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`UNITED STATES PATENT AND TRADEMARK OFFICE
`__________________________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`__________________________________
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`ILLUMINA, INC.
`Petitioner,
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`v.
`
`THE TRUSTEES OF COLUMBIA UNIVERSITY
`IN THE CITY OF NEW YORK
`Patent Owner.
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`Case TBD
`Patent 10,435,742
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`
`DECLARATION OF FLOYD ROMESBERG, PH.D.,
`IN SUPPORT OF PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 10,435,742
`
`
`
`
`
`
`
`
`Illumina Ex. 1131
`IPR Petition - USP 10,435,742
`
`
`
`
`
`TABLE OF CONTENTS
`
`Page No.
`
`I.
`
`BACKGROUND AND QUALIFICATIONS, AND PREVIOUS
`TESTIMONY ........................................................................................... 1
`
`A.
`
`B.
`
`Background and Qualifications ...................................................... 1
`
`Previous Testimony ........................................................................ 5
`
`II. MATERIALS CONSIDERED ................................................................. 5
`
`III. LEGAL STANDARD OF NONOBVIOUSNESS ................................... 6
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART .......................... 7
`
`V. THE ’742 PATENT .................................................................................. 7
`
`VI. TECHNICAL BACKGROUND AND STATE OF THE ART ............. 15
`
`A. Deoxyribonucleotides and DNA Were Known in the Art ........... 15
`
`B. Nucleotide Analogues Were Known in the Art ........................... 20
`
`1.
`
`Nucleotide analogues having a 3′-OH cap and a
`labeled base were known ................................................... 23
`
`a.
`
`b.
`
`It was known that the 3′-capping group should
`be small .................................................................... 24
`
`5-Substituted pyrimidine labels were
`commonly used ........................................................ 32
`
`VII. GROUND 1: OBVIOUSNESS OVER TSIEN IN VIEW OF
`HIATT .................................................................................................... 35
`
`A.
`
`Claim 1 Is Obvious Over Tsien In View Of Hiatt ....................... 35
`
`1.
`
`The structure depicted in Claim 1 is not new .................... 35
`-i-
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`
`
`TABLE OF CONTENTS
`(cont’d.)
`
`Page No.
`
`a.
`
`The nucleotide depicted in Claim 1 would have
`been obvious over Tsien .......................................... 36
`
`Limitation R(a) ................................................................... 39
`
`Limitation R(b) .................................................................. 49
`
`Limitations R(c) and wherein the 3′-oxygen and R
`bond is stable ...................................................................... 57
`
`Limitations R(d) and R(e) and wherein OR is not
`methoxy or ester ................................................................. 59
`
`Limitation “wherein tag represents a detectable
`fluorescent moiety” ............................................................ 60
`
`Limitation Y is a “chemically cleavable, chemical
`linker” ................................................................................. 61
`
`Limitation Y(a) .................................................................. 62
`
`Limitation Y(b) .................................................................. 66
`
`2.
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
`
`8.
`
`9.
`
`10. Limitation i) ....................................................................... 67
`
`11. Limitation ii) ...................................................................... 70
`
`12. Limitation iii) ..................................................................... 71
`
`13. Limitation iv) ..................................................................... 72
`
`14. Limitation v) ...................................................................... 73
`
`15. There was motivation to combine the disclosures
`within Tsien ........................................................................ 76
`
`-ii-
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`TABLE OF CONTENTS
`(cont’d.)
`
`Page No.
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`16. There was motivation to use a MOM capping group ........ 80
`
`17. There was a reasonable expectation of success ................. 89
`
`B.
`
`Claim 2 Is Obvious Over Tsien In View Of Hiatt ....................... 92
`
`VIII. GROUND 2: OBVIOUSNESS BASED ON DOWER IN VIEW
`OF PROBER AND IN FURTHER VIEW OF HIATT .......................... 93
`
`A.
`
`Claim 1 Is Obvious Over Dower In View Of Prober And In
`Further View Of Hiatt .................................................................. 93
`
`1.
`
`The structure depicted in Claim 1 is not new .................... 93
`
`a.
`
`The nucleotide depicted in Claim 1 would have
`been obvious over Dower in view of Prober ........... 94
`
`2.
`
`Limitation R(a) ................................................................... 98
`
`a.
`
`b.
`
`Dower discloses R(a) ............................................... 98
`
`Hiatt also discloses R(a) ........................................ 100
`
`Limitation R(b) ................................................................ 100
`
`Limitations R(c) and wherein the 3′-oxygen and R
`bond is stable .................................................................... 102
`
`Limitations R(d) and R(e) and wherein OR is not
`methoxy or ester ............................................................... 103
`
`Limitation “wherein tag represents a detectable
`fluorescent moiety” .......................................................... 108
`
`Limitation Y is a “chemically cleavable, chemical
`linker” ............................................................................... 109
`
`3.
`
`4.
`
`5.
`
`6.
`
`7.
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`-iii-
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`TABLE OF CONTENTS
`(cont’d.)
`
`Page No.
`
`8.
`
`9.
`
`Limitations Y(a) and Y(b) ............................................... 113
`
`Limitation i) ..................................................................... 115
`
`10. Limitation ii) .................................................................... 117
`
`11. Limitation iii) ................................................................... 120
`
`12. Limitation iv) ................................................................... 121
`
`13. Limitation v) .................................................................... 122
`
`14. There was a motivation to combine Dower and
`Prober ............................................................................... 123
`
`15. There was a motivation to use a “small” blocking
`group ................................................................................ 125
`
`16. There would have been a reasonable expectation of
`success .............................................................................. 129
`
`B.
`
`Claim 2 Is Obvious Over Dower In View Of Prober And In
`Further View Of Hiatt ................................................................ 130
`
`IX. GROUND 3: OBVIOUSNESS OVER TSIEN ................................... 130
`
`X. GROUND 4: OBVIOUSNESS OVER DOWER IN VIEW OF
`PROBER AND METZKER ................................................................. 138
`
`XI. CONCLUSION ..................................................................................... 148
`
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`-iv-
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
`
`1.
`
`I, Floyd Romesberg, Ph.D., have been retained by Knobbe, Martens,
`
`Olson & Bear, LLP, counsel for Illumina, Inc. (“Illumina”). I understand that
`
`Illumina is petitioning for inter partes review of U.S. Patent No. 10,435,742
`
`(“the ’742 patent,” Ex. 1004) and requests that the United States Patent and
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`Trademark Office cancel Claims 1-2 of the ’742 patent as unpatentable. The
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`following discussion and analysis provides my opinion as to why Claims 1-2 would
`
`have been obvious to a person of ordinary skill in the art in October of 2000.
`
`I. BACKGROUND AND QUALIFICATIONS, AND PREVIOUS
`TESTIMONY
`
`A. Background and Qualifications
`
`2.
`
`I, Floyd Romesberg, Ph.D., am the scientific founder and Distinguished
`
`Fellow of the biopharmaceutical company Synthorx Inc., which is based in San
`
`Diego, California, United States of America.
`
`3.
`
`I earned a Bachelor of Science in Chemistry from the Ohio State
`
`University in 1988.
`
`4.
`
`I earned a Master of Science in Chemistry in 1990 and a Doctor of
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`Philosophy in Chemistry in 1994 from Cornell University, where Professor David
`
`B. Collum served as my thesis advisor.
`
`5.
`
`From 1994 until 1998, I was a National Institutes of Health (NIH)
`
`postdoctoral research fellow at the University of California, Berkeley, where I
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`studied under Professor Peter G. Schultz.
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`6.
`
`From 1998 to June 2019, I was a professor in the Department of
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`Chemistry at The Scripps Research Institute.
`
`7.
`
`As a principal investigator, I have authored over 140 publications in
`
`peer-reviewed journals, including Nature, The Proceedings of the National Academy
`
`of Sciences of the United States of America, The Journal of the American Chemical
`
`Society, Angewandte Chemie International Edition, Biochemistry, Nucleic Acids
`
`Research, and The Journal of Physical Chemistry.
`
`8.
`
`I have authored or co-authored at least 33 invited review articles. In
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`addition, I have authored or co-authored at least 17 other publications during my
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`graduate and post-doctoral studies.
`
`9.
`
`Over 40 of the publications that I have authored as a principle
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`investigator are related to nucleotide analogues, including nucleotide analogues
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`bearing linkers for attachment of functionalities of interest to polynucleotides.
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`10.
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`I taught several graduate courses in the Department of Chemistry at The
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`Scripps Research Institute, including a Spectroscopy course (which included a
`
`section of mass spectroscopy) and a course on Bacteria and Antibiotics.
`
`11.
`
`I mentored numerous graduate students, post-doctoral researchers,
`
`interns, and research associates at The Scripps Research Institute.
`
`12.
`
`I have been an invited lecturer at multiple universities, symposiums,
`
`and conferences throughout the United States and abroad.
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`13.
`
`I have reviewed manuscripts as part of the peer-review process to
`
`determine whether they are acceptable for publication for numerous journals,
`
`including the Proceedings of the National Academy of Sciences, Science, Nature,
`
`The Journal of the American Chemical Society, Angewandte Chemie, Biochemistry,
`
`the Journal of Organic Chemistry, Bioorganic and Medicinal Chemistry Letters,
`
`Chemistry & Biology, Nucleic Acids Research, and Nucleosides, Nucleotides, and
`
`Nucleic Acids.
`
`14.
`
`I am a member of the American Chemical Society and the American
`
`Society for Microbiology.
`
`15.
`
`I served as a permanent member of the NIH Synthetic and Biological
`
`Chemistry (SBCA) study section that handles a significant percentage of the grants
`
`dealing with modified nucleotides for four years. Also, I regularly serve on various
`
`National Science Foundation (NSF) study sections, and my service on these study
`
`sections involves reviewing and determining the merits of numerous grant proposals.
`
`16.
`
`I have been awarded numerous research grants from the NIH, the NSF,
`
`the Office of Naval Research, Defense Advanced Research Projects Agency, and
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`several other sources, including federal funding for the synthesis and analysis of
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`nucleotide analogues and for the development of DNA polymerases specifically for
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`sequencing DNA.
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`17.
`
`I have been the recipient of multiple awards and honors, including the
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`Royal Society of Chemistry Award for Bioorganic Chemistry in 2018, the ACS San
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`Diego Chapter 2018 Scientist of the Year, elected as a National Academy of
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`Inventors Fellow in 2018, the ACS Nobel Laureate Signature Award for Graduate
`
`Education in Chemistry in 2015, Discover Magazine Technology Innovation Award
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`in 2004, the NSF Career Award in 2004, the Susan B. Komen Breast Cancer
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`Foundation Award in 2003, the Camille Dreyfus Teacher-Scholar Award in 2003,
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`the Baxter Foundation Fellow Award in 2002, the Mac Nevin Award in 1987, and
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`election to the Defense Science Study Group (DSSG) panel from 2008-2010.
`
`18.
`
`I am qualified to render an opinion in the field of nucleotide analogues,
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`DNA polymerases, and DNA sequencing techniques based on my experience in this
`
`field. Based on my expertise and qualifications, I am qualified to provide an opinion
`
`as to what a person of ordinary skill in the art would have understood, known, or
`
`concluded as of 2000. I have been doing research in this field since 1999. In
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`addition, the company Synthorx, which I started in 2014 and where I am now
`
`employed, was founded to commercialize the use of nucleotide analogs that I had
`
`developed in my lab during my time at The Scripps Research Institute, and which in
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`January this year was acquired by Sanofi.
`
`19. Attached as Exhibit 1097 is a copy of my curriculum vitae setting forth
`
`my educational experience, employment history, and publications.
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`
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
`
`B.
`
`Previous Testimony
`
`20.
`
`I previously testified as an expert witness in:
`
`• Illumina, Inc. v. Trustees of Columbia University, IPR2018-00291, -
`
`00318, -00322, -00385, regarding U.S. 9,718,852; U.S. 9,719,139; U.S.
`
`9,708,358; U.S. 9,725,480; and U.S. 9,868,985;
`
`• Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd., IPR2013-
`
`00128, regarding U.S. 7,057,026;
`
`• Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd., IPR2013-
`
`00266, regarding U.S. 8,158,346;
`
`• Intelligent Bio-Systems, Inc. v. Illumina Cambridge Ltd., IPR2013-
`
`00517, regarding U.S. 7,566,537;
`
`• Pacific Oxford Nanopore v. Pacific Biosciences, ITC-337-TA-1032;
`
`and
`
`• Illumina, Inc. v. Oxford Nanopore Technologies Ltd., ITC-337-TA-
`
`0991.
`
`II. MATERIALS CONSIDERED
`
`21. Attached as Exhibit 1132 is a listing of documents that I have
`
`considered and reviewed in connection with providing this declaration. In particular,
`
`I have reviewed the ’742 patent and the references it cites in the specification. See,
`
`e.g., Ex. 1004 (’742 patent) at 29:59-32:57 (“References”).
`
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
`
`III. LEGAL STANDARD OF NONOBVIOUSNESS
`
`22.
`
`I am not a patent attorney nor have I independently researched the law
`
`on patentability. I understand that 35 U.S.C. § 103 governs the determination of
`
`obviousness. I understand that 35 U.S.C. § 103 states:
`
`A patent may not be obtained though the invention is not identically
`disclosed or described as set forth in section 102 of this title, if the
`differences between the subject matter sought to be patented and the
`prior art are such that the subject matter as a whole would have been
`obvious at the time the invention was made to a person of ordinary skill
`in the art to which the subject matter pertains.
`
`23.
`
`I further understand that the four factors to be considered in an
`
`obviousness inquiry are: (1) the scope and content of the prior art; (2) the differences
`
`between the prior art and the claims; (3) the level of ordinary skill in the pertinent
`
`art; and (4) secondary considerations including long-felt need, commercial success,
`
`and unexpected results.
`
`24.
`
`I also understand that when there is some recognized reason to solve a
`
`problem, and there are a finite number of identified, predictable solutions, a person
`
`of ordinary skill in the art has good reason to pursue the known options within his
`
`or her technical grasp. If such an approach leads to the anticipated success, it is
`
`likely the product not of innovation but of ordinary skill and common sense. In such
`
`a circumstance, when a patent simply arranges old elements with each performing
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`the same function it had been known to perform and yields no more than one would
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`expect from such an arrangement, the combination is obvious.
`
`IV. THE PERSON OF ORDINARY SKILL IN THE ART
`
`25.
`
`I understand that obviousness is analyzed from the perspective of a
`
`hypothetical person of ordinary skill in the art. I understand that October 2000 is the
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`relevant time frame for analyzing the obviousness of the ’742 patent. A person of
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`ordinary skill in the art related to the ’742 patent would have been a member of a
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`team of scientists developing nucleotide analogues, researching DNA polymerases,
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`and/or addressing DNA sequencing techniques. Such a person would have held a
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`doctoral degree in chemistry, molecular biology, or a closely related discipline, and
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`had at least five years of practical academic or industrial laboratory experience.
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`Thus, a person of ordinary skill in the art includes a person having a doctoral degree
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`in a field related to chemistry, and at least five years of laboratory experience
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`directed toward the research and development of nucleotide analogues, DNA
`
`polymerases, and/or DNA sequencing. My opinions concerning the obviousness, as
`
`set forth herein, are from the perspective of a person of ordinary skill in the art, as
`
`set forth above.
`
`V. THE ’742 PATENT
`
`26. The ’742 patent (Ex. 1004) is directed to a “massive parallel method
`
`for decoding DNA and RNA.” Ex. 1004 at Title.
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`27. The ’742 patent has two claims:
`
`Claim 1. A thymine deoxyribonucleotide analogue having the
`structure:
`
`
`wherein R (a) represents a small, chemically cleavable, chemical group
`capping the oxygen at the 3′ position of the deoxyribose of the
`deoxyribonucleotide analogue, (b) does not
`interfere with
`recognition of the analogue as a substrate by a DNA polymerase, (c)
`is stable during a DNA polymerase reaction, (d) does not contain a
`ketone group, and (e) is not a –CH2CH=CH2 group;
`wherein OR is not a methoxy group or an ester group;
`wherein the covalent bond between the 3′-oxygen and R is stable during
`a DNA polymerase reaction;
`wherein tag represents a detectable fluorescent moiety;
`wherein Y represents a chemically cleavable, chemical linker which (a)
`does not interfere with recognition of the analogue as a substrate by
`a DNA polymerase and (b) is stable during a DNA polymerase
`reaction; and
`wherein the thymine deoxyribonucleotide analogue:
`
`i) is recognized as a substrate by a DNA polymerase,
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`ii) is incorporated at the end of a growing strand of DNA during a
`DNA polymerase reaction,
`
`iii) produces a 3′-OH group on the deoxyribose upon cleavage of R,
`
`iv) no longer includes a tag on the base upon cleavage of Y, and
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`v) is capable of forming hydrogen bonds with adenine or an adenine
`nucleotide analogue.
`
`Claim 2. A thymine deoxyribonucleotide analogue having the
`structure:
`
`
`wherein R (a) represents a small, chemically cleavable, chemical group
`capping the oxygen at the 3′ position of the deoxyribose of the
`deoxyribonucleotide analogue, (b) does not
`interfere with
`recognition of the analogue as a substrate by a DNA polymerase, (c)
`is stable during a DNA polymerase reaction, and (d) does not
`contain a ketone group;
`wherein OR is not a methoxy group, an ester group, or an allyl ether
`group;
`wherein the covalent bond between the 3′-oxygen and R is stable during
`a DNA polymerase reaction;
`wherein tag represents a detectable fluorescent moiety;
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`wherein Y represents a chemically cleavable, chemical linker which (a)
`does not interfere with recognition of the analogue as a substrate by
`a DNA polymerase and (b) is stable during a DNA polymerase
`reaction; and
`wherein the thymine deoxyribonucleotide analogue:
`
`i) is recognized as a substrate by a DNA polymerase,
`
`ii) is incorporated at the end of a growing strand of DNA during a
`DNA polymerase reaction,
`
`iii) produces a 3′-OH group on the deoxyribose upon cleavage of R,
`
`iv) no longer includes a tag on the base upon cleavage of Y, and
`
`v) is capable of forming hydrogen bonds with adenine or an adenine
`nucleotide analogue.
`
`28.
`
`In Claim 1, there are seven limitations relating to the 3′-O-R group:
`
`• wherein R (a) represents a small, chemically cleavable, chemical
`group capping the oxygen at the 3′ position of the deoxyribose of
`the deoxyribonucleotide analogue,
`
`• wherein R (b) does not interfere with recognition of the analogue
`as a substrate by a DNA polymerase,
`
`• wherein R (c) is stable during a DNA polymerase reaction,
`
`• wherein R (d) does not contain a ketone group;
`
`• wherein R (e) is not a –CH2CH=CH2 group;
`
`• wherein OR is not a methoxy group or an ester group;
`
`• wherein the covalent bond between the 3′-oxygen and R is stable
`during a DNA polymerase reaction.
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`29. There is one limitation for “tag”:
`
`• wherein tag represents a detectable fluorescent moiety.
`
`30. There are three limitations for Y:
`
`• wherein Y represents a chemically cleavable, chemical linker;
`
`• wherein Y (a) does not interfere with recognition of the analogue
`as a substrate by a DNA polymerase;
`
`• wherein Y (b) is stable during a DNA polymerase reaction.
`
`31. There are five limitations for the thymine deoxyribonucleotide
`
`analogue as a whole:
`
`• i) is recognized as a substrate by a DNA polymerase,
`
`• ii) is incorporated at the end of a growing strand of DNA during a
`DNA polymerase reaction,
`
`• iii) produces a 3′-OH group on the deoxyribose upon cleavage of
`R,
`
`• iv) no longer includes a tag on the base upon cleavage of Y, and
`
`• v) is capable of forming hydrogen bonds with adenine or an
`adenine nucleotide analogue.
`
`32. Claim 2 is an almost identical recitation of Claim 1. The sole difference
`
`is that Claim 1 recites that “R ... is not a –CH2CH=CH2 group,” whereas Claim 2
`
`omits this recitation and instead recites “wherein OR is not ... an allyl ether group.”
`
`I address the meaning of “an allyl ether group” below.
`
`33. A person of ordinary skill in the art would have understood that “allyl”
`
`has a specific meaning and refers to a specific chemical structure that, among other
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`IPR Petition – U.S. Patent No. 10,435,742
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`things, was widely used to modify (or “protect”) alcohols (R-OH). “R” in this
`
`structure refers to any of a wide variety of chemical structures with the only
`
`limitation being that the hydroxyl group (–OH) is attached to a carbon atom. As of
`
`2000, indeed at any relevant time, a person skilled in the art would have understood
`
`an “allyl ether” to refer to a chemical structure with the general formula of R-O-
`
`CH2-CH=CH2, where R the “R-O” part is the same as R-OH but with the hydrogen
`
`atom (H) replaced by the allyl protecting group. Thus, in the case of a modified
`
`nucleotide, an allyl ether at the 3′ position would have a structure of R-O-CH2-
`
`CH=CH2, where the oxygen (O) is attached to the 3′ carbon of the deoxyribose
`
`nucleotide of the DNA molecule, and R is the remainder of the nucleotide.
`
`34. A number of different references reflect this understanding. One such
`
`reference is the definition set forth by the International Union of Pure and Applied
`
`Chemistry (IUPAC), an organization which, among other things, defines
`
`standardized nomenclature for chemical compounds. For example, IUPAC
`
`published the Nomenclature of Organic Chemistry. Ex. 1109 (IUPAC). This
`
`compendium provides guidance for internationally agreed-upon nomenclature for
`
`organic compounds. Id. at xv. As explained in the publication, the IUPAC rules
`
`“are intended to be suitable for textbooks, journals and patents, for lexicons and
`
`similar compilations, and for indexes.” Id. at xvii. The IUPAC publication thus
`
`defines the words artisans use to refer to particular chemical structures.
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`35.
`
`In my experience, the IUPAC nomenclature represents the standard
`
`terminology used to describe chemical compounds. With respect to unsaturated
`
`hydrocarbons (e.g., organic molecules containing a double bond), the IUPAC
`
`nomenclature uses the name of the hydrocarbon in conjunction with “the endings
`
`‘-enyl’, ‘-ynyl’, ‘-dienyl’, etc.” Ex. 1109 (IUPAC) at 13. IUPAC, however, retained
`
`three exceptions to this general naming convention: vinyl (for ethenyl), allyl (for 2-
`
`propenyl), and isopropenyl (for 1-methylvinyl). Id. Thus, IUPAC explicitly
`
`recognizes that the term allyl refers to a specific chemical structure: 2-propenyl. In
`
`fact, this understanding was so widely held by skilled artisans in the field that IUPAC
`
`retained the term allyl to refer to the structure -CH2-CH=CH2 instead of assigning it
`
`a new name according to the articulated general standardized naming convention.
`
`Ex. 1109 (IUPAC) at 13; see also id. at 305 (explaining allyl is “preferred to 2-
`
`propenyl” and corresponds to the structure “CH2:CH.CH2—”). A person of skill in
`
`the art would have known that an an “allyl” group means a “-CH2-CH=CH2” group,
`
`whereas an allyl ether group means R-O-CH2-CH=CH2; it is simply an “allyl” group
`
`attached to the oxygen of an alcohol.
`
`36.
`
`In my experience, IUPAC’s definition of allyl as a specific functional
`
`group is consistent with the way the term is used by a skilled artisan. In fact, “allyl”
`
`is used consistently over a wide range of references, including dictionaries and
`
`treatises, to refer to the same single chemical structure. Ex. 1075 (Greene and Wuts)
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`-13-
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`at 67; Ex. 1110 (CRC Handbook) at 2-71; Ex. 1111 (McGraw-Hill Dictionary of
`
`Chemistry) at 24; Ex. 1112 (Vollhardt) at 503; Ex. 1113 (Solomons) at 254; Ex.
`
`1114 (Morrison) at 209. As a result, in my opinion, a skilled artisan would
`
`understand the term “allyl ether group” to refer to “an ether of -CH2-CH=CH2” (e.g.
`
`R-O-CH2-CH=CH2).
`
`37. The ’742 patent’s use of the terms “allyl” and “–CH2CH=CH2” is
`
`consistent with these conclusions. Throughout the specification, the terms are used
`
`interchangeably as represented by the repetition of one term followed immediately
`
`by the other term in parentheses. Ex. 1004 (’742 patent) at 3:41-42 (“It is known
`
`that MOM (–CH2OCH3) and allyl (–CH2CH=CH2) groups . . . .”), 3:49-50 (“ a MOM
`
`group (–CH2OCH3) or an allyl group (–CH2CH=CH2)”), 6:23-24 (“R=H, CH2OCH3
`
`(MOM) or CH2CH=CH2 (Allyl)”), 6:67 (“R=H, CH2OCH3 (MOM) or CH2CH=CH2
`
`(Allyl)”), 7:16 (“R=H, CH2OCH3 (MOM) or CH2CH=CH2 (Allyl)”), 23:23-26
`
`(“Primer (B) is synthesized using a modified C phosphoramidite whose 3'-OH is
`
`capped with either a MOM (–CH2OCH3) group or an allyl (–CH2CH=CH2)
`
`group . . . .”), 25:36-37 (“The MOM (–CH2OCH3) or allyl (–CH2CH=CH2) group is
`
`used . . . .”), 27:30-31 (“The MOM (–CH2OCH3) or allyl (–CH2CH=CH2)
`
`group . . . .”), Figure 7 (“R = H, CH2OCH3 (MOM) or CH2-CH=CH2 (Allyl)”),
`
`Figure 15A (“R = H, CH2OCH3 (MOM) or CH2-CH=CH2 (Allyl)”).
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`-14-
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
`
`38. A person of ordinary skill in the art would understand from the general
`
`nomenclature in the art, described above, and the serial repetition of “allyl (–
`
`CH2CH=CH2) group” and “CH2-CH=CH2 (Allyl)” throughout the ’742 patent that
`
`“an allyl ether group” as used in Claim 2 means “an ether of –CH2CH=CH2.”
`
`VI. TECHNICAL BACKGROUND AND STATE OF THE ART
`
`A. Deoxyribonucleotides and DNA Were Known in the Art
`
`39. Deoxyribonucleotides are found in nature and make up the building
`
`blocks of DNA.
`
` The chemical
`
`formula, nomenclature, and uses of
`
`deoxyribonucleotides were firmly established throughout the life sciences and taught
`
`in undergraduate textbooks long before October 2000. Ex. 1037 (Alberts) at 46-47,
`
`58-60, 98-103. For example, the arrangement of atoms comprising the naturally
`
`occurring thymine deoxyribonucleoside triphosphate were known to be:
`
`.
`Thymine deoxyribonucleoside triphosphate is commonly referred to by its simple
`
`acronym: “dTTP.” This nucleotide has several well-known features: a triphosphate,
`
`a deoxyribose (which includes a 3′-OH), and a thymine base. These features are
`
`highlighted in the following diagram, along with the conventional numbering of
`
`-15-
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`
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`deoxyribose carbon atoms from 1′ to 5′ and the numbering of thymine atoms from 1
`
`to 6:
`
`• triphosphate
`• deoxyribose
`• deoxyribose 3′-OH
`• thymine base
`
`Well-known features of dTTP
`
`
`
`Ex. 1037 (Alberts) at 58-59.
`
`40. A nucleoside is a molecule comprised of a sugar, generally ribose (or
`
`more specifically a deoxyribose in the case of DNA), and a heterocyclic base (such
`
`as thymine). A nucleotide has the same constituents as a nucleoside, yet it also
`
`contains at least one phosphate moiety, which is commonly attached to its 5′ end. A
`
`nucleotide may have one phosphate (a “nucleoside monophosphate”), two
`
`phosphates (a “nucleoside diphosphate”), or three phosphates (a “nucleoside
`
`triphosphate,” as shown above) bound to the sugar. Ex. 1037 (Alberts) at 59.
`
`41. The four deoxyribonucleoside triphosphates corresponding to the
`
`nucleotides that are naturally found in DNA are: “dATP” (corresponding to
`
`nucleobase adenine or “A”), “dGTP” (corresponding to the nucleobase guanine or
`
`“G”), “dCTP” (corresponding to the nucleobase cytosine or “C”), and “dTTP”
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`-16-
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`(corresponding to the nucleobase thymine or “T”). These nucleotides differ from
`
`each other by the base located at the 1′-position of the deoxyribose, as shown below:
`
`deoxyribonucleotide
`abbreviation
`
`base
`
`chemical formula
`
`dATP
`
`adenine
`(“A”)
`
`dGTP
`
`guanine
`(“G”)
`
`dCTP
`
`cytosine
`(“C”)
`
`dTTP
`
`thymine
`(“T”)
`
`
`
`-17-
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`42. Adenine and guanine are classified as purine bases, while cytosine and
`
`thymine are pyrimidines. Ex. 1037 (Alberts) at 58.
`
`43. A strand of DNA consists of deoxyribonucleotides in which the 5′-
`
`phosphate group of one nucleotide is attached to the 3′-oxygen of the preceding (5′)
`
`nucleotide:
`
`
`DNA is typically double-stranded, and the two strands bind to one another through
`
`hydrogen bonds between the bases of complementary nucleotides in each strand. In
`
`this complementary base pairing, ‘A’ nucleotides in one strand bind to ‘T’
`
`nucleotides in the other strand, and ‘C’ nucleotides in one strand bind to ‘G’
`
`nucleotides in the other strand. Ex. 1037 (Alberts) at 98-101.
`
`44. When DNA is synthesized (or “copied”), the two strands of DNA are
`
`separated. One of the single strands of DNA serves as a “template” to synthesize a
`
`-18-
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`new complementary strand. A polymerase enzyme incorporates nucleotides into a
`
`new strand of DNA having bases that are complementary to that of the template:
`
`
`The polymerase enzyme catalyzes the formation of a bond between the 3′-OH group
`
`of the preceding nucleotide (which is the terminal nucleotide of the growing strand)
`
`and the 5′-phosphate group of the nucleotide being incorporated into the growing
`
`strand. Ex. 1037 (Alberts) at 98-103. If the 3′-OH group of the last nucleotide is
`
`blocked or “capped” with a protecting group, the polymerase cannot incorporate
`
`another nucleotide into the growing strand until the protecting group is removed to
`
`regenerate or expose a 3′-OH group. Ex. 1031 (Tsien) at 12:22-13:29; Ex. 1039
`
`(Metzker) at 4259-60; Ex. 1004 (’984 patent) at 7:51-58, 3:4-17. The protecting
`
`group is also commonly referred to as a “blocking group” or a “capping group” and
`
`its removal is correspondingly often referred to as “deblocking” or “uncapping.”
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`-19-
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`Illumina v. Columbia
`IPR Petition – U.S. Patent No. 10,435,742
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`B. Nucleotide Analogues Were Known in the Art
`
`45. The sequence of nucleotides in DNA contains genetic information.
`
`Determining the sequence of nucleotides in DNA can help diagnose and treat
`
`diseases. There were several prior art methods for determining the sequence of
`
`DNA, including Sanger sequencing (e.g., Ex. 1040 (Sanger); Ex. 1041 (Prober)),
`
`and sequencing-by-synthesis (“SBS”). E.g., Ex. 1031 (Tsien); Ex. 1030 (Do
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