UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`PAR PHARMACEUTICAL, INC.,
`
`Petitioner,
`
`v.
`
`NOVARTIS AG,
`
`Patent Owner.
`
`
`
`Case IPR2016-00084
`
`Patent No. 5,665,772
`
`
`
`
`
`
`
`
`
`EXPERT DECLARATION
`OF WILLIAM R. ROUSH, PH.D.
`
`
`
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 1 of 194
`
`

`
`TABLE OF CONTENTS
`
`I.
`
`QUALIFICATIONS ........................................................................................ 1
`
`II. ASSIGNMENT ................................................................................................ 8
`
`III. SUMMARY OF OPINIONS ........................................................................... 9
`
`IV. LEGAL PRINCIPLES ................................................................................... 12
`
`A.
`
`Priority ................................................................................................. 12
`
`B. Obviousness ......................................................................................... 13
`
`C.
`
`Person Of Ordinary Skill In The Art ................................................... 17
`
`V.
`
`THE ’772 PATENT ....................................................................................... 18
`
`VI. GROUND 1: CLAIMS 1-3 AND 10 OF THE ’772 PATENT
`WOULD NOT HAVE BEEN OBVIOUS TO A PERSON OF
`ORDINARY SKILL IN THE ART IN VIEW OF MORRIS,
`LEMKE, YALKOWSKY, VAN DUYNE AND ROSSMANN ................... 21
`
`A. Dr. Jorgensen’s Arguments About The C40 Groups A
`POSA Would Consider Are Unsupported........................................... 23
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`Prior Art Rapamycin Derivatives Were Not
`Limited To Those With Small C40 Groups .............................. 24
`
`One Of Ordinary Skill In The Art Would Have
`Considered Substituents Containing Ester, Amide,
`Carboxylic Acid And/Or Phenol Groups .................................. 42
`
`The Structure Of Rapamycin Bound To FKBP-12
`Would Not Have Led One Of Ordinary Skill To
`Consider Only Dr. Jorgensen’s “Small”
`Substituents ............................................................................... 52
`
`Dr. Jorgensen Ignores Substituents Other Than
`Those Attached To C40 By An Oxygen Atom ......................... 58
`
`One Of Ordinary Skill Would Not Have Had A
`Reasonable Expectation Of Success ......................................... 64
`
`
`
`ii
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 2 of 194
`
`

`
`B. Dr. Jorgensen Does Not Compare The Properties Of
`Rapamycin With Other Known Immunosuppressants Or
`Explain Why A Person Of Ordinary Skill Knowing
`Those Comparative Properties Would Have Nevertheless
`Selected Rapamycin ............................................................................ 90
`
`1.
`
`2.
`
`3.
`
`4.
`
`Dr. Jorgensen’s Identification Of Rapamycin As A
`Lead Compound Based On Morris ........................................... 91
`
`Dr. Jorgensen Did Not Explain Why A Person Of
`Ordinary Skill Knowing The Properties Of Other
`Immunosuppressants Would Have Nevertheless
`Selected Rapamycin .................................................................. 97
`
`One Of Ordinary Skill In The Art Would Not Have
`Selected Rapamycin As A Lead Compound Based
`On Van Duyne ........................................................................ 103
`
`One Of Ordinary Skill In The Art Would Not Have
`Selected Rapamycin As A Lead Compound Based
`On Stella, Hughes, And Schiehser .......................................... 105
`
`C. Dr. Jorgensen’s Selection Of The C40 Position ............................... 107
`
`1.
`
`2.
`
`3.
`
`Dr. Jorgensen’s Discussion Of Rapamycin’s
`Binding And Effector Domains Based On
`Schreiber And Van Duyne Is Incorrect ................................... 108
`
`Dr. Jorgensen Improperly Relies On Van Duyne’s
`Three-Dimensional Coordinates Of Rapamycin
`Bound To FKBP-12 ................................................................ 113
`
`Dr. Jorgensen Ignores What Positions Were Being
`Modified In The Prior Art As A Whole .................................. 113
`
`D. Objective Indicia Of Non-Obviousness Support My
`Conclusion That Everolimus Would Not Have Been
`Obvious.............................................................................................. 123
`
`1.
`
`Novartis’s Zortress® And Afinitor® Products Are
`Covered By Claims 1-3 And/Or 8-10 Of The ’772
`Patent ....................................................................................... 124
`
`
`
`iii
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 3 of 194
`
`

`
`2.
`
`3.
`
`4.
`
`5.
`
`There Was A Long-Felt Need For A Safe And
`Effective Immunosuppressant Treatment ............................... 126
`
`Failure Of Others To Develop New
`Immunosuppressants To Prevent Transplant
`Rejection ................................................................................. 127
`
`Unexpected Results ................................................................. 128
`
`Conclusion .............................................................................. 130
`
`VII. GROUND 2: CLAIMS 8 AND 9 WOULD NOT HAVE BEEN
`OBVIOUS TO A PERSON OF ORDINARY SKILL IN
`LIGHT OF MORRIS, VAN DUYNE, ROSSMAN,
`YALKOWSKY, LEMKE AND HUGHES ................................................. 131
`
`
`
`
`
`iv
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 4 of 194
`
`

`
`I, William R. Roush, Ph.D., declare as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I am Professor of Chemistry and Executive Director of
`
`Medicinal Chemistry of the Scripps Research Institute in Jupiter, Florida (“Scripps
`
`Florida”). A copy of my curriculum vitae is included as Exhibit 2094. My
`
`educational background and my professional experience are summarized below.
`
`2.
`
`I obtained a Bachelor of Science degree in Chemistry from the
`
`University of California, Los Angeles in 1974, graduating summa cum laude. I
`
`obtained my Ph.D. in Chemistry from Harvard University in 1977. My Ph.D.
`
`thesis concerned the synthesis of a natural product known as dendrobine.
`
`3.
`
`After a year of post-doctoral work at Harvard (1977-78), I
`
`joined the faculty at the Massachusetts Institute of Technology (MIT) as an
`
`Assistant Professor of Chemistry. I taught chemistry courses and performed
`
`research at MIT from 1978 to 1987. My research interests included the total
`
`synthesis of natural products and the development of new synthetic methods.
`
`4.
`
`In 1987, I moved to Indiana University, where I ultimately
`
`became Distinguished Professor of Chemistry. At Indiana University, I initiated a
`
`research program on the design and synthesis of inhibitors of cysteine proteases.
`
`In 1997, I was appointed the Warner-Lambert/Parke-Davis Professor of Chemistry
`
`at the University of Michigan. This is an endowed chair established by a gift from
`
`
`
`1
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 5 of 194
`
`

`
`Parke-Davis to the University of Michigan. I subsequently served as the Chairman
`
`of the Department of Chemistry at the University of Michigan from 2002–2004.
`
`While at the University of Michigan, I served as Co-Director of the Life Sciences
`
`Initiative Commission, which conceived the Life Sciences Institute (LSI), and laid
`
`out the blueprint for its creation and development to stimulate interdisciplinary
`
`research in the biomedical sciences. I also continued to develop my research
`
`program focusing on the synthesis of biologically active natural products, the
`
`development of new synthetic methodology, and the design and development of
`
`inhibitors of cysteine proteases.
`
`5.
`
`In 2004, I was recruited to join the Scripps Research Institute at
`
`its new campus in Florida. I assumed my current positions—Executive Director of
`
`Medicinal Chemistry and Professor of Chemistry—in 2005. Scripps Florida is a
`
`branch of the well-known Scripps Research Institute, which is headquartered in La
`
`Jolla, California. The Scripps Research Institute is one of the leading biomedical
`
`research institutes in the world and is internationally recognized for its
`
`commitment to, and its basic research in, the fields of immunology, biology,
`
`chemistry, neurosciences, virology, autoimmune and cardiovascular diseases, and
`
`synthetic vaccine development. Particularly significant is the Scripps Research
`
`Institute’s study of the basic structure and design of biological molecules.
`
`
`
`2
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 6 of 194
`
`

`
`6.
`
`I currently serve as Executive Director of Medicinal Chemistry
`
`in the Drug Discovery Division of Scripps’ Translational Research Institute at
`
`Scripps Florida. In this position, I direct the research of twelve to sixteen (12–16)
`
`staff medicinal chemists who are charged with performing structure-activity
`
`relationship (“SAR”) studies to optimize drug candidates for several drug
`
`discovery projects internal to Scripps.
`
`7.
`
`Projects at Scripps Florida that have been performed under my
`
`directorship, or are still active, include the development and optimization of
`
`enzyme inhibitors for cancer targets, central nervous system diseases (e.g.,
`
`Parkinson’s disease), and metabolic diseases, among others. In addition, I
`
`personally direct an academic research program with eleven (11) graduate students
`
`and postdoctoral associates that is funded primarily by the National Institutes of
`
`Health (“NIH”). This program includes medicinal chemistry research projects
`
`focusing on development of agonists and antagonists of nuclear receptors,
`
`development of inhibitors of enzyme targets (including kinases, cysteine proteases,
`
`metallomatrix proteinases, histone deacetylates, and cytochrome P51, among
`
`others) and development of inhibitors of transporters responsible for active
`
`transport of molecules into and out of cells.
`
`8. Many of the medicinal chemistry projects that I am pursuing at
`
`Scripps Florida involve use of structure-based drug design. I have used X-ray
`
`
`
`3
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 7 of 194
`
`

`
`crystal structures of enzymes with bound inhibitors to understand mechanisms of
`
`enzyme inhibition and to design improved inhibitors of enzyme targets.
`
`9.
`
`In addition, I have used structure guided drug design techniques
`
`to develop inhibitors, including a Cyp51 inhibitor with activity against the parasite
`
`Trypanosoma cruzi. This work encompasses the use of X-ray crystallography and
`
`computer modeling to explore compounds to be tested as part of a SAR study.
`
`10.
`
`I am also currently engaged in an NIH funded project to
`
`develop antibody-drug conjugates—a novel class of prodrugs—in which the
`
`antibody targets specific cells, and the drug is cleaved by enzymes within the cell
`
`after the conjugate is internalized. Specific cleavage mechanisms being pursued
`
`include use of peptide linkers (to connect the drug to the antibody) that are
`
`specifically targeted by enzymes inside the cancer cell.
`
`11.
`
`I am well-known for my research on the synthesis of natural
`
`products, development of new synthetic methodology, and medicinal chemistry.
`
`While at MIT, Indiana University, the University of Michigan, and now at Scripps
`
`Florida, I have synthesized more than twenty-five (25) stereochemically complex,
`
`optically active natural products and more than six hundred (600) cysteine protease
`
`inhibitors, two of which have undergone detailed preclinical evaluation. We have
`
`also synthesized hundreds of inhibitors of kinases, metallomatric proteinases,
`
`cytochrome P51, and the monocarboxylate transporter, many of which are
`
`
`
`4
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 8 of 194
`
`

`
`optically active molecules. Compounds that we have optimized in each of these
`
`projects have proven highly effective in animal models of human disease.
`
`12. An important aspect of my work is understanding the
`
`biochemistry of the biological drug targets. Use of X-ray crystallography and
`
`molecular modeling is an important component of this work. I frequently work
`
`with biologists and pharmacologists on projects, and I regularly review and assess
`
`the results of biological experiments and use those results to make decisions about
`
`how to further improve the compounds that are the subjects of these medicinal
`
`chemistry research projects.
`
`13. From 2007 through 2014, I served as the Chairman of the
`
`Chemistry Coordination Committee of the Scripps Molecular Screening Center,
`
`which was one of four centers forming the Molecular Libraries Production Centers
`
`Network (MLPCN), an NIH-funded program which screened potential drug targets
`
`and performed SAR studies to optimize potential drug candidates.
`
`14.
`
`I have served a five-year term on the NIH Medicinal Chemistry
`
`Study Section, including two years as Chair. The Medicinal Chemistry Study
`
`Section reviewed research proposals in medicinal chemistry submitted to the NIH,
`
`and ranked these applications in terms of their scientific merit.
`
`15.
`
`I have presented my research in more than two hundred (200)
`
`invited lectures at universities and pharmaceutical companies. In addition, I have
`
`
`
`5
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 9 of 194
`
`

`
`been invited to deliver more than one hundred (~115) named, keynote, or plenary
`
`lectures at universities, national and international symposia, and conferences. All
`
`of the invited, named, keynote, and plenary lectures that I have presented during
`
`my career have been based on my research on compound synthesis and/or the
`
`biological evaluation of specific compounds that I have synthesized.
`
`16. Over the course of my academic career, I have taught many
`
`undergraduate and graduate courses in organic chemistry. The graduate courses
`
`have focused mainly on asymmetric synthesis, which is the making of
`
`stereochemically complex, optically active molecules.
`
`17.
`
`I have also repeatedly taught a two-and-a-half day short course
`
`entitled “Recent Advances in Organic Synthesis Methodology: Stereocontrolled
`
`Synthesis of Acyclic Organic Compounds” to members of the pharmaceutical
`
`industry in the United States, Canada, and Europe. The typical participants in this
`
`course are medicinal chemists with B.S., M.S., or Ph.D. backgrounds. The course
`
`material that I presented focused on methods for synthesis of stereochemically
`
`complex, biologically active molecules, including drug candidates.
`
`18.
`
`I have published extensively in the scientific literature and have
`
`authored or co-authored more than three hundred forty-five (345) papers relating to
`
`organic synthesis and medicinal chemistry. This includes more than fifty (50)
`
`
`
`6
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 10 of 194
`
`

`
`scientific articles dealing specifically with the synthesis and biochemical and/or
`
`biological evaluation of small molecule inhibitors or modulators of protein targets.
`
`19.
`
`I have received a number of awards for my research, including
`
`the Arthur C. Cope Scholar Award (1994) from the American Chemical Society,
`
`the Paul G. Gassmann Distinguished Service Award from the American Chemical
`
`Society Division of Organic Chemistry (2002), and the Ernest Guenther Award in
`
`the Chemistry of Natural Products from the American Chemical Society (2004). In
`
`2006, I was elected a Fellow of the American Association for the Advancement of
`
`Science, and in 2009, I was elected a Fellow of the American Chemical Society.
`
`20. From 1999 through July 2016, I was an Associate Editor of the
`
`Journal of the American Chemical Society. In addition, I am on the editorial board
`
`of Organic Letters and previously served on the editorial advisory board of
`
`Chemical Biology and Drug Design and the Journal of Organic Chemistry, among
`
`others. I am also a member of the Boards of Directors of Organic Syntheses, Inc.
`
`and Organic Reactions, Inc., which publish the Organic Syntheses and Organic
`
`Reactions monographs.
`
`21.
`
`I also regularly consult with pharmaceutical and biotechnology
`
`companies. These consultations focus, in general, on aspects of medicinal
`
`chemistry, synthetic chemistry, and process chemistry for companies engaged in
`
`drug discovery and development. I also participate, as a consultant, in strategic
`
`
`
`7
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 11 of 194
`
`

`
`planning exercises. The companies I currently consult with are Eli Lilly and
`
`Company and IFM Therapeutics. In the past I have also consulted with Pfizer Inc.,
`
`Genzyme Corporation, ArQule Inc., NeXstar Pharmaceuticals Inc., Lycera and
`
`GMP Immunotherapeutics, among others.
`
`22.
`
`I consider myself to be an expert in organic chemistry,
`
`including one in the field of medicinal chemistry.
`
`II. ASSIGNMENT
`
`23.
`
`I understand that Par Pharmaceutical, Inc. (“Par”) submitted a
`
`petition seeking inter partes review (the “Petition”) of claims 1-3 and 8-10 of U.S.
`
`Patent No. 5,665,772 (“the ’772 patent”). (Paper 2.) I further understand that in
`
`response to Par’s Petition, the Patent Trial and Appeal Board (the “Board”) of the
`
`United States Patent and Trademark Office issued a decision instituting inter
`
`partes review on the following grounds (the “Institution Decision”):
`
`Ground
`
`1
`
`2
`
`Challenged
`Claims
`1-3, 10
`
`8, 9
`
`
`(Paper 8 at 17-18.)
`
`References
`
`Morris, Van Duyne, Rossmann,
`Yalkowsky, and Lemke
`Morris, Van Duyne, Rossmann,
`Yalkowsky, Lemke, and Hughes
`
`Basis
`
`§ 103(a)
`
`§ 103(a)
`
`24.
`
`I have been asked by counsel for Novartis AG (“Novartis”) to
`
`provide my views on various principles of drug discovery and medicinal
`
`
`
`8
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 12 of 194
`
`

`
`chemistry, and to respond to certain opinions expressed in the October 26, 2015
`
`Declaration of William L. Jorgensen Ph.D. in Support of Petition for Inter Partes
`
`Review of U.S. Patent No. 5,665,772 (Ex. 1003) (the “Jorgensen Declaration” or
`
`“Jorgensen Dec.”) and the transcript of the August 9, 2016 Deposition of William
`
`L. Jorgensen, Ph.D. (Ex. 2091) (the “Jorgensen Deposition Transcript” or
`
`“Jorgensen Dep. Tr.”), as well as certain arguments in Par’s Petition and the
`
`Board’s Institution Decision, as discussed below, that are within my area of
`
`expertise.
`
`25. My opinions are based on my study of the ’772 patent, its file
`
`history, the Jorgensen Declaration and documents cited in that declaration, the
`
`Jorgensen Deposition Transcript, Par’s Petition, the Board’s Institution Decision,
`
`the other documents referred to below, and my knowledge and experience.
`
`III. SUMMARY OF OPINIONS
`
`26. As set forth below, I disagree with Dr. Jorgensen that one of
`
`ordinary skill in the art would have found claims 1-3 and 8-10 of the ’772 patent
`
`obvious. Unlike Dr. Jorgensen’s reliance on a few selected references, one of
`
`ordinary skill in the art would have considered the prior art as a whole. And based
`
`on that art, he or she would not have arrived at the invention claimed in the ’772
`
`patent or reasonably expected that the claimed compound everolimus would have
`
`the properties that it actually possesses.
`
`
`
`9
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 13 of 194
`
`

`
`27. First, Dr. Jorgensen never explains why one of ordinary skill in
`
`the art would have selected rapamycin as a lead compound from among the other
`
`known immunosuppressive agents in the art as of October 1992. At that time,
`
`rapamycin’s safety and efficacy in humans were unknown, and rapamycin had
`
`been reported to be toxic in large animals. In addition, one of rapamycin’s
`
`necessary biological targets was unknown. On the other hand, as of October 1992,
`
`there were multiple other immunosuppressive agents that either had been FDA-
`
`approved or were in clinical trials with promising results reported in the prior art.
`
`Dr. Jorgensen, however, never discusses these other immunosuppressive agents or
`
`explains why one of ordinary skill in the art would have selected rapamycin as a
`
`lead compound from among these other known compounds. Without selecting
`
`rapamycin as a lead compound, one of ordinary skill in the art would not have
`
`arrived at everolimus.
`
`28. Second, I disagree with Dr. Jorgensen that one of ordinary skill
`
`in the art would have considered modifying only the C40 position of rapamycin
`
`because the prior art disclosed modifications at many different positions.
`
`Furthermore, to select C40 for modification, Dr. Jorgensen improperly relies on
`
`three-dimensional coordinates of rapamycin bound to one of its target proteins,
`
`FKBP-12, that would not have been available to one of ordinary skill in the art as
`
`of October 1992.
`
`
`
`10
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 14 of 194
`
`

`
`29. Third, I disagree with Dr. Jorgensen that a person of ordinary
`
`skill would have limited modifications to rapamycin to only three small groups,
`
`one of which would lead to everolimus. Contrary to Dr. Jorgensen’s opinion that
`
`one of ordinary skill in the art would have tried the smallest possible
`
`modifications, there were numerous examples in the prior art of large
`
`modifications at rapamycin’s C40 position. And while Dr. Jorgensen excludes
`
`certain groups reported to increase water solubility based on their size or potential
`
`instability, the prior art reported numerous rapamycin derivatives and/or
`
`commercially approved drug products that contained the very groups Dr. Jorgensen
`
`excludes.
`
`30. Even if one of ordinary skill in the art had been motivated to
`
`make the specific modification at the C40 position to arrive at everolimus, I
`
`disagree that one of ordinary skill would have reasonably expected everolimus to
`
`have the same or similar immunosuppressive activity as rapamycin, or the unique
`
`combination of properties that everolimus actually has. Dr. Jorgensen’s own cited
`
`art indicated that effects of modifications to rapamycin’s activity were
`
`unpredictable. Dr. Jorgensen further admitted at deposition that it would have
`
`been unclear to one of ordinary skill in the art whether everolimus would have
`
`immunosuppressive activity, and thus, he or she would have had to conduct testing.
`
`Dr. Jorgensen’s reliance on three-dimensional coordinates of rapamycin bound to
`
`
`
`11
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 15 of 194
`
`

`
`FKBP-12 to conclude that everolimus’ immunosuppressive activity could
`
`reasonably be predicted is misplaced because rapamycin must also bind to an
`
`effector protein to have immunosuppressive activity. Thus, binding to FKBP-12
`
`alone would not have allowed one of ordinary skill in the art reasonably to predict
`
`immunosuppressive activity. But as of October 1992, that effector and how
`
`rapamycin interacts with the effector were unknown. In addition, the three-
`
`dimensional coordinates on which Dr. Jorgensen relies were not available as of
`
`October 1992. In sum, without making and testing everolimus, one of ordinary
`
`skill would not have reasonably predicted the effect of everolimus’ modifications
`
`at C40 on immunosuppressive activity.
`
`31. Lastly, objective indicia of non-obviousness, including a long-
`
`felt need for a safe and effective immunosuppressive agent, failure by others to
`
`develop an immunosuppressive agent, and everolimus’ unexpected properties, also
`
`support my conclusion that everolimus would not have been obvious to one of
`
`ordinary skill in the art.
`
`IV. LEGAL PRINCIPLES
`
`A.
`
`Priority
`
`32.
`
`I understand from counsel that a patentee can rely on the filing
`
`date of a priority application if the inventors were in possession of the claimed
`
`invention at the time the priority application was filed. For a claim to a compound
`
`
`
`12
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 16 of 194
`
`

`
`or a genus of compounds, possession of the invention can be shown by naming the
`
`compound or genus or illustrating the compound or genus with chemical diagrams.
`
`33.
`
`I understand that the ’772 patent claims priority to application
`
`GB9221220 (“GB ’220 priority application,” Ex. 2057), which was filed on
`
`October 9, 1992. Dr. Jorgensen and Par have used the October 9, 1992 date for
`
`the purposes of their analysis. (See Ex. 1003, Jorgensen Dec. ¶ 17; Ex. 2091,
`
`Jorgensen Dep. Tr. 9:14-21; Paper 2, Par Petition at 26.1) I have reviewed claims
`
`1-3 and 8-10 of the ’772 patent and agree that the GB ’220 priority application
`
`shows that the inventors were in possession of the inventions described in those
`
`claims as of October 9, 1992.
`
`B. Obviousness
`
`34. Novartis’s counsel has informed me that claims 1-3 and 8-10 of
`
`the ’772 Patent are “obvious” only if their subject matter, as a whole, would have
`
`been obvious to one of ordinary skill in the art as of the invention date, here,
`
`October 9, 1992. I understand that in an inter partes review, the petitioner has the
`
`burden of proving that the challenged patent claims are obvious by a
`
`
`1 Par states that the earliest priority date is “October 29, 1992,” but that is
`
`presumably a typographical error as the ’772 patent clearly claims priority to the
`
`October 9, 1992 GB ’220 priority application. (Ex. 2120, ’772 patent at 1.)
`
`
`
`13
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 17 of 194
`
`

`
`preponderance of the evidence—i.e., that the challenged claims are more likely
`
`obvious than not.
`
`35.
`
`I understand that obviousness is assessed from the vantage
`
`point of one of ordinary skill in the field of the invention and that factors such as:
`
`(i) the education level of those working in the field, including the inventor(s) of the
`
`patent-in-suit; (ii) the sophistication of the technology; (iii) the types of problems
`
`encountered in the art; (iv) the prior art solutions to those problems; and (v) the
`
`speed at which innovations are made, help establish the level of ordinary skill in
`
`the art.
`
`36.
`
`I further understand that the Board will determine whether an
`
`invention is obvious by assessing: (i) the level of ordinary skill in the art; (ii) the
`
`scope and content of the prior art; (iii) the differences between the prior art and
`
`subject matter claimed; and (iv) the existence of any objective evidence of non-
`
`obviousness (“objective indicia”), such as unexpected results, commercial success,
`
`long-felt but unmet needs, praise, and/or failure of others.
`
`37.
`
`In determining obviousness in cases involving new chemical
`
`compounds like everolimus, I understand that the Board will consider whether one
`
`of ordinary skill in the art would have selected the asserted prior art compound as a
`
`lead compound, or starting point, for further development and chemical
`
`modification. I understand that the lead compound selection, like other aspects of
`
`
`
`14
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 18 of 194
`
`

`
`the obviousness analysis, must be based on an analysis of the prior art as a whole.
`
`Such an analysis necessarily involves a comparison of the properties of the
`
`available options such that the person of ordinary skill is in a position to identify
`
`which of those compounds constitutes a natural choice for further development and
`
`chemical modification efforts. I understand that the person of ordinary skill may
`
`select more than one lead compound from the available options. I further
`
`understand that the Board will consider factors including whether the asserted prior
`
`art compound possessed promising useful properties and the extent to which it had
`
`been studied.
`
`38.
`
`I understand that the Board will also consider whether the prior
`
`art would have supplied one of ordinary skill in the art with a reason or motivation
`
`to modify a lead compound to make the claimed compound with a reasonable
`
`expectation of success. I further understand that the motivation to modify a lead
`
`compound need not be explicit in the art.
`
`39.
`
`In determining whether there would have been a reasonable
`
`expectation of success, I understand that the Board will consider whether there
`
`would have been a reasonable expectation of achieving the unique combination of
`
`properties possessed by the claimed compound; absolute predictability of the
`
`results is not required.
`
`
`
`15
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 19 of 194
`
`

`
`40.
`
`I understand that the Board will consider the existence of any
`
`objective evidence of non-obviousness or secondary considerations where there is
`
`a causal relationship or “nexus” between the patented invention and the objective
`
`evidence.
`
`41.
`
`I understand that unexpected results of a claimed compound are
`
`one type of objective evidence that show that a claimed compound would not have
`
`been obvious. I understand that the Board will consider whether the claimed
`
`compound possesses beneficial properties that a person of ordinary skill in the art,
`
`as of the invention date, would have found surprising or unexpected. To be
`
`evidence of non-obviousness, the results must be shown to be unexpected as
`
`compared to the closest prior art. However, there is no requirement that the
`
`claimed compound’s properties were fully known as of the invention date, or that
`
`the patent contain all of the work done in studying the claimed compound.
`
`42. Commercial success of a claimed compound is another type of
`
`objective evidence that a claimed compound invention would not have been
`
`obvious. I understand that it is not necessary for the claimed compound to be
`
`solely responsible for the commercial success.
`
`43. Failure of others to solve the problem addressed by the claimed
`
`compound is also objective evidence that a claimed compound invention is not
`
`obvious.
`
`
`
`16
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 20 of 194
`
`

`
`44. Acclaim or praise for the claimed compound is another type of
`
`objective evidence that a claimed compound invention is not obvious.
`
`45. Finally, I understand that it is improper in the obviousness
`
`analysis to use hindsight knowledge of the claimed compound itself.
`
`C.
`
`Person Of Ordinary Skill In The Art
`
`46.
`
`I understand that the qualifications of the person of ordinary
`
`skill in the art here are assessed as of October 9, 1992, the date on which the GB
`
`’220 priority application was filed. Dr. Jorgensen’s analysis also uses the October
`
`9, 1992 date. (See Ex. 1003, Jorgensen Dec. ¶ 17; Ex. 2091, Jorgensen Dep. Tr.
`
`8:22-9:2, 9:14-21.)
`
`47.
`
`I agree with Dr. Jorgensen that in general, the hypothetical
`
`person of ordinary skill in this art as of October 9, 1992, would have been someone
`
`with a Ph.D. in medicinal or organic chemistry; or alternatively, the person of
`
`ordinary skill in the art could have had a bachelor’s or master’s degree in
`
`medicinal or organic chemistry with practical experience in the field. (Ex. 1003,
`
`Jorgensen Dec. ¶ 45.)
`
`48. The person of ordinary skill in the art here would be working in
`
`the field of drug discovery and would have had access to individuals with
`
`knowledge and skills that he or she did not possess through formal training or
`
`personal experience. In addition to having access to persons with experience in
`
`
`
`17
`
`NOVARTIS EXHIBIT 2093
`Par v Novarits, IPR 2016-00084
`Page 21 of 194
`
`

`
`computer-aided drug design, crystallography, and biological testing, as Dr.
`
`Jorgensen states (Ex. 1003, Jorgensen Dec. ¶ 46), an organic or medicinal chemist
`
`working in the field of drug discovery would had have access to other individuals,
`
`including: someone with experience in immunology, anti-tumor agents and drug
`
`formulation development.
`
`V. THE ’772 PATENT
`
`49. The ’772 patent relates to, among other things, specific
`
`derivatives of rapamycin and methods of using those derivatives. I understand that
`
`Par has asserted that claims 1-3 and 8-10 of the ’772 patent are obvious and
`
`therefore unpatentable.2
`
`50. Claim 10 of the ’772 patent specifically claims the compound
`
`40-O-(2-hydroxyethyl)-rapamycin (using the ’772 patent’s numbering scheme),
`
`which is also called everolimus. (Ex. 2120, ’772 patent, claim 10 at col. 22, lines
`
`29-30, as corrected by Certificate of Correction dated June 30, 1998.) As Dr.
`
`Jorgensen states, everolimus, or the use thereof, falls within claim 10 and each of
`
`
`2 I have set forth claims 1-3 and 8-10 of the ’772 patent in the attached Addendum
`
`A. Throughout this declaration I refer to the version of the ’772 patent labeled Ex.
`
`2120 rather