UNITED STATES PATENT AND TRADEMARK OFFICE
`___________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`___________________
`
`NOVEN PHARMACEUTICALS, INC.,
`Petitioner
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
`
`___________________
`
`Inter Partes Review IPR2014-00550
`
`U.S. Patent No. 6,335,031
`
`REPLY DECLARATION OF AGIS KYDONIEUS, PH.D.
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:20) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`TABLE OF CONTENTS
`
`Page
`
`
`I.
`QUALIFICATIONS................................................................................. 1
`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 STRUCTUREOF
`RIVASTIGMINE AND DETERMINED THAT RIVASTIGMINE IS
`SUSCEPTIBLE TO OXIDATIVE DEGRADATION, WITHOUT
`NEEDING TO CONDUCT TESTING TO REACH THIS
`CONCLUSION........................................................................................ 9
`VII. DR. KLIBANOV MISCHARACTERIZES THE PRIOR ART AND
`MY OPINIONS REGARDING THE PRIOR ART.................................. 14
`A. Dr. Klibanov Mischaracterizes Enz (Exhibit 1002).........................14
`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
`
`B.
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:21) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`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
`
`APPENDICIES
`
`APPENDIX A: Sasaki (Exhibit 1005) Working Examples Calculation
`
`APPENDIX B: Calculation of Antioxidant Weight Percentage for Elmalem
`(Exhibit 1009)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:22) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`I, Agis Kydonieus, Ph.D., declare and state as follows:
`
`I.
`
`QUALIFICATIONS
`
`1.
`
`I previously submitted a Declarations in IPR2014-00550 (Exhibit 1010)
`
`setting forth my background and credentials. My curriculum vitae (Exhibit 1022)
`
`sets forth my education and experience in further detail, and I further explained my
`
`background during my January 13, 2015 deposition (Exhibit 1029 at 107:2-
`
`109:13).
`
`II.
`
`2.
`
`INFORMATION CONSIDERED
`In forming the opinions set forth herein, I have considered the documents
`
`and exhibits referenced by Patent Owners and those referenced by Dr. Klibanov in
`
`his declaration (Exhibit 2012). I have also relied on my own experiences and
`
`knowledge, and have also considered the documents referenced in my initial
`
`declaration (Exhibit 1010) and those I mentioned during my deposition (Exhibit
`
`1029).
`
`3.
`
`I have also considered the documents discussed herein, which include the
`
`following:
`
`(cid:120)
`
`(cid:120)
`
`The Board’s institution Decision for IPR2014-00550 (Paper 10).
`
`The transcript for the Novartis v Noven trial that was held
`
`December 1-3, 2014. (Exhibits 1025-1027.)
`
`(cid:20)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:23) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`(cid:120)
`
`Internal Novartis memorandum written by Dr. Tiemessen,
`
`N0272228-29.
`
`(Exhibit 1033.)
`
`Internal Novartis e-mail communication from Dr. Tiemessen to O.
`
`Garinot, N0272563. (Exhibit 1034.)
`
`Meeting minutes of the LTS-Sandoz (Novartis)
`
`working group, N0317247-64.
`
`(Exhibit 1035.)
`
`Excerpts of the confidential transcript of the October 17-18, 2012
`
`deposition of Dr. Henricus L.G.M. Tiemessen. (Exhibit 1036.)
`
`Morrison and Boyd 2nd Ed. 1992. (Exhibit 1038.)
`
`PDR Medical Dictionary, 1st Ed. 1995. (Exhibit 1039.)
`
`CRC Handbook of Chemistry and Physics. (Exhibit 1040.)
`
`U.S. Patent 7,683,205. (Exhibit 1041.)
`
`U.S. Patent 8,324,429. (Exhibit 1042.)
`
`Toronto Research Chemicals Inc. web page. (Exhibit 1044.)
`
`David Shamah, Alzheimer Drug Pioneer to Get Israel Prize,
`
`Professor Weinstock-Rosin, who developed Exelon, will be
`
`recognized for her work on Israel Independence Day, TIMES OF
`
`ISRAEL, Mar. 4, 2014. (Exhibit 1045.)
`
`(cid:120)
`
`Textbook of Polymer Science, Chapter 9 (Billmeyer, 2d ed. 1971).
`
`(Exhibit 1046.)
`
`(cid:21)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:24) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`(cid:120)
`
`Trial Opinion, Novartis v. Watson, No. 11-11077 at D.I. 414.
`
`(Exhibit 2002.)
`
`4.
`
`I understand, based on review of the Board’s institution Decision for
`
`IPR2014-00550 (Paper 10), that the board has instituted an inter partes review on
`
`the following grounds.
`
`(IPR 2014-00550, Paper 10 at 28.)
`
`III.
`
`SUMMARY
`
`5.
`
`I have reviewed Patent Owners’ Response (Paper 25) and Patent Owners
`
`do not contest that Enz is a proper starting point for obviousness of the ’031 patent.
`
`(Paper 25 at page 21; see Exhibit 1010 at ¶¶ 47-48.)
`
`6.
`
`I disagree, however, with Dr. Klibanov’s statement that “a POSA would
`
`not have been motivated to modify or improve the transdermal device in Example
`
`2 of Enz to include an antioxidant.” (Exhibit 2012 at ¶ 16.)
`
`7.
`
`I also disagree with Dr. Klibanov’s assertion that a POSA would not have
`
`predicted that rivastigmine would undergo oxidative degradation under
`
`pharmaceutically relevant conditions, and the addition of an antioxidant would not
`
`(cid:22)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:25) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`successfully reduce such oxidative degradation. (Exhibit 2012 at ¶ 35.)
`
`8.
`
`It is my opinion that a POSA would have reasonably predicted that
`
`rivastigmine would be susceptible to oxidative degradation, which means that a
`
`POSA would have understood, based on an analysis of the structure of
`
`rivastigmine, that rivastigmine was likely to undergo oxidative degradation in any
`
`given pharmaceutical formulation. The prior art also would have taught a POSA
`
`that rivastigmine was susceptible to oxidative degradation.
`
`9.
`
`Because a POSA would have understood that rivastigmine was likely to
`
`undergo oxidative degradation, the POSA would have been motivated to take steps
`
`to reduce or eliminate the oxidative degradation. A POSA would have understood
`
`that one commonly-used measure to counter oxidative degradation was adding an
`
`antioxidant to the formulation.
`
`10. Of course, whether rivastigmine would actually undergo oxidative
`
`degradation in a particular pharmaceutical formulation depends on the specific
`
`formulation. This is why, for a particular formulation, a POSA would conduct
`
`testing to confirm to what extent, if any, the drug in the formulation oxidatively
`
`degrades. But, whether rivastigmine oxidatively degrades, or does not degrade, in
`
`a specific formulation does not change the fact that a POSA would have been
`
`aware that rivastigmine was particularly susceptible to oxidation. Therefore, a
`
`POSA would certainly not have been surprised to see rivastigmine oxidatively
`
`(cid:23)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:26) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`degrade in a formulation. (Exhibit 1025 at 81:1-6.)
`
`11.
`
`Prior to January 1998, the addition of an antioxidant to reduce or
`
`eliminate oxidative degradation was a common and well-understood solution to
`
`that problem. (See Exhibit 1025 (Day 1 Trial Tr.) at 90:5-10, 98:16-99:14, 180:13-
`
`181:2, 183:3-6, 212:13-213:3; Exhibit 2017 (Remington’s) at 6 (page 1507)
`
`(stating that “Oxidation is a prime cause of product instability” and “Oxidation
`
`may be inhibited by the use of antioxidants”).) A POSA would have had a
`
`reasonable expectation that adding an antioxidant would be successful in reducing
`
`or eliminating oxidative degradation of rivastigmine. (See Exhibit 1025 at 188:21-
`
`189:11.)
`
`12. A POSA would have maintained a reasonable expectation that
`
`rivastigmine would have been compatible with at least one conventional
`
`antioxidant and reasonably expected that, if several of the commonly-used
`
`antioxidants listed in the Handbook (Exhibit 1003) were selected and tried, at least
`
`one would be effective. (See Exhibit 1025 at 147:3-148:10, 188:21-189:11.) Dr.
`
`Klibanov has not disputed that a POSA would have this expectation. (Exhibit
`
`1026 (Day 2 Trial Tr.) at 510:2-21.) And in my experience working in
`
`pharmaceutical development of transdermals prior to 1998, my colleagues and I
`
`were readily able to identify an antioxidant that would successfully stabilize
`
`particular formulations using known experimental methods, such as a simple
`
`(cid:24)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:27) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`matrix experiment, in which several antioxidants are evaluated at one time.
`
`(Exhibit 1025 at 147:3-148:10, 188:21-189:11.)
`
`IV.
`13.
`
`PERSON OF ORDINARY SKILL IN THE ART
`I disagree with Dr. Klibanov’s opinion that a POSA would not have been
`
`able to make predictions about physical or chemical properties of a compound
`
`based upon its chemical structure. (Exhibit 2012 at ¶ 25.) Dr. Klibanov does not
`
`dispute that “the person of ordinary skill would have knowledge of organic
`
`chemistry, or would collaborate with a person having knowledge of organic
`
`chemistry.” (Id.) Indeed, Dr. Klibanov asserts that one of the listed inventors of
`
`the ’031 patent, Dr. Tiemessen, worked on a team that included at least two Ph.D.
`
`chemists. (Id. at ¶ 162.)
`
`14. An introductory chemistry textbook, Morrison and Boyd (Exhibit 1038),
`
`published in 1992, confirms that a POSA would have been able to predict physical
`
`and chemical properties of a compound based upon its structure:
`
`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
`properties to expect of it—melting point, boiling point,
`specific gravity, the kinds of solvents the compound will
`
`(cid:25)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:28) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`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.
`
`(Exhibit 1038 at 6 (page 3); see also Exhibit 1016 (Ansel) at 11 (page 91); Exhibit
`
`2014 (Modern Pharmaceutics) at 5 (page 181).)
`
`15. A POSA would also have been able to predict whether a drug molecule is
`
`susceptible to oxidative degradation. (E.g., Exhibit 1011 (Dr. Schöneich opening
`
`declaration) at ¶ 12.)
`
`V.
`
`CLAIM CONSTRUCTION
`
`16.
`
`I disagree with Dr. Klibanov’s opinion as to how a POSA would interpret
`
`the scope of claim 15 of the ’031 patent. Dr. Klibanov states that “the claim
`
`cannot be read to include an equal or greater amount of the opposite enantiomer,
`
`and hence the racemic compound, as this would read the express (S)-enantiomer
`
`element out of the claim.” (Exhibit 2012 at ¶ 28.)
`
`17. Claim 15 of the ’031 patent recites as follows; as I disagree with Dr.
`
`Klibanov regarding the claim term “comprising,” which is written as “comprises”
`
`in claim 15, I have underlined the term “comprises”:
`
`(cid:26)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:20)(cid:19) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`15. A method of stabilizing (S)-N-ethyl-3-{(1-dimethylamino)ethyl}-
`N-methyl-phenyl-carbamate in free base or acid addition salt form
`(Compound A), wherein the method comprises forming a composition
`by combining Compound A with an amount of anti-oxidant effective
`to stabilize Compound A from degradation.
`
`(Exhibit 1001, ’031 patent, at 9:10-15.)
`18. A person of ordinary skill in the art would interpret the broadest
`
`reasonable scope of claim 15 in light of the specification to include a composition
`
`containing RA7.1
`
`19.
`
`It would make no sense to exclude equal or greater amounts of the (R)
`
`enantiomer, but not exclude excipients other than antioxidants. That Dr. Klibanov
`
`interprets the claim in such a selective manner demonstrates the faulty logic of his
`
`construction.
`
`20.
`
`It would also make no sense to exclude or limit the (R) enantiomer
`
`because it is undisputed that both the (R) and (S) enantiomers behave the same
`
`with respect to oxidative degradation. (Exhibit 1026 (Day 2 Trial Tr.) at 356:20-
`
`357:4.)
`
`21. Although a claim can be written to exclude an enantiomer, there is no
`
`1 As I explained in my opening declaration (Exhibit 1010 at ¶ 15), RA7 is a
`
`racemate that is comprised of an equal mixture of (S) and (R) enantiomers. The
`
`(S) enantiomer is known as rivastigmine.
`
`
`
`(cid:27)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:20)(cid:20) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`language in Claim 15 that would be understood by a POSA to exclude or limit the
`
`amount of the (R)-enantiomer. The term “comprising” (written “comprises”)
`
`would not be understood by a POSA to restrict the amount of the (R) enantiomer as
`
`Dr. Klibanov suggests.
`
`22.
`
`I am further advised by attorneys for Petitioners that “comprising” is
`
`construed as an inclusive term in interpreting claims, and that claims containing
`
`this term are not limited to the specific elements recited. While I have evaluated
`
`the claim language from the perspective of a POSA at the time of the invention,
`
`my opinion that a POSA would not understand this term to restrict the amount of
`
`(R) enantiomer is consistent with this advice.
`
`23. An example of claim language that a POSA would have understood to
`
`limit the amount of (R)-enantiomer is claim 1 of the ’176 patent (Exhibit 1024).
`
`This claim recites: “The (S)-[N-ethyl-3-[(1-dimethylamino)ethyl]-N-methyl-
`
`phenyl-carbamate enantiomer substantially free of its (R) isomer in free base or
`
`acid addition salt form.” (Exhibit 1024 at 6 (9:26-28) (emphasis added).)
`
`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
`
`acknowledge, and I agree, that testing is required to determine whether and to what
`
`(cid:28)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:20)(cid:21) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`extent rivastigmine will undergo oxidative degradation under pharmaceutically
`
`relevant conditions.” (Exhibit 2012 at, e.g., ¶¶ 52 (first bullet), 60 (first bullet), 74
`
`(first bullet), 168 (first bullet).) Dr. Klibanov does not cite to any testimony or
`
`statement of mine (or of Dr. Schöneich) to support this repeated assertion. If Dr.
`
`Klibanov is referring to testimony that he cites elsewhere in his declaration, I
`
`disagree with Dr. Klibanov’s statement as it is misleading. Dr. Klibanov appears
`
`to be referring to the concept that the occurrence of oxidation in a particular
`
`formulation is formulation dependent. (See Exhibit 2012 at, e.g., ¶¶ 49, 109.)
`
`While I do not disagree with that statement, I do disagree that testing would have
`
`been required to determine that rivastigmine is susceptible to oxidative degradation
`
`under pharmaceutically relevant conditions.
`
`25.
`
`It is my opinion that a POSA, being motivated to further develop the
`
`rivastigmine formulation and device of Enz (Exhibit 1002),2 would have analyzed
`
`the chemical structure of rivastigmine as part of preformulation to determine
`
`whether it was susceptible to degradation, including oxidative degradation. A
`
`POSA would have understood that testing was not required to determine that
`
`rivastigmine, based on its chemical structure, was susceptible to oxidative
`
`degradation. Testing was instead used by a POSA to assess the extent of oxidative
`
`2 Patent Owners do not contest that a POSA would have been motivated to start
`
`with Enz. (Paper 25 at page 21; see Exhibit 1010 at ¶¶ 47-48.)
`
`(cid:20)(cid:19)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:20)(cid:22) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`degradation in a particular formulation, once the drug compound of that
`
`formulation had been identified as susceptible to oxidative degradation. A POSA
`
`would not have been surprised to see that rivastigmine oxidatively degraded in a
`
`formulation because the POSA would have maintained a reasonable expectation of
`
`rivastigmine’s susceptibility to do so.
`
`26.
`
`In my over 35 years of pharmaceutical development experience, including
`
`transdermal formulation and product development work in the 1970’s and 1980’s, I
`
`worked as a member of a team that included an organic chemist or a person with
`
`knowledge of organic chemistry. (See Exhibit 1025 (Day 1 Trial Tr.) at 132:20-
`
`133:1; Exhibit 1022 (Kydonieus CV) at 1-3; Exhibit 1029 (Kydonieus Deposition)
`
`at 107:2-19.) In my experience, we consulted with an organic chemist to
`
`understand the susceptibility of a drug compound to oxidative degradation, and
`
`other types of degradation, early in the development process. (Exhibit 1025 at
`
`131:15-133:1; Exhibit 1029 at 107:2-19; Exhibit 1022 at 1-3.)
`
`27.
`
`It was routine for a POSA to make reasonable predictions as to whether a
`
`compound would have been susceptible to oxidative degradation early in the
`
`pharmaceutical development process (such as during preformulation), and such
`
`predictions were made prior to the “testing” that Dr. Klibanov says is required.
`
`(Exhibit 1025 (Day 1 Trial Tr.) at 146:21-148:10.)
`
`28.
`
`The prior art taught the POSA to analyze the chemical structure of a drug
`
`(cid:20)(cid:20)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:20)(cid:23) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`compound to make a reasonable prediction as to whether the drug would be
`
`susceptible to oxidative degradation, which is consistent with my experience. As
`
`one example, the 1985 book, “Introduction to Pharmaceutical Dosage Forms,” by
`
`Dr. Ansel, states as follows:
`
`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.
`
`Initial investigation begins through knowledge of the
`drug's chemical structure which allows the
`preformulation scientist to anticipate the possible
`degradation reactions.
`
`(Exhibit 1016 (Ansel) at 11, section entitled “Stability” (emphasis added); Exhibit
`
`2020 at 3.)
`
`29. As another example, the 1995 text Modern Pharmaceutics, which Dr.
`
`Klibanov testified was an authoritative text in pharmaceutics, (Exhibit 1026 (Day 2
`
`Trial Tr.) at 523:19-524:2), states that “through the application of functional group
`
`chemistry, it is possible to anticipate the potential modes of degradation that drug
`
`molecules will likely undergo.” (Exhibit 2014 at 5 (page 181); Exhibit 1026 (Day
`
`(cid:20)(cid:21)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:20)(cid:24) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`2 Trial Tr.) at 528:15-529:8.)
`
`30.
`
`The prior art confirms that the POSA was indeed instructed and
`
`encouraged to examine a drug molecule’s chemical structure in order to inform
`
`herself about likely degradation issues:
`
`31. Dr. Klibanov phrases the question at issue as “whether a compound such
`
`as rivastigmine would have undergone oxidative degradation under
`
`pharmaceutically relevant conditions.” (Exhibit 2012 at, e.g., ¶ 15.) To be clear,
`
`my discussion of a POSA’s evaluation during the pharmaceutical development
`
`process, and the pharmaceutics texts I reference above, of course refer to the
`
`evaluation of whether a compound would have undergone oxidative degradation
`
`under pharmaceutically relevant conditions. Because a POSA would have been
`
`(cid:20)(cid:22)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:20)(cid:25) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`endeavoring to make a pharmaceutical formulation, the POSA would necessarily
`
`have evaluated a drug’s likely modes of degradation under pharmaceutically
`
`relevant conditions.
`
`32.
`
`Patent Owners’ assert (Paper 25 (Response) at 18, 20) that certain
`
`commercial amine-containing compounds and certain commercial benzylic-carbon
`
`containing compounds were not reported to undergo oxidation. Patent Owners cite
`
`only the Physician’s Desk Reference (“PDR”) to support this assertion. A POSA,
`
`however, would have understood that the PDR does not report the modes of
`
`degradation of the drugs, but instead it is a listing of information for the
`
`prescribing of marketed drugs. Therefore, a POSA would not understand the
`
`silence of the PDR regarding degradation to in any way indicate that the drug is not
`
`susceptible to oxidative degradation.
`
`VII. DR. KLIBANOV MISCHARACTERIZES THE PRIOR ART AND MY
`OPINIONS REGARDING THE PRIOR ART.
`33. Dr. Klibanov mischaracterizes the prior art references, and my assertions
`
`regarding them, in his declaration.
`
`Dr. Klibanov Mischaracterizes Enz (Exhibit 1002).
`A.
`34. Dr. Klibanov states that “despite being aware of the teachings of Rosin
`
`relied upon by the Petitioner and Dr. Kydonieus, the inventor of Enz did not teach
`
`or suggest that rivastigmine underwent oxidative degradation under
`
`pharmaceutically relevant conditions and was not motivated to add an antioxidant
`
`(cid:20)(cid:23)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:20)(cid:26) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`in any rivastigmine pharmaceutical formulation.” (Exhibit 2012 at ¶ 57 (emphasis
`
`added).)
`
`35.
`
`I disagree with Dr. Klibanov’s opinion that Enz’s silence regarding
`
`adding an antioxidant is significant. A POSA would have been aware of
`
`rivastigmine’s propensity towards oxidation based on its structure. The
`
`transdermal formulation of Example 2 of Enz is not a finished composition, and
`
`thus the references’ silence would not discourage a POSA from adding an
`
`antioxidant to the formulations disclosed by Enz to address the problem.
`
`B.
`
`Dr. Klibanov Mischaracterizes Rosin(Exhibit 1008).
`
`36.
`
`I disagree with Dr. Klibanov’s statements regarding Rosin, as I explain
`
`below.
`
`37. Dr. Klibanov states that “Rosin discloses as ‘compounds of the invention’
`
`over 8 million chemical compounds . . . . [t]hose compounds are referred to in
`
`Rosin collectively as the ‘compounds of the invention.’ . . . RA7 is included among
`
`those millions of compounds.” (Exhibit 2012 at ¶ 63.)
`
`38.
`
`I disagree with the implication that RA7 is disclosed by Rosin as merely
`
`one among “millions” of compounds. A POSA would have understood the
`
`“compounds of the present invention” to be a small set of RA-series compounds
`
`that are claimed in Rosin and for which experimental data is disclosed in Rosin.
`
`(Exhibit 1029 at 78:16-79:10.)
`
`(cid:20)(cid:24)
`
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:40)(cid:91)(cid:75)(cid:76)(cid:69)(cid:76)(cid:87) (cid:20)(cid:19)(cid:22)(cid:20)
`(cid:49)(cid:82)(cid:89)(cid:72)(cid:81) (cid:89)(cid:17) (cid:49)(cid:82)(cid:89)(cid:68)(cid:85)(cid:87)(cid:76)(cid:86) (cid:68)(cid:81)(cid:71) (cid:47)(cid:55)(cid:54) (cid:47)(cid:82)(cid:75)(cid:80)(cid:68)(cid:81)(cid:81)
`(cid:44)(cid:51)(cid:53)(cid:21)(cid:19)(cid:20)(cid:23)(cid:16)(cid:19)(cid:19)(cid:24)(cid:24)(cid:19)
`(cid:20)(cid:27) (cid:82)(cid:73) (cid:25)(cid:22)
`
`

`
`39. A POSA would have understood that Rosin discloses experimental data
`
`based on oral, subcutaneous, and intravenous injection into rabbit subjects for
`
`eleven RA-series compounds, RA4, RA5, RA6, RA7, RA8, RA10, RA11, RA12, RA13,
`
`RA14, and RA15.
`
`3 Rosin identifies seven of these compounds as “[t]he most
`
`preferred compounds of the RA series,” RA4, RA5, RA6, RA7, RA8, RA14, and
`
`RA15,4 and claims three of these compounds, including RA7, along with a method
`
`of treatment using the three claimed compounds.5
`
`40. Moreover, the only excipients that Rosin states are “preferred” are the