`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
`
`v.
`
`
`
`
`
`ENZO LIFE SCIENCES, INC.,
`Patent Owner
`
`__________________
`
`
`
`Case IPR2016-00820
`
`U.S. Patent No. 7,064,197
`TITLE: SYSTEM, ARRAY AND NON-POROUS SOLID SUPPORT
`COMPRISING FIXED OR IMMOBILIZED NUCLEIC ACIDS
`Issue Date: June 20, 2006
`
`__________________
`
`DECLARATION OF GREGORY BUCK, Ph.D.
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`Exhibit 2001 Page 1
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`Enzo Exhibit 2001
`Hologic, Inc. v. Enzo Life Sciences, Inc.
`Case IPR2016-00820
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`Case IPR2016-00820
`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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`VI. LEVEL OF ORDINARY SKILL IN THE ART ........................................... 18
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`VII. TECHNICAL BACKGROUND ................................................................... 19
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`VIII. OPINIONS ..................................................................................................... 23
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`A.
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`Fish Does Not Anticipate Any Of Claims 1, 6, 8, 9, 12, 13, 14,
`15, 16, 27, 31, 32, 33, 34, 41, 61, 62, 63, 68, 69, 70, 72, 73, 74,
`79, 100, 191, 192, 193, 194, 212, 213, 219, 222, 225, 226, 227,
`230, 233, Or 236. ................................................................................. 23
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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. .............................................................. 23
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`Fish Does Not Disclose Single-Stranded Nucleic Acid
`Strands Fixed Or Immobilized To A Non-Porous Solid
`Support. ..................................................................................... 24
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`Fish Does Not Disclose Single-Stranded Nucleic Acids
`Fixed Or Immobilized To A Non-Porous Solid Support
`In Hybridizable Form. ............................................................... 30
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`Exhibit 2001 Page 2
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`The Hybridization Described In Diehl Is Not Applicable
`a.
`To Fish. ........................................................................... 32
`
`b.
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`The ’197 Patent Prosecution History Does Not Support
`Petitioner’s Inherency Theory. ....................................... 39
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`4.
`
`Fish Does Not Disclose 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. ................ 41
`
`B.
`
`Fish, Standing Alone, Does Not Render Obvious Any Of
`Claims 31, 64, 68, 101, 192, Or 195. .................................................. 43
`
`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. ........................................................................... 43
`
`2.
`
`Fish Does Not Disclose Fixed Or Immobilized RNA. ............. 46
`
`C.
`
`Fish In View Of Gilham Does Not Render Obvious Any Of
`Claims 38, 78, Or 218. ........................................................................ 48
`
`D. VPK Does Not Anticipate Any Of Claims 1, 6, 8, 9, 12, 13, 14,
`15, 27, 31, 32, 34, 61, 62, 63, 68, 69, 70, 72, 74, 79, 100, 191,
`192, 193, 194, 213, 219, 226, 227, Or 236. ......................................... 53
`
`1.
`
`2.
`
`The ’197 Patent Provides Written Description For The
`Genus Of “Non-Porous Solid Supports.” ................................. 53
`
`VPK Does Not Anticipate Any of Claims 1, 6, 8, 9, 12,
`13, 14, 15, 27, 31, 32, 34, 61, 62, 63, 68, 69, 70, 72, 74,
`79, 100, 191, 192, 193, 194, 213, 219, 226, 227, Or 236 ......... 59
`
`a.
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`b.
`
`c.
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`Independent Claims 1, 6, 8, 9, 12, 13, 14, 15, And 27 ... 62
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`Dependent Claims 31, 68, And 192 ................................ 66
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`Dependent Claims 79, 219, And 236 .............................. 68
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`Exhibit 2001 Page 3
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`Dependent Claims 32, 34, 61, 62, 63, 69, 70, 72, 74, 100,
`d.
`191, 193, 194, 213, 226, And 227 .................................. 69
`
`E.
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`F.
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`Noyes In View Of VPK And Ramachandran Does Not Render
`Obvious Any Of Claims 16, 38, 64, 78, 101, 195, 218, 222, Or
`230.
` ................................................................................................... 70
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`VPK In View Of Metzgar Does Not Render Obvious Any Of
`Claims 33, 41, 73, 212, 225, Or 233. .................................................. 80
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`Exhibit 2001 Page 4
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`I.
`INTRODUCTION
`I, Gregory Buck, Ph.D., a resident of Richmond, Virginia over 18 years of
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`
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`age, hereby declare as follows:
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`1.
`
`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 1, 6, 8, 9,
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`12, 13, 14, 15, 16, 27, 31, 32, 33, 34, 38, 41, 61, 62, 63, 64, 68, 69, 70, 72, 73, 74,
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`78, 79, 100, 101, 191, 192, 193, 194, 195, 212, 213, 218, 219, 222, 225, 226, 227,
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`230, 233, and 236 of U.S. Patent No. 7,064,197 (Ex. 1001, “the ’197 Patent”). I
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`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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`
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`Exhibit 2001 Page 5
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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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`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
`5.
`I have reviewed and considered the documents and other materials
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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 to this Declaration.
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`My analysis of those materials, combined with the specialized knowledge that I
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`have obtained over the course of my education and career, form the bases for my
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`opinions in this declaration.
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`III. MATERIALS REVIEWED
`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”); P. T.
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`Exhibit 2001 Page 6
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`Gilham, “Immobilized Polynucleotides and Nucleic Acids,”
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`Immobilized
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`Biochemicals and Affinity Chromatography (R. B. Dunlap (ed.)), 1974 (Ex. 1019,
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`“Gilham”); Frank Diehl et al., “Manufacturing DNA microarrays of high spot
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`homogeneity and reduced background signal,” Nucleic Acids Research, Vol. 31,
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`2001 (Ex. 1021, “Diehl”); A. C. Van Prooijen-Knegt, et al. “In Situ Hybridization
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`of DNA 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”). I
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`have also reviewed and analyzed the exhibits cited in this declaration.
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`IV. EDUCATION AND EXPERIENCE
`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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`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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`Exhibit 2001 Page 7
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`8.
`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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`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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`Exhibit 2001 Page 8
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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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`14. After receiving my doctorate, I held two postdoctoral fellowships at
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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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`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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`Exhibit 2001 Page 9
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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 metagenomics of the interaction of
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`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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`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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`Exhibit 2001 Page 10
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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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`17. Since 1991, I have held the position of Associate Professor of
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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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`18. Since 1996, I have held the position of Professor of Microbiology and
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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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`19. Since 2000, I have been Director of the Center for the Study of
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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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`National Science Foundation, and European, Israeli, and Brazilian scientific
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`foundations.
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`Exhibit 2001 Page 11
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`22.
`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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`Exhibit A.
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`V. LEGAL STANDARDS
`25. Enzo’s attorneys have explained to me the legal standards that apply
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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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`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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`Exhibit 2001 Page 12
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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 present in the process or product described in the prior art
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`reference. I understand that probabilities or possibilities are insufficient to show
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`that a prior art reference inherently discloses something beyond what it discloses
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`explicitly.
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`Exhibit 2001 Page 13
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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.
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`Similarly, a claim is invalid for obviousness if two or more prior art references in
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`combination disclose, expressly or inherently, every claim limitation so as to
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`render the claim, as a whole, obvious to a POSITA at the time the invention was
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`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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`Exhibit 2001 Page 14
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`the prior art to form the invention. For example, the inventive contribution of a
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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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`32.
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`I also understand that conclusory statements are insufficient to support
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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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`Exhibit 2001 Page 16
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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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`35.
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`I further understand that a reference qualifies as prior art for an
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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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`36. 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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`Exhibit 2001 Page 17
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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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`37.
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`I further understand that an invention is not obvious to try where
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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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`VI. LEVEL OF ORDINARY SKILL IN THE ART
`38.
`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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`39.
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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
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`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.
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`
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`Exhibit 2001 Page 18
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`40.
`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 May 9, 1985, the filing date of a continuation-in-part
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`application that led to the ’197 Patent.
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`41. Based upon the considerations described above, I have concluded that
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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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`42.
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`I was a person of at least ordinary skill in the relevant art by 1978.
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`VII. TECHNICAL BACKGROUND
`43. The ’197 Patent relates to nucleic acid detection technology that can
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`be used, among other things, to detect pathogens or diagnose disease by detecting
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`the presence or quantity of certain genetic material, such as nucleotide sequences
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`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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`
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`Exhibit 2001 Page 19
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`radioactive labels or signaling moieties can be used to identify hybridized nucleic
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`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.) Among other applications, the techniques of the
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`’197 Patent can be used for detecting a pathogen or diagnosing a disease by
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`detecting the presence or quantity of certain genetic material, such as nucleotide
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`sequences or genes in a sample. (Ex. 1001, at 1:27-32, 5:40-44, 5:60-6:9, 6:23-
`
`32.)
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`44. One method of detection involves attachment of such nucleotide
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`sequences to solid supports. Traditionally, these solid support hybridization tests
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`were composed of porous materials, such as filters and membranes. (See, e.g., Ex.
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`1001, at 6:23-32.)
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`45. The use of porous supports had several disadvantages. For example,
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`the wash step of an assay using a porous support required more fluid and multiple
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`iterations to wash unhybridized nucleic acids out of the pores of the support. The
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`porous support also caused noise due to difficulty in washing unhybridized nucleic
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`acids from the support. In addition, nucleic acids immobilized in the pores of the
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`support were less accessible due to the means of fixation, and as a result, less
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`amenable to hybridization.
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`
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`Exhibit 2001 Page 20
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`46. The inventors of the ‘197 Patent developed technology that facilitates
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`the use of non-porous solid supports in hybridization detection tests. (See, e.g., Ex.
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`1001, at 6:23-32, 8:36-40, 9:22-30, 11:25-29.)
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`47. Attaching nucleotide sequences to these non-porous solid supports can
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`be done by using special chemistry on the non-porous solid support that helps
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`nucleotide sequences attach to the support. (See, e.g., Ex. 1001, at 8:37-60, 11:30-
`
`39.)
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`48. Using this chemistry, the nucleotide sequences can bind to the support
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`in a form that remains capable of hybridizing to a matching nucleotide sequence
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`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.)
`
`49. The ‘197 Patent also teaches the use of non-radioactive labels or
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`signaling moieties to identify the hybridized nucleic acid strands that indicate the
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`presence of nucleic acids of interest in the samples. (See, e.g., Ex. 1001, at 6:15-
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`48, 7:35-49.)
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`50. Nucleic acids bound to non-porous solid supports are generally more
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`accessible than nucleic acids bound to porous supports. Because less fluid is
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`required, the solutions of labeled nucleotide sequences are more concentrated,
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`resulting in more rapid and efficient hybridization. In addition, because liquid
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`does not absorb into or flow through a non-porous solid support as it does through
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`
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`Exhibit 2001 Page 21
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`filter paper, smaller amounts of fluid can be used for non-porous solid support
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`hybridization. The use of non-porous solid supports also results in less non-
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`specific binding and higher resolution of results (e.g., more spots per area).
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`51. The use of non-porous solid supports results in quicker and more
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`effective washing steps to rid the support of unhybridized labeled nucleotide
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`sequences because the unhybridized labeled nucleic acids do not need to diffuse in
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`and out of the pores in a filter.
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`52. The use of non-porous solid supports facilitates automation and large
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`scale commercial use based upon more rapid reaction times and the accessibility of
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`the nucleic acids on the external surface of the support.
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`53. The advantages of non-porous solid supports can be realized in many
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`formats, including flat plates and curved materials, such as wells.
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`54. A non-radioactive label is a safer, faster, and cheaper alternative to a
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`radioactive label.
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`55. Because non-radioactive labels do not introduce radioactivity into a
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`lab environment, they are therefore safer for scientists and researchers involved in
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`nucleic acid detection.
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`56. Non-radioactive labeling techniques reduce the time required to
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`perform nucleic acid detection. The use of radioactive labels involved a
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`complicated and time-consuming process of exposing phot