UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
`
`v.
`
`CIPLA LTD.,
`Patent Owner.
`
`Patent No. 8,168,620
`Issue Date: May 1, 2012
`Title: COMBINATION OF AZELASTINE AND STEROIDS
`
`
`
`
`Inter Partes Review No.: IPR2017-00807
`
`
`
`
`
`PETITIONER’S RESPONSE TO PATENT OWNER’S
` MOTION FOR OBSERVATIONS ON CROSS-EXAMINATION OF
`PETITIONER’S REPLY WITNESSES: DR. ROBERT SCHLEIMER, DR.
`MAUREEN DONOVAN, AND JOHN C. STAINES, JR
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`
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`
`
`
`
`ARGENTUM PHARMACEUTICALS LLC,
`Petitioner
`
`v.
`
`CIPLA LTD.,
`Patent Owner.
`
`Patent No. 8,168,620
`Issue Date: May 1, 2012
`Title: COMBINATION OF AZELASTINE AND STEROIDS
`
`
`
`
`Inter Partes Review No.: IPR2017-00807
`
`
`
`
`
`PETITIONER’S RESPONSE TO PATENT OWNER’S
` MOTION FOR OBSERVATIONS ON CROSS-EXAMINATION OF
`PETITIONER’S REPLY WITNESSES: DR. ROBERT SCHLEIMER, DR.
`MAUREEN DONOVAN, AND JOHN C. STAINES, JR
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`Petitioner Argentum Pharmaceuticals LLC (“Petitioner”) hereby responds to
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`Patent Owner’s motion for observations regarding the cross-examinations of Dr.
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`Robert Schleimer, Dr. Maureen Donovan, and John C. Stains, Jr. (Paper 44,
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`hereafter “Mot.”). Office Patent Trial Practice Guide, 77 Fed. Reg. 48756 at
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`48767-68 (August 14, 2012).
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`Observation #1: Patent Owner’s assertion that Dr. Schleimer’s testimony is
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`undermined by his adoption of the statements in footnote 1 of his second
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`declaration (EX1144) misapprehends the deposition testimony and the claims.
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`Footnote 1 made clear that Dr. Schleimer did not consider the specific limitations
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`of claims 4 and 42-44 because “[Petitioner] asked a formulation expert to weigh in
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`on them,” and that otherwise Dr. Schleimer considers “the combination of
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`azelastine and fluticasone in a formulation suitable for nasal administration to be
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`obvious for claims 4 and 42-44 for the same reasons as all the claims discussed [in
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`the declaration].” EX1144, n.1. Claims 4 and 42-44 all depend from claim 1,
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`making Dr. Schleimer’s opinions as to claim 1 relevant to claims 4 and 42-44.
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`Observation #2: Patent Owner’s assertions misapprehend Dr. Schleimer’s
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`deposition testimony. Dr. Schleimer explained that from a layperson’s perspective,
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`the clinical practice of conjunctive therapy most closely approximates the claimed
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`invention. EX2179, 42:17-44:17. Dr. Schleimer also recognized that in the
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`context of this legal proceeding where “prior art” might be restricted to printed
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`
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`1
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`
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`publications only, Segal and Cramer would be the strongest prior art. Id. Dr.
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`Schleimer also noted that adoption of that prior art “does change [his] opinion”
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`relative to his layman consideration of prior clinical use. Id.
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`Observation #3: Patent Owner’s assertions based on Dr. Schleimer’s
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`testimony regarding Howarth and Nielsen both mischaracterize his testimony and
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`ignore other relevant testimony. As to Howarth (EX2041), Dr. Schleimer
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`explained that Howarth’s assertion of lack of clinical benefit was unsupported, and
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`that Howarth overlooked the additivity of azelastine and fluticasone during the first
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`two weeks of administration (EX2179, 66:2-20),which Dr. Schleimer explained in
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`greater detail in his declaration (EX1144, ¶¶32-36). Regarding Nielsen (EX2042),
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`Dr. Schleimer explained that the authors’ goal was to “definitively establish that
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`steroids are superior to antihistamines, but when it came to discussing the
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`combination, they kind of gave it short shift” and that “they begrudgingly admit
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`that the combination has some marginal benefits but the cost is an issue” (EX2179,
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`73:6-9, 12-15), which was also discussed in more detail in Dr. Schleimer’s
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`declaration (EX1144, ¶¶37-38). Dr. Schleimer also noted that one of Cipla’s own
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`experts disagreed with the conclusions of these papers. Id., ¶39.
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`Observation #4: Patent Owner’s assertions regarding what Dr. Schleimer
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`explained in relation to Ratner 2008 (EX1045) grossly mischaracterizes the
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`deposition testimony. The testimony ascribed to Dr. Schleimer only occurred
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`2
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`
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`when he was asked to read aloud a quote from Ratner 2008 (EX2179, 96:13-19)—
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`this was not Dr. Schleimer’s own testimony regarding Ratner. Instead, when asked
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`“doesn’t this statement imply that six years later the authors were surprised by the
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`efficacy of their regimen?” Dr. Schleimer explained that “[t]o me, as I've testified,
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`a POSA would have anticipated an additivity, and a POSA would have looked at
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`these results and thought, yeah, that makes sense” and “[w]hy they wrote it’s
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`unanticipated and to what extent it truly reflects the views of all the authors, I
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`cannot comment.” Id., 98:2-21.
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`Observation #5: Patent Owner’s assertions that Dr. Schleimer relied on
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`post-invention publications to support his obviousness conclusions mischaracterize
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`the testimony and ignores other relevant testimony. Dr. Schleimer testified that it
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`was well-known before the priority date that azelastine’s onset was 15-30 minutes.
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`EX2179, 103:15-104:11, 109:11-13. Dr. Schleimer then explained that because
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`Dr. Carr affirmatively contested the fast onset of azelastine, he felt it was important
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`to find support both before and after the priority date showing that Dr. Carr’s
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`arguments were incorrect. Id., 104:19-105:22.
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`Observation #6: Patent Owner’s assertion that Dr. Donovan undermined
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`her credibility when she stood by her trial demonstratives is false. Dr. Donovan
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`explained that the purpose of the chart in EX2177 was not to communicate to the
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`Court the advantages and drawbacks of all of the tonicity agents shown. EX2178,
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`3
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`55:11-18. Dr. Donovan also testified on numerous occasions regarding the fact
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`that while all of the listed materials were obvious tonicity agents, there were
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`advantages to glycerine and drawbacks to sodium chloride and dextrose that would
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`cause a POSA to prefer glycerine over the other choices. EX2178, 44:16-45:5;
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`45:17-46:3; 54:15-55:6; 56:1-19; see also EX1145, ¶¶68-70 (same).
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`Observation #7: Patent Owner’s assertion that Dr. Donovan’s deposition
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`testimony contradicts her testimony that a motivation existed to “use the three
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`preservatives as recited in claims 42-44” and to “avoid using dextrose”
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`mischaracterizes the testimonial record. When asked if there was no need for
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`dextrose when using the preservatives from Flonase in a combination fluticasone
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`azelastine formulation, Dr. Donovan testified that a “POSA always holds out the
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`possibility that they will have some undesired failure of their system and then the
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`dextrose will serve as a great growth media.” EX2178, 66:20-67:13. Dr.
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`Donovan’s declaration also explains that “[s]ugars like dextrose are known for
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`aiding bacterial growth when used in low concentrations.” EX1145, ¶69. This is
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`further corroborated by Dr. Donovan in her deposition. EX2178, 71:18-72:7.
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`Additionally, Dr. Donovan also testified that there is “always a concern that your
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`antimicrobial preservatives will fail under some use challenge” and that one can
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`“address that concern through the use of adequate antimicrobial preservatives.”
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`Id., 67:4-9; 73:5-8.
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`4
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`Observation #8: Patent Owner’s assertion that Dr. Donovan’s deposition
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`testimony relating to whether two amine structures in azelastine are tertiary amines
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`undercuts her testimony that azelastine is a monovalent cation misapprehends the
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`testimony. Dr. Donovan testified that azelastine contains only one functional
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`group that would be characterized as a tertiary amine. EX2178, 124:7-125:1;
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`126:5-8, 16-19. Dr. Donovan also testified that unless the pH were extreme (e.g.,
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`below 0 or 1, or near 14 and above), azelastine contains only a single protonation
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`site. Id., 128:16-130:1. In her declaration, Dr. Donovan also referenced Dr.
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`Smyth’s opinion that “[i]n a pharmaceutical aqueous solution, the tertiary amine of
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`azelastine will have a [singular] positive charge,” which translates to azelastine
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`behaving like a monovalent cationic drug in solution. EX1145, ¶28; EX2150, ¶47.
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`The testimony highlighted by Patent Owner relates to counsel’s questions asking
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`what the other two amines in azelastine would be called, i.e., what technical term
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`would be used to describe those other functional groups. EX2178, 125:12-16.
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`That issue was not within the scope of Dr. Donovan’s testimony or expertise (id.,
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`126:1-4, 15-16), nor is it relevant.
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`Observation #9: Dr. Donovan’s testimony that a final formulation must
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`administer the dose that was intended to be administered is irrelevant to her
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`disagreement with Dr. Smyth’s construction of a “dosage form that is suitable for
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`nasal administration.” Dr. Donovan testified that a dosage form is suitable for
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`5
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`nasal administration if it is able to administer the dose that was intended to be
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`administered and to do so, a POSA would use chemical analysis to determine the
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`amount of drug the spray was delivering. EX2178, 138:19-139:2; 163:21-164:17.
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`Dr. Donovan’s testimony does not support Dr. Smyth’s proffered claim
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`construction of “pharmaceutical formulations that are tolerable to patients, that are
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`homogeneous, and that can be suitably deposited on the nasal mucosa.” Dr.
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`Donovan’s declaration explains in detail that Dr. Govindarajan’s recreations of
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`Cramer Example III were physically stable and provided a successful nasal spray,
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`which were the relevant issues with respect to these tests. EX1145, ¶¶34-40.
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`Observation #10: Patent Owner’s assertion that Dr. Donovan conceded that
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`Dr. Govindarajan’s recreations of Cramer Example III were not a “dosage form
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`suitable for a nasal administration” is a misstatement of the record. Dr. Donovan’s
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`declaration explains in detail that Dr. Govindarajan’s recreations “could be
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`delivered as a fine spray using a nasal spray pump.” EX1145, ¶40. Dr. Donovan
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`testified that Dr. Govindarajan’s first recreation of Cramer Example III was “his
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`first mixing of materials” in response to a question on whether visual observation
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`“doesn’t foreclose the possibility that the composition is not uniformly
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`resuspended.” EX2178, 197:11-198:9. Dr. Donovan further explained that each of
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`the three batches Dr. Govindarajan recreated were found to be physically stable
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`and exhibited behaviors of a pharmaceutically acceptable suspension. EX1145,
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`6
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`¶¶34, 40. The relevance of Dr. Govindarajan’s recreations of Cramer Example III
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`relates only to the fact that the formulations were adequately suspended and stable,
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`and could be adequately sprayed, not whether they were in a “dosage form suitable
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`for a nasal administration.” Dr. Donovan was never asked at her deposition and
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`never testified that Dr. Govindarajan’s recreations of Cramer Example III were not
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`in a “dosage form suitable for a nasal administration.”
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`Observation #11: Patent Owner’s assertion that Dr. Donovan did not “call
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`into question” in the related district court proceeding the difference in the grades of
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`viscosity of HPMC used by Drs. Herpin and Govindarajan mischaracterizes the
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`testimonial record. Dr. Donovan testified that she “was certainly aware of” the
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`HPMC viscosity grade difference for the Apotex case, but simply could not “recall
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`a paragraph that speaks directly to the viscosity grade of the HPMC.” EX2178,
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`172:19-173:10; 174:6-9. Dr. Donovan denied the suggestion that this issue was
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`not meaningful enough to point out in her reply report in the Apotex case. Id.,
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`173:20-22. Instead, Dr. Donovan testified repeatedly that the Apotex case involved
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`other issues, other experts, was “a different litigation.” Id., 173:8-10, 14-19;
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`174:19-175:3.
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`Observation #12: Patent Owner’s assertion that Dr. Donovan’s testimony
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`regarding azelastine dissociating into electrolytes undercuts her conclusion that
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`azelastine hydrochloride would not have been viewed by a POSA as incompatible
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`7
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`with MCC/CMC is false and unsupported by the testimonial record. Dr.
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`Donovan’s declaration explains that azelastine hydrochloride would be understood
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`to dissociate to a monovalent cation in an aqueous media. EX1145, ¶28. Dr.
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`Donovan also testified only that cations and anions are “broadly classified as
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`electrolytes.” EX2178, 120:4-7. As to the compatibility of azelastine
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`hydrochloride with MCC/CMC, Dr. Donovan explained in her declaration that
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`MCC/CMC are compatible with monovalent cationic drugs like azelastine.
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`EX1145, ¶¶18-29. Patent Owner cites no other evidence to support its conclusion
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`in this observation, nor is any connection apparent.
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`Observation #13: Patent Owner’s assertion that Dr. Donovan admitted that
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`the two-preservative combinations in Astelin® and Flonase® were sufficient to
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`inhibit bacterial growth mischaracterizes the deposition testimony. Dr. Donovan
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`testified that there is “always a concern that your antimicrobial preservatives will
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`fail under some use challenge,” and that one can “address that concern through the
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`use of adequate antimicrobial preservatives.” EX2178, 67:4-9; 73:5-8. Dr.
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`Donovan further explains in her declaration why a POSA would have been
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`motivated to select the three preservatives used at issue here. EX1145, ¶¶59-66.
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`Observation #14: Patent Owner’s assertion that Dr. Donovan’s failure to
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`rely on “prior art” to support a pH of 3 or below being “suitable for nasal
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`administration” speaks to the weight and credibility of Dr. Donovan’s conclusions
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`8
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`is without merit. Dr. Donovan cites both to claim 45 of the ’620 patent as well as
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`Dr. Smyth’s own deposition testimony to support her conclusion that a pH of 3 or
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`below is suitable for nasal administration. EX1145, ¶46; EX1143, 79:9-20;
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`EX1001, claims 1, 45.
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`Observation #15: Patent Owner’s assertion that Dr. Donovan “admitted that
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`Dr. Govindarajan’s visual observations alone are insufficient to show a uniform
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`suspension” misstates the testimonial record. Dr. Donovan never testified that
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`visual observations alone are insufficient to show a uniform suspension. Dr.
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`Donovan testified that she would “use whatever information I'm provided and
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`discern whether I think it makes logical sense.” EX2178, 196:21-197:1. She
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`further testified that when recreating Cramer Example III, Dr. Govindarajan used a
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`methodology entirely consistent with how she believes a POSA would approach
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`the problems he was given, and that she has no reason to not believe the notations
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`Dr. Govindarajan recorded. EX2178, 197:2-9. Dr. Donovan also testified that a
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`chemical analysis is “not what one does with the first formulation mixing attempt
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`that you undertake as a formulation development scientist.” Id., 197:17-198:9; see
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`also 195:6-8. Lastly, Dr. Donovan testified that she was “willing to believe” that
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`Dr. Govindarajan readily and uniformly resuspended the solid. Id., 196:3-9.
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`Observation #16: Patent Owner’s assertion that Mr. Staines’ deposition
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`testimony undercuts his credibility and undermines “his conclusions that rebates
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`9
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`
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`and copayment programs were primary drivers of Dymista® sales”
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`mischaracterizes the testimonial record. Mr. Staines’ declaration explains in detail
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`how rebates and copayment programs resulted in low net prices for Dymista, and
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`that analysis does not rely on identification of specific portions of sales. EX1040,
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`¶¶119-125. As to impact of Dymista rebates, and comparison to other drugs, Mr.
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`Staines testified that he analyzed Dymista’s rebates using documentation and his
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`experience (EX2180, 15:15-16:4), which can be found in his declaration at
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`paragraphs 63 and 124, and Ex. 2a. Similarly, Mr. Staines testified about the
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`impact of Dymista’s copayment program including the existence of other common
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`copayment programs that do not reduce prices to those close to generics. EX2180,
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`22:19-24:14.
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`Observation #17: Patent Owner’s assertion that Mr. Staines conceded that
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`documents he relied upon did not provide support for his assertions regarding
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`constraints of Meda’s salesforce in paragraph 127 of his declaration
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`mischaracterizes the deposition testimony. Paragraph 127 specifically references
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`the 2015 GlobalData study (EX2053), and Mr. Staines specifically recited that
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`study when asked “what was your basis for characterizing Mr. Jarosz's opinions as
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`being limited to primary care physicians?” See EX2180, 36:2-37:19. While Mr.
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`Staines acknowledged there was no explicit statement in EX2053 regarding
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`Primary Care Physicians, he explained there is an inference that “if [Meda] have a
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`10
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`
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`good presence with respiratory market, that means that [in] the other market,
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`[Meda] doesn’t.” EX2180, 39:13-15.
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`Observation #18: Patent Owner’s assertion that Mr. Staines’ deposition
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`testimony relating to the 2012 and 2013 Dymista discount rates “under cuts Mr.
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`Staines’ credibility and undercuts his conclusions that Dymista’s 47% rebate in
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`2015 is atypical” misapprehends the deposition testimony relative to Mr. Staines’
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`declaration. Mr. Staines stated in his declaration that “[t]he discounts through
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`2015, however, are comparatively large for brand drugs,” not that those in 2012
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`and 2013 were atypical. EX1040, ¶124. As for “atypical,” Mr. Staines specifically
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`testified that the “47% discount is atypically large for innovative brand
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`pharmaceuticals that have no bioequivalent generic competitors.” EX1040, ¶63.
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`Observation #19: Patent Owner’s assertion regarding Mr. Staines’
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`deposition testimony relating to blocking patents misapprehends the testimony
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`relative to Mr. Staines’ declaration. Mr. Staines’ statement that the ultimate
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`opinion as to blocking “is not my opinion” is consistent with his declaration, which
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`explains the basis of his assumption that the blocking patents existed. EX1040,
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`¶108. Consistent with his declaration, Mr. Staines testified “[i]t’s possible that [the
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`blocking patents] could [block]. I could foresee that they would inhibit or impede
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`somebody from developing a product if they’re not sure when somebody is going
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`
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`11
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`to launch or when they’re going to be able to launch, and that would be an
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`impediment or disincentive to develop.” EX2180, 89:21-90:5.
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`Observation #20: Patent Owner’s assertions regarding Mr. Staines’
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`testimony relating to “novel features” misapprehends his deposition testimony and
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`the testimony provided in his declaration. Regarding “novel features,” Mr. Staines
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`explained that “when I say something is novel, I’m using it in a layman’s sense”
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`and that “to the extent that ‘novel’ has some patent law implication here, I’m not
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`using it in that sense, and I don’t have an opinion in that way.” EX2180, 86:1-7.
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`This is consistent with his declaration which states “[i]n other words, there must be
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`a causal correlation, or ‘nexus,’ between the purported merits of the claimed
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`invention and the success of the product,” where Mr. Staines testified during his
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`deposition that he assumed “all the features of Dymista are in some way or form
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`claimed in the patent, but I don’t have a technical knowledge of what specific
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`things.” EX1140, ¶106; EX2180, 85:7-11.
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`Respectfully submitted,
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`12
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`Dated: April 24, 2018
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`
`
`By: /Michael R. Houston/
`Michael Houston
`Registration No. 58,486
`FOLEY & LARDNER LLP
`321 North Clark Street, Suite 2800
`Chicago, Illinois 60654
`Telephone: 312-832-4500
`Facsimile: 312-832-4700
`mhouston@foley.com
`
`Counsel for Petitioner
`Argentum Pharmaceuticals LLC
`
`
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`13
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`CERTIFICATION OF SERVICE
`
`The undersigned hereby certifies that a copy of the foregoing
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`PETITIONER’S RESPONSE TO PATENT OWNER’S MOTION FOR
`
`OBSERVATIONS ON CROSS-EXAMINATION OF PETITIONER’S
`
`REPLY WITNESSES: DR. ROBERT SCHLEIMER, DR. MAUREEN
`
`DONOVAN, AND JOHN C. STAINES, JR was served on April 24, 2018, on
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`Counsel for Patent Owner via electronic mail to the following:
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`
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`
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`Dated: April 24, 2018
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`dvarughe-PTAB@skgf.com
`dsterlin-PTAB@skgf.com
`alarock-PTAB@skgf.com
`ueverett-PTAB@skgf.com
`
`
`
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`
`
`By: /Michael R. Houston/
`Michael Houston
`Registration No. 58,486
`Counsel for Petitioner
`
`
`
`
`
`
`
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