UNITED STATES PATENT AND TRADEMARK OFFICE
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`____________
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`ILLUMINA, INC.
`Petitioner
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`v.
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`THE SCRIPPS RESEARCH INSTITUTE
`Patent Owner
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`____________
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`INTER PARTES REVIEW OF U.S. PATENT NO. 6,060,596
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`ENCODED COMBINATORIAL CHEMICAL LIBRARIES
`____________
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`DECLARATION OF BRIAN M. STOLTZ, PH.D.
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`Page 1 of 144
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`ILMN EXHIBIT 1007
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`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`____________
`
`ILLUMINA, INC.
`Petitioner
`
`v.
`
`THE SCRIPPS RESEARCH INSTITUTE
`Patent Owner
`
`____________
`
`INTER PARTES REVIEW OF U.S. PATENT NO. 6,060,596
`
`ENCODED COMBINATORIAL CHEMICAL LIBRARIES
`____________
`
`DECLARATION OF BRIAN M. STOLTZ, PH.D.
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`
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`Page 1 of 144
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`ILMN EXHIBIT 1007
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`I.
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`Table of Contents
`INTRODUCTION ........................................................................................... 1
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`II. QUALIFICATIONS ........................................................................................ 3
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`III. SUMMARY OF OPINIONS ........................................................................... 6
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`IV. BACKGROUND ............................................................................................. 9
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`A.
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`Preparing Bifunctional Molecules .......................................................10
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`B. Use of Oligonucleotide Tags to Track Molecules ..............................11
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`C.
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`Split and Pool Synthesis Facilitated the Rapid Synthesis of
`Large Numbers of Polymers ...............................................................12
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`D. Dower’s Alternating Parallel Synthesis Technique ............................15
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`E.
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`The Prior Art Recognized the Benefits of Synthesizing on a
`Solid Phase Support and Screening in Solution, and Provided
`the Means to Do So .............................................................................20
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`V. OVERVIEW OF THE ’596 PATENT ..........................................................23
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`A.
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`B.
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`The Specification of the ’596 Patent ...................................................23
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`Interpretation of Certain Claim Terms in the ’596 Patent ..................26
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`1.
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`2.
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`“linker molecule” ......................................................................27
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`Polymer A comprising “chemical units represented by
`the formula (Xn)a” and identifier oligonucleotide C
`“represented by the formula (Zn)a” ...........................................29
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`VI. THE BIFUNCTIONAL MOLECULES AND LIBRARIES IN
`CLAIMS 1-6 AND 10-17 OF THE ’596 PATENT ARE OBVIOUS
`OVER DOWER ALONE OR IN VIEW OF JUBY OR NELSON ................32
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`A. Dower Alone Renders the Claims of the ’596 Patent Obvious ..........33
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`1.
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`2.
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`3.
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`4.
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`Dower uses alternating parallel synthesis to produce
`bifunctional molecules ..............................................................33
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`Each chemical unit in Dower’s bifunctional molecule is
`identified by a corresponding oligonucleotide identifier
`unit.............................................................................................34
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`Dower describes a “linker molecule” .......................................36
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`Dower describes the subject matter of the remaining
`claims of the ’596 patent ...........................................................38
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`B. Motivation to Remove the Bead from Dower’s Bifunctional
`Molecules ............................................................................................39
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`C.
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`D.
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`Juby Describes a Multifunctional Linker for Attaching an
`Oligonucleotide to a Polymer on a Releasable Solid Support ............41
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`Nelson Describes Multifunctional Linkers for Attaching an
`Oligonucleotide to a Polymer ..............................................................43
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`E. Motivation to Combine Dower with Either Juby or Nelson ...............46
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`1.
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`2.
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`Known benefits of solid phase synthesis and solution
`phase screening would have led the skilled artisan to
`attach oligomers and oligonucleotide tags to a solid
`support through a cleavable linker ............................................47
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`The art provided multifunctional linkers for synthesizing
`on a solid support but screening in solution .............................50
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`F.
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`The Skilled Artisan Would Have Reasonably Expected Success
`in Combining Dower’s Method with the Linkers of Juby or
`Nelson ..................................................................................................54
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`G. Additional Copies of the Oligonucleotide Tag on Dower’s Bead ......56
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`H.
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`The ’596 Patent Does Not Demonstrate Any Unexpected
`Results .................................................................................................57
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`I.
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`Summary of Opinions on Obviousness ...............................................57
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`VII. CLAIMS 1-6 AND 10-17 LACK ADEQUATE WRITTEN
`DESCRIPTION SUPPORT IN THE PRIORITY APPLICATIONS ...........71
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`A.
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`The ’596 Patent Claims a Genus of Bifunctional Molecules ..............74
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`1.
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`2.
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`Polymers ....................................................................................75
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`Identifier oligonucleotides ........................................................78
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`B.
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`Insufficient Examples in the Priority Applications .............................80
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`C. No Guidance on Structural Features Common to All Members
`of the Claimed Genus ..........................................................................81
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`1.
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`2.
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`3.
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`4.
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`Polymers ....................................................................................82
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`Identifier oligonucleotides ........................................................83
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`An example of an oligosaccharide-oligonucleotide
`bifunctional molecule ................................................................84
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`Reaction conditions can impact bifunctional molecule
`structure .....................................................................................89
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`VIII. CLAIMS 1-6 AND 10-17 ARE ANTICIPATED BY U.S. PATENT
`NO. 5,573,905 ................................................................................................91
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`IX. CONCLUSION ..............................................................................................99
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`I, Brian M. Stoltz, Ph.D., declare as follows:
`
`I.
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`INTRODUCTION
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`1.
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`I have been retained by Finnegan, Henderson, Farabow, Garrett &
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`Dunner, LLP on behalf of Illumina, Inc. as an independent consultant in this
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`proceeding before the U.S. Patent and Trademark Office. Although I am being
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`compensated at my normal consulting rate of $650.00 per hour for the time I spend
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`on this matter, my compensation in no way depends on the outcome of this
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`proceeding or the content of my testimony, and I have no other interest in this
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`proceeding.
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`2.
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`I have been asked to consider certain issues regarding U.S. Patent No.
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`6,060,596 (“the ’596 patent”) (Ex. 1001). The claims of the ’596 patent are
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`directed to bifunctional molecules having the components A—B—C, wherein A is
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`a polymer comprising a linear series of chemical units, B is a linker molecule, and
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`C is an identifier oligonucleotide. Id. at 43:1-14. The identifier oligonucleotide C
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`comprises a linear series of unit identifier nucleotide sequences, each of which
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`identifies a corresponding chemical unit in polymer A. Id. The claims also recite
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`libraries of these bifunctional molecules. Id. at 44:4-5. The claimed bifunctional
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`molecules, and the method of synthesis discussed in the specification of the ’596
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`patent, are illustrated below:
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`'596 PATENT
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` J REPEAT
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`Polymer
`HAN
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`Linker
`"BU
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`Oligonucleotide
`HCH
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`for monomer unit at position n
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`= monomer unit (e.g. amino acid)
`at position 11
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`= identifer oligonucleotide unit
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`2
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`3.
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`I have been asked to analyze whether a person of ordinary skill in the
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`art at the time of the purported invention (“the skilled artisan”) would have found
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`the claimed bifunctional molecules and libraries obvious in view of the prior art;
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`whether the examples and other disclosure in the priority applications of the ’596
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`patent provide adequate written description support for the claimed subject matter;
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`and whether a published patent deriving from one of the ’596 patent’s priority
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`applications anticipates the claims in light of the lack of an earlier effective priority
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`date for the ’596 patent.
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`4.
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`In preparing this declaration, I have reviewed the ’596 patent and the
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`other documents discussed below and listed in Appendix B.
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`II. QUALIFICATIONS
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`5.
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`I am currently a Professor of Chemistry at the California Institute of
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`Technology (“Caltech”) in Pasadena, CA. My primary area of expertise is organic
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`chemistry, particularly the design, synthesis, and analysis of biologically active
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`molecules.
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`6.
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`I earned a B.S. degree in Chemistry from Indiana University of
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`Pennsylvania in 1993, an M.S. in organic chemistry from Yale University in 1996,
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`and a Ph.D. in organic chemistry from Yale University in 1997. From 1997-2000,
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`I conducted postdoctoral research at Yale University under the direction of
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`3
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`Professor J. L. Wood and at Harvard University under the direction of Professor E.
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`J. Corey.
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`7.
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`I became a Professor of Chemistry at Caltech in 2007. Previously, I
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`was an Associate Professor of Chemistry at Caltech from December 2005 to
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`January 2007, and an Assistant Professor Chemistry at Caltech from July 2000 to
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`December 2005. I also served as the Executive Officer of Chemistry at Caltech
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`from October 2010 to December 2012. I have trained many post-doctoral fellows,
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`as well as undergraduate and graduate students.
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`8.
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`For over 15 years, I have taught graduate and undergraduate courses
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`in organic chemistry and synthetic methodologies at Caltech. These courses
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`include modules on oligonucleotide synthesis, polymer synthesis, and chemical
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`linkage, among other topics.
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`9.
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`I have acted as a chemistry consultant or scientific advisory board
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`member for several pharmaceutical and chemical companies, including Materia,
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`Vertex Pharmaceuticals, Amyris, and Cytokinetics, and others. I have also served
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`on the editorial board of several organic chemistry journals, including Chemical
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`Science, Organic Syntheses, and the European Journal of Organic Chemistry.
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`10.
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`I have performed extensive research in the field of organic chemical
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`synthesis, publishing nearly 200 peer-reviewed journal articles and book chapters.
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`Much of my work and corresponding articles relate to the synthesis of structurally
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`complex biologically active molecules, including the total synthesis of complex
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`natural products. I have also directed the research of graduate students and post-
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`doctoral researchers working in this area. My research interests include the design
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`and development of unique and efficient synthetic strategies, natural product
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`synthesis, and characterization of complex molecules possessing interesting
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`structural, biological, and physical properties. My work has also led to several
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`patents and patent applications in the U.S. and abroad.
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`11.
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`I have received professional awards for my research and teaching,
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`including the 2015 Mukaiyama Award from the Society of Synthetic Organic
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`Chemistry in Japan. I have also received awards and recognition for excellence in
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`research and teaching, including election as a Fellow of the American Association
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`for the Advancement of Science (AAAS) in 2006. My research has been
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`supported by NIH grants, a Presidential Early Career Award in Science and
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`Engineering (PECASE), an Amgen Young Investigator Award, an Abbott
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`Laboratories New Faculty Award, and a National Science Foundation CAREER
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`Award, among other funding sources.
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`12. A full description of my background and qualifications can be found
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`in my curriculum vitae attached to this declaration as Appendix A.
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`III. SUMMARY OF OPINIONS
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`13. The opinions I provide in this declaration are based on the documents
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`I reviewed and my knowledge, experience, and professional judgment. In forming
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`my opinions, I reviewed the ’596 patent, its corresponding priority applications
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`(U.S. Application No. 08/665,511, filed June 18, 1996, and U.S. Application No.
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`07/860,445, filed March 30, 1992 (Ex. 1006 and 1004), U.S. Patent No. 6,143,497
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`to Dower et al. (“Dower”) (Ex. 1008) and its corresponding earliest priority
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`application (U.S. Patent Application No. 07/762,522, “Dower App.”) (Ex. 1009),
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`Juby et al. (Juby et al., Tetrahedron Lett. 32(7):879-82 (1991)) (“Juby”) (Ex.
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`1010), U.S. Patent No. 5,141,813 to Nelson (“Nelson”) (Ex. 1011) and its
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`corresponding priority application (U.S. Patent Application No. 07/399,658,
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`“Nelson App.”) (Ex. 1012), and the other supporting materials on the state of the
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`art cited in this declaration. As Dower is a patent that claims priority back to an
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`application filed before the claimed priority date of the ’596 patent, I have been
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`informed that it qualifies as prior art. Dower was filed on March 6, 1998, as U.S.
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`Patent Application No. 09/036,599 (Ex. 1030), and issued on November 7, 2000.
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`It claims priority to U.S. Patent Application Nos. 08/484,085, filed June 7, 1995
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`(Ex. 1014) and 07/762,522, filed September 18, 1991 (“Dower App.”) (Ex. 1009).
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`I therefore provide citations to Dower’s original application (Ex. 1009 (Dower
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`App.)) filed on September 18, 1991. Likewise, I cite to Nelson’s application (Ex.
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`1012 (Nelson App.)) filed on August 28, 1989. The underlying applications have
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`substantially the same disclosures as their respective patents.
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`14.
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`I have evaluated the prior art discussed in this declaration in light of
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`what the person of ordinary skill in the art would have understood at the claimed
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`priority date of March 30, 1992. In my opinion, a skilled artisan would have had
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`an advanced degree (typically a Ph.D.) in organic chemistry or biochemistry, and
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`two or more years of practical experience in organic chemical synthesis, including
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`synthesis of linear polymers.
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`15. Based on my evaluation of the claimed subject matter, the available
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`prior art, and the level of ordinary skill at the time of the claimed invention, it
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`would have been obvious for the person of ordinary skill to prepare bifunctional
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`molecules and libraries of such molecules as claimed in the ’596 patent. One of
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`ordinary skill would have been motivated to prepare those molecules and libraries
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`and would have had a reasonable expectation of success in doing so.
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`16.
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`In particular, Dower describes substantially the same alternating
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`parallel synthesis described in the ’596 patent to attach an oligomer to an
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`oligonucleotide identifier tag through linker molecules flanking a bead, where each
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`unit in the identifier tag identifies a corresponding monomer in the oligomer,
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`thereby generating bifunctional molecules and libraries of such molecules. Ex.
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`1009 (Dower App.) at abstract, p. 4, ll. 13-21, p. 12, ll. 32-35, p. 20, ll. 19-36; see
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`also ¶¶35-40 below. The linker molecules in Dower operatively link the oligomer
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`to an oligonucleotide identifier tag, and yield a structure corresponding to the
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`bifunctional molecule claimed in the ’596 patent. See, e.g., ¶¶73 and 79-81 below.
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`Dower alone therefore renders claims 1-6 and 10-17 of the ’596 patent obvious.
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`17. Although I believe that a bifunctional molecule is fully compatible
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`with an embedded linker including a bead, should the Board disagree and conclude
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`that the bifunctional molecules claimed in the ’596 patent cannot include a solid
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`support such as a bead, the prior art provided several alternative linkers that had
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`been used to attach a peptide to an oligonucleotide. For instance, the prior art
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`included the cleavable linkers of Juby and Nelson that were used to attach an
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`oligonucleotide to a peptide, where the molecules could be released from solid
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`supports. See, e.g., ¶¶90-93 and 96-103 below. The skilled artisan would have
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`been motivated to combine Dower with either of these references and would have
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`had a reasonable expectation of success in doing so. See, e.g., ¶¶109-122 below.
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`Dower in combination with Juby or Nelson therefore also renders claims 1-6 and
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`10-17 of the ’596 patent obvious.
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`18. Finally, as I explain below in paragraphs 127-163, the ’596 patent
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`lacks adequate written description support for claims 1-6 and 10-17 and thus is not
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`entitled to claim a priority date before March 3, 1998 for those claims. As such,
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`the earlier publication of the first priority application claimed by the ’596 patent,
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`which published as U.S. Patent No. 5,573,905 and has an identical disclosure,
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`anticipates the claims. See, e.g., ¶166 below.
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`IV. BACKGROUND
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`19. To assist in the understanding of my opinions, I first explain certain
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`background concepts and terms used in the ’596 patent.
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`20. By the early 1990s, researchers understood that they needed to screen
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`many molecules to facilitate various areas of chemical discovery, including drug
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`discovery. An emerging area of chemistry in the early 1990s, combinatorial
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`chemistry, was viewed as a promising strategy for synthesizing large numbers of
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`potentially active compounds for screening. But while compounds, particularly
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`polymeric peptides, could be synthesized, deconvoluting the identity of screened
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`compounds was considered a challenge.
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`21. As explained below, methods for synthesizing polymers (see, e.g.,
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`¶¶22, 23, and 29), tracking a polymer’s identity (e.g., using a reporter molecule or
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`molecular tag) (see, e.g., ¶¶24-26), and screening the resultant polymers for
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`biological activity (see, e.g. ¶¶30 and 31) were known in the art before March 30,
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`1992. One known technique involved creating a bifunctional molecule by
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`conjugating a polymer such as a peptide to an oligonucleotide.
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`A.
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`Preparing Bifunctional Molecules
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`22. Bifunctional polymer-oligonucleotide conjugates were known well
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`before the earliest claimed filing date of the ’596 patent. In 1988, Chu and Orgel
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`published a general method of ligating an oligonucleotide to either another
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`oligonucleotide or to a peptide via a modified phosphoramidate linker, similar to
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`the linking strategy exemplified in the ’596 patent. Ex. 1013 (Chu and Orgel,
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`Nucleic Acids Res. 16(9):3671-91 (1988)) at Abstract; Ex. 1001 (’596 patent) at
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`25:4-8.
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`23. Likewise, Juby (Ex. 1010) reported other methods of preparing
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`peptide-oligonucleotide conjugates. Juby described direct synthesis on a solid
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`Teflon support with a multifunctional branched linker. Ex. 1010 (Juby) at Fig. 1,
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`reproduced below. Accordingly, a skilled artisan at the time of the ’596 patent’s
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`purported invention would have been familiar with methods for synthesizing and
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`conjugating an oligonucleotide to a peptide.
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`FIG. 1: Synthesis of a peptide-oligonucleotide conjugate as described by Juby
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`et al.
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`B. Use of Oligonucleotide Tags to Track Molecules
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`24.
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`In the early 1990s, the art had recognized several functional
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`advantages of oligonucleotide tags, including the ease of synthesis, amplification,
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`and sequencing that made them effective tagging agents. For example,
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`WO1990014441A1 to Dollinger (“Dollinger”) (Ex. 1015), which published on
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`November 11, 1990, discussed nucleic acid taggants that use the order of the
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`nucleic acids in the tag to provide information about an attached material.
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`Dollinger discussed using such taggants with a diverse array of materials and
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`highlighted the ease of tracking the tagged materials via polymerase chain reaction
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`(PCR) amplification of the tag. Id. at p. 5, ll. 10-14 and p. 7, ll. 20-26.
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`25. One main purpose for tagging polymers with oligonucleotides was to
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`facilitate library screening (this is still a main purpose for tagging today). Ex. 1043
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`(A. Chan et al., Curr. Opin. Chem. Biol. 26:55-61 (2015)) (reporting that in vitro
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`screening is “especially amenable to the evaluation of large, chemically diverse,
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`DNA-encoded libraries” because “DNA can be readily replicated,” providing the
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`“advantage of simultaneously evaluating thousands or even millions of
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`compounds”); see also Ex. 1009 (Dower App.) at Fig. 1 and Abstract. Identifying
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`an effective therapeutic agent often required screening through many potential
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`molecules. For instance, the skilled artisan might screen a library of small
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`molecules for desirable biochemical properties, as is commonly done in drug
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`development.
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`26. A screening library often contained thousands of peptides, from which
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`candidates would be identified. For instance, Houghten et al., Nature 354(6348):
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`84-86 (1991) stated that library screening required generating “the requisite
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`number (millions) of individual peptides.” Ex. 1016 (Houghten Nature) at
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`Abstract. Houghten noted that this created a need for synthetic techniques that
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`could produce a large library of peptides, while also having a way to systematically
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`identify the amino acid sequence of each candidate peptide. Id. at Abstract; see
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`also Ex. 1009 (Dower App.) at p. 3, l. 28-30.
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`C.
`
`Split and Pool Synthesis Facilitated the Rapid Synthesis of Large
`Numbers of Polymers
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`27. By the early 1990s, researchers working in academic and commercial
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`settings had not only developed techniques for synthesizing bifunctional
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`molecules, they had also recognized the need for techniques to efficiently
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`synthesize large numbers of molecules to screen for potential therapeutic agents
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`and to rapidly identify the sequences or structures of the potential therapeutic
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`agents.
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`28. Dower stated in 1991 that “[p]rior methods of preparing large
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`numbers of different oligomers have been painstakingly slow when used at a scale
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`sufficient to permit effective or random screening.” Ex. 1009 (Dower App.) at p. 2,
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`l. 28-30. Similarly, in 1991, Houghten Nature noted that existing methods for
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`synthesizing and screening large numbers of peptides were limited by their
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`“inability to generate and screen the requisite number (millions) of individual
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`peptides.” Ex. 1016 (Houghten Nature) at Abstract.
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`29. Combinatorial split and pool synthetic procedures, such as those
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`described in Dower and Houghten Nature, permitted the synthesis of large
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`numbers of different oligomers. Ex. 1009 (Dower App.) at Fig. 1; Ex. 1016
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`(Houghten Nature) at Abstract; see also Ex. 1017 (Lam et al., Nature
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`354(6348):82-84 (1991)) and Ex. 1018 (Furka et al., Int. J. Pept. Protein Res.
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`37(6):487-93 (1991)) for similar methods. Those procedures coupled amino acids
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`stochastically (i.e., randomly) to different resin beads apportioned into separate
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`reaction vessels, pooling and splitting the beads, then repeating the process until a
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`desired peptide length was reached. Both Dower and the ’596 patent discuss the
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`same split and pool method. Ex. 1009 (Dower App.) at Fig. 1 and p. 12, l. 32 – p.
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`13, 19; Ex. 1001 (’596 patent) at 2:55-63. The figure below from Dower illustrates
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`the split and pool synthesis scheme used to generate large numbers of molecules
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`for screening.
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`Reproduced from Fig. 1 in Ex. 1009 (Dower App.).
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`30. While split and pool methods provided an easy way to prepare peptide
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`libraries, the resulting peptides still required time-consuming sequencing after
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`screening. Methods of sequencing peptides were available by the early 1990s, but
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`they were more difficult and costly to perform than oligonucleotide sequencing.
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`Ex. 1019 (Walsh et al., Ann. Rev. Biochem. 50:261-84 (1981)) at p. 262, ¶3
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`(“recent advances in DNA sequencing technology provide more rapid methods”);
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`see also Ex. 1020 (Ivanetich et al., FASEB J. 7(12):1109-14 (1993)) at Table 4
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`(showing the mean set-up charge for protein sequencing was $117 compared to
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`$41 for DNA sequencing).
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`D. Dower’s Alternating Parallel Synthesis Technique
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`31. A group of researchers at Affymax Technologies N.V. addressed the
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`difficulty of preparing peptide libraries while also tracking the sequences or
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`structures of species in the library. The researchers synthesized an oligomer (a
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`type of polymer) in parallel with a linked oligonucleotide identification tag. They
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`described their work in Dower, which is prior art to the ’596 patent and was filed
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`on September 18, 1991. This method generally overcame the deficiencies
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`associated with identifying peptides generated stochastically in a combinatorial
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`library.
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`32. Dower describes a technique for synthesizing bifunctional molecules
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`using the same alternating parallel synthesis discussed in the ’596 patent: “A
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`Page 19 of 144
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`general stochastic method for synthesizing random oligomers on particles is
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`disclosed. A further aspect of the invention relates to the use of identification tags
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`on the particles to facilitate identification of the sequence of the monomers in the
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`oligomer.” Ex. 1009 (Dower App.) at Abstract.
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`33. Dower describes bifunctional molecules corresponding to those
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`described and claimed in the ’596 patent. Dower provides an “oligomer …
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`composed of a sequence of monomers,” a bead and flanking “linker molecule,”
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`and “an oligonucleotide identifier tag” comprising identifier units, each of which
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`identifies a corresponding monomer unit in the oligomer. Id. at p. 3, l. 37 – p. 4, l.
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`3, and p. 4, ll. 20-24. Specifically, as in the ’596 patent, the units in Dower’s
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`identifier tag record the position and structure of the monomers (chemical units) in
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`the oligomer with a one-to-one correspondence between the monomers and
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`identifier tag units. Id. at p. 4, ll. 13-15 and 29-31. The oligomer and
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`oligonucleotide identifier tag are operatively linked. This chemical structure and
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`function corresponds to the “A—B—C” formula claimed in the ’596 patent.
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`34. Dower defines an “oligomer” as a “sequence of monomers, the
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`monomers being any member of the set of molecules which can be joined together
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`to form an oligomer or polymer.” Id. at p. 3, l. 37 – p. 4, l. 3. Dower states that the
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`“identifier tag” provides a way “to identify the sequence of monomers in the
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`oligomer.” Id. at p. 4, ll. 14-15. An identifier tag may contain nucleotide identifier
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`16
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`Page 20 of 144
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`units, which Dower describes as “a natural, high density information storage
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`medium.” Id. at p. 20, ll. 4-5.
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`35. To synthesize oligomers linked to corresponding oligonucleotide
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`identifier tags, Dower assembles monomer units (such as amino acids, nucleic
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`acids, carbohydrates, lipids, or polyesters) and nucleotide units in alternating steps
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`on a solid support. Id. at p. 3, l. 35 – p. 4, l. 12. Dower assembles the units in the
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`oligonucleotide identifier tag “base-by-base before, during, or after the
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`corresponding oligomer (e.g., peptide) synthesis step,” and describes an alternative
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`“block-by-block” approach, attaching a unit containing multiple nucleotides in a
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`single linear block that “carries the monomer-type information” after each added
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`monomer. Id. at p. 20, ll. 21-35. Dower discusses various techniques for attaching
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`the identifier units, including attaching them all directly to a bead, or attaching the
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`units in a linear fashion outward from linker molecules flanking the bead. Id. at p.
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`4, ll. 20-21, and p. 20, l. 21 – p. 21, l. 10.
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`36. The linear attachment of units in the oligonucleotide identifier tag
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`“preserv[es] the order of the steps in the linear array of the oligonucleotide chain as
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`it grows in parallel with the oligomer.” Id. at 20, ll. 25-27. As Dower states, the
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`position of each nucleotide unit relative to the linker records the position and
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`identity of each corresponding monomer. Id. at p. 20, ll. 34-35. As a result,
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`17
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`Page 21 of 144
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`sequencing the oligonucleotide identifier tag identifies the structure of the
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`corresponding oligomer. Id. at p. 18, ll. 36-39; see also p. 20, ll. 7-16.
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`37. For example, Dower describes an oligomer having three monomer
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`units attached in the order A-C-B, with corresponding nucleotide identifier tag
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`sequences “attached to one another in the order of the steps: A, A-C, A-C-B.” Id.
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`at p. 18, ll. 9-35. When the identifier units are attached in a linear fashion to “one
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`another in the order of the steps,” each monomer unit will have a corresponding
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`nucleotide identifier unit in the oligonucleotide identifier tag providing both
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`monomer position and identity information. Id. at p. 18, ll. 29-35.
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`38. The overall number of units in the oligomer and corresponding
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`oligonucleotide identifier tag will depend on the total number of split and pool
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`reaction steps applied during synthesis. Dower describes a variety of such lengths,
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`such as about 20 monomer units, or preferably 3 to 8 monomer units. Id. at p. 16,
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`l. 11.
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`39. Dower’s alternating synthesis uses split and pool synthetic methods to
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`produce a library of bifunctional molecules. First, Dower apportions solid supports
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`between reaction vessels. Second, Dower attaches a monomer unit and its
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`corresponding oligonucleotide identifier tag to each solid support directly or
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`through a linker. Third, Dower pools the solid supports. And fourth, Dower
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`repeats the apportionment and attachment steps, continuing this process until the
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`18
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`Page 22 of 144
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`oligomers in the library reach a desired length. Id. at p. 12, l. 32 - p. 13, l. 19.
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`Notably, Dower’s alternating synthesis is highly similar to the only method for
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`synthesizing bifunctional molecules described in the ’596 patent.
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`40. The schematic below illustrates Dower’s method.
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`19
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`Page 23 of 144
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`E.
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`The Prior Art Recognized the Benefits of Synthesizing on a Solid
`Phase Support and Screening in Solution, and Provided the
`Means to Do So
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`41.
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`It was known in the art in the early 1990s that polymers could be
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`generated more efficiently in the solid phase, but screened more effectively in the
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`solution phase. For example, U.S. Patent No. 5,504,190 (“Houghten”) (Ex. 1021),
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`filed as U.S. Application No. 08/253,854 on June 3, 1994 (Ex. 1035), taught the
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`importance of synthesizing polymer library members on a solid support, such as a
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`resin or porous glass bead, to increase production efficiency and library size. Ex.
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`1022 (Houghten App.) at p. 2, ll. 26-30, and p. 3, ll. 6-10 and 29-32.1 But
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`Houghten also discussed the benefits of releasing the synthesized polymers from
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`the solid support to facilitate solution phase screening. Id. at p. 9, l. 27 – p. 10, l. 2
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`and p. 21, ll. 18-23. Those benefits include reducing steric hindrance, avoiding
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`altered binding kinetics, and preserving normal interactions with receptors and
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`1 As Houghten is a patent that claims priority back to an application filed before
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`the claimed priority date of the ’596 patent, I have been informed that it qualifies
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`as prior art. I therefore provide citations to Houghten’s priority application, U.S.
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`Application No. 07/797,551 (“Houghten App.”) (Ex. 1022) filed on November 19,
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`1991, which I have been informed is substantially identical to the issued patent.
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`20
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`Page 24 of 144
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`other binding sites. Id.; see also Nygren et al., J. Immunol. Methods 101(1):63-71
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`(1987) (“Nygren”) (Ex. 1023) at p. 63.
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`42. Other publications by the early 1990s provided multiple linkers
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`suitable to attach oligonucleotides to polymers on a solid support, where the solid
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`support could then be released after synthesis.
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`43.
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`Juby, for example, discussed methods and linkers for synthesizing
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`peptide-oligonucleotide conjugates on solid supports that could be released after
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`synthesis. In one embodiment, Juby linked a peptide (Z-D-Phe-L-Phe-Gly, Z =
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`benzyloxycarbonyl) to an oligonucleotide through a linker on a Teflon solid
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`support. Ex. 1010 (Juby) at Summary and p. 879-80. As shown in Figure 1, Juby
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`released the Teflon support after attaching the peptide to the oligonucleotide
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`through the linker. Id. at p. 879.
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`44. U.S. Patent No. 5,141,813 (Nelson) likewise described methods for
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`synthesizing peptide-oligonucleotide conjugates and linkers on solid supports that
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`could be released after synthesis. Nelson provided examples of su
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