
`2026 Whatling, Carl et al., “Expression Microarrays,” Ch. 2 from
`Microarrays & Microplates – Applications in Biomedical Sciences
`(Ye, S. and Day, I.N.M. eds.) (2003).
`
`2027
`
`Enzo Biochem, Inc. SEC Form 8-K dated July 20, 2015.
`
`2028
`
`Enzo Biochem, Inc. SEC Form 8-K dated Oct. 9, 2015.
`
`2029
`
`Enzo Biochem, Inc. SEC Form 8-K dated Jan. 6, 2016.
`
`2030
`
`Enzo Biochem, Inc. SEC Form 8-K dated July 1, 2016.
`
`2031
`
`2032
`
`2033
`
`2034
`
`Plaintiff’s Supplemental Infringement Charts for Siemens Healthcare
`Diagnostics, served on Sept. 30, 2014 in C.A. No. 12-cv-505-LPS (D.
`Del.) (cover pleading only).
`
`Plaintiff’s Supplemental Infringement Charts for Affymetrix, served
`on Sept. 30, 2014 in C.A. No. 12-cv-433-LPS (D. Del.) (cover
`pleading only).
`
`Plaintiff’s Supplemental Infringement Charts for Agilent
`Technologies, served on Sept. 30, 2014 in C.A. No. 12-cv-434-LPS
`(D. Del.) (cover pleading only).
`
`Plaintiff’s Supplemental Infringement Charts for Illumina, served on
`Sept. 30, 2014 in C.A. No. 12-cv-435-LPS (D. Del.) (cover pleading
`only).
`
`2035
`
`Enzo “Invention Record and Report,” Barbara Thalenfeld and
`Kenneth Johnston (May 1982).
`
`2036 Weetall, H.H. and Filbert, A.M., “Porous Glass for Affinity
`Chromatography Applications,” from Methods in Enzymology,
`Volume XXXIV, Affinity Techniques, Enzyme Purification: Part B
`(Jakoby, W. and Wilchek, M. eds.) (1974).
`
`2037
`
`2038
`
`Enzo Laboratory Notebook, Dollie M.W. Kirtikar, entitled “T4
`Expts,” (1982).
`
`Enzo Laboratory Notebook (Number 126), Barbara Thalenfeld, (July-
`August 1982).
`
`2039
`
`Enzo Laboratory Notebook (Number 127), Barbara Thalenfeld, (July-
`
`
`
`ix
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`DESCRIPTION
`
`Enzo
`Exhibit
`No.
`
`2040
`
`2041
`
`September 1982).
`
`Enzo Experiment Record, Barbara Thalenfeld and Kenneth Johnston,
`(June 1982).
`
`Enzo Laboratory Notebook Pages, Barbara Thalenfeld, (May-August
`1982).
`
`2042
`
`Declaration of Gregory Buck, Ph.D.
`
`2043
`
`Declaration of Barry Weiner.
`
`x
`
`
`
`
`
`
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`I.
`
`INTRODUCTION
`
`
`
`The Board should confirm the patentability 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 (Ex. 1001, “the ’197 Patent”). Petitioner’s anticipation and obviousness
`
`challenges fail because Petitioner’s alleged prior art references, alone or in
`
`combination, do not meet all the limitations of any challenged claim. Petitioner’s
`
`obviousness grounds also fail to establish a reason to combine or modify
`
`references as the Petitioner proposes. The declaration testimony of Gregory Buck,
`
`Ph.D., a professor and research scientist with more than thirty-five years of
`
`experience in molecular biology and nucleic acid detection (Ex. 2042 ¶¶ 7-24) and
`
`the deposition testimony of Petitioner’s own declarant, confirms that the claims are
`
`patentable over Petitioner’s alleged prior art.
`
`II. OVERVIEW OF THE ’197 PATENT
`
`The ’197 Patent generally relates to novel and non-obvious techniques for
`
`nucleic acid detection involving non-porous solid supports. Nucleic acid strands
`
`can be attached to non-porous solid supports in hybridizable form for use in
`
`hybridization based nucleic acid detection tests. (Ex. 1001, 6:23-32, 8:37-60, 9:22-
`
`30, 11:25-39; Ex. 2042 ¶¶ 47-62.)
`
`1
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`III. FISH DOES NOT ANTICIPATE ANY CLAIMS IN GROUND 1.
`
`The standard for anticipation is exacting: a “claim is anticipated only if 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. v. Union Oil Co. of
`
`California, 814 F.2d 628, 631 (Fed. Cir. 1987). Fish cannot anticipate any of the
`
`challenged claims because it does not disclose all of the limitations of any
`
`challenged claim.
`
`A. Independent Claims 1, 6, 8, 9, 12, 13, 14, 15, And 27.
`
`The challenged independent claims of the ’197 Patent are directed to nucleic
`
`acid strands that are fixed to non-porous solid supports in hybridizable form,
`
`meaning that their method of fixation causes them to be capable of binding through
`
`Watson-Crick base pairing to a complementary nucleic acid sequence. (See
`
`Petition, 14 (citing Ex. 1010, 10).) In particular, among other limitations, each of
`
`claims 1, 6, 8, 9, 12, 13, 14, 15, and 27 (“the challenged independent claims”)
`
`require that a nucleic acid strand1 be “fixed or immobilized” to a “non-porous solid
`
`support” in “hybridizable form.”
`
`
`1 The term “nucleic acid strands” as used herein collectively refers to the following
`
`limitations of the challenged independent claims: “at least one single-stranded
`
`nucleic acid” (claims 1, 6, and 27), “single-stranded nucleic acid” (claims 12 and
`
`
`
`2
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`Fish purportedly describes a microradioimmunoassay
`
`for detecting
`
`antibodies of systemic lupus erythematosus (“SLE”) patients by non-sequence
`
`specific binding of labeled antibody proteins to dsDNA. (Ex. 1006, 534; Nelson
`
`Tr. 80:24-81:4.) Unlike the nucleic acid hybridization detection methods of the
`
`’197 Patent, Fish’s approach for detecting antibodies does not
`
`involve
`
`hybridization of nucleic acids. (Nelson Tr. 51:4-15.) Further, Fish’s experimental
`
`data does not support inferences that Petitioner makes in characterizing the
`
`reference’s disclosure. Rather, as explained below, that data is insufficient for a
`
`person of ordinary skill in the art (“POSITA”) to conclude that single-stranded
`
`nucleic acids were necessarily fixed or immobilized to the plastic supports used in
`
`Fish, let alone in hybridizable form.
`
`As shown below, Fish does not anticipate any of the challenged claims
`
`because it does not disclose (1) nucleic acid strands “fixed or immobilized,” (2) in
`
`“hybridizable form” on a non-porous solid support.
`
`1.
`Fish Does Not Disclose Nucleic Acid Strands Fixed Or
`Immobilized To A Non-Porous Solid Support.
`
`Fish involves a “solid phase microradioimmunoassay … for measurement of
`
`anti-dsDNA (dsDNA) antibodies.” (Ex. 1006, 534.) In the Decision to Institute
`
`
`13), “nucleic acid” (claims 9 and 14), or “DNA or RNA” (claims 8 and 15). DNA
`
`(deoxyribonucleic acid) and RNA (ribonucleic acid) are both nucleic acids.
`
`3
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`(hereinafter referred to as “Decision”), the Board relied on Petitioner’s allegations
`
`that Fish supposedly discloses nucleic acid strands “fixed or immobilized” to a
`
`non-porous solid support through its use of single-stranded DNA (“ssDNA”) (a
`
`mixture of poly-dA and poly-dC or denatured calf thymus DNA) as a control in
`
`one of the experiments described. (Decision, 12.) But Fish does not expressly or
`
`inherently disclose any single-stranded nucleic acid that is “fixed or immobilized”2
`
`to a non-porous solid support.
`
`Fish does not describe any experiments that tested, let alone confirmed,
`
`whether single-stranded nucleic acids actually bound to the disclosed PLL-coated
`
`wells. (Ex. 2042 ¶¶ 67-71, 76-77.) Petitioner’s declarant, Dr. Nelson, testified that
`
`the Fish researchers (1) performed an experiment to show that dsDNA—not
`
`ssDNA—would bind to PLL-coated polyvinyl wells, and (2) although they could
`
`have performed a similar experiment on ssDNA, they did not. (Nelson Tr. 62:13-
`
`17, 62:22-63:19.)
`
`Although no dispute exists that the Fish researchers failed to perform or
`
`disclose any experiments establishing that ssDNA would bind to PLL-coated wells,
`
`
`2 “Fixed or immobilized” means “bound.” (Ex. 1010, 14-15 (construing “fixed or
`
`immobilized” to mean “bound” in the related litigations involving the ’197
`
`Patent).)
`
`4
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`the Board explained that “it appears that they already knew that ssDNA would bind
`
`to PLL coated wells.” (Decision, 13 (citing Ex. 1006, 538, right col. ¶ 1).) The
`
`record now available shows otherwise. A POSITA at the time of the Fish
`
`inventions would not have expected that ssDNA would bind to PLL-coated
`
`polyvinyl plates. (Ex. 2042 ¶ 73.) In fact, even the Fish researchers themselves
`
`did not believe that DNA would bind to polyvinyl plates based on the reports of
`
`other scientists in the field. (Ex. 2042 ¶ 74; Ex. 1006, 535.) Thus, the suggestion
`
`in Fish that ssDNA may bind to PLL-treated plastic—that “[t]his positive control
`
`for the nuclease S1 activity suggests that single-stranded nucleic acid, bound to
`
`PLL treated plastic, remains susceptible to the hydrolic activity of the enzyme”—
`
`was merely an assumption—derived from an experiment designed to show that the
`
`poly(dA-dT) used was in fact double-stranded—made without supporting data of
`
`ssDNA binding to plastic. That unsupported assumption that ssDNA may have
`
`bound to plastic wells is not evidence that ssDNA actually bound and is thus
`
`insufficient to show that the disclosure in Fish anticipates any of the challenged
`
`claims.
`
`Further, contrary to Petitioner’s claims, the results in Fish Figures 1, 3, and 4
`
`simply do not suggest, much less “prov[e],” that ssDNA was or could have bound
`
`to the PLL-coated wells in the experiment. (See Decision, 13; Petition, 23; Ex.
`
`2042 ¶¶ 78-89; Ex. 1006, 539.) As Petitioner’s declarant’s deposition testimony
`
`5
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`confirmed, the Fish assay by its very nature cannot establish whether ssDNA
`
`bound to the plastic wells. (Ex. 2042 ¶¶ 79-84.) Indeed, Dr. Nelson testified that
`
`the Fish authors designed the assay to detect the presence of antibodies that they
`
`presumed to be bound specifically to double-stranded DNA using radioactively
`
`labeled anti-human IGG antibodies which will bind to any antibody present.
`
`(Nelson Tr. 80:15-81:18.) Given that human serum was used in the experiments,
`
`however, no grounds exist to conclude with reasonable certainty that the generic,
`
`radioactively labeled anti-human IGG antibodies used in fact bound to dsDNA
`
`specific IGG rather than to some other IGG present in the human serum. Because
`
`Figures 1, 3, 4 depict the results of experiments that were not designed to
`
`determine whether single-stranded nucleic acids bound to PLL-coated wells, those
`
`results fail to demonstrate, as Petitioner contends, the presence of single-stranded
`
`nucleic acids bound to the wells. (Ex. 2042 ¶¶ 70-71, 82.)
`
`Moreover, the Figure 1 results—the figure which Petitioner claims
`
`purportedly shows single-stranded nucleic acids attached to the wells—cannot
`
`reliably, much less conclusively, show whether single-stranded nucleic acids are
`
`necessarily present in those wells.
`
`First, Dr. Nelson admitted that the Figure 1 results could be the result of
`
`antibody binding that did not involve DNA at all. (Ex. 2042 ¶¶ 83-85; Nelson Tr.
`
`88:23-89:5, 115:11-23.) In fact, he admitted that the Fish results showed multiple
`
`6
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`instances of such non-DNA-specific binding where radioactive signals were
`
`detected in wells that contained no nucleic acids whatsoever:
`
`15 Q So in at least some cases, they got
`16 more radioactivity off the well that admittedly
`17 could not possibly have DNA in it compared to
`18 the well that did have DNA in it; correct?
`19 A Correct.
`
`(Nelson Tr. 106:2-25, 117:15-25, 107:1-9.) This non-DNA-specific binding
`
`resulted from the Fish assay design as explained below.
`
`The Fish assay involved the following primary steps: (1) treat PLL-coated
`
`wells with various nucleic acids; (2) add to the wells human serum supposedly
`
`containing, among other things (including other antibodies), antibodies that would
`
`bind to double-stranded DNA; (3) detect the presence of the bound antibodies
`
`specific for double-stranded DNA using a radioactively-labeled anti-IGG antibody.
`
`(Nelson Tr. 80-83.) Thus, the results depicted in the various figures showed, as Dr.
`
`Nelson confirmed,
`
`radioactive signals
`
`indicating only
`
`the presence of
`
`radioactively-labeled anti-human IGG antibody in the wells. (Nelson Tr. 84:9-15.)
`
`Thus, to conclude that the figure’s radioactive signals actually indicate the
`
`presence of any DNA attached to the wells requires two assumptions: (1) the
`
`radioactively-labeled anti-IGG antibody bound only to dsDNA specific antibody
`
`(as opposed to other antibodies present in human serum) present in the well; and
`
`(2) any dsDNA specific antibody bound only to dsDNA attached to the wells. But,
`
`7
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`as Dr. Nelson’s testimony confirms, no way exists to confirm the truth of those
`
`cascading assumptions. Dr. Nelson explained that the radioactively-labeled anti-
`
`human IGG antibody is not specific to any dsDNA specific antibody present in the
`
`human serum added to the wells. (Nelson Tr. 82:20-83:4 (“it will detect any
`
`human antibody”); 82:20-83:11 (“[i]f there is human antibody in that well, [anti-
`
`human IGG antibody] will detect it”).) Thus, the Fish disclosure does not reliably
`
`indicate, either expressly or inherently, the presence of nucleic acids attached to
`
`the purported solid support.
`
`Second, even assuming that the disclosed radioactive signals actually
`
`indicated the presence of nucleic acids attached to the wells, one could not reliably
`
`or conclusively determine whether those nucleic acids were single-stranded. As
`
`explained above, the Fish researchers designed the assay to use an antibody they
`
`believed would specifically bind to double-stranded DNA. (Nelson Tr. 80:16-20.)
`
`Therefore, any detected signals would indicate the presence of double-stranded
`
`nucleic acids, not single-stranded nucleic acids. Although the experiments used
`
`ssDNA as a control, that ssDNA was intended to confirm that the poly(dA-dT)
`
`used was purely double-stranded, not whether ssDNA bound to the trays. (See Ex.
`
`1006, 538).
`
`8
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`For the foregoing reasons, the fully developed record demonstrates that Fish
`
`does not expressly or inherently disclose single-stranded nucleic acid strands
`
`“fixed or immobilized” to a non-porous solid support.
`
`2.
`Fish Does Not Expressly Or Inherently Disclose Nucleic
`Acid Strands In Hybridizable Form.
`
`Although it admits that “Fish does not expressly disclose that the fixed or
`
`immobilized ssDNA would be ‘in hybridizable form,’” (Petition, 25),3 Petitioner
`
`claims that Fish inherently discloses a nucleic acid strand in “hybridizable form”
`
`because the ssDNA used in one of the experiments in Fish is supposedly
`
`“necessarily capable of binding through Watson-Crick base pairing.” (Id., 25.)
`
`The Board relied on that inherency argument and Dr. Nelson’s supporting opinions
`
`in instituting the Petition, stating that “the bound ssDNA will hybridize when
`
`complementary DNA is present in appropriate hybridization conditions.”
`
`(Decision, 13-14.) However, the record lacks any facts to support that statement,
`
`which—if taken to mean that any ssDNA is necessarily present in hybridizable
`
`form—reads the pertinent claim language out of the claim entirely. Indeed, as
`
`explained below, Fish does not disclose sufficient information about the various
`
`factors and conditions affecting hybridization for a POSITA to determine whether
`
`
`3 Emphasis has been added unless otherwise indicated.
`
`
`
`9
`
`

`
`Case IPR2016-00820
`U.S. Patent No. 7,064,197
`
`
`
`the ssDNA in the Fish experiments would hybridize if complementary DNA were
`
`present.
`
`To the extent any nucleic acid strands actually bound to the wells in Fish, no
`
`disclosure exists to establish that those bound nucleic acids were fixed in
`
`“hybridizable form,” much less sufficient evidence to establish inherency. To
`
`establish anticipation under a theory of inherency, Petitioner must show that Fish
`
`unavoidably teaches nucleic acids fixed or immobilized to a non-porous solid
`
`support in “hybridizable form.” Agilent Techs., Inc. v. Affymetrix, Inc., 567 F.3d
`
`1366, 1383 (Fed. Cir. 2009); see also In re Oelrich, 666 F.2d 578, 581 (CCPA
`
`1981) (“Inherency, however, may not be established by probabilities or
`
`possibilities. The mere fact that a certain thing may result from a given set of
`
`circumstances is not sufficient.”). Petitioner does not—and cannot—identify any
`
`evidence that any bound nucleic acids in Fish would unavoidably hybridize to
`
`other nucleic acids.
`
`First, Fish does not disclose nucleic acid hybridization in any manner. No
`
`dispute exists that nucleic acids (allegedly) bound to the wells did not actually
`
`hybridize in any of Fish’s experiments. (Nelson Tr. 138:7-13, 148:3-6.) The
`
`experiments in Fish are not nucleic a