Case IPR2017-00181
`U.S. Patent No. 7,064,197
`
`
`
`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 IPR2017-00181
`
`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 IPR2017-00181
`U.S. Patent No. 7,064,197
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`
`
`TABLE OF CONTENTS
`
`
`I.
`
`INTRODUCTION ........................................................................................... 1
`
`Page
`
`II.
`
`’197 PATENT OVERVIEW ........................................................................... 2
`
`III. FISH DOES NOT ANTICIPATE ANY CLAIM IN GROUND 1. ................ 2
`
`A.
`
`Independent Claims 17, 19, And 25. ..................................................... 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. ........................................... 8
`
`i.
`
`ii.
`
`Petitioner’s Reliance on Diehl Does Not Establish That
`Fish Inherently Discloses ssDNA In Hybridizable Form. ..
`
` .............................................................................. 13
`
`The ‘197 Patent Prosecution History Does Not Support
`Petitioner’s Inherency Theory. ....................................... 18
`
`3.
`
`Fish Does Not Disclose An “Array.” ........................................ 19
`
`B. Dependent Claims 105, 106, 114, 116, 119, 128, 129, 131, 150,
`152, 178, 180, 186, And 187. .............................................................. 20
`
`IV. FISH, STANDING ALONE, DOES NOT RENDER OBVIOUS ANY
`CLAIM IN GROUND 2. ............................................................................... 21
`
`A.
`
`Claim 131. ........................................................................................... 22
`
`B.
`
`Claims 130 and 154. ............................................................................ 25
`
`V.
`
`FISH IN VIEW OF METZGAR AND SATO DOES NOT RENDER
`OBVIOUS ANY CLAIM IN GROUND 3. .................................................. 27
`
`A.
`
`Petitioner Did Not Establish That Fish In View Of Metzgar
`And Sato Meets All the Limitations Of Claims 120 Or 189. .............. 27
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`Case IPR2017-00181
`U.S. Patent No. 7,064,197
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`B.
`
`Petitioner Did Not Establish That A POSITA Would Have
`Combined Fish, Metzgar, And Sato Or That A POSITA Would
`Have Had A Reasonable Expectation Of Success. ............................. 28
`
`VI. FISH IN VIEW OF GILHAM DOES NOT RENDER OBVIOUS
`ANY CLAIM IN GROUND 4. ..................................................................... 32
`
`A.
`
`B.
`
`Petitioner Did Not Establish That Fish In View Of Gilham
`Meets All the Limitations Of Claims 113 Or 185. .............................. 32
`
`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. ....................................... 32
`
`VII. VPK IS NOT PRIOR ART TO THE CHALLENGED CLAIMS. ............... 36
`
`A.
`
`The Challenged Claims Are Entitled To The Filing Date Of The
`1983 Application. ................................................................................ 37
`
`1.
`
`2.
`
`The 1983 Application’s Examples Of Non-Porous Solid
`Supports Provide Sufficient Written Description For The
`Genus Of “Non-Porous Solid Supports.” ................................. 37
`
`Factually
`On
`Rely
`Arguments
`Petitioner’s
`Distinguishable Cases, Incorrect Statements Of Law, Or
`Both. ........................................................................................ 41
`
`B.
`
`The Invention of the Challenged Claims Was Conceived and
`Reduced to Practice Before VPK’s Effective Date Of October
`1982. ................................................................................................... 43
`
`1.
`
`2.
`
`Legal Standards For Antedating An Alleged 35 U.S.C.
`§ 102(a) Reference In An Inter Partes Review. ....................... 43
`
`Enzo’s Inventors Conceived And Reduced to Practice
`The Challenged Claims’ Subject Matter Before October
`1982. ........................................................................................ 44
`
`VIII. VPK IN VIEW OF METZGAR DOES NOT RENDER OBVIOUS
`ANY CLAIM IN GROUND 5. ..................................................................... 59
`
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`Case IPR2017-00181
`U.S. Patent No. 7,064,197
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`A. VPK In View Of Metzgar Does Not Teach, Suggest, Or
`Disclose Every Limitation Of Any Challenged Claim. ...................... 59
`
`1.
`
`2.
`
`Independent Claims 17, 19, And 25. ........................................ 59
`
`Dependent Claims 105, 106, 114, 119, 120, 128, 129,
`131, 150, 151, 152, 178, 180, 186, And 189............................. 60
`
`B.
`
`Petitioner Did Not Establish A Reason To Combine VPK And
`Metzgar. ............................................................................................... 63
`
`IX. VPK IN VIEW OF NOYES, METZGAR, AND RAMACHANDRAN
`DOES NOT RENDER OBVIOUS ANY CLAIM IN GROUND 6. ............. 64
`
`A.
`
`Petitioner Did Not Establish That The Combination Of Noyes,
`VPK, Metzgar, And Ramachandran Meets All Limitations Of
`The Challenged Claims. ...................................................................... 64
`
`B.
`
`Petitioner Did Not Establish A Reason To Combine VPK,
`Metzgar, Noyes, And Ramachandran. ................................................ 66
`
`X.
`
`SECONDARY CONSIDERATIONS CONFIRM THE NON-
`OBVIOUSNESS OF THE CHALLENGED CLAIMS. ................................ 68
`
`XI. CONCLUSION .............................................................................................. 69
`
`
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`iii
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`Case IPR2017-00181
`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) ............................................................................ 28
`
`Agilent Techs., Inc. v. Affymetrix, Inc.,
`567 F.3d 1366 (Fed. Cir. 2009) .............................................................................. 9
`
`Bilstad v. Wakalopulos,
`386 F.3d 1116 (Fed. Cir. 2004) ..................................................................... 38, 41
`
`Borror v. Herz,
`666 F.2d 569 (CCPA 1981) .................................................................................. 44
`
`CFMT, Inc. v. Yieldup Int’l. Corp.,
`349 F.3d 1333 (Fed. Cir. 2003) ............................................................................ 22
`
`Corning, Inc. v. DSM IP Assets B.V.,
`Case IPR2013-00053, Paper 66 (PTAB May 1, 2014) ........................................ 44
`
`Haemonetics Corp. v. Baxter Healthcare Corp.,
`607 F.3d 776 (Fed. Cir. 2010) ....................................................................... 12, 61
`
`Hartness Int’l Inc. v. Simplimatic Eng’g Co.,
`819 F. 2d 1100 (Fed. Cir. 1987) ........................................................................... 20
`
`Holmwood v. Sugavanam,
`948 F.2d 1236 (Fed. Cir. 1991) ............................................................................ 43
`
`Hologic, Inc. v. Enzo Life Sciences, Inc., Case IPR2016-00822, Paper 8 (PTAB
`Oct. 4, 2016) ................................................................................................. passim
`
`Hybritech Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986) ............................................................................ 43
`
`In re Fine,
`837 F.2d 1071 (Fed. Cir. 1988) ..................................................................... 27, 60
`
`
`
`iv
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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) ....................................................................... 26, 34
`
`In re Nuvasive, 842 F.3d 1376 (Fed. Cir. 2016) ............................................... 32, 67
`
`In re Oelrich,
`666 F.2d 578 (CCPA 1981) .................................................................................... 9
`
`In re Rasmussen,
`650 F.2d 1212 (CCPA 1981) ................................................................................ 38
`
`In re Ratti,
`270 F.2d 810 (CCPA 1959) .................................................................................. 27
`
`In re Smythe,
`480 F.2d 1376 (CCPA 1973) ......................................................................... 38, 41
`
`Lampi Corp. v. American Power Prods., Inc.,
`228 F.3d 1365 (Fed. Cir. 2000) ..................................................................... 37, 42
`
`LizardTech v. Earth Resource Mapping, Inc.,
`424 F.3d 1336 (Fed. Cir. 2005) ............................................................................ 41
`
`Lockwood v. Am. Airlines, Inc.,
`107 F.3d 1565 (Fed. Cir. 1997) ............................................................................ 37
`
`Mahurkar v. C.R. Bard, Inc.,
`79 F.3d 1572 (Fed. Cir. 1998) .............................................................................. 43
`
`Martek Biosciences Corp. v. Nutrinova, Inc.,
`579 F.3d 1363 (Fed. Cir. 2009) ..................................................................... 37, 41
`
`Par Pharm., Inc. v. TWI Pharms., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014) ......................................................... 22, 27, 32, 60
`
`Price v. Symsek,
`988 F.2d 1187 (Fed. Cir. 1991) ............................................................................ 43
`
`Princeton Biochemicals, Inc. v. Beckman Coulter, Inc.,
`411 F.3d 1332 (Fed. Cir. 2005) ............................................................................ 36
`
`
`
`v
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`Case IPR2017-00181
`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) ..................................................................... 41, 42
`
`Ralston Purina Co. v. Far-Mar-Co, Inc.,
`777 F.2d 1570 (Fed. Cir. 1985) ............................................................................ 37
`
`Sequenom, Inc. v. Bd. Trs. of Leland Stanford Jr. Univ.,
`Case IPR2013-00390, Paper 45 (PTAB Nov. 25, 2014) ...................................... 44
`
`TriVascular, Inc. v. Samuels,
`812 F.3d 1056 (Fed. Cir. 2016) ............................................................................ 66
`
`Verdegaal Bros. v. Union Oil Co. of California,
`814 F.2d 628 (Fed. Cir. 1987) ................................................................................ 2
`
`Statutes
`
`35 U.S.C. § 102(a) ................................................................................................... 43
`
`35 U.S.C. § 102(b) ................................................................................................... 36
`
`Regulations
`
`37 C.F.R. § 1.131 ..................................................................................................... 44
`
`37 C.F.R. § 42.104(b)(4) ....................................................................... 22, 27, 32, 60
`
`Rules
`
`Fed. R. Evid. 803(16) ............................................................................................... 45
`
`Fed. R. Evid. 803(6) ................................................................................................. 45
`
`Fed. R. Evid. 807 ..................................................................................................... 40
`
`
`
`All citations to 35 U.S.C. § 102 in this paper refer to the pre-AIA statute.
`
`All emphases are added unless otherwise noted.
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`vi
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`Case IPR2017-00181
`U.S. Patent No. 7,064,197
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`
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`Enzo
`Exhibit No.
`2101
`
`2102
`
`2103
`2104
`
`2105
`2106
`2107
`2108
`2109
`2110
`2111
`
`2112
`
`2113
`
`2114
`
`2115
`
`2116
`
`2117
`
`2118
`
`PATENT OWNER’S EXHIBIT LIST
`
`DESCRIPTION
`
`Declaration of Gregory Buck, Ph.D. in Case IPR2016-00822 (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., IPR Case Nos. 2016-00820 and
`2016-00822 on Dec. 21, 2016.
`Meinkoth, Judy and Wahl, Geoffrey, “Review: Hybridization of
`Nucleic Acids Immobilized on Solid Supports,” Analytical
`
`
`
`vii
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`Case IPR2017-00181
`U.S. Patent No. 7,064,197
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`Enzo
`Exhibit No.
`
`
`
`DESCRIPTION
`
`2119
`
`2120
`
`2121
`
`2122
`
`2123
`
`2124
`2125
`
`2126
`
`2127
`2128
`2129
`2130
`2131
`
`2132
`
`2133
`
`2134
`
`2135
`
`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/cel
`ls/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.
`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 Seimens
`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).
`Enzo “Invention Record and Report,” Barbara Thalenfeld and
`
`
`
`viii
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`

`Case IPR2017-00181
`U.S. Patent No. 7,064,197
`
`Enzo
`Exhibit No.
`
`
`
`DESCRIPTION
`
`2136
`
`2137
`
`2138
`
`2139
`
`2140
`
`2141
`
`2142
`
`2143
`
`Kenneth Johnston (May 1982).
`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 IPR2016-00822
`(January 11, 2017).
`Declaration of Barry Weiner in Case IPR2016-00822.
`
`
`
`
`
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`

`Case IPR2017-00181
`U.S. Patent No. 7,064,197
`
`I.
`
`INTRODUCTION
`
`
`
`The Board should deny institution on the Petition filed by Becton, Dickinson
`
`and Company (“Petitioner” or “BD”) against claims 17, 19, 25, 105, 106, 113, 114,
`
`116, 119, 120, 128, 129-131, 150-152, 154, 178, 180, 185-187, and 189
`
`(collectively, “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
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`also do not establish a reason to combine or modify references as 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 molecular
`
`biology and nucleic acid detection (Ex. 2142 ¶¶ 7-24), and the deposition
`
`testimony of Petitioner’s declarant, Dr. Norman Nelson, in Case IPR2016-00822—
`
`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 IPR2016-00822 (Exhibits 2101, 2142, and 2143), with
`
`the same exhibit numbers as the exhibits in Case IPR2016-00822.
`
`1
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`Case IPR2017-00181
`U.S. Patent No. 7,064,197
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`II.
`
`’197 PATENT OVERVIEW
`
`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.) Several claimed inventions of the ’197 Patent involve detection of
`
`nucleic acids through the hybridization of nucleic acid strands fixed to non-porous
`
`solid supports to other nucleic acid sequences with non-radioactive signaling
`
`moieties affixed to the resulting double-stranded nucleic acids. (Ex. 1001, 6:15-48,
`
`7:35-49.) As Dr. Buck explains, traditionally, solid support hybridization assays
`
`used porous supports, such as filters and membranes; POSITAs in the early 1980s
`
`did not believe that non-porous supports could be used for nucleic acid
`
`hybridization. (Ex. 2142 ¶¶ 50-58.)
`
`
`
`III. FISH DOES NOT ANTICIPATE ANY CLAIM IN GROUND 1.
`
`Fish cannot anticipate any of the claims challenged in Ground 1 because it
`
`does not disclose all of the limitations of any challenged claim. Verdegaal Bros. v.
`
`Union Oil Co. of California, 814 F.2d 628, 631 (Fed. Cir. 1987).
`
`A.
`
`Independent Claims 17, 19, And 25.
`
`Claims 17, 19, and 25, the challenged independent claims of the ’197 Patent,
`
`are directed to arrays of nucleic acid strands that are fixed to non-porous solid
`
`2
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`U.S. Patent No. 7,064,197
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`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 Paper 1 (the “Petition”), 13 (citing Ex. 1010, 10).) In
`
`particular, among other limitations, each of claims 17, 19, and 25 (“the challenged
`
`independent claims”) require that “an array” of “single-stranded nucleic acids” be
`
`“fixed or immobilized” to a “non-porous solid 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. 2117,
`
`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. 2117, 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,” (3) in an “array” on a non-porous solid support.
`
`3
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`Case IPR2017-00181
`U.S. Patent No. 7,064,197
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`
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`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. (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. 2142 ¶¶ 68-91.) At his deposition in the related matter Case IPR2016-
`
`00822, 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. (Ex. 2117, 62:13-17, 63:1-19.)
`
`
`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
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`Case IPR2017-00181
`U.S. Patent No. 7,064,197
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`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. 2142 ¶ 73.) In fact, even the Fish
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`researchers themselves did not believe that DNA would bind to polyvinyl plates.
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`(Ex. 2142 ¶ 74; Ex. 1006, 535.) Thus, the suggestion in Fish that ssDNA may bind
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`to PLL-treated plastic—that “[t]his positive control for the nuclease S1 activity
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`suggests that single-stranded nucleic acid, bound to PLL treated plastic, remains
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`susceptible to the hydrolic activity of the enzyme”—was merely an assumption
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`derived from an experiment designed to show that the poly(dA-dT) used was in
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`fact double-stranded, made without supporting data of ssDNA binding to plastic.
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`That unsupported assumption that ssDNA may have bound to plastic wells is not
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`evidence that ssDNA actually bound and is thus insufficient to show that the
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`disclosure in Fish anticipates any of the challenged claims. (Ex. 1006, 535.)
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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. 2142 ¶¶ 78-91;
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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. 2142 ¶¶ 82-86.) 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. 2117, 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. 2142 ¶¶ 82-86.)
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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. 2142 ¶¶ 83-85; Ex. 2117,
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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. (Ex. 2117, 106:2-
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`25, 117:15-25, 107:1-9.)
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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. 2117, 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. 2117, 84:9-
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`15.) To conclude that the figures’ radioactive signals actually indicate the presence
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`of any DNA attached to the wells requires two assumptions: (1) the radioactively-
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`labeled anti-IGG antibody bound only to dsDNA specific antibody (as opposed to
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`other antibodies present in human serum) present in the well; and (2) any dsDNA
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`specific antibody bound only to dsDNA attached to the wells. But no way exists to
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`confirm the truth of those cascading assumptions because the radioactively-labeled
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`anti-human IGG antibody is not specific to any dsDNA specific antibody present
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`in the human serum added to the wells. (Ex. 2117, 82:20-83:4, 82:20-83:11.)
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`Thus, the Fish disclosure does not reliably indicate, either expressly or inherently,
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`the presence of nucleic acids attached to 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 acid 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. 2117, 80:17-20.)
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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, 22), 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., 22.) In
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`Case IPR2016-00822, the Board relied on that inherency argument and Dr.
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`Nelson’s supporting opinions in instituting the Petition, stating that “the bound
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`ssDNA will hybridize when complementary DNA is present in appropriate
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`hybridization conditions.” Hologic, Inc. v. Enzo Life Sciences, Inc., Case
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`IPR2016-00822, Paper 8, at 13-14 (PTAB Oct. 4, 2016). However, the records in
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`both that proceeding and this proceeding lack any facts to support that statement,
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`which—if taken to mean that any ssDNA is necessarily present in hybridizable
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`form—reads the pertinent claim language out of the claims entirely. Indeed, as
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`explained below, Fish does not disclose sufficient information about the various
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`factors and conditions affecting hybridization for a POSITA to determine whether
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`the ssDNA in the Fish experiments would hybridize if complementary DNA were
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`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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`Petitioner does not—and cannot—identify any evidence that any bound nucleic
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`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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`hybridized in any of Fish’s experiments. (Ex. 2117, 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. 2117, 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. 2117, 137:17-138:6.) Nor does Fish suggest that those
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`nucleic acids can or will hybridize. (Ex. 2142 ¶ 99; Ex. 2117, 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. 2117, 143:5-12.) Those factors include, among others, the
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`type and length of nucleic acids, the nature of the solid support, the attachment
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`methodology and chemistry, and the hybridization conditions, such as temperature,
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`salt, and pH. (Ex. 2142 ¶¶ 94-98; Ex. 2117, 143:5-12, 151:25-152:7, 149:10-18,
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`145:10-17, 155:5-15; 142:16-25.) For example, a single-stranded nucleic acid may
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`be bound to a support in a way that renders it in