Case IPR2016-00822
`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 IPR2016-00822
`
`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
`
`
`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 IPR2016-00822
`
`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 IPR2016-00822
`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 OF CLAIMS 17, 19, 25, 105,
`106, 114, 116, 119, 128, 129, 150, 152, 178, 180, 186, OR 187. ................... 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. .......................... 3
`
`Fish Does Not Expressly Or Inherently Disclose Nucleic
`Acid Strands In Hybridizable Form. ........................................... 8
`
`i.
`
`ii.
`
`The Hybridization Described In Diehl Is Wholly
`Inapplicable To Fish. ...................................................... 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, 150, 152,
`178, 180, 186, And 187 ....................................................................... 20
`
`IV. FISH, STANDING ALONE, DOES NOT RENDER OBVIOUS ANY
`OF CLAIMS 130, 131, 151, OR 154. ........................................................... 21
`
`A.
`
`Claim 131 ............................................................................................ 21
`
`B.
`
`Claims 130 and 154 ............................................................................. 25
`
`V.
`
`FISH IN VIEW OF METZGAR AND SATO DOES NOT RENDER
`OBVIOUS CLAIM 120 OR CLAIM 189. .................................................... 26
`
`A.
`
`Petitioner Did Not Establish That Fish In View Of Metzgar
`And Sato Meets All Of The Limitations Of Claims 120 Or 189. ....... 26
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`Case IPR2016-00822
`U.S. Patent No. 7,064,197
`B.
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`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. ............................. 27
`
`VI. FISH IN VIEW OF GILHAM DOES NOT RENDER OBVIOUS
`CLAIM 113 OR CLAIM 185. ....................................................................... 31
`
`A.
`
`B.
`
`Petitioner Did Not Establish That Fish In View Of Gilham
`Meets All Of The Limitations Of Claims 113 Or 185. ....................... 31
`
`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 ANY CHALLENGED CLAIM. ................. 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
`
`Petitioner’s Arguments Rely On Factually
`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
`
`
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`ii
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`U.S. Patent No. 7,064,197
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`VIII. VPK IN VIEW OF METZGAR DOES NOT RENDER OBVIOUS
`ANY OF CLAIMS 17, 19, 25, 105, 106, 114, 119, 120, 128, 129, 131,
`150, 151, 152, 178, 180, 186, OR 189. .......................................................... 59
`
`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 OF CLAIMS 113, 116, 130,
`154, 185, OR 187. .......................................................................................... 64
`
`A.
`
`B.
`
`Petitioner Did Not Establish That The Combination Of Noyes,
`VPK, Metzgar, And Ramachandran Meets All Limitations Of
`The Challenged Claims. ...................................................................... 64
`
`Petitioner Did Not Establish A Reason To Combine VPK,
`Metzgar, Noyes, And Ramachandran. ................................................ 66
`
`X.
`
`SECONDARY CONSIDERATIONS OF NON-OBVIOUSNESS .............. 69
`
`XI. CONCLUSION .............................................................................................. 69
`
`
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`iii
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`Case IPR2016-00822
`U.S. Patent No. 7,064,197
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`Cases
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`TABLE OF AUTHORITIES
`
`Page(s)
`
`ActiveVideo Networks, Inc. v. Verizon Commc’ns, Inc.,
`694 F.3d 1312 (Fed. Cir. 2012) ......................................................... 27, 29, 32, 68
`
`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) ..................................................................... 21, 60
`
`Corning, Inc. v. DSM IP Assets B.V.,
`Case IPR2013-00053 (PTAB May 1, 2014) ........................................................ 44
`
`Dynamic Drinkware, LLC v. Nat’l Graphics, Inc.,
`800 F.3d 1375 (Fed. Cir. 2015) ..................................................................... 36, 43
`
`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) ............................................................................ 21
`
`Holmwood v. Sugavanam,
`948 F.2d 1236 (Fed. Cir. 1991) ............................................................................ 43
`
`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
`
`In re Gordon,
`733 F.2d 900 (Fed. Cir. 1984) ....................................................................... 26, 34
`
`
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`U.S. Patent No. 7,064,197
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`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006) .............................................................................. 29
`
`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) .................................................................................. 26
`
`In re Smythe,
`480 F.2d 1376 (CCPA 1973) ......................................................................... 38, 41
`
`Int’l Bus. Machines Corp. v. Intellectual Ventures II LLC,
`Case IPR2014-00587 (PTAB Nov. 6, 2015) ................................................. 36, 43
`
`Kinetic Techs., Inc. v. Skyworks Solutions, Inc.,
`Case IPR2014-00529, (PTAB Sept. 23, 2014) .............................................. 29, 67
`
`KSR Int’l Co. v. Teleflex, Inc.,
`550 U.S. 398 (2007) .......................................................................... 25, 27, 30, 32
`
`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) ......................................................... 21, 27, 32, 60
`
`
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`v
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`U.S. Patent No. 7,064,197
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`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
`
`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 (PTAB Nov. 25, 2014) ...................................................... 43
`
`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
`
`37 C.F.R. § 1.131 ..................................................................................................... 44
`
`Rules
`
`Fed. R. Evid. 803(16) ............................................................................................... 45
`
`Fed. R. Evid. 803(6) ................................................................................................. 45
`
`Fed. R. Evid. 807 ..................................................................................................... 40
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`vi
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`Case IPR2016-00822
`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
`
`PATENT OWNER’S EXHIBIT LIST
`
`DESCRIPTION
`
`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 IPR2016-00820.
`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.
`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).
`
`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).
`
`2116
`
`Smith, G.L.F. et al., “’Reverse’ DNA Hybridization Method for the
`
`
`
`vii
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`
`
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`Case IPR2016-00822
`U.S. Patent No. 7,064,197
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`Enzo
`Exhibit No.
`
`
`
`DESCRIPTION
`
`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
`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.
`
`2117
`
`2118
`
`2119
`
`2120
`
`2121
`
`2122
`
`2123
`
`2124
`
`2125
`
`2126
`
`2127
`
`2128
`
`2129
`
`2130
`
`
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`viii
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`Case IPR2016-00822
`U.S. Patent No. 7,064,197
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`DESCRIPTION
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`Enzo
`Exhibit No.
`2131
`
`2132
`
`2133
`
`2134
`
`2135
`
`2136
`
`2137
`
`2138
`
`2139
`
`2140
`
`2141
`
`2142
`
`2143
`
`
`
`
`
`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
`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.
`
`Declaration of Barry Weiner.
`
`ix
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`Case IPR2016-00822
`U.S. Patent No. 7,064,197
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`I.
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`INTRODUCTION
`
`
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`The Board should confirm the patentability of 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
`
`also fail to establish a reason to combine or modify references as 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. 2142 ¶¶ 7-24) and the deposition testimony
`
`of Petitioner’s own declarant, confirm that the challenged claims are patentable.
`
`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
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`1
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`moieties affixed to the resulting double-stranded nucleic acids. (Ex. 1001, 6:15-48,
`
`7:35-49.) Dr. Gregory Buck explains in his Declaration that traditionally, solid
`
`support hybridization assays used porous supports, such as filters and membranes,
`
`and that “conventional wisdom” in the art in the early 1980s weighed against the
`
`use of non-porous supports because of skepticism as to whether non-porous
`
`supports would be viable for nucleic acid hybridization. (Ex. 2142 ¶ 50-58.)
`
`III. FISH DOES NOT ANTICIPATE ANY OF CLAIMS 17, 19, 25, 105,
`106, 114, 116, 119, 128, 129, 150, 152, 178, 180, 186, OR 187.
`
`Fish cannot anticipate any of the challenged claims because it does not
`
`disclose all 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.
`
`The challenged independent claims of the ’197 Patent are directed to arrays
`
`of 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 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.”
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`2
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`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,” (3) in an “array” 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
`
`(hereinafter referred to as “Decision”), the Board relied on Petitioner’s allegations
`
`that Fish supposedly discloses nucleic acid strands “fixed or immobilized” to a
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`non-porous solid support through its use of single-stranded DNA (“ssDNA”) (a
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`mixture of poly-dA and poly-dC or denatured calf thymus DNA) as a control in
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`one of the experiments described. (Decision, 12.) But Fish does not expressly or
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`inherently disclose any single-stranded nucleic acid that is “fixed or immobilized”1
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`to a non-porous solid support.
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`Fish does not describe any experiments that tested, let alone confirmed,
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`whether single-stranded nucleic acids actually bound to the disclosed PLL-coated
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`wells. (Ex. 2142 ¶¶ 68-91.) Petitioner’s declarant, Dr. Nelson, testified that the
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`Fish researchers (1) performed an experiment to show that dsDNA—not ssDNA—
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`would bind to PLL-coated polyvinyl wells, and (2) although they could have
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`performed a similar experiment on ssDNA, they did not. (Nelson Tr. 62:13-17,
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`63:1-19.)
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`Although no dispute exists that the Fish researchers failed to perform or
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`disclose any experiments establishing that ssDNA would bind to PLL-coated wells,
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`the Board explained that “it appears that they already knew that ssDNA would bind
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`to PLL coated wells.” (Decision, 12 (citing Ex. 1006, 538, right col. ¶ 1).) The
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`record now available shows otherwise. A POSITA at the time of the Fish
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`1 “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
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`Patent).)
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`inventions would not have expected that ssDNA would bind to PLL-coated
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`polyvinyl plates. (Ex. 2142 ¶ 73.) In fact, even the Fish researchers themselves
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`did not believe that DNA would bind to polyvinyl plates. (Ex. 2142 ¶ 74; Ex.
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`1006, 535.) Thus, the suggestion in Fish that ssDNA may bind to PLL-treated
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`plastic—that “[t]his positive control for the nuclease S1 activity suggests that
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`single-stranded nucleic acid, bound to PLL treated plastic, remains susceptible to
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`the hydrolic activity of the enzyme”—was merely an assumption derived from an
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`experiment designed to show that the poly(dA-dT) used was in fact double-
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`stranded, made without supporting data of ssDNA binding to plastic. That
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`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.)2
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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 Decision, 13; Petition, 23; Ex.
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`2142 ¶¶ 78-91; Ex. 1006, 539.) As Petitioner’s declarant’s deposition testimony
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`confirmed, the Fish assay by its very nature cannot establish whether ssDNA
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`bound to the plastic wells. (Ex. 2142 ¶¶ 82-86.) Indeed, Dr. Nelson testified that
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`2 Emphasis has been added unless otherwise indicated.
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`the Fish authors designed the assay to detect the presence of antibodies that they
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`presumed to be bound specifically to double-stranded DNA using radioactively
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`labeled anti-human IGG antibodies which will bind to any antibody present.
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`(Nelson Tr. 80:15-81:18.) Given that human serum was used in the experiments,
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`however, no grounds exist to conclude with reasonable certainty that the generic,
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`radioactively labeled anti-human IGG antibodies used in fact bound to dsDNA
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`specific IGG rather than to some other IGG present in the human serum. Because
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`Figures 1, 3, 4 depict the results of experiments that were not designed to
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`determine whether single-stranded nucleic acids bound to PLL-coated wells, those
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`results fail to demonstrate, as Petitioner contends, the presence of single-stranded
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`nucleic acids bound to the wells. (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; Nelson Tr.
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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. (Nelson Tr. 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), antibodies that would
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`bind to double-stranded DNA; (3) detect the presence of the bound antibodies
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`specific for double-stranded DNA using a radioactively-labeled anti-IGG antibody.
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`(Nelson Tr. 80-83.) Thus, the results depicted in the various figures showed, as Dr.
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`Nelson confirmed,
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`radioactive signals
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`indicating only
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`the presence of
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`radioactively-labeled anti-human IGG antibody in the wells. (Nelson Tr. 84:9-15.)
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`To conclude that the figures’ radioactive signals actually indicate the presence of
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`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. (Nelson Tr. 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. (Nelson Tr. 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).
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`For the foregoing reasons, the fully developed record demonstrates that Fish
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`does not expressly or inherently disclose single-stranded nucleic acid strands
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`“fixed or immobilized” to a non-porous solid support.
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`2.
`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.)
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`The Board relied on that inherency argument and Dr. Nelson’s supporting opinions
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`in instituting the Petition, stating that “the bound ssDNA will hybridize when
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`complementary DNA is present in appropriate hybridization conditions.”
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`(Decision, 13-14.) However, the record lacks 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 claim 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); see also In re Oelrich, 666 F.2d 578, 581 (CCPA
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`1981). Petitioner does not—and cannot—identify any evidence that any bound
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`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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`hybridized in any of Fish’s experiments. (Nelson Tr. 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. (Nelson Tr. 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. (Nelson Tr. 137:17-138:6.) Nor does Fish suggest that those
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`nucleic acids can or will hybridize. (Ex. 2142 ¶ 99; Nelson Tr. 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
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