`
`
`
`
`
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`MODERNATX, INC.
`Petitioner
`
`v.
`
`CUREVAC AG
`Patent Owner
`
`U.S. Patent No. 8,383,340
`_____________________
`
`Inter Partes Review Case No. Unassigned
`_____________________
`
`DECLARATION OF PROF. DAVID HORNBY, PH.D.
`
`
`
`
`
`1
`
`MTX1002
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`TABLE OF CONTENTS
`
`I. 
`II. 
`III. 
`IV. 
`V. 
`VI. 
`
`B. 
`
`3. 
`
`Introduction ................................................................................................. 1 
`My Background and Qualifications ............................................................. 2 
`Summary of Opinions .................................................................................. 5 
`List of Documents I Considered in Formulating My Opinions .................. 12 
`Person of Ordinary Skill in the Art ............................................................ 17 
`State of the Art Before December 22, 2006 ............................................... 18 
`A.  Before 2006, Researches Desired Large Quantities of Pure
`RNA for Use in a Variety of RNA-based Applications ..................... 19 
`Ion-pair Reversed-Phase High Performance Liquid
`Chromatography (IP RP HPLC) was a Standard Tool for
`Purifying RNA ................................................................................... 21 
`1. 
`Overview of HPLC, RP HPLC, and IP RP HPLC .................. 22 
`IP RP HPLC was Routinely Used
`for RNA
`2. 
`Purification Before 2006 ......................................................... 27 
`IP RP HPLC was Also Applicable for Large Scale
`(Preparative) Purification of RNA ........................................... 29 
`C.  Polystyrenedivinylbenzene (PSDVB) was a Known Material
`for Use as the Stationary Phase in PR RP HPLC ............................... 30 
`D.  Non-Alkylated PSDVB was Known and Used to Purify
`RNA .................................................................................................. 34 
`E.  Porous PSDVB was Known and Used for Purification of
`RNA .................................................................................................. 36 
`The '340 Patent Specification and Claims .................................................. 38 
`VII. 
`VIII.  Claim Construction .................................................................................... 40 
`IX. 
`Summary Chart of Analysis Over the Art .................................................. 42 
`X. 
`The Basis of my Analysis with Respect to Anticipation ............................ 43 
`XI. 
`Ground 1: Gjerde I Discloses Every Limitation of Claims 1-5, 8, 10-
`22, and 26, as Claimed, and Would Have Enabled a POSA to
`Practice the Claimed Invention without Undue Experimentation .............. 44 
`The Basis of my Analysis with Respect to Obviousness ........................... 81 
`XII. 
`XIII.  Ground 2: Claims 1, 3, 4, 6-19, and 21-26 would have been obvious
`over the combination of Zhang and Lloyd ................................................. 83 
`
`
`
`
`
`2
`
`

`

`
`
`
`
`2. 
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`A.  Claim 1 .............................................................................................. 84 
`1. 
`A POSA Would Have Had a Reason to Combine
`Zhang and Lloyd ...................................................................... 92 
`A POSA Would Have Had a Reasonable Expectation
`of Success ................................................................................ 93 
`B.  Claims 3 and 4. .................................................................................. 95 
`C.  Claims 6 and 7 ................................................................................... 99 
`D.  Claim 8. ........................................................................................... 102 
`E.  Claim 9. ........................................................................................... 104 
`F.  Claim 10. ......................................................................................... 106 
`G.  Claim 11. ......................................................................................... 109 
`H.  Claims 12-14. .................................................................................. 111 
`I.  Claims 15 and 16. ............................................................................ 114 
`J.  Claim 17 .......................................................................................... 117 
`K.  Claims 18 and 19 ............................................................................. 119 
`L.  Claims 21 and 22. ............................................................................ 122 
`M.  Claims 23-25 ................................................................................... 125 
`N.  Claim 26. ......................................................................................... 128 
`XIV.  Ground 3: Claim 2 Would Have Been Obvious Over
`the
`Combination of Sullenger and Lloyd ....................................................... 130 
`A.  Claim 2. ........................................................................................... 131 
`1. 
`A POSA would have had a reason to combine
`Sullenger and Lloyd ............................................................... 133 
`A POSA Would Have Had a Reasonable Expectation
`of Success .............................................................................. 134 
`XV.  Ground 4: Claim 5 Would Have Been Obvious Over
`the
`Combination of Zhang, Lloyd, and
`the 2004-2005 Polymer
`Laboratories Catalog ................................................................................ 137 
`A.  Claim 5. ........................................................................................... 137 
`1. 
`A POSA Would Have Had a Reason to Combine
`Zhang, Lloyd, and
`the 2004-2005 Polymer
`Laboratories Catalog ............................................................ 140 
`A POSA Would Have Had a Reasonable Expectation
`of Success .............................................................................. 142 
`XVI.  Ground 5: Claim 20 Would Have Been Obvious Over the
`Combination of Zhang, Lloyd and Gjerde II ........................................... 144 
`A.  Claim 20. ......................................................................................... 144 
`
`2. 
`
`2. 
`
`
`
`
`
`3
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`1. 
`
`2. 
`
`A POSA Would Have Had a Reason to Combine
`Lloyd, Zhang, and Gjerde II .................................................. 145 
`A POSA Would Have Had a Reasonable Expectation
`of Success .............................................................................. 147 
`XVII.  No Objective Evidence Supports Non-Obviousness of the Claimed
`Methods ................................................................................................... 148 
`A.  CureVac did not Compare the Results to the Closest Prior
`Art .................................................................................................... 149 
`B.  CureVac Tested Methods that are Not Commensurate in
`Scope with the Claims ..................................................................... 150 
`C.  The Results Achieved With the Claimed Methods Are Due
`to a Feature That Was Disclosed in Prior Art .................................. 153 
`XVIII.  Conclusion ............................................................................................... 154 
`
`
`
`
`
`
`4
`
`

`

`
`
`
`I, David Hornby, Ph.D., hereby declare as follows.
`I.
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`Introduction
`1.
`
`I am over the age of eighteen (18) and competent to make this
`
`declaration.
`
`2.
`
`I have been retained as an expert witness on behalf of MODERNATX,
`
`INC. ("MODERNA") for the above-captioned inter partes review (IPR). I am being
`
`compensated for my time in connection with this IPR at my standard consulting
`
`rate, which is $450 per hour.
`
`3.
`
`I understand that this Declaration accompanies a petition for IPR
`
`involving U.S. Patent No. 8,383,340 ("the '340 patent") (EX1001), which resulted
`
`from U.S. Patent Application No. 12/520,172 ("the '172 application"), which
`
`entered the U.S. national stage from PCT No. PCT/EP2007/011294 filed on
`
`December 20, 2007. I understand that the PCT (Patent Cooperation Treaty) filing
`
`date is the U.S. filing date under the law. I also understand that the '340 patent
`
`alleges priority benefit of German Patent Application DE 10 2006 061 015, filed
`
`on December 22, 2006. I refer to this date throughout this declaration.
`
`4. The '340 patent names Thomas Ketterer, Florian Von Der Mulbe,
`
`Ladislaus Reidel, and Thorsten Mutzke as inventors. The '340 patent was issued
`
`on February 26, 2013. I understand that, according to the United States Patent and
`
`Trademark Office ("USPTO") records, the '340 patent is currently assigned to
`
`
`
`- 1 -
`
`5
`
`

`

`
`
`
`
`
`
`CureVac AG ("the patentee"). Throughout this declaration, I refer to the patentee
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`as "CureVac."
`
`5.
`
`In preparing this Declaration, I have reviewed the '340 patent and each
`
`of the documents cited herein, in light of general knowledge in the art. In
`
`formulating my opinions, I have relied upon my experience, education, and
`
`knowledge in the relevant art. In formulating my opinions, I have also considered
`
`the viewpoint of a person of ordinary skill in the art ("POSA") (i.e., a person of
`
`ordinary skill in the field of purifying nucleic acids, as defined further below in §
`
`V) prior to December 22, 2006.
`
`II. My Background and Qualifications
`6.
`I am an expert in the field of nucleic acid biochemistry, which
`
`includes manipulation, analysis, purification, and applications of nucleic acids. I
`
`have been actively working in this field since prior to 1985. I received my B.Sc. in
`
`Biochemistry in 1980, and my Ph.D. in Biochemistry in 1984, both from the
`
`University of Sheffield. I was a postdoctoral research associate at Department of
`
`Biochemistry, University of Sheffield in 1984, then a postdoctoral research
`
`associate at Biozentrum der Universitat Basel from 1985-1986.
`
`7.
`
`I became a lecturer in the Department of Biochemistry, University of
`
`Sheffield from 1986-1990. In 1990, I was awarded an EMBO fellowship at the
`
`Gene Expression Program of EMBL, Heidelberg. I became a lecturer from 1990-
`
`- 2 -
`
`6
`
`

`

`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`1994, and then a senior lecturer from 1994-1998, in the Department of Molecular
`
`Biology and Biotechnology, University of Sheffield. Since 1993, I have also been
`
`a visiting scientist at Department of Molecular Biology, the Scripps Research
`
`Institute, La Jolla, CA.
`
`8.
`
`I became a Professor of Biochemistry at the Department of Molecular
`
`Biology and Biotechnology, University of Sheffield in 1999 and served in this
`
`capacity until 2007. From 2007-2012, I was Head of the Department of Molecular
`
`Biology and Biotechnology, University of Sheffield. Since 2013, I have been a
`
`Professor of Biochemistry in the Department of Molecular Biology and
`
`Biotechnology, University of Sheffield. Since 2013, I have also been a Director of
`
`Research and Innovation for Liverpool Life Science University Technical College.
`
`9.
`
`I have served other roles in my professional career, including as a
`
`Director of Invector Ltd. from 1997-1999, where I was a co-founder, and as a
`
`Director of Protealysis Ltd. from 2002-2008, where I was also a co-founder.
`
`Invector Ltd. and Protealysis Ltd. were both based on nucleic acid separation and
`
`stabilization technologies.
`
`10.
`
`I was a Director of the Transgenomic Research Laboratory from
`
`1999-2002. There, I was directly involved in developing separation methods of
`
`RNA using HPLC. Additionally, I served as a Director of Combigen Ltd. from
`
`2004-2014, and as Acting Chair of BioServ UK Ltd. from 2011-2012.
`
`- 3 -
`
`7
`
`

`

`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`11.
`
`In my various professional positions, I have made significant
`
`contributions to the field of nucleic acid purification, including developing
`
`methods for the isolation and analysis of both DNA and RNA. See, e.g., "High-
`
`throughput analysis of nucleic acid modification reactions using ion-pair reveres-
`
`phase high-performance liquid chromatography," Anal. Biochem., 301(2):290-7
`
`(2000);
`
`"Isolation of
`
`single-stranded DNA using denaturing DNA
`
`chromatography," Anal. Biochem., 284(1):164-7 (2002). My work has resulted in
`
`the publication of more than 60 papers and nine textbook chapters. I am also an
`
`inventor on multiple patents, the majority of which are in the field of nucleic acid
`
`purification. I have co-authored two books in the field of nucleic acid purification.
`
`See, e.g., Gjerde, D.T., Hanna, C.P. and Hornby, D., DNA Chromatography,
`
`Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim, Germany, 2002; and Gjerde,
`
`D.T., Hoang L., and Hornby D., RNA Purification and Analysis: Sample
`
`Preparation, Extraction, Chromatography, Wiley-VCH Verlag GmbH & Co.
`
`KGaA, Weinheim, Germany, 2009.
`
`12.
`
`In addition to my educational training, and professional and research
`
`experiences described above, I have kept abreast of the field of nucleic acid
`
`biochemistry and biology by reading scientific literature, conferring with
`
`colleagues in the field, attending and presenting at scientific conferences, and
`
`presenting at invited lectures. I have served as a peer reviewer for several
`
`- 4 -
`
`8
`
`

`

`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`scientific journals including: Nucleic Acids Research, FEBS Letters, Biochemical
`
`Journal, Biochemistry, Molecular Microbiology, and Journal of Molecular
`
`Biology. I have also served as an Editor for International Journal of Biophysics
`
`since 2009. I have also served on advisory boards for a number of companies and
`
`organizations, e.g., Varian Inc., PhyNexus, Bioline (now Meridian), and
`
`Transgenomic Ltd (now Precipio).
`
`13. Accordingly, I am an expert in the field of nucleic acid biochemistry,
`
`and have been since prior to December 2006. For that reason, I am qualified to
`
`provide an opinion as to what a skilled person would have understood, known, or
`
`concluded before December 22, 2006.
`
`III. Summary of Opinions
`14. Claims 1-26 of the
`
`'340 patent are directed to methods of
`
`chromatographic purification of RNA using a porous non-alkylated
`
`polystyrenedivinylbenzene ("PSDVB") material as the stationary phase. EX1001,
`
`19:57- 22:29.
`
`15.
`
`In this declaration, I consider the RNA purification methods of the
`
`'340 patent in relation to the state of the art as of December 22, 2006. The prior art
`
`references that I considered when comparing the claims of the '340 patent to the
`
`state of the art included U.S. Patent No. 6,576,133 ("Gjerde I") (EX1004), a
`
`review article by Lloyd ("Lloyd") (EX1005), a review article by Zhang ("Zhang")
`
`- 5 -
`
`9
`
`

`

`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`(EX1038), a review article by Sullenger ("Sullenger") (EX1039), U.S. Patent No.
`
`6,066,258 ("Gjerde II") (EX1006), and the 2004-2005 Polymer Laboratories
`
`Catalog (EX1024). I also considered the file history of the '340 patent (EX1021)
`
`and other exhibits cited herein. A summary of my opinions follows.
`
`16.
`
` Zhang is a review article that discusses antisense strategies and their
`
`use for human therapeutics. EX1038, 11:1. Zhang provides examples of antisense
`
`agents, such as ribozymes, antisense oligonucleotides, and small interfering
`
`RNAs. Id. Zhang further teaches that antisense therapeutics is "a viable and
`
`effective gene therapy approach," and that "more preclinical and clinical
`
`investigations [of antisense agents] are anticipated to take place in the near
`
`future." Id.
`
`17. Sullenger is a review article that teaches that another example of a
`
`therapeutic application of RNA is "immunotherapy using mRNA." EX1039,
`
`256:1:3-257:1:4. Sullenger teaches that "the RNA therapeutic developmental
`
`pipeline is burgeoning and the next generation of RNA-based therapeutics are
`
`quickly making its way through pre-clinical studies." Id., 257:1:5. Further,
`
`according
`
`to Sullenger, "the preclinical experience suggests
`
`that cancer
`
`vaccination with [mRNA-based immunotherapy] may constitute a highly effective
`
`and broadly application treatment for patients with recurring cancer." Id., 257:1:3.
`
`- 6 -
`
`10
`
`

`

`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`18. Gjerde I, Gjerde II, and Lloyd all disclose methods of purifying RNA
`
`using polystyrenedivinylbenzene-based (PSDVB) columns by means of ion-pair
`
`reversed-phase high performance liquid chromatography (IP RP HPLC). EX1004,
`
`1:28-32; 3:60-64; 7:24-31; 7:53-64; 13:27-31; 31:30-35; EX1006, 9:54-55; 20:41-
`
`44; 23:48-52; EX1005, 223:Abstract; 228:1:2; 226:Fig. 1. Gjerde I, Gjerde II, and
`
`Lloyd also provide detailed descriptions of IP RP HPLC methods for purifying
`
`RNA, including buffers, conditions, elution strategies, etc. EX1004, 1:28-32;
`
`3:60-64; 7:24-31; 7:53-64; 13:27-31; 31:30-35; EX1006, 9:54-55; 20:41-44;
`
`23:48-52; EX1005, 223:Abstract; 228:1:2; 226:Fig. 1. Gjerde I and Lloyd
`
`specifically teach porous non-alkylated PSDVB columns for purifying RNA.
`
`EX1005, 224:2:3; 225:1:1; EX1004, 31:30-56; 23:6-33. Lloyd further teaches that
`
`its methods are especially suited for production of "large quantities" of
`
`oligonucleotides, such as antisense agents. EX1005, 226:1:1-227:2:1.
`
`19. The 2004-2005 Polymer Laboratories Catalog teaches that porous
`
`non-alkylated PSDVB columns are "ideal for oligonucleotide analysis." EX1024,
`
`105:1:1. Also, the 2003-2004 Polymer Laboratories Catalog teaches that the
`
`PLRP-S material has different pore and particles sizes. EX1024, 84, 126. And the
`
`2004-2005 Polymer Laboratories Catalog teaches that with PLRP-S, it is possible
`
`to purify "small oligonucleotides, typically 20-30 mer," as well as "even very large
`
`oligomers." Id., 105:1:2-2-1.
`
`
`
`- 7 -
`
`11
`
`

`

`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`20. As discussed more fully below, Gjerde I teaches all elements of
`
`claims 1-5, 8, 10-22, and 26 of the '340 patent, arranged as claimed. The detailed
`
`descriptions in Example 10 (which prepares a porous non-alkylated HPLC
`
`PSDVB column), together with additional teachings in Gjerde I, would have
`
`enabled a POSA to use the claimed methods without undue experimentation.
`
`EX1004, 1:28-32; 3:60-64; 7:24-31; 7:53-64; 13:27-31; 31:30-35. Therefore,
`
`Gjerde I anticipates claims 1-5, 8, 10-22, and 26 of the '340 patent.
`
`21. As also discussed in detail below, claims 1, 3, 4, 6-19 and 21-26 of the
`
`'340 patent would have been obvious in view of Zhang and Lloyd. Because Zhang
`
`teaches of more pre-clinical and clinical trials with antisense agents, a POSA
`
`would have had a reason to purify large quantities of RNA. EX1038, 11:1. Indeed,
`
`it was known in the art that "preparative separation methods must be created and
`
`scaled up" for "antisense discovery research and clinical development." EX1047,
`
`203:2-3. Further, the art generally taught that "kilograms are required" for clinical
`
`trials of antisense drugs, and that antisense "drug markets range from kilogram to
`
`metric ton levels." Id., 204:1. And a POSA would have known, based on general
`
`knowledge in the art, that preparative scale amounts of RNA were required for
`
`RNA based pre-clinical and clinical research because therapy in even a single
`
`patient could require doses between "0.1 mg/kg and 100 mg/kg body weight/day
`
`of active ingredients." EX1051, 94:14-21 (disclosing doses of small inhibitory
`
`- 8 -
`
`12
`
`

`

`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`RNAs); EX1049, ¶¶[204], [354]-[355] (disclosing administering "10, 30, 100, and
`
`300 mg/m2/day" of ribozymes in a Phase I/II clinical trial). A POSA would have
`
`had a reason to use the method of Lloyd to purify large quantities of antisense
`
`RNA of Zhang because Lloyd would have taught a POSA that its method was
`
`suited for purifying antisense oligonucleotides on a preparative scale. EX1005,
`
`227:1:2-2:1. And given Lloyd's teachings, and the general state of the art, a
`
`POSA would have reasonably expected that the methods of Lloyd would have
`
`been successful for purifying antisense RNA. EX1008, 1:2:1-2; Abstract;
`
`EX1006, 14:27-30; EX1015, Abstract; EX1023,110:1:3; EX 1005, 223:Abstract,
`
`225:2:1; Fig. 1; EX1024, 105:2:1. Lloyd further discloses additional details of the
`
`methods, such that together Lloyd and Zhang disclose all elements of claims 1, 3,
`
`4, 6-19 and 21-26, as discussed below. EX1005, 223:Abstract; 225:1:1; 225:2:1,
`
`226:Fig. 1.
`
`22.
`
`I also discuss in detail, below, that claim 2 of the '340 patent would
`
`have been obvious over Sullenger in view of Lloyd. Sullenger would have
`
`informed a POSA that "inexhaustible amounts" of mRNA were produced for
`
`RNA-based human immunotherapy applications. EX1039, 257:1:1; 257:1:2. And
`
`a POSA would have known that "kilogram-" to "metric ton-"scale quantity of
`
`RNA would be needed for RNA-based pre-clinical and clinical application.
`
`EX1047, 204:1; EX1051, 94:14-21; EX1049, ¶¶[204], [354]-[355]. In looking for
`
`- 9 -
`
`13
`
`

`

`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`a method to purify large quantities of mRNA, a POSA would have looked at
`
`Lloyd because Lloyd teaches that its method is suitable for "produc[ing] large
`
`quantities of well-defined oligonucleotides in an economic and timely fashion for
`
`clinical trials." EX1005, 227:1:2-2:1. And given Lloyd's teachings, and the
`
`general state of the art, a POSA would have reasonably expected to use the
`
`methods of Lloyd for purifying mRNA of Sullenger. EX1008, 1:2:1-2; Abstract;
`
`EX1006, 14:27-30; EX1015, Abstract; EX1023,110:1:3; EX1008, Abstract;
`
`EX1005, 223:Abstract, 225:2:1; Fig. 1; EX1024, 105:2:1.
`
`23.
`
`In addition, claim 5 of the '340 patent would have been obvious in
`
`view of Zhang, Lloyd, and the 2004-2005 Polymer Laboratories Catalog. As
`
`discussed above, the teachings of Zhang would have given a POSA a reason to
`
`purify large quantities of antisense RNA. And a POSA would have had a reason to
`
`look to the method of Lloyd for this purpose, as discussed above. A POSA would
`
`have further had a reason combine the teachings of the 2004-2005 Polymer
`
`Laboratories Catalog with the teachings of Zhang and Lloyd because the 2004-
`
`2005 Polymer Laboratories Catalog also teaches that PLRP-S columns having the
`
`particle sizes that are claimed in claim 5 "are ideal for oligonucleotide analysis."
`
`EX1024, 105:1. And, given these teachings, and the general state of the art, a
`
`POSA would have reasonably expected to use the methods of Lloyd for purifying
`
`antisense RNA of Zhang. EX1008, 1:2:1-2; Abstract; EX1006, 14:27-30;
`
`- 10 -
`
`14
`
`

`

`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`EX1015, Abstract; EX1023,110:1:3; EX1008, Abstract; EX1005, 223:Abstract,
`
`225:2:1; Fig. 1; EX1024, 105:2:1.
`
`24. Further, claim 20 of the '340 patent would have been obvious in view
`
`of Zhang, Lloyd, and Gjerde II. As discussed above, the teaching of Zhang would
`
`have given a POSA a reason to purify large quantities of antisense RNA, such as
`
`ribozyme, siRNA, and AS-ODNs. And a POSA would have had a reason to look
`
`to the method of Lloyd for this purpose, as discussed above. A POSA would have
`
`further had a reason to combine the teachings of Gjerde II to elute antisense RNA
`
`of Zhang isocratically because Gjerde II teaches that "by using a combination of
`
`gradient and isocratic elution conditions, the resolving power of a system can be
`
`enhanced for a particular size range of DNA." EX1006, 25:27-30. Additionally,
`
`given the general knowledge in the art, a POSA would have known that "for some
`
`[purification] processes, a highly precise isocratic … composition" may be
`
`required. EX1034, 9:16-21. And given Lloyd and Gjerde II's teachings of using a
`
`PSDVB column for RNA purification, and the general state of the art, a POSA
`
`would have reasonably expected to use the methods of Lloyd for purifying
`
`antisense RNA of Zhang. EX1008, 1:2:1-2; Abstract; EX1006, 14:27-30;
`
`EX1015, Abstract; EX1023,110:1:3; EX1005, 223:Abstract, 225:2:1; Fig. 1;
`
`EX1024, 105:2:1.
`
`- 11 -
`
`15
`
`

`

`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`25.
`
`In addition, evidence of objective indicia that I reviewed does not
`
`change my opinion that claims 1-26 of the '340 patent would have been obvious to
`
`a POSA, as I explain in detail in Section VII.
`
`IV. List of Documents I Considered in Formulating My Opinions
`26.
`In formulating my opinions, I have considered all the references and
`
`documents cited herein, including those listed below.
`
`MTX
`
` Exhibit #
`
`1001
`
`1003
`1004
`
`1005
`
`1006
`
`1007
`
`1008
`
`1009
`
`Description
`
`Ketterer, T., et al., "Method for Purifying RNA on a Preparative
`Scale By Means of HPLC," U.S. Patent No. 8,383,340 (filed on
`October 20, 2009; issued on February 26, 2013)
`Curriculum Vitae of David Peter Joseph Hornby, Ph.D.
`Gjerde, D., et al., "Method and System for RNA Analysis by
`Matched Ion Polynucleotide Chromatography," U.S. Patent No.
`6,576,133 (filed on January 2, 2001; issued on June 10, 2003)
`(Gjerde I)
`Lloyd, L, et al., "Rigid polymerics: the future of oligonucleotide
`analysis and Purification," J. Chromatogr. A 1009: 223-230 (2003)
`Gjerde, D., et al., "Polynucleotide Separations on Polymeric
`Separation Media," U.S. Patent No. 6,066,258 (filed on October 30,
`1998; issued on May 23, 2000) (Gjerde II)
`Bonn, G., et al., "Nucleic Acid Separation on Alkylated Nonporous
`Polymer Beads," U.S. Patent No. 5,585,236 (filed on November 17,
`1993; issued on December 17, 1996)
`Azarani, A. and Hecker, K.H., "RNA analysis by ion-pair reversed-
`phase high performance liquid chromatography," Nucleic Acids Res.
`29: 1-9 (2000)
`Huck, C.W., et al., "Polystyrene/Divinylbenzene Based Monolithic
`and Encapsulated Capillary Columns for the Analysis of Nucleic
`Acids by High-Performance Liquid Chromatography-Electrospray
`Ionization Mass Spectrometry," Eng. Life Sci. 5: 431-432 (2005)
`
`- 12 -
`
`16
`
`

`

`MTX
`
` Exhibit #
`
`1010
`
`1011
`
`1012
`
`1013
`
`1014
`
`1015
`
`1016
`
`1017
`
`1018
`
`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`Description
`
`Huck, C. W. and Bonn, G.K., "Poly(Styrene-Divinylbenzene) Based
`Media for Liquid Chromatography," Chem. Eng. Technol. 28: 1457-
`1472 (2005)
`Bidlingmeyer, B. and Wang, Q., "Additives for reversed-phase
`HPLC mobile phases," U.S. Patent Application Publication No.
`2005/0011836 (filed on July 17, 2003; published on January 20,
`2005)
`Oefner, P.J. and Huber, C.G., "A decade of high-resolution liquid
`chromatography of nucleic acids on styrene–divinylbenzene
`copolymers," J. Chromatogr. B 782:27-55 (2002)
`Huber, C., et al., "Method And Apparatus For Separating
`Polynucleotides Using Monolithic Capillary Columns," WO
`2001/055713 (filed on January 25, 2001; published on August 2,
`2001)
`Viklund, C., et al., "Monolithic, 'Molded', Porous Materials with
`High Flow Characteristics for Separations, Catalysis, or Solid-Phase
`Chemistry: Control of Porous Properties during
`Polymerization," Chem. Mater. 8: 744-750 (1996)
`McFarland, G. D. and Borer, P.N., "Separation of oligo-RNA by
`reverse-phase HPLC," Nucleic Acids Res. 7: 1067-1080 (1979)
`Morgan, R.L. and Celebuski, J. E., "Large-scale purification of
`haptenated oligonucleotides using high-performance liquid
`chromatography," J. Chromatogr. 536: 85-93 (1991)
`Nielsen, M.D., et al., "High-performance liquid chromatography
`purification of 26-bp serial analysis of gene expression ditags results
`in higher yields, longer concatemers, and substantial time savings,"
`Anal. Biochem. 313: 128-132 (2003)
`Oberacher, H., "Capillary monoliths for the analysis of nucleic
`acids by high-performance liquid chromatography–electrospray
`ionization mass spectrometry," Trends in Anal. Chem. 21: 166-174
`(2002)
`
`- 13 -
`
`17
`
`

`

`MTX
`
` Exhibit #
`
`1019
`
`1020
`
`1021
`1022
`
`1023
`
`1024
`
`1025
`
`1026
`
`1027
`
`1028
`1029
`
`1030
`
`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`Description
`
`Necina, R., et al., "Method And Device For Isolating And Purifying
`A Polynucleotide of Interest On A Manufacturing Scale," WO
`2003/051483 (filed on December 16, 2002; published on June 26,
`2003)
`Oberacher, H., et al., "Characterization of some physical and
`chromatographic properties of monolithic poly(styrene–co-
`divinylbenzene) columns," J. Chromatogr. A 1030: 201-208 (2004)
`File History for U.S. Patent No. 8,383,340
`Gjerde, D., et al., "Process For Performing Polynucleotide
`Separations," U.S. Patent No. 6,156,206 (filed on June 2,1999; issued
`on December 5, 2000)
`Georgopoulos, D.E. and Leibowitz, M.J., "Use of high-performance
`liquid chromatographic fractionation of large RNA molecules in the
`assay of group I intron ribozyme activity," J. Chromatogr. A 868:
`109-114 (2000)
`Chromatography Products from Polymer Laboratories, Catalog Issue
`3, 2004-2005
`Tweeten, K.A. and Tweeten, T.N., "Reversed-Phase
`Chromatography of Proteins on Resin-Based Wide-Pore Packings,"
`J. Chromatogr. 359: 111 – 119 (1986)
`Lloyd, L.L., "Rigid macroporous copolymers as stationary phases in
`high-performance liquid chromatography," J. Chromatogr. 544: 201-
`217 (1991)
`DNA Chromatography, Gjerde, Hanna and Hornby (Eds.) Wiley-
`VCH Verlag GmbH & Co. KGaA 2002
`LC GC Europe European Directory 17:124-128 (August 2004)
`Svec, F., "Chapter 2: Organic Polymer Support Materials," in HPLC
`of Biological Macromolecules, Chromatographic Sciences Series
`Volume 87, Gooding, K.M. and Regnier, F.E. (Eds.), pp. 17-48,
`Marcel Dekker, Inc. 2002
`Drager, R.R. and Regnier, F.R., "High-Performance Anion-Exchange
`Chromatography of Oligonucleotides," Anal. Biochem. 145: 47-56
`(1985)
`
`- 14 -
`
`18
`
`

`

`MTX
`
` Exhibit #
`
`1031
`
`1032
`
`1033
`
`1034
`
`1035
`
`1036
`
`1037
`
`1038
`
`1039
`
`1040
`
`1041
`
`1042
`
`
`
`
`
`
`
`Inter Partes Review of USPN 8,383,340
`Declaration of David Hornby, Ph.D (EX1002)
`
`Description
`
`Barik, S. and Bitko, V., "Prospects of RNA interference therapy in
`respiratory viral diseases: update 2006," Expert Opin. Biol. Ther. 6:
`1151-1160 (2006)
`Putral, L.N., et al., "RNA Interference for the Treatment of Cancer,"
`Drug News Perspect. 19: 317-324 (2006)
`"Chapter 26: An Introduction to Chromatographic Separations," and
`"Chapter 28: High-Performance Liquid Chromatography," in
`Principles of Instrumental Analysis, 5th Ed., pp. 674-696, 725-765,
`Skoog, Holler and Nieman (Eds.) Saunders College Publishing 1992
`Taylor, P.D., et al., "MIPC Column Cleaning System and Process,"
`U.S. Patent No. 6,136,195 (filed April 2, 1999; published October
`24, 2000)
`Glossary from Molecular Biology of the Cell, 3rd Ed., pp. G-1 to G-
`23, Alberts et al. (Eds.) Garland Publishing 1994
`Rathore, A.S. and Velayudhan, A., "Chapter 1: An Overview of
`Scale-Up in Preparative Chromatography," in Scale -Up and
`Optimization in Preparative Chromatography, Chromatographic
`Sciences Series Volume 88, Rathore, A.S. and Velayudhan, A. (Eds.),
`pp. 5-36, Marcel Dekker, Inc. 2003
`Lloyd, L.L., et al., "Oligonucleotide analysis by anion exchange
`HPLC," Bioseparation 2: 207-215 (1991)
`Zhang, Y.C., et al., "Antisense Inhibition – Oligonucleotides,
`Ribozymes and siRNAs," in Antisense Therapeutics, 2nd Ed., Phillips
`(Eds.), pp. 11-34, Humana Press, Inc. 2005
`Sullenger, B.A. and Gilboa, E., "Emerging clinical applications of
`RNA," Nature 418: 252-258 (2002)
`Steitz, T.A. and Moore, P.B., "RNA, the first macromolecular
`catalyst: the ribosome is a ribozyme," TRENDS in Biochem. Sci. 28:
`411-418 (2003)
`Kieft, J.S. and Batey, R.T., "A general method for rapid and
`nondenaturing purification of RNAs," RNA 10: 988–995 (2004)
`Green, P., et al., "The Role of Antisense RN