Paper No. ____
`Date Filed: April 28, 2015
`
`On Behalf Of:
`
`Novartis AG and LTS Lohmann Therapie-Systeme AG
`
`By:
`
`Raymond R. Mandra
`ExelonPatchIPR@fchs.com
`(212) 218-2100
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`NOVEN PHARMACEUTICALS INC.
`AND MYLAN PHARMACEUTICALS INC.,
`Petitioners
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
`
`Inter Partes Review No. 2014-005501
`
`U.S. Patent 6,335,031
`
`PATENT OWNERS’ MOTION FOR OBSERVATIONS ON
`CROSS-EXAMINATION OF CHRISTIAN SCHÖNEICH, Ph.D.
`
`1 Case IPR2015-00268 has been joined with this proceeding.
`
`
`Date Filed: April 28, 2015
`
`On Behalf Of:
`
`Novartis AG and LTS Lohmann Therapie-Systeme AG
`
`By:
`
`Raymond R. Mandra
`ExelonPatchIPR@fchs.com
`(212) 218-2100
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`NOVEN PHARMACEUTICALS INC.
`AND MYLAN PHARMACEUTICALS INC.,
`Petitioners
`
`v.
`
`NOVARTIS AG AND LTS LOHMANN THERAPIE-SYSTEME AG,
`Patent Owners
`
`Inter Partes Review No. 2014-005501
`
`U.S. Patent 6,335,031
`
`PATENT OWNERS’ MOTION FOR OBSERVATIONS ON
`CROSS-EXAMINATION OF CHRISTIAN SCHÖNEICH, Ph.D.
`
`1 Case IPR2015-00268 has been joined with this proceeding.
`
`
`
`I.
`
`A POSA Would Not Have Reasonably Predicted That
`Rivastigmine Undergoes Oxidative Degradation Under
`Pharmaceutically Relevant Conditions Based On Its Structure
`
`At Ex. 1048, page 22, line 6 to page 23, line 22, Dr. Schöneich testified that
`
`the bond dissociation energy “does not tell you under which conditions you form
`
`radicals in any chemical reaction.”2 This testimony is relevant to Dr. Schöneich’s
`
`assertion that a bond’s strength was not a theoretical issue in ¶ 8 of Ex. 1032. This
`
`testimony is relevant because it demonstrates that a POSA would not have
`
`reasonably predicted that rivastigmine would undergo oxidative degradation under
`
`pharmaceutically relevant conditions based on its structure.
`
`At Ex. 1048, page 21, line 9 to page 22, line 5, Dr. Schöneich admitted that
`
`Carey and Sundberg (Ex. 1007 at 693) provides only “relative reactivities, not
`
`absolute reactivities” of aromatic hydrocarbons. (See also Ex. 1032 at ¶ 9.) The
`
`testimony is relevant to Dr. Schöneich’s assertion that a POSA would have
`
`predicted that rivastigmine is “susceptible” to oxidative degradation based on its
`
`structure in ¶ 14 of Ex. 1032. This testimony is relevant because it demonstrates
`
`that a POSA would not have reasonably predicted that rivastigmine would undergo
`
`oxidative degradation under pharmaceutically relevant conditions based on its
`
`structure.
`
`2 At Ex. 1048, page 7, line 25 to page 8, line 3, Dr. Schöneich agreed that answers
`
`he gave during cross-examination applied in both IPR proceedings.
`
`1
`
`
`
`At Ex. 1048, page 75, line 9 to page 76, line 7, Dr. Schöneich admitted that,
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`other than protonation, the structure of the drug is the same irrespective of the
`
`dosage form. This testimony is relevant to Dr. Schöneich’s assertion that a POSA
`
`would have predicted that rivastigmine is “susceptible” to oxidative degradation
`
`based on its structure in ¶ 15 of Ex. 1032. This testimony is relevant because Dr.
`
`Schöneich further admitted that, although the structure of the drug is the same, the
`
`dosage form can determine whether or not an antioxidant is required. (Ex. 1048 at
`
`70:21-71:12.) Thus a POSA would not have reasonably predicted from its
`
`structure that rivastigmine would undergo oxidative degradation under
`
`pharmaceutically relevant conditions or require an antioxidant.
`
`At Ex. 1048, page 16, lines 6 to 16 and page 108, lines 6 to 19, Dr.
`
`Schöneich admitted that there is no prior art literature that sets out the mechanism
`
`or site of oxidative degradation of rivastigmine and that he did not know what
`
`products are formed by its oxidative degradation. This testimony is relevant to Dr.
`
`Schöneich’s assertion that a POSA would have predicted that rivastigmine is
`
`“susceptible” to oxidative degradation based on its benzylic carbon-hydrogen bond
`
`and adjacent tertiary amine in ¶ 14 of Ex. 1032. This testimony is relevant because
`
`it shows that Dr. Schöneich’s structural theory is unproven.
`
`At Ex. 1048, page 96, line 2 to 5, Dr. Schöneich testified that
`
`dextromethorphan is “susceptible” to oxidative degradation at the benzylic
`
`2
`
`
`
`position. This testimony is relevant to Dr. Schöneich’s assertion that the benzylic
`
`position is “especially susceptible to oxidation” in ¶ 11 of Ex. 1032. This
`
`testimony is relevant because, even though dextromethorphan has a benzylic
`
`carbon, it was reported in the art to be “very stable,” “[s]table under all normal
`
`conditions of storage,” and to show “[e]xcellent stability” under pharmaceutically
`
`relevant conditions. (Ex. 2012 at ¶¶ 139-143.) Thus theoretical “susceptibility” to
`
`oxidative degradation does not correlate with the pharmaceutical reality of whether
`
`a compound undergoes oxidative degradation under pharmaceutically relevant
`
`conditions or requires an antioxidant.
`
`At Ex. 1048, page 100, lines 7 to 19 and page 101, line 21 to page 102, line
`
`8, Dr. Schöneich admitted that Boccardi 1994 reports that the 10-keto degradant of
`
`dextromethophan was found only in “trace amounts” during preformulation (a fact
`
`he omitted from his Reply Declaration) and that Boccardi 1994 does not report the
`
`conditions under which those trace amounts formed. (See also Ex. 2050 at 433.)
`
`This testimony is relevant to Dr. Schöneich’s opinion that Boccardi 1994 teaches a
`
`POSA that dextromethorphan is “susceptible” to oxidative degradation without the
`
`accelerated conditions described in Boccardi 1989 in ¶ 62 of Ex. 1032. This
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`testimony is relevant because it contradicts that opinion and demonstrates that Dr.
`
`Schöneich mischaracterized the teaching of Boccardi 1994.
`
`At Ex. 1048, page 96, line 18 to page 17, line 14, Dr. Schöneich admitted
`
`3
`
`
`
`that Boccardi 1989 states that “the irradiation of an aqueous or acidic solution of
`
`[dextromethorphan hydrobromide] in the absence of Fe(III) ions did not induce any
`
`decomposition, irrespective of the presence or absence of molecular oxygen.” (See
`
`also Ex. 1019 at 308.) This testimony is relevant to Dr. Schöneich’s opinion that
`
`Boccardi 1989 teaches a POSA that dextromethorphan is “susceptible” to oxidative
`
`degradation without the accelerated conditions described in that article in ¶ 62 of
`
`Ex. 1032. This testimony is relevant because it shows that Boccardi 1989 reports
`
`that dextromethorphan does not oxidize in the absence of Fe(III) ions and that Dr.
`
`Schöneich mischaracterized the teaching of Boccardi 1989.
`
`At Ex. 1048, page 100, line 20 to page 102, line 8 and page 113, line 13 to
`
`page, 114, line 14, Dr. Schöneich alleged that the Boccardi 1989 and 1994
`
`references teach that dextromethorphan had stability problems and that a POSA
`
`would have been concerned by trace amounts of degradation during preformulation
`
`because Boccardi 1994 does not disclose the conditions under which the degradant
`
`formed. This testimony is relevant to those opinions. This testimony is relevant
`
`because it is contradicted by the express teaching in the art that dextromethorphan
`
`is “very stable” under pharmaceutically relevant conditions. (Ex. 2012 at ¶¶ 139-
`
`143.)
`
`At Ex. 1048, page 48, lines 16 to 23, Dr. Schöneich admitted that he did not
`
`cite any literature indicating that any of the multiple real-world pharmaceutical
`
`4
`
`
`
`compounds having structural features in common with rivastigmine undergoes
`
`oxidative degradation under pharmaceutically relevant conditions. This testimony
`
`is relevant to Dr. Schöneich’s assertion that a POSA would have predicted that
`
`rivastigmine is “susceptible” to oxidative degradation based on its structure in ¶ 14
`
`of Ex. 1032. The testimony is relevant because there are multiple real-world
`
`pharmaceutical compounds having structural features in common with
`
`rivastigmine but that were not reported to contain an antioxidant in their
`
`commercial formulations or undergo oxidative degradation under pharmaceutically
`
`relevant conditions, thereby confirming that (1) a POSA would not have
`
`reasonably predicted that rivastigmine would undergo oxidative degradation under
`
`pharmaceutically relevant conditions based on its structure, and (2) it is the
`
`structure of the molecule as a whole that determines stability. (Ex. 2012 at ¶¶ 132,
`
`133 & n.15.)
`
`At Ex. 1048, page 49, line 13 to page 50, line 16, Dr. Schöneich admitted
`
`that he could have—but chose not—to search for literature or conduct any testing
`
`to demonstrate that any of the multiple real-world pharmaceutical compounds
`
`having structural features in common with rivastigmine undergoes oxidative
`
`degradation under pharmaceutically relevant conditions. At Ex. 1048, page 51,
`
`line 9 to page 52, line 3, Dr. Schöneich further admitted that he could have—but
`
`chose not—to search for how many pharmaceutical compounds contain a benzylic
`
`5
`
`
`
`carbon-hydrogen bond adjacent to a tertiary amine. This testimony is relevant to
`
`Dr. Schöneich’s assertion that a POSA would have predicted that rivastigmine is
`
`“susceptible” to oxidative degradation based on its structure in ¶ 14 of Ex. 1032.
`
`This testimony is relevant because it establishes that Dr. Schöneich’s structural
`
`theory is unproven.
`
`At Ex. 1048, page 51, lines 3 to 8, Dr. Schöneich admitted that, other than
`
`nicotine, he did not rely on any pharmaceutical compound with a benzylic carbon-
`
`hydrogen bond adjacent to a tertiary amine. This testimony is relevant to Dr.
`
`Schöneich’s assertion that a POSA would have predicted that rivastigmine is
`
`“susceptible” to oxidative degradation based on its structure in ¶ 14 of Ex. 1032.
`
`This testimony is relevant because there are multiple real-world pharmaceutical
`
`compounds having structural features in common with rivastigmine but that were
`
`not reported to contain an antioxidant in their commercial formulations and were
`
`not reported to undergo oxidative degradation under pharmaceutically relevant
`
`conditions. (Ex. 2012 at ¶¶ 132, 133 & n.15.)
`
`At Ex. 1048, page 79, line 5 to page 83, line 10, Dr. Schöneich admitted that
`
`hydroxyzine hydrochloride was commercially available in two liquid formulations
`
`and hydroxyzine pamoate was commercially available in a liquid formulation.
`
`(See also Ex. 2022 at 73, 77, 82.) Hydroxyzine has a benzylic carbon-hydrogen
`
`bond with an adjacent amine. (Ex. 1032 at ¶ 47.) This testimony is relevant to Dr.
`
`6
`
`
`
`Schöneich’s assertion that some of Dr. Klibanov’s multiple real-world
`
`pharmaceutical compounds having structural features in common with
`
`rivastigmine were formulated as dry dosage forms to avoid oxidative degradation
`
`in ¶ 47 of Ex. 1032. This testimony is relevant because it demonstrates that not all
`
`of the multiple real-world pharmaceutical compounds having structural features in
`
`common with rivastigmine were formulated as dry dosage forms.3
`
`At Ex. 1048, page 84, lines 10 to 16, Dr. Schöneich admitted that he did not
`
`provide any evidence that any alternative measures were taken to avoid oxidative
`
`degradation of any of Dr. Klibanov’s multiple real-world pharmaceutical
`
`compounds having a benzylic hydrogen-carbon bond (and an amine). This
`
`testimony is relevant to Dr. Schöneich’s assertion that the benzylic and tertiary
`
`positions are “especially susceptible to oxidation” in ¶ 11 of Ex. 1032. The
`
`testimony is relevant because it demonstrates that theoretical “susceptibility” to
`
`oxidative degradation does not correlate with pharmaceutical realities and that it is
`
`3 If Petitioners argue in response that these hydroxyzine formulations were
`
`formulated as salts to prevent oxidation, Patent Owners note that Dr. Schöneich’s
`
`opinion that such salts will not undergo oxidative degradation (Ex. 1048 at 77:9-
`
`14) is unsupported (Ex. 1048 at 103:22-104:10) and he has not provided any
`
`evidence that the salt forms of hydroxyzine were selected to avoid oxidative
`
`instability.
`
`7
`
`
`
`the structure of the molecule as a whole that determines stability under
`
`pharmaceutically relevant conditions.
`
`At Ex. 1048, page 52, line 4 to page 53, line 15, Dr. Schöneich admitted that
`
`when nicotine oxidizes it turns yellow or brown and that it is reasonable to assume
`
`that the statement “On exposure to air, [nicotine] turns brown” means oxidation.
`
`(See also Ex. 2024 at col. 2, ll. 31-32.) This testimony is relevant to Dr.
`
`Schöneich’s assertions that nicotine’s “susceptibility” to oxidation is not listed in
`
`the PDR and that a POSA would not conclude from the absence of a reported
`
`antioxidant in the PDR that a compound does not oxidatively degrade under
`
`pharmaceutically relevant conditions in ¶ 46 of Ex. 1032. The testimony is
`
`relevant because Dr. Schöneich admitted that the PDR entries for the nicotine
`
`transdermal devices Prostep and Habitrol both state that nicotine “turns brown on
`
`exposure to air” and “[a] POSA would certainly see this as a warning that nicotine
`
`would undergo oxidative degradation.” (Ex. 1048 at 55:7-58:18; Ex. 2022 at 27,
`
`46.) Dr. Schöneich’s assertions in ¶ 46 of Ex. 1032 are thus erroneous and the
`
`absence of any indication of oxidative instability in the PDR for any of Dr.
`
`Klibanov’s multiple real-world pharmaceutical compounds suggests that those
`
`compounds were not known to undergo oxidative degradation under
`
`pharmaceutically relevant conditions.
`
`At Ex. 1048, page 61, line 19 to page 62, line 20, Dr. Schöneich admitted
`
`8
`
`
`
`that 21 C.F.R. § 201.57 (4-1-1997 edition) concerning the “[s]pecific requirements
`
`on content and format of labeling for human prescription drugs” provides that the
`
`“Description” section of the labeling shall contain “[i]f appropriate, other
`
`important chemical or physical information.” (See also Ex. 2060 at 1.) This
`
`testimony is relevant to Dr. Schöneich’s assertions that the “susceptibility” of
`
`nicotine to oxidation is not listed in the PDR in ¶ 46 of Ex. 1032. The testimony is
`
`relevant because it contradicts that opinion. As Dr. Schöneich further admitted, the
`
`“Description” section of the labeling for the nicotine transdermal devices Prostep
`
`and Habitrol state that nicotine “turns brown on exposure to air.” (Ex. 1048 at
`
`54:22-25, 65:3-66:2; Ex. 2022 at 27, 46.) That there is no indication of oxidaitive
`
`instability in the PDR for Dr. Klibanov’s multiple real-world pharmaceutical
`
`compounds with structural features in common with rivastigmine suggests that
`
`those compounds were not known to oxidatively degrade under pharmaceutically
`
`relevant conditions.
`
`At Ex. 1048, page 13, line 18 to page 14, line 20, Dr. Schöneich admitted
`
`that he had not produced a single document in which rivastigmine was called an
`
`olefin or alkene. This testimony is relevant to Dr. Schöneich’s opinion that the
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`oxidation of rivastigmine is similar to the oxidation of olefins in ¶ 31 of Ex. 1032.
`
`This testimony is relevant because it contradicts that opinion.
`
`At Ex. 1048, page 15, lines 12 to 15, Dr. Schöneich testified that when an
`
`9
`
`
`
`unsubstituted olefin oxidizes, it cannot form an N-oxide. This testimony is
`
`relevant to Dr. Schöneich’s opinion that the oxidation of rivastigmine is similar to
`
`the oxidation of olefins in ¶ 31 of Ex. 1032. This testimony is relevant because it
`
`is now known that when rivastigmine oxidizes, it forms an N-oxide. (Ex. 1048 at
`
`19:10-12; Ex. 2059 at N0002403.)
`
`At Ex. 1048, page 92, lines 5 to 15 and page 110, line 21 to page 111, line
`
`12, Dr. Schöneich testified that a POSA could “draw a conclusion about what to
`
`reasonably expect from a molecule” and would “reasonably expect that
`
`rivastigmine would undergo oxidative degradation.” This testimony is relevant to
`
`Dr. Schöneich’s prior testimony that a POSA would need to conduct testing to
`
`determine whether rivastigmine oxidatively degrades under pharmaceutically
`
`relevant conditions. (Ex. 1025 at 96:10-18.) This testimony is relevant because it
`
`shows that Dr. Schöneich contradicted his prior testimony.
`
`II.
`
`Dr. Schöneich’s Opinions Are Unsupported
`
`At Ex. 1048, page 103, line 22 to page 104, line 10, Dr. Schöneich admitted
`
`that he did not cite any document in support of his opinion that “the salt form of a
`
`drug is generally less susceptible to oxidation than the free base.” This testimony
`
`is relevant to Dr. Schöneich’s assertion that some real-world pharmaceutical
`
`compounds having structural features in common with rivastigmine were
`
`formulated as salts to avoid oxidation in ¶ 47 of Ex. 1032. This testimony is
`
`10
`
`
`
`relevant because it demonstrates that Dr. Schöneich’s opinion is unsupported.
`
`At Ex. 1048, page 71, line 21 to page 73, line 7, Dr. Schöneich admitted that
`
`there are reasons other than oxidative instability to select a dry dosage form
`
`including, for example, patient convenience of an oral formulation and hydrolytic
`
`instability. This testimony is relevant to Dr. Schöneich’s assertion that some real-
`
`world pharmaceutical compounds having structural features in common with
`
`rivastigmine were formulated as dry dosage forms to avoid oxidation in ¶ 47 of Ex.
`
`1032. The testimony is relevant because Dr. Schöneich further admitted that he
`
`did not provide any evidence that a dry dosage form was selected was to avoid
`
`oxidation. (Ex. 1048 at 73:8-15.) Dr. Schöneich’s assertion is thus unsupported;
`
`that a compound is formulated as a dry dosage form does not establish that it is
`
`“susceptible” to oxidation or that measures were taken to avoid oxidation.
`
`At Ex. 1048, page 73, line 20 to page 74, line 12, Dr. Schöneich admitted
`
`that Ex. 2021 states that “oxidation can occur . . . in the solid state to some extent.”
`
`This testimony is relevant to Dr. Schöneich’s assertion that some real-world
`
`pharmaceutical compounds were formulated as dry dosage forms to avoid
`
`oxidation in ¶ 47 of Ex. 1032. The testimony is relevant because it demonstrates
`
`that Dr. Schöneich’s assertion is unsupported; that a compound is formulated as a
`
`dry dosage form does not establish that it is “susceptible” to oxidation or that
`
`measures were taken to avoid oxidation.
`
`11
`
`
`
`At Ex. 1048, page 78, line 14 to page 79, line 4, Dr. Schöneich admitted that
`
`he did not provide any evidence that alternative measures were taken to avoid
`
`oxidation of any of Dr. Klibanov’s real-world pharmaceutical compounds having
`
`structural features in common with rivastigmine. The testimony is relevant to Dr.
`
`Schöneich’s assertion that “the formulator may have taken other steps not listed on
`
`the label, like the exclusion of oxygen, to prevent oxidation” in ¶ 48 of Ex. 1032.
`
`This testimony is relevant because it demonstrates that Dr. Schöneich’s assertion is
`
`unsupported and that his structural theory is unproven.
`
`At Ex. 1048, page 102, line 9 to page 103, line 21, Dr. Schöneich admitted
`
`that he did not cite any document in support of his opinion that “[a] POSA would
`
`have understood that the presence of the basic tertiary amines in one molecule [of
`
`physostigmine] would facilitate hydrolysis of the carbamate group on other
`
`[physostigmine] molecules.” This testimony is relevant to Dr. Schöneich’s opinion
`
`that Dr. Klibanov is incorrect that it is the molecule as a whole that determines
`
`stability ¶ 22 of Ex. 1032. This testimony is relevant because it demonstrates that
`
`Dr. Schöneich’s opinion is unsupported.
`
`III. A POSA Would Not Have Combined Rosin Or Elmalem With Enz
`
`At Ex. 1048, page 70, lines 3 to 6 and page 70, line 21 to page 71, line 12,
`
`Dr. Schöneich admitted that the dosage form is significant and can determine
`
`whether or not an antioxidant is required. This testimony is relevant to Petitioners’
`
`12
`
`
`
`assertion that a POSA would have been motivated by Rosin or Elmalem to add an
`
`antioxidant to the rivastigmine transdermal device in Enz on page 11 to 12 of
`
`Petitioner’s Reply (Paper 31). The testimony is relevant because Dr. Kydonieus
`
`admitted that Rosin and Elmalem discuss only oral and injectable formulation;
`
`neither discloses transdermal formulations. (Ex. 1025 at 249:16-18, 257:14-19.)
`
`IV.
`
`In His Reply Declaration, Dr. Schöneich
`Mischaracterized Dr. Klibanov’s Opinions
`
`At Ex. 1048, page 25, line 12 to page 26, line 20, Dr. Schöneich agreed that
`
`the hydrolysis of both monomethyl and dialkyl carbamates has been “studied
`
`experimentally since the 1930s,” and that the mechanisms by which monomethyl
`
`and dialkyl carbamates undergo hydrolysis had been “experimentally determined
`
`as of 1998.” The testimony is relevant to Dr. Schöneich’s assertion in ¶ 28 of Ex.
`
`1032 that Dr. Klibanov used functional group chemistry to make predictions
`
`regarding stability. This testimony is relevant because Dr. Schöneich further
`
`admitted that Dr. Klibanov opined that through testing, it is possible to determine
`
`the chemical and physical properties of a compound. (Ex. 1048 at 28:10 -29:5.)
`
`Thus Dr. Schöneich mischaracterized Dr. Klibanov’s opinions.
`
`At Ex. 1048, page 31, line 14 to page 32, line 2 and page 32, line 18 to page
`
`33, line 9, Dr. Schöneich confirmed that Dr. Klibanov relied on “experimentation”
`
`and “many years of testing” as a basis for his opinion that a POSA would have
`
`understood that the chemical instability of monomethyl carbmates in aqueous
`
`13
`
`
`
`solution was due primarily to hydrolysis and that substituting a dialkyl carbamate
`
`for a monomethyl carbamate greatly decreased susceptibility to hydrolysis. (See
`
`also Ex. 2012 at ¶¶ 82, 87.) This testimony is relevant to Dr. Schöneich’s assertion
`
`in ¶ 28 of Ex. 1032 that Dr. Klibanov used functional group chemistry to make
`
`predictions regarding stability. This testimony is relevant because Dr. Schöneich
`
`further admitted that Dr. Klibanov opined that through testing, it is possible to
`
`determine the chemical and physical properties of a compound. (Ex. 1048 at
`
`28:10-29:5.) Thus Dr. Schöneich mischaracterized Dr. Klibanov’s opinions.
`
`At Ex. 1048, page 35, lines 12 to 20, Dr. Schöneich agreed that Dr. Klibanov
`
`also relied on numerous real-world examples of pharmaceutical compounds to
`
`demonstrate that the structure of the molecule as a whole determines stability.
`
`This is relevant to Dr. Schöneich’s assertion in ¶ 27 of Ex. 1032 that the only
`
`support that Dr. Klibanov provided for his opinion was the ’548 Patent. (See also
`
`Ex. 1048 at 33:10-34:17.) This testimony is relevant because it demonstrates that
`
`Dr. Schöneich mischaracterized Dr. Klibanov’s opinions and that, in support of his
`
`opinion that the structure of the molecule as a whole determines stability, Dr.
`
`Klibanov relied on the ’548 Patent and numerous real-world pharmaceutical
`
`compounds with structural features in common with rivastigmine that were not
`
`reported to contain an antioxidant in their commercial formulations or oxidatively
`
`degrade under pharmaceutically relevant conditions. (Ex. 2012 at ¶¶ 132, 137
`
`14
`
`
`
`n.16.)
`
`At Ex. 1048, page 42, lines 4 to 21 and page 45, line 13 to page 46, line 19,
`
`Dr. Schöneich confirmed that Dr. Klibanov relied not only on the absence of an
`
`antioxidant in the commercial formulations of multiple real-world pharmaceutical
`
`compounds having structural features in common with rivastigmine but also the
`
`absence of any scientific literature reporting that those compounds undergo
`
`oxidative degradation under pharmaceutically relevant conditions in support of Dr.
`
`Klibanov’s opinions that (1) a POSA would not have reasonably expected
`
`rivastigmine to undergo oxidative degradation under pharmaceutically relevant
`
`conditions based on its structure and (2) that it is the molecule as a whole that
`
`determines stability. This testimony is relevant because it demonstrates that in ¶¶
`
`43, 44 of Ex. 1032, Dr. Schöneich mischaracterized Dr. Klibanov’s opinions and
`
`that Dr. Klibanov’s opinions in his Declaration are not inconsistent with his prior
`
`trial testimony. (See also Ex. 1048 at 41:3-20, 44:25-46:11.)
`
`At Ex. 1048, page 88, line 23 to page 90, line 12, Dr. Schöneich confirmed
`
`that Dr. Klibanov did not admit that there were any structural features that a POSA
`
`would recognize as making rivastigmine particularly susceptible to oxidation. This
`
`is relevant to Dr. Schöneich’s assertion in ¶ 50 of Ex. 1032 that Dr. Klibanov made
`
`such an admission. This testimony is relevant because it demonstrates that Dr.
`
`Schöneich mischaracterized Dr. Klibanov’s opinions.
`
`15
`
`
`
`Dated: April 28, 2015
`
`Respectfully submitted,
`
`/s/ Raymond R. Mandra
`Raymond R. Mandra
`Registration No. 34,382
`FITZPATRICK, CELLA, HARPER
`& SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100
`
`16
`
`
`
`CERTIFICATE OF SERVICE
`
`I certify that a copy of the foregoing PATENT OWNERS’ MOTION FOR
`
`OBSERVATIONS ON CROSS-EXAMINATION OF CHRISTIAN
`
`SCHÖNEICH, Ph.D. was served on April 28, 2015 by causing them to be sent by
`
`email to counsel for Petitioners at the following email addresses:
`
`Steven J. Lee (slee@kenyon.com)
`
`Michael K. Levy (mlevy@kenyon.com)
`
`Chris Coulson (ccoulson@kenyon.com)
`
`Joseph M. Reisman (BoxMylan2@knobbe.com)
`
`Jay R. Deshmukh (BoxMylan2@knobbe.com)
`
`William R. Zimmerman (BoxMylan@knobbe.com)
`
`Dated: April 28, 2015
`
`/s/ Raymond R. Mandra
`Raymond R. Mandra
`Registration No. 34,382
`FITZPATRICK, CELLA, HARPER
`& SCINTO
`1290 Avenue of the Americas
`New York, NY 10104-3800
`Tel. 212-218-2100
`
`1
`
`
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