Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`
`
`BECTON, DICKINSON AND COMPANY,
`Petitioner
`
`
`
`v.
`
`
`
`ENZO LIFE SCIENCES, INC.,
`Patent Owner
`
`__________________
`
`
`
`Case IPR2017-00172
`
`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 PRELIMINARY 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 IPR2017-00172
`U.S. Patent No. 7,064,197
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`TABLE OF CONTENTS
`
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`Page
`
`II. OVERVIEW OF THE ’197 PATENT ............................................................ 2
`
`III. FISH DOES NOT ANTICIPATE ANY CLAIM 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. .......................... 4
`
`Fish Does Not Expressly Or Inherently Disclose Nucleic
`Acid Strands In Hybridizable Form. ........................................... 9
`
`i.
`
`ii.
`
`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, 31-34, 41, 61-63, 68-70, 72-74, 79, 100,
`191-194, 212, 213, 219, 222, 225-227, 230, 233, And 236. ............... 22
`
`IV. FISH, STANDING ALONE, DOES NOT RENDER OBVIOUS ANY
`CLAIM IN GROUND 2. ............................................................................... 23
`
`A.
`
`Claims 31, 68, And 192. ...................................................................... 24
`
`B.
`
`Claims 64, 101, And 195. .................................................................... 27
`
`V.
`
`FISH IN VIEW OF GILHAM DOES NOT RENDER OBVIOUS
`ANY CLAIM IN GROUND 3. ..................................................................... 29
`
`A.
`
`Petitioner Did Not Establish That Fish In View Of Gilham
`Meets All Of The Limitations Of Claims 38, 78, Or 218. .................. 29
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`Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`B.
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`Petitioner Did Not Establish That A POSITA Would Have Had
`A Reason To Combine Fish And Gilham Or That A POSITA
`Would Have Had A Reasonable Expectation Of Success. ................. 29
`
`VI. VPK IS NOT PRIOR ART TO THE CHALLENGED CLAIMS. ............... 33
`
`A.
`
`The Challenged Claims Are Entitled To The Filing Date Of The
`1983 Application. ................................................................................ 34
`
`1.
`
`2.
`
`The 1983 Application’s Examples of Non-Porous Solid
`Supports Provide Sufficient Written Description for the
`Genus of “Non-Porous Solid Supports.” .................................. 35
`
`Factually
`on
`Rely
`Arguments
`Petitioner’s
`Distinguishable Cases, Incorrect Statements of Law, Or
`Both. ........................................................................................ 38
`
`B.
`
`The Invention of the Challenged Claims Was Conceived and
`Reduced to Practice Before VPK’s Effective Date Of October
`1982. ................................................................................................... 40
`
`1.
`
`2.
`
`Legal Standards For Antedating An Alleged 35 U.S.C.
`§ 102(a) Reference In An Inter Partes Review. ....................... 40
`
`Enzo’s Inventors Conceived And Reduced to Practice
`The Challenged Claims’ Subject Matter Before October
`1982. ........................................................................................ 41
`
`VII. VPK DOES NOT ANTICIPATE ANY CLAIM IN GROUND 4. ............... 55
`
`A.
`
`Independent Claims 1, 6, 8, 9, 12-15, And 27. ................................... 55
`
`B.
`
`Claims 31, 32, 34, 61, 62, 63, 68-70, 72, 74, 79, 100, 191-194,
`213, 219, 226, 227, And 236. .............................................................. 58
`
`VIII. VPK IN VIEW OF NOYES AND RAMACHANDRAN DOES NOT
`RENDER OBVIOUS ANY CLAIM IN GROUND 5. ................................. 61
`
`A.
`
`Petitioner Did Not Establish That Noyes, VPK, And
`Ramachandran Meet All Of The Limitations Of Any
`Challenged Claim. ............................................................................... 61
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`Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`B.
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`Petitioner Did Not Establish That A POSITA Would Combine
`VPK, Noyes, And Ramachandran. ...................................................... 63
`
`IX. VPK IN VIEW OF METZGAR DOES NOT RENDER OBVIOUS
`ANY CLAIM IN GROUND 6. ..................................................................... 65
`
`X.
`
`SECONDARY CONSIDERATIONS CONFIRM THE NON-
`OBVIOUSNESS OF THE CHALLENGED CLAIMS. ................................ 67
`
`XI. CONCLUSION .............................................................................................. 68
`
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`Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`TABLE OF AUTHORITIES
`
`Page(s)
`
`Cases
`
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) ............................................................................ 29
`
`Agilent Techs., Inc. v. Affymetrix, Inc.,
`567 F.3d 1366 (Fed. Cir. 2009) ............................................................................ 10
`
`Bilstad v. Wakalopulos,
`386 F.3d 1116 (Fed. Cir. 2004) ............................................................... 35, 38, 39
`
`Borror v. Herz,
`666 F.2d 569 (CCPA 1981) .................................................................................. 41
`
`CFMT, Inc. v. Yieldup Int’l. Corp.,
`349 F.3d 1333 (Fed. Cir. 2003) ............................................................... 23, 29, 66
`
`Corning, Inc. v. DSM IP Assets B.V.,
`Case IPR2013-00053, Paper 66 (PTAB May 1, 2014) ........................................ 41
`
`Haemonetics Corp. v. Baxter Healthcare Corp.,
`607 F.3d 776 (Fed. Cir. 2010) ....................................................................... 13, 59
`
`Hartness Int’l Inc. v. Simplimatic Eng’g Co.,
`819 F. 2d 1100 (Fed. Cir. 1987) .................................................................... 22, 58
`
`Holmwood v. Sugavanam,
`948 F.2d 1236 (Fed. Cir. 1991) ............................................................................ 41
`
`Hologic, Inc. v. Enzo Life Sciences, Inc., Case IPR2016-00820, Paper 8 (PTAB
`Oct. 4, 2016) ................................................................................................. passim
`
`Hybritech Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986) ............................................................................ 40
`
`In re Fine,
`837 F.2d 1071 (Fed. Cir. 1988) ............................................................................ 66
`
`
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`U.S. Patent No. 7,064,197
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`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) ................................................................. 28, 31, 63
`
`In re Nuvasive, Inc., 842 F.3d 1376 (Fed. Cir. 2016) ....................................... 64, 66
`
`In re Oelrich,
`666 F.2d 578 (CCPA 1981) .................................................................................. 10
`
`In re Rasmussen,
`650 F.2d 1212 (CCPA 1981) ................................................................................ 35
`
`In re Ratti,
`270 F.2d 810 (CCPA 1959) ..................................................................... 28, 31, 63
`
`In re Smythe,
`480 F.2d 1376 (CCPA 1973) ......................................................................... 35, 38
`
`Lampi Corp. v. American Power Prods., Inc.,
`228 F.3d 1365 (Fed. Cir. 2000) ..................................................................... 34, 40
`
`LizardTech v. Earth Resource Mapping, Inc.,
`424 F.3d 1336 (Fed. Cir. 2005) ..................................................................... 38, 39
`
`Lockwood v. Am. Airlines, Inc.,
`107 F.3d 1565 (Fed. Cir. 1997) ............................................................................ 34
`
`Mahurkar v. C.R. Bard, Inc.,
`79 F.3d 1572 (Fed. Cir. 1998) .............................................................................. 40
`
`Martek Biosciences Corp. v. Nutrinova, Inc.,
`579 F.3d 1363 (Fed. Cir. 2009) ..................................................................... 34, 38
`
`Par Pharm., Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ............................................................... 23, 29, 66
`
`Price v. Symsek,
`988 F.2d 1187 (Fed. Cir. 1991) ............................................................................ 41
`
`Princeton Biochemicals, Inc. v. Beckman Coulter, Inc.,
`411 F.3d 1332 (Fed. Cir. 2005) ............................................................................ 33
`
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`U.S. Patent No. 7,064,197
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`Purdue Pharma L.P. v. Faulding Inc.,
`230 F.3d 1320 (Fed. Cir. 2000) ............................................................................ 39
`
`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) ...................................... 41
`
`Tech. Licensing Corp. v. Videotek, Inc.,
`545 F.3d 1316 (Fed. Cir. 2008) ............................................................................ 39
`
`TriVascular, Inc. v. Samuels,
`812 F.3d 1056 (Fed. Cir. 2016) ............................................................................ 63
`
`Tronzo v. Biomet,
`156 F.3d 1154 (Fed. Cir. 1998) ............................................................................ 39
`
`Verdegaal Bros. v. Union Oil Co. of California,
`814 F.2d 628 (Fed. Cir. 1987) ................................................................... 2, 55, 58
`
`Statutes
`
`35 U.S.C. § 102(a) ................................................................................................... 40
`
`35 U.S.C. § 102(b) ................................................................................................... 33
`
`Regulations
`
`37 C.F.R. § 1.131 ..................................................................................................... 41
`
`37 C.F.R. § 42.104(b)(4) ............................................................................. 23, 29, 66
`
`Rules
`
`Fed. R. Evid. 803(16) ............................................................................................... 42
`
`Fed. R. Evid. 803(6) ................................................................................................. 42
`
`Fed. R. Evid. 807 ..................................................................................................... 37
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`Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`All citations to 35 U.S.C. § 102 in this paper refer to the pre-AIA statute.
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`All emphases are added unless otherwise noted.
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`Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`PATENT OWNER’S EXHIBIT LIST
`
`DESCRIPTION
`
`Declaration of Gregory Buck, Ph.D in Case IPR2016-00820 (July 7,
`2016).
`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).
`[Reserved]
`[Reserved]
`[Reserved]
`[Reserved]
`[Reserved]
`[Reserved]
`Herzer, Sibylle and Englert, David, “Nucleic Acid Hybridization,”
`Ch. 14 from Molecular Biology Problem Solver: A Laboratory Guide
`(Gerstein, Alan ed.) (2001).
`Spiegelman, George et al., “Kinetics of Ribonucleic Acid-
`Deoxyribonucleic Acid Membrane Filter Hybridization,”
`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., Case IPR2016-00820 and 2016-
`00822 on Dec. 21, 2016.
`2018 Meinkoth, Judy and Wahl, Geoffrey, “Review: Hybridization of
`
`Enzo
`Exhibit
`No.
`2001
`
`2002
`
`2003
`2004
`
`2005
`2006
`2007
`2008
`2009
`2010
`2011
`
`2012
`
`2013
`
`2014
`
`2015
`
`2016
`
`2017
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`
`
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`Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`Enzo
`Exhibit
`No.
`
`
`
`DESCRIPTION
`
`2019
`
`2020
`
`2021
`
`2022
`
`2023
`
`2024
`2025
`
`Nucleic Acids Immobilized on Solid Supports,” Analytical
`Biochemistry, 138, 267-284 (1984).
`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.
`Excerpt from File History for U.S. Patent No. 7,064,197 – Nov. 26,
`2004 Office Action.
`U.S. Patent No. 4,732,847 to Stuart et al., issued Mar. 22, 1988.
`Sigma-Aldrich Particle Size Conversion Table, obtained from:
`http://www.sigmaaldrich.com/chemistry/stockroom-reagents/learning-
`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).
`Enzo Biochem, Inc. SEC Form 8-K dated July 20, 2015.
`Enzo Biochem, Inc. SEC Form 8-K dated Oct. 9, 2015.
`Enzo Biochem, Inc. SEC Form 8-K dated Jan. 6, 2016.
`Enzo Biochem, Inc. SEC Form 8-K dated July 1, 2016.
`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).
`
`2027
`2028
`2029
`2030
`2031
`
`2032
`
`2033
`
`2034
`
`
`
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`Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`Enzo
`Exhibit
`No.
`2035
`
`
`
`DESCRIPTION
`
`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).
`Enzo Laboratory Notebook, Dollie M.W. Kirtikar, entitled “T4
`Expts,” (1982).
`Enzo Laboratory Notebook (Number 126), Barbara Thalenfeld, (July-
`August 1982).
`Enzo Laboratory Notebook (Number 127), Barbara Thalenfeld, (July-
`September 1982).
`Enzo Experiment Record, Barbara Thalenfeld and Kenneth Johnston,
`(June 1982).
`Enzo Laboratory Notebook Pages, Barbara Thalenfeld, (May-August
`1982).
`Declaration of Gregory Buck, Ph.D in Case IPR2016-00820 (January
`11, 2017).
`Declaration of Barry Weiner in Case IPR2016-00820.
`
`2037
`
`2038
`
`2039
`
`2040
`
`2041
`
`2042
`
`2043
`
`
`
`
`
`x
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`Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`I.
`
`INTRODUCTION
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`
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`The Board should deny institution on the Petition filed by Becton, Dickinson
`
`and Company (“Petitioner” or “BD”) against 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,
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`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 do not establish a reason to combine or modify references as
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`Petitioner proposes. The declaration testimony of Gregory Buck, Ph.D.,1 a
`
`professor and research scientist with more than thirty-five years of experience in
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`molecular biology and nucleic acid detection (Ex. 2042 ¶¶ 7-24), and the
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`deposition testimony of Petitioner’s declarant, Dr. Norman Nelson, in Case
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`IPR2016-00820—which involves the same patent and the same claims—confirm
`
`that Petitioner did not establish a reasonable likelihood of prevailing against any
`
`claim in this proceeding. The Board should deny institution.
`
`
`1 With this paper, Enzo submits the same exhibits Dr. Buck and Mr. Weiner cited
`
`in their declarations in Case IPR2016-00820 (Exhibits 2001, 2042, and 2043), with
`
`the same exhibit numbers as the exhibits in Case IPR2016-00820.
`
`1
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`Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`II. OVERVIEW OF THE ’197 PATENT
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`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.)
`
`III. FISH DOES NOT ANTICIPATE ANY CLAIM 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
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`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”)
`
`2
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`Case IPR2017-00172
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`U.S. Patent No. 7,064,197
`require that a nucleic acid strand2 be “fixed or immobilized” to a “non-porous solid
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`support” in “hybridizable form.”
`
`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; Ex. 2017,
`
`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. (Ex. 2017, 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.
`
`
`2 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
`
`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
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`Case IPR2017-00172
`U.S. Patent No. 7,064,197
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`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.) Contrary to 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, Fish does not expressly or
`
`inherently disclose any single-stranded nucleic acid that is “fixed or immobilized”3
`
`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.) At his deposition in the related matter Case
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`IPR2016-00820, Petitioner’s declarant, Dr. Nelson, testified that the Fish
`
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`3 “Fixed or immobilized” means “bound.” (Ex. 1010, 14-15 (construing “fixed or
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`immobilized” to mean “bound” in the related litigations involving the ’197
`
`Patent).)
`
`4
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`U.S. Patent No. 7,064,197
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`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. (Ex. 2017, 62:13-17,
`
`62:22-63:19.)
`
`No dispute exists that the Fish researchers failed to perform or disclose any
`
`experiments establishing that ssDNA would bind to PLL-coated wells. Moreover,
`
`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.)
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`Thus, the suggestion in Fish that ssDNA may bind to PLL-treated plastic—that
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`“[t]his positive control for the nuclease S1 activity suggests that single-stranded
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`nucleic acid, bound to PLL treated plastic, remains susceptible to the hydrolic
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`activity of the enzyme”—was merely an assumption—derived from an experiment
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`designed to show that the poly(dA-dT) used was in fact double-stranded—made
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`without supporting data of ssDNA binding to plastic. That unsupported
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`assumption that ssDNA may have bound to plastic wells is not evidence that
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`ssDNA actually bound and is thus insufficient to show that the disclosure in Fish
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`anticipates any of the challenged claims.
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`Further, contrary to Petitioner’s claims, the results in Fish Figures 1, 3, and 4
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`simply do not suggest, much less “prov[e],” that ssDNA was or could have bound
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`to the PLL-coated wells in the experiment. (See Petition, 23; Ex. 2042 ¶¶ 78-89;
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`Ex. 1006, 539.) As Petitioner’s declarant’s deposition testimony confirmed, the
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`Fish assay by its very nature cannot establish whether ssDNA bound to the plastic
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`wells. (Ex. 2042 ¶¶ 79-84.) Indeed, Dr. Nelson testified that the Fish authors
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`designed the assay to detect the presence of antibodies that they presumed to be
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`bound specifically to double-stranded DNA using radioactively labeled anti-
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`human IGG antibodies which will bind to any antibody present. (Ex. 2017, 80:15-
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`81:18.) Given that human serum was used in the experiments, however, no
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`grounds exist to conclude with reasonable certainty that the generic, radioactively
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`labeled anti-human IGG antibodies used in fact bound to dsDNA specific IGG
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`rather than to some other IGG present in the human serum. Because Figures 1, 3,
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`and 4 depict the results of experiments that were not designed to determine
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`whether single-stranded nucleic acids bound to PLL-coated wells, those results fail
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`to demonstrate the presence of single-stranded nucleic acids bound to the wells.
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`(Ex. 2042 ¶¶ 70-71, 82.)
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`Moreover, the Figure 1 results—the figure which Petitioner claims
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`purportedly shows single-stranded nucleic acids attached to the wells—cannot
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`reliably, much less conclusively, show whether single-stranded nucleic acids are
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`necessarily present in those wells.
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`First, Dr. Nelson admitted that the Figure 1 results could be the result of
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`antibody binding that did not involve DNA at all. (Ex. 2042 ¶¶ 83-85; Ex. 2017,
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`88:23-89:5, 115:11-23.) In fact, he admitted that the Fish results showed multiple
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`instances of such non-DNA-specific binding where radioactive signals were
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`detected in wells that contained no nucleic acids whatsoever:
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`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.
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`(Ex. 2017, 106:2-25, 117:15-25, 107:1-9.) This non-DNA-specific binding
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`resulted from the Fish assay design as explained below.
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`The Fish assay involved the following primary steps: (1) treat PLL-coated
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`wells with various nucleic acids; (2) add to the wells human serum supposedly
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`containing, among other things (including other antibodies), certain antibodies that
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`would bind to double-stranded DNA; (3) detect the presence of the bound
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`antibodies specific for double-stranded DNA using a radioactively-labeled anti-
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`IGG antibody. (Ex. 2017, 80-83.) Thus, the results depicted in the various figures
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`showed, as Dr. Nelson confirmed, radioactive signals indicating only the presence
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`of radioactively-labeled anti-human IGG antibody in the wells. (Ex. 2017, 84:9-
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`15.) Thus, to conclude that the figure’s radioactive signals actually indicate the
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`presence of any DNA attached to the wells requires two assumptions: (1) the
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`radioactively-labeled anti-IGG antibody bound only to dsDNA specific antibody
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`(as opposed to other antibodies present in human serum) present in the well; and
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`(2) any dsDNA specific antibody bound only to dsDNA attached to the wells. But,
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`as Dr. Nelson’s testimony confirms, no way exists to confirm the truth of those
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`cascading assumptions. Dr. Nelson explained that the radioactively-labeled anti-
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`human IGG antibody is not specific to any dsDNA specific antibody present in the
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`human serum added to the wells. (Ex. 2017, 82:20-83:4 (“it will detect any human
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`antibody”); 82:20-83:11 (“[i]f there is human antibody in that well, [anti-human
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`IGG antibody] will detect it”).) Thus, the Fish disclosure does not reliably
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`indicate, either expressly or inherently, the presence of nucleic acids attached to
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`the purported solid support.
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`Second, even assuming that the disclosed radioactive signals actually
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`indicated the presence of nucleic acids attached to the wells, one could not reliably
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`or conclusively determine whether those nucleic acids were single-stranded. As
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`explained above, the Fish researchers designed the assay to use an antibody they
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`believed would specifically bind to double-stranded DNA. (Ex. 2017, 80:16-20.)
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`Therefore, any detected signals would indicate the presence of double-stranded
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`nucleic acids, not single-stranded nucleic acids. Although the experiments used
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`ssDNA as a control, that ssDNA was intended to confirm that the poly(dA-dT)
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`used was purely double-stranded, not whether ssDNA bound to the trays. (See Ex.
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`1006, 538). Thus, Fish does not expressly or inherently disclose single-stranded
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`nucleic acid strands “fixed or immobilized” to a non-porous solid support.
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`2.
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`Fish Does Not Expressly Or Inherently Disclose Nucleic
`Acid Strands In Hybridizable Form.
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`Although it admits that “Fish does not expressly disclose that the fixed or
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`immobilized ssDNA would be ‘in hybridizable form,’” (Petition, 25), Petitioner
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`claims that Fish inherently discloses a nucleic acid strand in “hybridizable form”
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`because the ssDNA used in one of the experiments in Fish is supposedly
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`“necessarily capable of binding through Watson-Crick base pairing.” (Id., 25.) In
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`Case IPR2016-00820, the Board relied on that inherency argument and Dr.
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`Nelson’s supporting opinions, stating that “the bound ssDNA will hybridize when
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`complementary DNA is present in appropriate hybridization conditions.”
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`Hologic, Inc. v. Enzo Life Sciences, Inc., Case IPR2016-00820, Paper 8, at 13-14
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`(PTAB Oct. 4, 2016). However, the records in both that proceeding and this
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`proceeding lack any facts to support that statement, which—if taken to mean that
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`any ssDNA is necessarily present in hybridizable form—reads the pertinent claim
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`language out of the claims entirely. Indeed, as explained below, Fish does not
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`disclose sufficient information about the various factors and conditions affecting
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`hybridization for a POSITA to determine whether the ssDNA in the Fish
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`experiments would hybridize if complementary DNA were present.
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`To the extent any nucleic acid strands actually bound to the wells in Fish, no
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`disclosure exists to establish that those bound nucleic acids were fixed in
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`“hybridizable form,” much less sufficient evidence to establish inherency. To
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`establish anticipation under a theory of inherency, Petitioner must show that Fish
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`unavoidably teaches nucleic acids fixed or immobilized to a non-porous solid
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`support in “hybridizable form.” Agilent Techs., Inc. v. Affymetrix, Inc., 567 F.3d
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`1366, 1383 (Fed. Cir. 2009); In re Oelrich, 666 F.2d 578, 581 (CCPA 1981)
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`(“Inherency, however, may not be established by probabilities or possibilities. The
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`mere fact that a certain thing may result from a given set of circumstances is not
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`sufficient.”). Petitioner does not—and cannot—identify any evidence that any
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`bound nucleic acids in Fish would unavoidably hybridize to other nucleic acids.
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`First, Fish does not disclose nucleic acid hybridization in any manner. No
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`dispute exists that nucleic acids (allegedly) bound to the wells did not actually
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`hybridize in any of Fish’s experiments. (Ex. 2017, 138:7-13, 148:3-6.) The
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`experiments in Fish are not nucleic acid hybridization assays, nor were they
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`designed to result in hybridization of nucleic acid. (Ex. 2017, 51:4-15.) Fish does
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`not describe the nucleic acids used in the experimental assays as being fixed in
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`hybridizable form. (Ex. 2017, 137:17-138:6.) Nor does Fish suggest that those
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`nucleic acids can or will hybridize. (Ex. 2042 ¶ 99; Ex. 2017, 137:17-138:13.)
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`Second, Fish fails to disclose sufficient information regarding the various
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`factors and conditions that affect hybridization to allow a POSITA to determine
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`whether any bound ssDNA would be capable of hybridizing with other nucleic
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`acids. Dr. Nelson admitted that “many factors can impact whether, under a given
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`set of circumstances or a given set of conditions, a nucleic acid in a sample will or
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`will not hybridize with a complementary nucleic acid sequence that’s also present
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`in the sample.” (Ex. 2017, 143:5-12.) Those factors include, among others, the
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`type and length of nucleic acids, the nature of the solid su