Case IPR2016-00822
`U.S. Patent No. 7,064,197
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________
`
`
`
`HOLOGIC, INC.,
`Petitioner
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`
`
`
`
`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
`
`__________________
`
`DECLARATION OF GREGORY BUCK, Ph.D.
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`
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`Exhibit 2142 Page 1
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`Enzo Exhibit 2142
`Hologic, Inc. v. Enzo Life Sciences, Inc.
`Case IPR2016-00822
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`

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`Case IPR2016-00822
`U.S. Patent No. 7,064,197
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`TABLE OF CONTENTS
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`Page
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`I. 
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`II. 
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`INTRODUCTION ........................................................................................... 5 
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`BASES FOR OPINIONS ................................................................................ 6 
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`III.  MATERIALS REVIEWED ............................................................................ 6 
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`IV.  EDUCATION AND EXPERIENCE ............................................................... 7 
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`V. 
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`LEGAL STANDARDS ................................................................................. 12 
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`A.  Anticipation ......................................................................................... 13 
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`B.  Obviousness ......................................................................................... 14 
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`C.  Obvious To Try ................................................................................... 17 
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`D. 
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`Invention Date ..................................................................................... 18 
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`VI.  LEVEL OF ORDINARY SKILL IN THE ART ........................................... 19 
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`VII.  TECHNICAL BACKGROUND ................................................................... 20 
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`VIII.  OPINIONS ..................................................................................................... 24 
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`A. 
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`Fish Does Not Anticipate Any Of Claims 17, 19, 25, 105, 106,
`114, 116, 119, 128, 129, 150, 152, 178, 180, 186, Or 187. ................ 24 
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`1. 
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`2. 
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`3. 
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`Fish Does Not Involve Nucleic Acid Hybridization
`Detection Technology. .............................................................. 24 
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`Fish Does Not Disclose Single-Stranded Nucleic Acid
`Strands Fixed or Immobilized To a Non-Porous Solid
`Support. ..................................................................................... 25 
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`Fish Does Not Disclose Single-stranded Nucleic Acids
`Fixed Or Immobilized To A Non-Porous Solid Support
`In Hybridizable Form. ............................................................... 42 
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`Exhibit 2142 Page 2
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`U.S. Patent No. 7,064,197
`Fish Does Not Unavoidably Teach Single-Stranded
`i. 
`Nucleic Acids that Are Capable of Hybridization. ......... 43 
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`ii. 
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`iii. 
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`The Hybridization Described In Diehl Is Not Applicable
`To Fish. ........................................................................... 50 
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`The ’197 Patent Prosecution History Does Not Support
`Petitioner’s Inherency Theory. ....................................... 59 
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`4. 
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`Fish Does Not Disclose an “Array” .......................................... 63 
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`B. 
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`Fish, Standing Alone, Does Not Render Obvious Any Of
`Claims 130, 131, 151, Or 154. ............................................................ 65 
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`1. 
`
`Fish Does Not Teach Or Suggest a Fixed or Immobilized
`Nucleic Acid that Comprises a Nucleic Acid Sequence
`Complementary to a Nucleic Acid Sequence of Interest
`Sought to be Identified, Quantified or Sequenced. ................... 65 
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`2. 
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`Fish Does Not Disclose Fixed or Immobilized RNA. .............. 69 
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`C. 
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`D. 
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`Fish In View of Metzgar and Sato Does Not Render Obvious
`Claim 120 or Claim 189. ..................................................................... 70 
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`Fish In View Of Gilham Does Not Render Obvious Any Of
`Claims 113 Or 185. ............................................................................. 76 
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`E. 
`
`VPK Is Not Prior Art. .......................................................................... 81 
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`1. 
`
`2. 
`
`The ’197 Patent Provides Written Description For The
`Genus Of “Non-Porous Solid Supports.” ................................. 81 
`
`Enzo’s Inventors Reduced the Challenged Claims To
`Practice Before VPK’s Effective Date of October 1982. ......... 87 
`
`F. 
`
`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. .......................................................122 
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`1. 
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`Independent Claims 17, 19, and 25 .........................................127 
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`Exhibit 2142 Page 3
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`Case IPR2016-00822
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`U.S. Patent No. 7,064,197
`Dependent Claims 105, 106, 114, 119, 120, 128, 129,
`2. 
`131, 150, 151, 152, 178, 180, 186, And 189...........................131 
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`
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`G.  Noyes In View Of VPK, Metzgar, And Ramachandran Does
`Not Render Obvious Any Of Claims 113, 116, 130, 154, 185,
`Or 187. ...............................................................................................136 
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`H. 
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`Secondary Considerations of Non-Obviousness ...............................147 
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`Exhibit 2142 Page 4
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`Case IPR2016-00822
`U.S. Patent No. 7,064,197
`I.
`INTRODUCTION
`I, Gregory Buck, Ph.D., a resident of Richmond, Virginia over 18 years of
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`age, hereby declare as follows:
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`1.
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`I have personal knowledge of all of the matters about which I testify
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`in this declaration.
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`2.
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`Desmarais LLP retained me on behalf of Enzo Life Sciences, Inc.
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`(“Enzo”) to provide my technical opinions and testimony about claims 17, 19, 25,
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`105, 106, 113, 114, 116, 119, 120, 128, 129, 130, 131, 150, 151, 152, 154, 178,
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`180, 185, 186, 187, and 189 of U.S. Patent No. 7,064,197 (Ex. 1001, “the ’197
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`Patent”). I refer to those claims as the “challenged claims.”
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`3.
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`I am being compensated for my work in this proceeding and receiving
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`reimbursement for expenses incurred in the course of my work. My compensation
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`is not contingent in any way on either the opinions I have reached or the outcome
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`of this case.
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`4.
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`I was also retained on behalf of Enzo to provide technical opinions
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`and testimony on infringement and validity issues regarding the ’197 patent in
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`certain district court cases. I have provided an expert report and/or export
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`testimony in the following matters: Enzo Life Sciences, Inc. v. Agilent
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`Technologies Inc., Civil Action No. 1:12-cv-434 (D. Del.); Enzo Life Sciences, Inc.
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`v. Illumina Inc., Civil Action No. 1:12-cv-435 (D. Del.); Enzo Life Sciences, Inc. v.
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`Exhibit 2142 Page 5
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`Case IPR2016-00822
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`U.S. Patent No. 7,064,197
`Becton Dickinson and Company et al., Civil Action No. 1:12-cv-105 (D. Del.);
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`Enzo Life Sciences, Inc. v. Life Technologies Corp., Civil Action No. 1:12-cv-105
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`(D. Del.); and Enzo Life Sciences, Inc. v. Roche Molecular Systems Inc. et al., Civil
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`Action No. 1:12-cv-106 (D. Del.).
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`II. BASES FOR OPINIONS
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`I have reviewed and considered the documents and other materials
`5.
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`listed below in Section III in light of my specialized knowledge provided by my
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`education, training, research, and experience, as summarized in Section IV and
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`described in detail in my CV, which is provided as Appendix 1. My analysis of
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`those materials, combined with the specialized knowledge that I have obtained
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`over the course of my education and career, form the bases for my opinions in this
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`declaration.
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`III. MATERIALS REVIEWED
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`6.
`I have reviewed and analyzed the parties’ papers and exhibits in this
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`proceeding, including the ’197 Patent and its file history; Hologic’s Corrected
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`Petition and associated exhibits, including at least Falk Fish and Morris Ziff, “A
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`Sensitive Solid Phase Microradioimmunoassay For Anti-Double Stranded DNA
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`Antibodies,” Arthritis and Rheumatism, Vol. 24, No.3 (March 1981) (Ex. 1006,
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`“Fish”); U.S. Patent No. 3,572,892 to Metzgar (Ex. 1009, “Metzgar”); Sato et al.,
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`“Cell Surface Charge and Cell Division in Escherichia coli after X radiation.”
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`Exhibit 2142 Page 6
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`Radiation Research 87, 646-656 (1981) (Ex. 1034, “Sato”); P. T. Gilham,
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`“Immobilized Polynucleotides and Nucleic Acids,” Immobilized Biochemicals and
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`Affinity Chromatography (R. B. Dunlap (ed.)), 1974 (Ex. 1019, “Gilham”); Frank
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`Diehl et al., “Manufacturing DNA microarrays of high spot homogeneity and
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`reduced background signal,” Nucleic Acids Research, Vol. 31, 2001 (Ex. 1021,
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`“Diehl”); A. C. Van Prooijen-Knegt, et al. “In situ Hybridization of DNA
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`Sequences in Human Metaphase Chromosomes Visualized by an Indirect
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`Fluorescent Immunocytochemical Procedure,” Experimental Cell Research 141,
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`397-407 (October 1982) (Ex. 1008, “VPK”); Barbara E. Noyes and George R.
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`Stark, “Nucleic Acid Hybridization Using DNA Covalently Coupled to Cellulose,”
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`Cell, Vol. 5, 301-310 (July 1975) (Ex. 1007; “Noyes”); B. Ramachandran and D.
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`D. Perlmutter, “Effects of Immobilization of the Kinetics of Enzyme-Catalyzed
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`Reactions. I. Glucose Oxidase in a Recirculation Reactor System,” Biotechnology
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`and Bioengineering, Vol. XVIII, 669-684 (1976) (Ex. 1028, “Ramachandran”);
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`and the Board’s Decision to Institute. I have also reviewed and analyzed the
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`exhibits cited in this declaration.
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`IV. EDUCATION AND EXPERIENCE
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`7.
`As demonstrated by the brief summary of my qualifications below and
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`my professional experience described in my curriculum vitae (attached as
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`Exhibit 2142 Page 7
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`Appendix 1), I have significant academic experience in molecular genetics and
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`nucleic acid detection technologies associated with the ’197 Patent.
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`8.
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`I am a Professor of Microbiology and Immunology, the Director of
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`the Center for the Study of Biological Complexity, and the Director of the Nucleic
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`Acids Core Laboratory at the Virginia Commonwealth University (“VCU”).
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`9.
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`I have had first-hand knowledge of the state of the art of and
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`terminology for molecular genetics and nucleic acid detection technologies since
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`no later than 1978—several years before the January 27, 1983 filing of the original
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`patent application that led to the ’197 Patent.
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`10.
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`I have been working in the field of molecular genetics and nucleic
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`acid detection technology as a research scientist for over thirty-five years.
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`11.
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`I received a Bachelor’s degree of Science in Genetics from the
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`University of Wisconsin in 1975.
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`12.
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`I received a Master’s degree of Science in Microbiology and
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`Immunology from the University of Washington in 1978.
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`13.
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`I received a doctoral degree of Science in Microbiology and
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`Immunology from the University of Washington in 1978. My course of study and
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`research involved the application of contemporary molecular technologies,
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`including nucleic acid hybridization technologies, nucleic acid labeling and
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`detection technologies, and DNA sequencing technologies, to the study of
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`Exhibit 2142 Page 8
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`toxinogenic and non-toxinogenic bacteriophages associated with the bacterial
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`etiological agent of diphtheria; i.e., Corynebacterium diphtheria. My doctoral
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`thesis is entitled “Molecular characterization of ß-converting and γ-nonconverting
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`corynebacteriophages and isolation of the gene for diphtheria toxin.” That thesis is
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`the culmination of my research involving the molecular genetics of the bacterial
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`viruses that integrate into the genomes of susceptible C. diphtheria and convert
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`those bacteria to the capacity to cause the lethal childhood disease called
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`diphtheria. While working on my doctorate, I co-authored several research
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`articles, including but not limited to the following entitled: “Relationship between
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`β- converting and γ- non-converting corynebacteriophage DNA”; “Identification of
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`DNA restriction fragments of β-converting corynebacteriophage that carry the gene
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`for diphtheria toxin”; “Genetic elements novel for Corynebacterium diphtheria:
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`specialized transducing elements and transposons”; and “Physical mapping of β-
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`converting and γ non-converting corynebacteriophage genomes.”
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` After receiving my doctorate, I held two postdoctoral fellowships at
`14.
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`the Institut Pasteur in Paris France. From 1981 to 1982, I served as a Charge de
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`Recherche in the Unit of Parasitology at the Institut Pasteur. From 1982 to 1985, I
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`served as a National Institutes of Health Senior Fellow in the same unit. As a
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`postdoctoral investigator at the Institute Pasteur, I studied the molecular basis of
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`the capability of so-called ‘African Trypanosomes’ to genetically alter the nature
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`Exhibit 2142 Page 9
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`of the major glycoprotein that comprises their immunologically relevant surface
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`coat. In this work, I authored research articles (listed in my CV) on the following
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`subjects, for example: DNA rearrangements of the major surface glycoprotein
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`gene of the African Trypanosomes, the genomic environment of variant surface
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`antigen genes, and the expression of the most important and most consistently
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`expressed surface glycoprotein gene, VSG-1 gene in Trypanosoma equiperdum.
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`15.
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`I joined VCU in 1984 as an Assistant Professor of Microbiology and
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`Immunology. I have held various positions in addition to my academic duties,
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`including as a Member of the Massey Cancer Research Center (1986-present),
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`Director of the Molecular Biology and Genetics program (1992-1998), and
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`Director of the Nucleic Acids Core Laboratory at VCU (1986-present). My
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`responsibilities in these positions included primarily establishment and oversight of
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`an independent and extramurally funded research program developing and
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`applying state-of-the-art molecular technologies in the study of infectious diseases,
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`including Chagas’ Disease, African
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`trypanosomiasis, Pneumocystis carinii
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`pneumonia, Cryptosporidiosis, and many other diseases that affect human health.
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`Most recently, my focus has been on the study of metagenomics of the interaction
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`of the human microbiome and its host.
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`16.
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`In addition, as Director of the Nucleic Acids Core Laboratory at VCU,
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`and member of the Massey Cancer Center, I have been head of the team with
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`Exhibit 2142 Page 10
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`responsibility for ensuring that University investigators have access to the full
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`spectrum of nucleic acid based technologies, including but not limited to synthetic
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`nucleic acids labeled in various ways to permit detection or other analysis of
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`specific gene or RNA targets, in their research efforts.
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` Since 1991, I have held the position of Associate Professor of
`17.
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`Microbiology and Immunology at the VCU with similar responsibilities but higher
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`expectations than I had as an Assistant Professor.
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` Since 1996, I have held the position of Professor of Microbiology and
`18.
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`Immunology at the VCU, again with similar responsibilities but expanded
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`expectations from those that I had as Associate Professor.
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` Since 2000, I have been Director of the Center for the Study of
`19.
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`Biological Complexity at the VCU, with the responsibility of oversight of the
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`faculty, staff and programs of the Center.
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`20.
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`I am a past or present member of several honorary and professional
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`societies, including the American Society for Microbiology, the American
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`Association for the Advancement of Science, the American Association of
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`Biomedical Resource Facilities, NIH’s Human Microbiome Project, and NSF’s
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`Assembling the Tree of Life Program, etc.
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`21.
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`I have served on national and international review panels, including
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`but not limited to those associated with the National Institutes of Health, the
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`Exhibit 2142 Page 11
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`U.S. Patent No. 7,064,197
`National Science Foundation, and European, Israeli, and Brazilian scientific
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`foundations.
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`22.
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`I have authored and co-authored over 125 peer-reviewed primary
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`research articles for various journals including Nature, Science, and PNAS, among
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`many others, and made contributions to multiple technical books and manuals.
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`23.
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`I have been continuously funded by extramural funding agencies (e.g.,
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`NSF and NIH) for my research since 1981, and have been Principal Investigator on
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`grants totaling over $40 million dollars. I have participated in prestigious national
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`research endeavors including the NSF Assembling the Tree of Life Project, NIH’s
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`Human Microbiome Project 1, and NIH’s Human Microbiome Project 2. I have
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`been funded by important philanthropic organizations, including the Howard
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`Hughes Medical Institute, and the Bill and Melinda Gates Foundation.
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`24.
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`In addition to the summary I have provided here, I describe my
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`education, experience, awards, honors, and publications in greater detail in my CV,
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`Appendix 1.
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`V. LEGAL STANDARDS
` Enzo’s attorneys have explained to me the legal standards that apply
`25.
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`in this case. My understanding of those standards is described below. I am not an
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`attorney, and I do not have formal training in the law regarding patents. I have
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`Exhibit 2142 Page 12
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`U.S. Patent No. 7,064,197
`used my understanding of the following legal principles set forth in this section in
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`reaching my opinions.
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`A. Anticipation
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`26.
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`I understand that to anticipate a claim of a patent, a prior art reference
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`must disclose, either expressly or inherently, all limitations of a claim as those
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`limitations are arranged in the claim. I further understand that two references
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`cannot be combined for anticipation purposes (even if one is incorporated into
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`another by reference) unless there is a particularized identification in the allegedly
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`anticipatory reference of the material incorporated and a clear indication in the
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`allegedly anticipatory reference of where that material is found in the second
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`reference. I further understand that prior art printed publications must enable one
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`of ordinary skill in the art to make the invention without undue experimentation in
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`order to anticipate the claimed invention. I understand that a claimed invention is
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`anticipated if that invention is described in another inventor’s U.S. Patent that was
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`filed earlier in the United States.
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`27.
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`I understand that a limitation is disclosed inherently in a reference
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`only if it is necessarily or unavoidably present in the process or product described
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`in the prior art reference. I understand that probabilities or possibilities are
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`insufficient to show that a prior art reference inherently discloses something
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`beyond what it discloses explicitly.
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`B. Obviousness
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`28.
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`I understand that a claim is invalid for obviousness if the differences
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`between the invention and the prior art are such that the subject matter as a whole
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`would have been obvious at the time the invention was made to a person having
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`ordinary skill in the art (“POSITA”) to which the subject matter pertains. I further
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`understand that in order for a claim to be obvious, the prior art must teach, suggest,
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`or disclose every claim limitation so as to render the claim, as a whole, obvious to
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`a POSITA at the time the invention was made.
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`29.
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`I understand that obviousness is ultimately a question of law based on
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`a determination of a number of factual issues. Those factual issues relate to: (1)
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`the scope and content of the prior art, (2) the differences between the prior art and
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`the claimed invention as a whole, (3) the level of ordinary skill in the art at the
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`time the invention was made, and (4) objective secondary considerations that
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`reflect the contemporaneous response to the invention at the time, such as
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`commercial success, long-felt need, and failure of others.
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`30.
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`I understand that the obviousness inquiry takes place at the time of the
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`invention. Therefore, care must be taken to avoid the impermissible use of
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`hindsight in an obviousness analysis. I understand that it is improper to use the
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`invention as a plan or template for hindsight reconstruction of bits and pieces of
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`the prior art to form the invention. For example, the inventive contribution of a
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`Exhibit 2142 Page 14
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`patent may lie in defining a problem in a new way. By merely presenting someone
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`of skill in the art with the identical problem and telling him or her to make the
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`patented invention, it often becomes virtually certain that the artisan will succeed
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`in making the invention. However, the obviousness inquiry must show by clear
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`and convincing evidence that a POSITA at the time of the invention would have
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`recognized the specific problem recognized by the inventor and found it obvious to
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`perform the inventor’s methods to solve that problem.
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`31.
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`It is my further understanding that a patent claim composed of several
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`elements is not proved obvious merely by demonstrating that each of its elements
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`was, independently, known in the prior art. There must be an apparent reason why
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`it would have been obvious to modify the prior art to arrive at the claimed
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`invention. I understand that in order to avoid impermissibly applying hindsight, a
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`helpful insight into the obviousness determination is whether there is a teaching,
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`suggestion or motivation in the prior art that would lead one of ordinary skill in the
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`art to combine the elements. When there is no suggestion for the proposed
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`combination, or when the prior art suggests something other than the combination,
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`this weighs against a finding of obviousness. Counsel for Enzo has informed me
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`that the patent challenger has the burden to show that a person of ordinary skill in
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`the relevant field had a reason to combine the elements in the manner claimed
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`when asserting obviousness in view of a combination of references.
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`I also understand that conclusory statements are insufficient to support
`32.
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`the legal conclusion of obviousness. Instead, I understand that the Petitioner must
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`articulate a basis on which it concludes that it would have been obvious to make
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`the claimed invention.
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`33.
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`I also understand that when the prior art “teaches away” from
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`combining prior art references or certain known elements, discovery of a
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`successful means of combining them is more likely to be non-obvious. I further
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`understand that a reference may be said to teach away when a person of ordinary
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`skill, upon reading the reference, would be discouraged from following the path set
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`out in the invention, or would be led in a direction divergent from the path that was
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`taken by the applicant. I also understand that a reference may teach away from a
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`use when that use would render the result inoperable.
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`34.
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`I understand that there is no suggestion or motivation to make a
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`modification to a prior art reference if the proposed modification would render the
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`prior art invention unsatisfactory for its intended purpose. I also understand that an
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`obviousness allegation cannot be supported by a combination of references that
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`would require a substantial reconstruction and redesign of the elements shown in
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`the primary reference as well as a change in the basic principle under which the
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`primary reference was designed to operate.
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`I further understand that a reference qualifies as prior art for an
`35.
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`obviousness determination only when it is analogous to the claimed invention,
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`meaning that it is in the field of the inventor’s endeavor or if a person of ordinary
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`skill would reasonably have consulted the reference and applied its teachings in
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`seeking a solution to the problem that the inventor was attempting to solve.
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`C. Obvious To Try
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` An invention may be found obvious if it would have been obvious to a
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`person having ordinary skill in the art to try a course of conduct constituting or
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`resulting in the invention. When there is a design need or market pressure to solve
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`a problem and there are a finite number of identified, predictable solutions, a
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`person of ordinary skill has good reason to pursue the known options within his or
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`her technical grasp. However, I understand that evidence of obviousness,
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`especially when that evidence is proffered in support of an “obvious-to-try” theory,
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`is insufficient unless it indicates that the possible options skilled artisans would
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`have encountered were “finite,” “small,” or “easily traversed,” and that skilled
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`artisans would have had a reason to select the route that produced the claimed
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`invention. I understand that the nature of the science or technology must be
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`considered in assessing the level of predictability, and that the biotechnological
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`arts have been recognized as being unpredictable. I understand that procedures
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`characterized by trial and error may indicate unpredictability.
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`Exhibit 2142 Page 17
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`I further understand that an invention is not obvious to try where
`37.
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`vague prior art does not guide an inventor toward a particular solution. For
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`example, where there are numerous possible solutions and the prior art gives no
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`indication of which is likely to be successful, “obvious to try” does not prove
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`obviousness. Similarly, if what was “obvious to try” was to explore a new
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`technology or general approach that seemed to be a promising field of
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`experimentation, but the prior art gave only general guidance as to the particular
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`form of the claimed invention or how to achieve it, then a finding of obviousness is
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`not warranted.
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`D.
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`38.
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`Invention Date
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`I understand that VPK cannot be prior art to the claims unless VPK
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`was published or made otherwise publicly accessible prior to the invention date of
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`the claims.
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`39.
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`I understand that one way an invention date prior to VPK can be
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`established is by showing an “actual reduction to practice” of the claimed
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`invention prior to VPK’s publication date, which Petitioner alleges is October
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`1982.
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`40.
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`I understand that “actual reduction to practice” occurs when the
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`claimed invention has been sufficiently developed such that it works for its
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`intended purposes.
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`I understand that another way that an invention date prior to VPK can
`41.
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`be established is by showing a “conception” of the claimed invention before
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`VPK’s publication date, coupled with reasonable diligence starting just before
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`VPK’s publication date and running either to the filing date of the patent
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`application describing the claimed invention (which is called constructive
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`reduction to practice) or to an actual reduction to practice of the claimed invention.
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`VI. LEVEL OF ORDINARY SKILL IN THE ART
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`42.
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`I have been informed by Enzo’s attorneys that obviousness is
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`considered from the perspective of a POSITA at the time of the invention.
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`
`43.
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`I understand that several factors are considered in determining the
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`level of ordinary skill in the art, including the educational level of active workers
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`in the field, the types of problems encountered in the art, the nature of prior art
`
`solutions to those problems, prior art patents and publications, the activities of
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`others, the sophistication of the technology involved, and the rapidity of
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`innovations in the field.
`
`44.
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`
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`I have been informed by Enzo’s attorneys that the ’197 Patent has an
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`effective filing date of January 23, 1983. Accordingly, my analysis in this case is
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`based on the perspective of a POSITA as of January 23, 1983, but it would also be
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`equally applicable as of the May through September 1982 time frame, when the
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`Enzo inventors reduced the invention to practice, or to May 9, 1985, the filing date
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`of a continuation-in-part application that led to the ’197 Patent.
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` Based upon the considerations described above, I have concluded that
`45.
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`a POSITA of the patented inventions as of the filing in January 1983 of the original
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`patent application (or the filing of the continuation-in-part application in May
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`1985) and throughout the priority chain of applications that led to the ’197 Patent,
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`would have had a Ph.D. in chemistry, biochemistry, biophysics, molecular
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`microbiology, or molecular biology related to nucleic acid chemistry or molecular
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`genetics. Alternatively, a person of ordinary skill could have had a Bachelor’s or
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`Master’s degree in one of the foregoing areas and at least two to three years of
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`research experience related to nucleic acids chemistry or molecular genetics.
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`
`46.
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`I was a person of at least ordinary skill in the relevant art by 1978.
`
`VII. TECHNICAL BACKGROUND
`
` The ’197 Patent relates to nucleic acid detection technology that can
`47.
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`be used, among other things, to detect pathogens or diagnose disease by detecting
`
`the presence or quantity of certain genetic material, such as nucleotide sequences
`
`or genes. (See, e.g., Ex. 1001, at 1:27-32, 5:40-44, 5:60-6:9, 6:23-32.) Non-
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`radioactive labels or signaling moieties can be used to identify hybridized nucleic
`
`acid strands that indicate the presence of a nucleic acid of interest in a sample.
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`(Ex. 1001, at 6:15-48, 7:35-49.)
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`
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` One method of detection involves attachment of such nucleotide 48.
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`sequences to solid supports. Traditionally, these solid support hybridization tests
`
`were composed of porous materials, such as filters and membranes. (See, e.g., Ex.
`
`1001, at 6:23-32; Nelson Tr. 236:12-237:20 (confirming that classical methods of
`
`hybridizing nucleic acids on solid supports involved either porous supports or cells
`
`fixed in situ).)
`
` The use of porous supports had several disadvantages. For example,
`49.
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`the wash step of an assay using a porous support required more fluid and multiple
`
`iterations to wash unhybridized nucleic acids out of the pores of the support. For
`
`example, nucleic acids immobilized in the pores of the support were less accessible
`
`due to the means of fixation and, as a result, less amenable to hybridization. They
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`also created “noise” in subsequent detection steps due to the difficulty of washing
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`unhybridized nucleic acids from the pores of the supports.
`
` Conventional wisdom in the art in the early 1980s weighed against the
`50.
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`use of non-porous supports. That conventional wisdom was based on skepticism
`
`as to whether non-porous supports would be viable for nucleic acid hybridization
`
`chemistry at least because: 1) non-porous supports have a low surface area for
`
`nucleic acid binding; 2) even if nucleic acid could be fixed to a non-porous solid
`
`support, it was thought to be unlikely that the nucleic acid would remain in
`
`hybridizable form once fixed; and 3) even if nucleic acid could be fixed to a non-
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`porous solid support, it was thought to be unlikely that the hybridization kinetics
`
`would allow hybridization of the fixed nucleic acid.
`
` The inventors of the ‘197 Patent developed technology that facilitates
`51.
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`the use of non-porous solid supports in hybridization detection tests. (See, e.g., Ex.
`
`1001, at 6:23-32, 8:36-40, 9:22-30, 11:25-29.)
`
` Attaching nucleotide sequences to these non-porous solid supports can
`52.
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`be done by using special chemistry on the non-porous solid support that helps
`
`nucleotide sequences attach to the support. (See, e.g., Ex. 1001, at 8:37-60, 11:30-
`
`39.)
`
` Using this chemistry, the nucleotide sequences can bind to the support
`53.
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`in a form that remains capable of hybridizing to a matching nucleotide sequence
`
`and in sufficient quantity that they can be detected with labeled probes. (See, e.g.,
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`Ex. 1001, at 9:22-30.)
`
`54.
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` The ‘197 Patent also teaches the use of non-radioactive labels or
`
`signaling moieties to identify the hybridized nucleic acid s