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`Noven Pharmaceuticals, Inc.
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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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`NOVEN PHARMACEUTICALS, INC.,
`Petitioner
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`v.
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`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
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`_________________________________
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`
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`Inter Partes Review No.: 2014-00549
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`U.S. Patent 6,316,023
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`REPLY DECLARATION OF AGIS KYDONIEUS, PH.D.
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`TABLE OF CONTENTS
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`Page
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`QUALIFICATIONS................................................................................. 1
`I.
`INFORMATION CONSIDERED ............................................................. 1
`II.
`SUMMARY ............................................................................................ 3
`III.
`IV. PERSON OF ORDINARY SKILL IN THE ART ...................................... 6
`V.
`CLAIM CONSTRUCTION ...................................................................... 7
`VI. A POSA WOULD HAVE ANALYZED THE STRUCTURE OF
`RIVASTIGMINE AND DETERMINED THAT RIVASTIGMINE IS
`SUSCEPTIBLE TO OXIDATIVE DEGRADATION, WITHOUT
`NEEDING TO CONDUCT TESTING TO REACH THIS
`CONCLUSION. ..................................................................................... 10
`VII. DR. KLIBANOV MISCHARACTERIZES THE PRIOR ART AND
`MY OPINIONS REGARDING THE PRIOR ART. ................................. 14
`A. Dr. Klibanov Mischaracterizes Enz (Exhibit 1002). ........................ 15
`B.
`Dr. Klibanov Mischaracterizes Rosin (Exhibit 1008). ..................... 15
`C. Dr. Klibanov Mischaracterizes Elmalem (Exhibit 1009). ................ 24
`D. Dr. Klibanov Mischaracterizes Sasaki (Exhibit 1005). .................... 34
`VIII. A POSA WOULD HAVE BEEN MOTIVATED TO COMBINE THE
`TEACHINGS OF THE PRIOR ART TO ADDRESS THE
`EXPECTED SUSCEPTIBILITY OF RIVASTIGMINE TO
`OXIDATIVE DEGRADATION BY ADDING AN ANTIOXIDANT. ..... 43
`A. A POSA Would Not Draw a Distinction Between Enz, Rosin
`and Elmalem Based on Modes of Drug Administration. ................. 44
`A POSA Would Have Considered Prior Art Regarding RA7
`(Rosin and Elmalem) as Relevant to Rivastigmine. ........................ 47
`C. A POSA Would Have Been Motivated to Combine Enz and
`Ebert. ........................................................................................... 48
`IX. ROSIN (EXHIBIT 1008) WOULD HAVE BEEN UNDERSTOOD
`BY A POSA TO CLAIM RIVASTIGMINE. ........................................... 49
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`B.
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`X. A POSA WOULD HAVE HAD A REASONABLE EXPECTATION
`THAT ADDING AN ANTIOXIDANT WOULD SUCESSSFULLY
`REDUCE OR ELIMINATE OXIDATIVE DEGRADATION OF
`RIVASTIGMINE. .................................................................................. 50
`XI. THE INVENTOR’S EXPERIENCE SUPPORTS MY ANALYSIS. ......... 53
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`APPENDICIES
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`APPENDIX A: Sasaki (Exhibit 1005) Working Examples Calculation
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`APPENDIX B: Calculation of Antioxidant Weight Percentage for Elmalem
`(Exhibit 1009)
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`I, Agis Kydonieus, Ph.D., declare and state as follows:
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`I.
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`QUALIFICATIONS
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`1.
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`I previously submitted a Declarations in IPR2014-00549 (Exhibit 1010)
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`setting forth my background and credentials. My curriculum vitae (Exhibit 1023)
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`sets forth my education and experience in further detail, and I further explained my
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`background during my January 13, 2015 deposition (Exhibit 1030 at 107:2-
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`109:13).
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`II.
`2.
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`INFORMATION CONSIDERED
`In forming the opinions set forth herein, I have considered the documents
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`and exhibits referenced by Patent Owners and those referenced by Dr. Klibanov in
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`his declaration (Exhibit 2012). I have also relied on my own experiences and
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`knowledge, and have also considered the documents referenced in my initial
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`declaration (Exhibit 1010) and those I mentioned during my deposition (Exhibit
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`1030).
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`3.
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`I have also considered the documents discussed herein, which include the
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`following:
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`•
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`•
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`The Board’s institution Decision for IPR2014-00549 (Paper 10).
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`The transcript for the Novartis v Noven trial that was held
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`December 1-3, 2014. (Exhibits 1026-1028.)
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`•
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`•
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`•
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`Internal Novartis memorandum written by Dr. Tiemessen,
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`N0272228-29. (Exhibit 1033.)
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`Internal Novartis e-mail communication from Dr. Tiemessen to O.
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`Garinot, N0272563. (Exhibit 1034.)
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` Meeting minutes of the LTS-Sandoz (Novartis)
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`working group, N0317247-64. (Exhibit 1035.)
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`Excerpts of the confidential transcript of the October 17-18, 2012
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`deposition of Dr. Henricus L.G.M. Tiemessen. (Exhibit 1036.)
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`• Morrison and Boyd, 2nd Ed. 1992. (Exhibit 1038.)
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`•
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`•
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`•
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`•
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`•
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`•
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`PDR Medical Dictionary, 1st Ed. 1995. (Exhibit 1039.)
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`CRC Handbook of Chemistry and Physics. (Exhibit 1040.)
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`U.S. Patent 7,683,205. (Exhibit 1041.)
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`U.S. Patent 8,324,429. (Exhibit 1042.)
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`Toronto Research Chemicals Inc. web page. (Exhibit 1044.)
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`David Shamah, Alzheimer Drug Pioneer to Get Israel Prize,
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`Professor Weinstock-Rosin, who developed Exelon, will be
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`recognized for her work on Israel Independence Day, TIMES OF
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`ISRAEL, Mar. 4, 2014. (Exhibit 1045.)
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`•
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`Textbook of Polymer Science, Chapter 9 (Billmeyer, 2d ed. 1971).
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`(Exhibit 1046.)
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`•
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`Trial Opinion, Novartis v. Watson, No. 11-11077 at D.I. 414.
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`(Exhibit 2002.)
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`4.
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`I understand, based on review of the Board’s institution Decision for
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`IPR2014-00549 (Paper 10), that the board has instituted an inter partes review on
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`the following grounds.
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`
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`(IPR 2014-00549, Paper 10 at 25.)
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`III. SUMMARY
`I have reviewed Patent Owners’ Response (Paper 25) and Patent Owners
`5.
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`do not contest that Enz is a proper starting point for obviousness of the ’023 patent.
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`(Paper 25 at page 22; see Exhibit 1010 at ¶¶ 46-47.)
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`6.
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`I disagree, however, with Dr. Klibanov’s statement that “a POSA would
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`not have been motivated to modify or improve the transdermal device in Example
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`2 of Enz to include an antioxidant.” (Exhibit 2012 at ¶ 16.)
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`7.
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`I also disagree with Dr. Klibanov’s assertion that a POSA would not have
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`predicted that rivastigmine would undergo oxidative degradation under
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`pharmaceutically relevant conditions, and the addition of an antioxidant would not
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`successfully reduce such oxidative degradation. (Exhibit 2012 at ¶ 35.)
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`8.
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`It is my opinion that a POSA would have reasonably predicted that
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`rivastigmine would be susceptible to oxidative degradation, which means that a
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`POSA would have understood, based on an analysis of the structure of
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`rivastigmine, that rivastigmine was likely to undergo oxidative degradation in any
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`given pharmaceutical formulation. The prior art also would have taught a POSA
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`that rivastigmine was susceptible to oxidative degradation.
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`9.
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`Because a POSA would have understood that rivastigmine was likely to
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`undergo oxidative degradation, the POSA would have been motivated to take steps
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`to reduce or eliminate the oxidative degradation. A POSA would have understood
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`that one commonly-used measure to counter oxidative degradation was adding an
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`antioxidant to the formulation.
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`10. Of course, whether rivastigmine would actually undergo oxidative
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`degradation in a particular pharmaceutical formulation depends on the specific
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`formulation. This is why, for a particular formulation, a POSA would conduct
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`testing to confirm to what extent, if any, the drug in the formulation oxidatively
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`degrades. But, whether rivastigmine oxidatively degrades, or does not degrade, in
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`a specific formulation does not change the fact that a POSA would have been
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`aware that rivastigmine was particularly susceptible to oxidation. Therefore, a
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`POSA would certainly not have been surprised to see rivastigmine oxidatively
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`degrade in a formulation. (Exhibit 1026 at 81:1-6.)
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`11. Prior to January 1998, the addition of an antioxidant to reduce or
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`eliminate oxidative degradation was a common and well-understood solution to
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`that problem. (See Exhibit 1026 (Day 1 Trial Tr.) at 90:5-10, 98:16-99:14, 180:13-
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`181:2, 183:3-6, 212:13-213:3; Exhibit 2017 (Remington’s) at 6 (page 1507)
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`(stating that “Oxidation is a prime cause of product instability” and “Oxidation
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`may be inhibited by the use of antioxidants”).) A POSA would have had a
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`reasonable expectation that adding an antioxidant would be successful in reducing
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`or eliminating oxidative degradation of rivastigmine. (See Exhibit 1026 at 188:21-
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`189:11.)
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`12. A POSA would have maintained a reasonable expectation that
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`rivastigmine would have been compatible with at least one conventional
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`antioxidant and reasonably expected that, if several of the commonly-used
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`antioxidants listed in the Handbook (Exhibit 1003) were selected and tried, at least
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`one would be effective. (See Exhibit 1026 at 147:3-148:10, 188:21-189:11.) Dr.
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`Klibanov has not disputed that a POSA would have this expectation. (Exhibit
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`1027 (Day 2 Trial Tr.) at 510:2-21.) And in my experience working in
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`pharmaceutical development of transdermals prior to 1998, my colleagues and I
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`were readily able to identify an antioxidant that would successfully stabilize
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`particular formulations using known experimental methods, such as a simple
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`matrix experiment, in which several antioxidants are evaluated at one time.
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`(Exhibit 1026 at 147:3-148:10, 188:21-189:11.)
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`IV. PERSON OF ORDINARY SKILL IN THE ART
`I disagree with Dr. Klibanov’s opinion that a POSA would not have been
`13.
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`able to make predictions about physical or chemical properties of a compound
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`based upon its chemical structure. (Exhibit 2012 at ¶ 25.) Dr. Klibanov does not
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`dispute that “the person of ordinary skill would have knowledge of organic
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`chemistry, or would collaborate with a person having knowledge of organic
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`chemistry.” (Id.) Indeed, Dr. Klibanov asserts that one of the listed inventors of
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`the ’023 patent, Dr. Tiemessen, worked on a team that included at least two Ph.D.
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`chemists. (Id. at ¶ 162.)
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`14. An introductory chemistry textbook, Morrison and Boyd (Exhibit 1038),
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`published in 1992, confirms that a POSA would have been able to predict physical
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`and chemical properties of a compound based upon its structure:
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`A molecule is often represented by a picture or
`model….The atomic nuclei are represented by
`letters…and the electrons that join them by lines or
`dots….Interpreted in terms of structural theory, they tell
`us a good deal about the compound whose molecules
`they represent: how to go about making it; what physical
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`properties to expect of it—melting point, boiling point,
`specific gravity, the kinds of solvents the compound will
`dissolve in, even wither it will be colored or not; what
`kind of chemical behavior to expect—the kind of
`reagents the compound will react with and the kind of
`products that will be formed, whether it will react rapidly
`or slowly. We would know all this about a compound
`that we have never encountered before, simply on the
`basis of its structural formula and what we understand its
`structural formula to mean.
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`(Exhibit 1038 at 6 (page 3); see also Exhibit 1016 (Ansel) at 11 (page 91); Exhibit
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`2014 (Modern Pharmaceutics) at 5 (page 181).)
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`15. A POSA would also have been able to predict whether a drug molecule is
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`susceptible to oxidative degradation. (E.g., Exhibit 1011 (Dr. Schöneich opening
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`declaration) at ¶ 12.)
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`V. CLAIM CONSTRUCTION
`I disagree with Dr. Klibanov’s opinion as to how a POSA would interpret
`16.
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`the scope of claims 1-2, 4-5 and 7-8 of the ’023 patent. Dr. Klibanov states that
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`“the claim cannot be read to include an equal or greater amount of the opposite
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`enantiomer, and hence the racemic compound, as this would read the express (S)-
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`enantiomer element out of the claim.” (Exhibit 2012 at ¶ 28.)
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`17. For example, Claim 1 of the ’023 patent recites as follows; as I disagree
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`with Dr. Klibanov regarding the claim term “comprising,” which is written as
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`“comprises” in claim 1, I have underlined the term “comprises”:
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`1. A pharmaceutical composition comprising 1 to 40 weight percent
`of (S)-N-ethyl-3-[(1-dimethylamino)ethyl]-N-methylphenyl
`carbamate in the form of a in free base or acid addition salt, 0.01 to
`0.5 weight percent of an antioxidant, and a diluent or carrier, wherein
`the weight percents are based on the total weight of the
`pharmaceutical composition.
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`(Exhibit 1001, ’023 patent, at 5 (8:17-22).)
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`18. A person of ordinary skill in the art would interpret the broadest
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`reasonable scope of claim 1 in light of the specification to include a composition
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`containing RA7.1
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`19.
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`It would make no sense to exclude equal or greater amounts of the (R)
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`enantiomer, but not exclude other excipients. That Dr. Klibanov interprets the
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`claim in such a selective manner demonstrates the faulty logic of his construction.
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`20.
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`It would also make no sense to exclude or limit the (R) enantiomer
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`because it is undisputed that both the (R) and (S) enantiomers behave the same
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`with respect to oxidative degradation. (Exhibit 1027 (Day 2 Trial Tr.) at 356:20-
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`1 As I explained in my opening declaration (Exhibit 1010 at ¶ 15), RA7 is a
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`racemate that is comprised of an equal mixture of (S) and (R) enantiomers. The
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`(S) enantiomer is known as rivastigmine.
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`357:4.)
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`21. Although a claim can be written to exclude an enantiomer, there is no
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`language in Claim 1 that would be understood by a POSA to exclude or limit the
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`amount of the (R)-enantiomer. The term “comprising” (written “comprises”)
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`would not be understood by a POSA to restrict the amount of the (R) enantiomer as
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`Dr. Klibanov suggests.
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`22.
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`I am further advised by attorneys for Petitioners that “comprising” is
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`construed as an inclusive term in interpreting claims, and that claims containing
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`this term are not limited to the specific elements recited. While I have evaluated
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`the claim language from the perspective of a POSA at the time of the invention,
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`my opinion that a POSA would not understand this term to restrict the amount of
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`(R) enantiomer is consistent with this advice.
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`23. An example of claim language that a POSA would have understood to
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`limit the amount of (R)-enantiomer is claim 1 of the ’176 patent (Exhibit 1025).
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`This claim recites: “The (S)-[N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-
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`phenyl-carbamate enantiomer substantially free of its (R) isomer in free base or
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`acid addition salt form.” (Exhibit 1025 at 6 (9:26-28) (emphasis added).)
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`VI. A POSA WOULD HAVE ANALYZED THE STRUCTURE OF
`RIVASTIGMINE AND DETERMINED THAT RIVASTIGMINE IS
`SUSCEPTIBLE TO OXIDATIVE DEGRADATION, WITHOUT
`NEEDING TO CONDUCT TESTING TO REACH THIS
`CONCLUSION.
`24. Dr. Klibanov repeatedly states that “Drs. Kydonieus and Schöneich
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`acknowledge, and I agree, that testing is required to determine whether and to what
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`extent rivastigmine will undergo oxidative degradation under pharmaceutically
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`relevant conditions.” (Exhibit 2012 at, e.g., ¶¶ 52 (first bullet), 60 (first bullet), 74
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`(first bullet), 168 (first bullet).) Dr. Klibanov does not cite to any testimony or
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`statement of mine (or of Dr. Schöneich) to support this repeated assertion. If Dr.
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`Klibanov is referring to testimony that he cites elsewhere in his declaration, I
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`disagree with Dr. Klibanov’s statement as it is misleading. Dr. Klibanov appears
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`to be referring to the concept that the occurrence of oxidation in a particular
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`formulation is formulation dependent. (See Exhibit 2012 at, e.g., ¶¶ 49, 109.)
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`While I do not disagree with that statement, I do disagree that testing would have
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`been required to determine that rivastigmine is susceptible to oxidative degradation
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`under pharmaceutically relevant conditions.
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`25.
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`It is my opinion that a POSA, being motivated to further develop the
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`rivastigmine formulation and device of Enz (Exhibit 1002),2 would have analyzed
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`2 Patent Owners do not contest that a POSA would have been motivated to start
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`with Enz. (Paper 25 at page 22; see Exhibit 1010 at ¶¶ 46-47.)
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`the chemical structure of rivastigmine as part of preformulation to determine
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`whether it was susceptible to degradation, including oxidative degradation. A
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`POSA would have understood that testing was not required to determine that
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`rivastigmine, based on its chemical structure, was susceptible to oxidative
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`degradation. Testing was instead used by a POSA to assess the extent of oxidative
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`degradation in a particular formulation, once the drug compound of that
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`formulation had been identified as susceptible to oxidative degradation. A POSA
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`would not have been surprised to see that rivastigmine oxidatively degraded in a
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`formulation because the POSA would have maintained a reasonable expectation of
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`rivastigmine’s susceptibility to do so.
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`26.
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`In my over 35 years of pharmaceutical development experience, including
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`transdermal formulation and product development work in the 1970’s and 1980’s, I
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`worked as a member of a team that included an organic chemist or a person with
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`knowledge of organic chemistry. (See Exhibit 1026 (Day 1 Trial Tr.) at 132:20-
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`133:1; Exhibit 1023 (Kydonieus CV) at 1-3; Exhibit 1030(Kydonieus Deposition)
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`at 107:2-19.) In my experience, we consulted with an organic chemist to
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`understand the susceptibility of a drug compound to oxidative degradation, and
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`other types of degradation, early in the development process. (Exhibit 1026 at
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`131:15-133:1; Exhibit 1030 at 107:2-19; Exhibit 1022 at 1-3.)
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`27.
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`It was routine for a POSA to make reasonable predictions as to whether a
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`compound would have been susceptible to oxidative degradation early in the
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`pharmaceutical development process (such as during preformulation), and such
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`predictions were made prior to the “testing” that Dr. Klibanov says is required.
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`(Exhibit 1026 (Day 1 Trial Tr.) at 146:21-148:10.)
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`28. The prior art taught the POSA to analyze the chemical structure of a drug
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`compound to make a reasonable prediction as to whether the drug would be
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`susceptible to oxidative degradation, which is consistent with my experience. As
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`one example, the 1985 book, “Introduction to Pharmaceutical Dosage Forms,” by
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`Dr. Ansel, states as follows:
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`One of the most important activities of
`preformulation work is the evaluation of the physical
`and chemical stability of the pure drug substance. . . .
`Stability studies conducted in the preformulation phase
`include solid state stability of the drug alone, solution
`phase stability, and stability in the presence of expected
`excipients.
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`Initial investigation begins through knowledge of the
`drug's chemical structure which allows the
`preformulation scientist to anticipate the possible
`degradation reactions.
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`(Exhibit 1016 (Ansel) at 9, section entitled “Stability” (emphasis added); Exhibit
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`2020 at 3.)
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`29. As another example, the 1995 text Modern Pharmaceutics, which Dr.
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`Klibanov testified was an authoritative text in pharmaceutics, (Exhibit 1027 (Day 2
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`Trial Tr.) at 523:19-524:2), states that “through the application of functional group
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`chemistry, it is possible to anticipate the potential modes of degradation that drug
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`molecules will likely undergo.” (Exhibit 2014 at 5 (page 181); Exhibit 1027 (Day
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`2 Trial Tr.) at 528:15-529:8.)
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`30. The prior art confirms that the POSA was indeed instructed and
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`encouraged to examine a drug molecule’s chemical structure in order to inform
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`herself about likely degradation issues:
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`31. Dr. Klibanov phrases the question at issue as “whether a compound such
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`as rivastigmine would have undergone oxidative degradation under
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`pharmaceutically relevant conditions.” (Exhibit 2012 at, e.g., ¶ 15.) To be clear,
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`my discussion of a POSA’s evaluation during the pharmaceutical development
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`process, and the pharmaceutics texts I reference above, of course refer to the
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`evaluation of whether a compound would have undergone oxidative degradation
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`under pharmaceutically relevant conditions. Because a POSA would have been
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`endeavoring to make a pharmaceutical formulation, the POSA would necessarily
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`have evaluated a drug’s likely modes of degradation under pharmaceutically
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`relevant conditions.
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`32. Patent Owners’ assert (Paper 25 (Response) at 18, 20) that certain
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`commercial amine-containing compounds and certain commercial benzylic-carbon
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`containing compounds were not reported to undergo oxidation. Patent Owners cite
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`only the Physician’s Desk Reference (“PDR”) to support this assertion. A POSA,
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`however, would have understood that the PDR does not report the modes of
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`degradation of the drugs, but instead it is a listing of information for the
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`prescribing of marketed drugs. Therefore, a POSA would not understand the
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`silence of the PDR regarding degradation to in any way indicate that the drug is not
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`susceptible to oxidative degradation.
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`VII. DR. KLIBANOV MISCHARACTERIZES THE PRIOR ART AND MY
`OPINIONS REGARDING THE PRIOR ART.
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`33. Dr. Klibanov mischaracterizes the prior art references, and my assertions
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`regarding them, in his declaration.
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`A. Dr. Klibanov Mischaracterizes Enz (Exhibit 1002).
`34. Dr. Klibanov states that “despite being aware of the teachings of Rosin
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`relied upon by the Petitioner and Dr. Kydonieus, the inventor of Enz did not teach
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`or suggest that rivastigmine underwent oxidative degradation under
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`pharmaceutically relevant conditions and was not motivated to add an antioxidant
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`in any rivastigmine pharmaceutical formulation.” (Exhibit 2012 at ¶ 57 (emphasis
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`added).)
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`35.
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`I disagree with Dr. Klibanov’s opinion that Enz’s silence regarding
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`adding an antioxidant is significant. A POSA would have been aware of
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`rivastigmine’s propensity towards oxidation based on its structure. The
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`transdermal formulation of Example 2 of Enz is not a finished composition, and
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`thus the references’ silence would not discourage a POSA from adding an
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`antioxidant to the formulations disclosed by Enz to address the problem.
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`B. Dr. Klibanov Mischaracterizes Rosin (Exhibit 1008).
`I disagree with Dr. Klibanov’s statements regarding Rosin, as I explain
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`36.
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`below.
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`37. Dr. Klibanov states that “Rosin discloses as ‘compounds of the invention’
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`over 8 million chemical compounds . . . . [t]hose compounds are referred to in
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`Rosin collectively as the ‘compounds of the invention.’ . . . RA7 is included among
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`those millions of compounds.” (Exhibit 2012 at ¶ 63.)
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`38.
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`I disagree with the implication that RA7 is disclosed by Rosin as merely
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`one among “millions” of compounds. A POSA would have understood the
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`“compounds of the present invention” to be a small set of RA-series compounds
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`that are claimed in Rosin and for which experimental data is disclosed in Rosin.
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`(Exhibit 1030 at 78:16-79:10.)
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`39. A POSA would have understood that Rosin discloses experimental data
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`based on oral, subcutaneous, and intravenous injection into rabbit subjects for
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`eleven RA-series compounds, RA4, RA5, RA6, RA7, RA8, RA10, RA11, RA12, RA13,
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`RA14, and RA15.
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`3 Rosin identifies seven of these compounds as “[t]he most
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`preferred compounds of the RA series,” RA4, RA5, RA6, RA7, RA8, RA14, and
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`RA15,4 and claims three of these compounds, including RA7, along with a method
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`of treatment using the three claimed compounds.5
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`3 The data is disclosed in Tables 1, 2, and 3 of Rosin. Melting points for the eleven
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`compounds are also disclosed at Column 10, Lines 28-35. (Exhibit 1008 at 6-7
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`(10:9-11:16).) The multiple experiments, in which the RA-series compounds were
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`administered orally, subcutaneously, and by intravenous injection are described in
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`column 9, lines 23-68.
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`4 Exhibit 1008 at 7 (12:56-57).
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`5 Exhibit 1008 at 8 (14:11-30). Claim 3 recites RA7 and pharmacologically-
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`acceptable salts thereof. (Exhibit 1008 at 8 (14:17-19).) Claim 4 recites a method
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`40. Moreover, the only excipients that Rosin states are “preferred” are the
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`antioxidants sodium metabisulfite and ascorbic acid. (Exhibit 1008 at 5 (7:51-53).)
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`41. Rosin’s statement that “[p]referred antioxidants for use with the
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`compounds of the present invention include sodium metabisulphite and ascorbic
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`acid” reinforces my opinion that Rosin’s language is directed towards this small set
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`of RA-series compounds. (Exhibit 1008 at 5 (7:51-53) (emphasis added).)
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`42. Therefore, a POSA would have understood Rosin’s disclosure to teach the
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`combination of the three claimed “most preferred” RA-series compounds (which
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`includes RA7) and the “preferred” antioxidants sodium metabisulfite and ascorbic
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`acid because these are the compounds and excipients singled out for preferential
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`reference:6
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`of treating diseases and conditions including Alzheimer’s by administering a
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`therapeutically-effective amount of the compounds claimed in claims 1-3. (Id. at 8
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`(14:20-30).)
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`6 Dr. Klibanov’s only support for his assertion that “Rosin does not teach or
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`suggest that an antioxidant is required for any of the ‘compounds of the invention,’”
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`is a citation to my deposition at Page 78, lines 8-15. (Exhibit 2012 at ¶ 66.) I did
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`not, however, make such a statement. (Exhibit 1030 (Kydonieus Tr.) at 78:8-15.)
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`(Exhibit 1008 at 5 (7:51-53), 7 (12:56-57), and 8 (14:11-17-19).)
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`43. A POSA would have understood the disclosure that “[p]referred
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`antioxidants” (Exhibit 1008 at 7:51-53) to mean that the inventors of Rosin had
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`learned, via hands-on experience with certain RA-series compounds, which
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`antioxidants worked best with those RA-series compounds that had been actually
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`tested, and which were then claimed as the invention. (See Exhibit 1030,
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`Kydonieus Tr. at 73:4-24.) Therefore, a POSA would have understood from the
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`disclosure of Rosin that there was a reasonable expectation that these antioxidants
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`would succeed in reducing oxidative degradation of the RA-series compounds in a
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`pharmaceutical formulation.
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`44. Dr. Klibanov further states that “Dr. Kydonieus agrees that a POSA
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`would have understood that the chemical stability of millions of ‘compounds of the
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`invention’ would vary unpredictably and that differences in stability would have to
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`be determined by testing.” (Exhibit 2012 at ¶ 67.) This is not what I said at
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`deposition, (Exhibit 1030 (Kydonieus Tr.) at 72:21-73:3) and I certainly do not
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`agree that chemical stability would “vary unpredictably” as Dr. Klibanov asserts.
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`As I explain in Paragraphs 24-31, a POSA would have understood that the
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`chemical stability of a compound can be predicted based upon its chemical
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`structure. This concept is also explained by Dr. Schöneich. (Exhibit 1026 (Day 1
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`Trial Tr.) at 48:2-49:19, 74:17-76:10.) Moreover, a POSA would not have to
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`determine the susceptibility to oxidative degradation of compounds by testing.
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`(Paragraphs 24-31.)
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`45. Dr. Klibanov further states that “Rosin specifically teaches that RA7
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`shows greater chemical stability than the prior art compound physostigmine.”
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`(Exhibit 2012 at ¶ 60 (page 34).) I disagree that Rosin teaches that RA7 shows
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`greater stability than physostigmine. Dr. Klibanov’s statement is a
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`mischaracterization of Rosin.
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`46. Dr. Klibanov does not cite to any documents, or any portion of Rosin, in
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`support of his statement. (Id.) I assume that Dr. Klibanov is relying on the two
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`portions of Rosin that he later cites in support of his statement that Rosin
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`“suggests” greater stability,” at Paragraph 66 of his declaration. The first reference
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`to Column 3, line 37-39 does not mention any RA-series compound, including
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`RA7. (Exhibit 2012 at ¶ 66 (citing Exhibit 1008 at 3:37-39.) The second portion
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`of Rosin to which Dr. Klibanov refers 7 actually says that RA7 and other preferred
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`compounds have a greater in vivo (meaning inside the body) potency than
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`physostigmine, particularly when administered orally. (Exhibit 1008 at 11:22-35.)
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`Rosin then states that this greater in vivo potency “may be due to” a list of four
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`possible reasons, including “slower metabolic degradation or/and excretion,” “a
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`higher lipid solubility,” “more efficient absorption from the gastro-intestinal tract,”
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`or “greater chemical stability.”8 (Id. at 11:29-35.) Dr. Klibanov does not assert
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`that there is any link between in vivo potency and greater oxidative stability under
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`pharmaceutically relevant conditions.
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`7 I address his second reference (which is the only one that refers to the RA-series
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`compounds), above.
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`8 Dr. Klibanov also selectively quotes from another reference, Weinstock 1986
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`(Exhibit 2036), to incorrectly imply that it, too, states that compounds like RA7
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`have “greater chemical stability.” (Exhibit 2012 at ¶ 96, footnote 9.) But, as with
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`Rosin, in reality Weinstock 1986 refers to the same four potential reasons to which
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`Rosin refers: slower metabolism in the body, higher lipid solubility, more efficient
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`absorption from the gastro-intestinal tract, or greater chemical stability. (Exhibit
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`2036 at 11 (page 546).)
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`47. Dr. Klibanov also asserts that, because the purported disclosure in the
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`prior art of “greater chemical stability” of rivastigmine or RA7 over physostigmine,
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`a POSA would conclude that “both rivastigmine and physostigmine were stable
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`toward oxidation.” (Exhibit 2012 at ¶ 48.)
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`48.
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`I disagree that the prior art taught that rivastigmine was stable toward
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`oxidation.9 Even if Rosin were taken to say that RA7 has “greater chemical
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`stability” than physostigmine, a POSA would not conclude from this disclosure
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`that RA7 was stable or not susceptible to oxidative degradation. Rosin describes
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`physostigmine as “chemically unstable,” with a short half-life of 20-40 minutes.
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`(Exhibit 1008 at 1:33-37.) Rosin explains that monomethyl derivatives, like
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`physostigmine, “tend to be unstable in solution and hydrolyse readily at
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`physiological pH.” (Exhibit 1008 at 2:45-47.) A POSA would have understood
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`that, logically, any comparison of RA7 to a “chemically unstable” compound like
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`physostigmine at best means that RA7 is more stable than an unstable compound.
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`A POSA would not have understood this to mean that RA7 was oxidatively stable
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`or that it doesn’t require an antioxidant, as Dr. Klibanov contends.
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`49. Dr. Klibanov further asserts that I “acknowledge” that Rosin teaches that
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`9 The remainder of the prior art references that I discuss in this declaration do not
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`show that rivastigmine was understood to be “stable” to oxidative degradation,
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`either, for the reasons I discuss herein.
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`RA7 “could be p