`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________
`
`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
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`PETITIONER REPLY TO PATENT OWNER RESPONSE
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`Segal expressly suggests combining azelastine and fluticasone in a
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`The clinical art also motivated a POSA to combine azelastine and
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`CIPLA’s criticisms contradict its positions in obtaining other patents
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`Patent No. 8,168,620
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`Reply to Patent Owner Response
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`TABLE OF CONTENTS
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`INTRODUCTION ........................................................................................... 1
`I.
`CLAIM CONSTRUCTION ............................................................................ 1
`II.
`III. AMPLE MOTIVATION TO COMBINE EXISTED IN THE ART .............. 3
`A.
`nasal spray ............................................................................................. 4
`B.
`fluticasone ............................................................................................. 4
`IV. A POSA’S REASONABLE EXPECTATION IS WELL-EVIDENCED .... 10
`A. Monovalent cationic drugs, like azelastine, were routinely included
`with MCC and CMC ........................................................................... 11
`B.
`in this family ........................................................................................ 12
`C.
`Cipla misleadingly cites GlaxoSmithKline’s research ........................ 13
`D. Dr. Govindarajan successfully recreated a suitable nasal spray from
`Cramer’s Example ............................................................................... 13
`V.
`AND THE FLONASE® LABEL .................................................................. 15
`VI. DYMISTA® SHOWS NO UNEXPECTED EFFICACY OR SIDE-
`EFFECTS ....................................................................................................... 18
`A. Dymista®’s efficacy is the same as conjunctive-use .......................... 19
`B.
`Dymista®’s onset of action is expected, and the same as azelastine .. 21
`C.
`Dymista®’s side effects are worse than azelastine or fluticasone ...... 22
`VII. SECONDARY CONSIDERATIONS DO NOT OVERCOME THE
`STRONG CASE OF OBVIOUSNESS ......................................................... 23
`A.
`Lack of Nexus to the Challenged Claims ............................................ 23
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`CLAIMS 42-44 ARE OBVIOUS OVER SEGAL, HETTCHE, PHILLIPPS,
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`Dymista® did not satisfy long-felt unmet needs ................................. 24
`B.
`FDA skepticism was directed only to Cipla’s proposed experiments 24
`C.
`D. Dymista®’s “Industry Praise” is not reflective of its results .............. 25
`E. Meda did not try to co-formulate Azelastine and Fluticasone ............ 25
`F.
`The Meda-Cipla license does not demonstrate a nexus ...................... 26
`G.
`Cipla’s copying evidence lacks nexus ................................................. 27
`H.
`obviousness ......................................................................................... 27
`I.
`Blocking patents undercut nexus......................................................... 28
`CONCLUSION ........................................................................................................ 29
`CERTIFICATE OF COMPLIANCE WITH 37 C.F.R. § 42.24(C)(1) .................... 30
`CERTIFICATE OF SERVICE ................................................................................ 31
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`Cipla’s commercial-success arguments fail to rebut the strong case of
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`TABLE OF AUTHORITIES
`
` Page(s)
`
`Cases
`
`AstraZeneca LP v. Breath Ltd.,
`88 F. Supp. 3d 326 (D.N.J.), aff’d, 603 F. App’x 999 (Fed. Cir.
`2015) ................................................................................................................... 26
`
`Bristol-Myers Squibb v. Teva Pharm. USA,
`752 F.3d 967 (Fed. Cir. 2014) ............................................................................ 18
`
`In re Epstein,
`32 F.3d 1559 (Fed. Cir. 1994) ............................................................................ 14
`
`Galderma Labs. L.P. v. Tolmar Inc.,
`737 F.3d 731 (Fed. Cir. 2013) ............................................................................ 29
`
`Lampi Corp. v. Am. Power Prods., Inc.,
`228 F.3d 1365 (Fed. Cir. 2000) .......................................................................... 13
`
`Merck & Co. v. Biocraft Laboratories, Inc.,
`874 F.2d 804 (Fed. Cir. 1989) .............................................................................. 4
`
`Ohio Willow Wood Co. v. Alps S., LLC,
`735 F.3d 1333 (Fed. Cir. 2013) .......................................................................... 23
`
`In re Paulsen,
`30 F.3d 1475 (Fed. Cir. 1994) .............................................................................. 2
`
`Richardson-Vicks Inc. v. Upjohn Co.,
`122 F.3d 1476 (Fed. Cir. 1997) ............................................................................ 1
`
`Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc.,
`200 F.3d 795 (Fed. Cir. 1999) .............................................................................. 2
`
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`Patent No. 8,168,620
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`I.
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`INTRODUCTION
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`The prior art teachings in this case are remarkably clear. The two drugs
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`required by the claims, azelastine and fluticasone, were already commercialized
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`nasal sprays as of the filing date, with doctors regularly prescribing the two
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`together to treat severe AR. The Segal reference provides clear motivational
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`teachings for combining these two drugs into a single spray—which would have
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`satisfied even the more rigid TSM test pre-KSR. Nor does the ’620 Patent describe
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`any critical formulation requirements, using only well-known excipients in
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`standard concentrations to arrive at the claimed formulation, thus disproving any
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`litigation-inspired allegations regarding reasonable expectation of success.
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`Hemmed in by these indisputable prior art teachings, Cipla offers selective-
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`but-misleading excerpts from the record to create an impression of uncertainty in
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`the art, and a superficial appearance of secondary considerations. None of Cipla’s
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`arguments withstand scrutiny, nor do they overcome the overwhelming
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`obviousness of the challenged claims. Richardson-Vicks Inc. v. Upjohn Co., 122
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`F.3d 1476, 1484 (Fed. Cir. 1997) (finding “combination” drug obvious over
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`secondary considerations).
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`II. CLAIM CONSTRUCTION
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`Cipla advances a claim construction of “pharmaceutical formulations that
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`are tolerable to patients, that are homogeneous, and that be suitably deposited onto
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`the nasal mucosa” for the claim terms “nasal spray” and “suitable for nasal
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`administration.” POR, 8-9. This construction should not be adopted for several
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`reasons.
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`First, the Board should only construe claim terms as needed to resolve the
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`parties’ controversy. Vivid Techs., Inc. v. Am. Sci. & Eng’g, Inc., 200 F.3d 795,
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`803 (Fed. Cir. 1999). Here, all of the §103 prior art references are expressly
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`directed to nasal sprays suitable for nasal administration. E.g., EX1007, 2:12-17;
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`EX1009, 32:57-60; EX1010, 1; EX1012, Abstract, 4-6. Hettche and Phillipps
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`disclose Astelin® and Flonase®, respectively, and Segal discloses aqueous
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`compositions formulated as nasal drops or sprays that are both isotonic and pH-
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`adjusted, making construction of these claim terms unnecessary. EX1012, 6;
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`EX1004, ¶¶24, 32.
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` Second, any special definitions for claim terms must be set forth with
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`reasonable clarity, deliberateness, and precision. In re Paulsen, 30 F.3d 1475,
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`1480 (Fed. Cir. 1994). Entirely skipping the claims and specification, Cipla argues
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`that its proposed construction was used during prosecution to distinguished the
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`prior art (i.e., Cramer). POR, 9. However, during prosecution, Cipla at most
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`distinguished Cramer based on settling/caking over time, its alleged difficulty in
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`being sprayed, and its osmolality. EX1002, 223. Cipla’s construction should not
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`be adopted because: it is not commensurate with its remarks regarding Cramer; the
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`Examiner did not rely on Cipla’s remarks in allowing the claims (see EX1002,
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`143-146); and the proposed construction is hopelessly vague (EX1145, ¶¶7-11).
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`Third, Cipla’s real motive is to use its proposed construction to improperly
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`import even more limitations into the claims, such as Dr. Smyth’s attempt to
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`import a pH limitation of 4 to 8 into the claims in order to distinguish Cramer
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`(CIP2150, ¶40), despite claim 45’s call for a pH of 3 to 7. Similarly, Dr. Smyth
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`argues that the terms “nasal spray” and “suitable for nasal administration” are
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`equivalents (EX2150, ¶23; EX1143, 60:9-19; 62:20-22, 85:9-11), effectively
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`importing the limitation of “nasal spray” into the claims via this alleged
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`equivalency. This argument ignores claims 13 and 14, which expressly cover nasal
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`drops—which are markedly distinct from nasal sprays (EX1143, 51:7–53:9),
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`creating an inconsistency Dr. Smyth was unable to reconcile (Id., 60:9–65:5).
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`III. AMPLE MOTIVATION TO COMBINE EXISTED IN THE ART
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`Before June 2002, a POSA would have been motivated to combine
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`azelastine hydrochloride (“azelastine”) and fluticasone propionate (“fluticasone”)
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`in a single nasal formulation in view of any of Segal, Cramer, or the clinical art.
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`Contrary to Cipla’s assertions (POR, 10-27), it is not hindsight for a POSA to do
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`what the prior art expressly recommends.
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`A.
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`Segal expressly suggests combining azelastine and fluticasone in a
`nasal spray
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`Cipla’s endless hindsight arguments flatly ignore the motivations found in
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`Segal, a reference included in both instituted obviousness grounds. Petitioner cited
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`Segal as motivation for its express teaching to combine azelastine and fluticasone
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`into a single nasal product for treating allergic rhinitis (AR). Pet., 22, 25-33, 35;
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`EX1003, ¶80. Cipla does not dispute this teaching in its Response, and Cipla’s
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`expert, Dr. Carr, does not even mention Segal in his 71-page declaration. EX1142
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`249:18–250:20; EX1144, ¶¶11-12.
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`Segal’s motivation to combine is akin to that in Merck v. Biocraft (874 F.2d
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`804, 806 (Fed. Cir. 1989)), where a prior art reference disclosed a multitude of
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`combinations for a known use, rendering a two-drug pharmaceutical obvious. Id.,
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`807. Because “all disclosures of the prior art, including unpreferred embodiments,
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`must be considered,” (Id.) Cipla’s anticipation arguments, absent from its
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`Response, do not apply to obviousness. As a matter of law, the Board should find
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`motivation to combine azelastine and fluticasone in a nasal spray as expressly
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`taught by Segal.
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`B.
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`The clinical art also motivated a POSA to combine azelastine and
`fluticasone
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`The clinical art before June 2002 provides overwhelming motivation for a
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`POSA to combine azelastine and fluticasone in a single nasal formulation. Pet.,
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`35-39. The treatment Guidelines (collectively EX1019, EX1022, and EX1024)—
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`which reflect clinical practice of the time—recommend combination therapy using
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`antihistamines and intranasal steroids (INS). Pet., 35-36; EX1144, ¶13. Dykewicz
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`expressly recommends the use of INS with intranasal antihistamines and discusses
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`only azelastine. EX1019, 505; Pet., 35. Clearly, the physicians behind the
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`Guidelines found such combinations beneficial.
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`The wide-spread practice of using antihistamines combined with INS to treat
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`AR is reflected in the numerous references and studies of record. EX1144, ¶¶13,
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`28-29, 42. Berger, Juniper ’97, and Nielsen (“[a] combination of antihistamine and
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`INCS is often used in clinical practice”) are just a few of the references
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`acknowledging this practice. Id. The Dymista® authors even note, “reports of the
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`use of these agents [azelastine and fluticasone] in combination are common.”
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`EX1045, 74; see also CIP2165 at 7 (same).
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`Consistent with this practice, all four of the physicians who testified at the
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`Cipla v. Apotex trial had co-prescribed azelastine and fluticasone prior to 2002.
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`EX1144 ¶41. Copies of Dr. Acetta’s patient notes established exactly this.1 Id.
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`1 Waiting until the evening before this Reply was due, Cipla refused Petitioner’s
`request for these records and would not allow Apotex to provide them either.
`EX1158.
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`Cipla’s experts, including Dr. Carr, also admitted to co-prescribing the
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`combination. Id. ; EX1142, 6:8–11:15. Cipla’s other expert, Dr. Kaliner, admitted
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`that before June 2002, “the combination of a nasal steroid and an antihistamine
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`was the best treatment I can give,” and recommended the combination to other
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`allergists. CIP2021, 498:4-7, 488:12–490:7; EX1144, ¶39.
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`In discussions with the FDA, Cipla’s licensee acknowledged that the
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`rationale for its combination product came from allergists who treated many of
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`their SAR patients with both azelastine and fluticasone nasal sprays (EX2165, 7),
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`which is essentially an admission that a motivation to combine existed before
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`Cipla’s filing date. Cipla cannot credibly claim hindsight bias.
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`Cipla’s assertion that the art showed no clinical benefit to co-administration
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`of steroids and antihistamines (POR, 12-16) is wrong. At a minimum, beneficial
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`effects were seen in all shorter studies of 1-3 weeks and in the early weeks of the
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`6-week Juniper’89 study. EX1003, ¶¶83-91; EX1144, ¶¶15-27. The outcome of
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`the 8-week study by Benincasa is explained by the complementarity of
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`antihistamines and steroids in treating, respectively, early phase reaction (EPR)
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`and late phase reaction (LPR) symptoms. Pet., 35-36; EX1144, ¶¶27-31, 58.
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`Antihistamines were known to mitigate initial EPR symptoms such as sneezing and
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`itching, while steroids address LPR symptoms that develop hours later, e.g.,
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`congestion. While steroids exert their full effect on all AR symptoms over days or
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`weeks, the effects of the antihistamine on EPR symptoms were readily observed in
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`the shorter studies. EX1144, ¶¶7-9. Expectedly, as the studies progressed, the
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`effect of the steroid eventually dominated, meaning that studies looking only at
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`endpoints or mean TNSS scores missed the antihistamine effects. Id., ¶14.
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`Rather than addressing these well-known phenomena, Dr. Carr simply
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`disparages or ignores data that does not support his view. His analyses of Drouin
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`and Brooks are illustrative. Dr. Carr asserts that the improvement observed for the
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`antihistamine/INS combination over the steroid alone in Drouin is “less than that
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`shown by the typical placebo group” and without clinical benefit. POR, 14;
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`CIP2147, ¶59. Yet the difference between the two groups in Drouin is at least as
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`large, if not larger, than that observed for Dymista® versus fluticasone, as
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`evidenced by Dr. Carr’s own paper. EX1144, ¶¶15-18. Adjusting for the
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`difference in TNSS scales, the advantage of the combination over steroid in Drouin
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`is 1 point while that of Dymista® is 0.8—indicating that Drouin’s results are at
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`least as clinically relevant as Dymista®’s. Id. Cipla’s criticism of Brooks (POR,
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`14) is equally flawed. Dr. Carr cherry-picks a single statement from Brooks and
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`ignores all other data to the contrary. EX1144, ¶¶19-23.
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`Consistent with Segal and the clinical art, a POSA would also have wanted
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`to combine azelastine and fluticasone to take advantage of known
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`complementarity. Pet., 36-38. First, like other antihistamine/steroid pairs,
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`azelastine and fluticasone address EPR and LPR symptoms to provide faster and
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`more complete relief of severe AR symptoms. Id.; EX1003, ¶¶53-54. Cipla does
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`not contest this other than to incorrectly assert that EPR and LPR symptoms cannot
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`be clinically distinguished. EX1144, ¶¶7-9. Second, azelastine was known to have
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`a fast onset of action that complemented the slower-developing effects of
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`fluticasone, just as salmeterol did in Advair. Id., 46; infra VI.C. Third,
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`azelastine’s anti-inflammatory properties were known to act on LPR symptoms as
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`well as EPR symptoms. EX1003, ¶¶62-67.
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`Cipla’s allegation that the in vivo action of antihistamines was thought to be
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`redundant with steroids (POR, 18) is a mischaracterization. Howarth focused
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`solely on whether antihistamines could be used in long-term prophylactic treatment
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`of AR. EX1144, ¶¶32-36. Howarth’s conclusion was based on undisclosed
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`“limited studies” that did not involve azelastine or address EPR/LPR short-term
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`complementarity. Id. Cipla’s other reviews did not address complementarity and
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`ignored data that contradicted their conclusions. Id. ¶¶37-38. On this record, a
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`POSA would hardly conclude that antihistamines and steroids have redundant in
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`vivo mechanisms of action. Id.
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`A POSA would also have expected improved compliance for a combined
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`azelastine/fluticasone nasal spray to avoid the inconvenience of multiple spray
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`products and assure adequate dosing. Pet., 38; EX1012, 2:2-3, 1:15-20. Cipla’s
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`argument that the art had disproven this premise (POR, 20-22) overreaches. Cipla
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`provides no evidence that tablet-number studies—cited in Shenfield—are relevant
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`to nasal-spray dosing. EX1144, ¶45. Certainly, its licensee didn’t think so, as
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`Meda expressly represented to the FDA that “compliance is an issue” and
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`Dymista® “would be better than the individual ingredients because patients would
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`not have to take four sprays of medication at one time.” CIP2165, 7; EX1144
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`¶45.
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`Cipla’s argument that azelastine’s side effects would dissuade a POSA from
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`selecting it rather than an oral antihistamine (POR, 21-23) has no basis in fact.
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`Cipla’s quotation of a pediatric review does not show compliance is improved in
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`adults by selecting an oral medication that tastes good. EX1041, 462. While
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`azelastine may show a temporary bad taste if it runs down the back of the throat,
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`this is temporary and not noticed by the majority of patients. EX1144, ¶51. Cipla
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`cites no evidence suggesting lack of compliance because of bad taste. Id. Cipla’s
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`Figure 1 (POR, 22) is scientifically invalid. Id. ¶¶49-51; infra §VI.C.
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`Cipla’s characterization of the “on-demand” nature of the Guidelines’
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`instructions to combine antihistamines and INS (POR, 20) fails to support its hind-
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`sight allegations. As shown above, the art as whole demonstrates that conjunctive
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`use of antihistamines and INS—including azelastine/fluticasone—for treatment of
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`severe AR was wide-spread before 2002, and that the combination showed clinical
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`efficacy. Nothing in the Guidelines mandates that a fixed-dose regimen for
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`combined therapy should never be used. While the Guidelines discourage certain
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`practices, no such warnings are attached to the use of antihistamines and INS.
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`EX1144 ¶40.
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`IV. A POSA’S REASONABLE EXPECTATION IS WELL-EVIDENCED
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`By 2002, fluticasone and azelastine were already available in FDA-approved
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`aqueous nasal-spray formulations (Flonase® and Astelin®). EX1008; EX1010.
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`Segal and Cramer both taught aqueous nasal-spray solution-suspensions using
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`well-known excipients. EX1145, ¶8. In addition, Dr. Smyth admits that (i)
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`adjusting pH, osmolality, and viscosity using suitable agents was known; (ii) both
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`Astelin and Flonase included viscosity and tonicity-adjusting agents; and (iii) the
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`prior known tonicity-adjuster glycerin acted as expected when included in
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`Dymista. EX2021, 640:16-19; 651:17-19; 654:2-19; EX1143, 59:1-10, 70:2-
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`72:20. With such knowledge , a POSA would have reasonably expected success in
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`formulating a nasal spray with both drugs, especially given the numerous
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`suspension-solution drugs already in the art. EX1004, ¶¶35,59-61; EX1145, ¶¶18-
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`40, 50-55.
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`Cipla conceives of “significant problems” to impugn this reasonable
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`expectation (POR, 28-29), but as discussed below, no such problems existed
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`(EX1145, ¶¶12-29). Further, Cipla attempts a distraction by narrowly obsessing on
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`Cramer’s Example III, while blatantly avoiding verifying Dr. Govindarajan’s
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`successful Example III formulations. EX1145, ¶30-55.
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`A. Monovalent cationic drugs, like azelastine, were routinely
`included with MCC and CMC
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`Well before the ’620 patent, mixtures of MCC and CMC (e.g., Avicel®
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`RC591) were known to provide stable aqueous pharmaceutical suspensions with
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`monovalent cationic drugs (“MCDs”) like azelastine. EX1145, ¶21-29. When
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`dissolved, azelastine is a MCD. EX1145, ¶28. Ignoring product guides and prior
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`art specifically discussing Avicel® RC591 suspensions, Cipla cites selectively to
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`Leiberman to allege incompatability of azelastine with Avicel® RC591. CIP2150,
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`¶¶45-47; EX1145, ¶¶18-29. Indeed, Dr. Smyth admits he didn’t consult
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`Lieberman’s citations or any art describing MCDs with Avicel® RC591. EX1143,
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`40:9-21.
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`A POSA would not be so willfully ignorant of the pertinent art, but instead
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`would be well-versed on up-to-date source material. EX1145, ¶20. Notably,
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`Lieberman’s statement on Avicel RC® 591 cites to FMC Corp. (CIP2113, 24, 61
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`n.51), which itself teaches that CMC is incompatible with di- and trivalent salts.
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`EX1146, 8. Critically, monovalent salts, like azelastine, are not called out as
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`problematic. EX1145, ¶20.
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`A POSA would also be aware of multiple successfully-formulated aqueous
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`solution-suspension formulations reported in the art that include one or more
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`MCDs with Avicel® RC591, including a 1997 patent describing stable aqueous
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`suspensions of multiple MCDs together with Avicel® RC 591. EX1154,
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`Examples 1-4; EX1145, ¶¶21-25. In fact, even suspensions including both a MCD
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`and Avicel® RC591 formulated as a nasal spray were already known. EX1155,
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`3:54-56; Examples 1-3; EX1145, ¶26.
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`B. CIPLA’s criticisms contradict its positions in obtaining other
`patents in this family
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`Cipla asserts that a POSA’s understanding in preparing the claimed nasal
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`sprays could only come from the specific examples in the patent showing
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`particular ingredients and concentrations. EX2150, ¶32; EX1143, 113:15-21.
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`Cipla thereby contends that Hettche, Phillipps, Segal, and Cramer all lack
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`“meaningful guidance” enabling a POSA to make the claimed combination. POR,
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`33, 39. Yet Cipla only asserts this view when convenient.
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`Two continuations of
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`the
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`’620 patent
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`(EX1166, EX1167) claim
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`compositions “suitable for nasal administration” that include azelastine and
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`ciclesonide—a steroid essentially insoluble in water (EX1151). However, neither
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`the ’620 patent nor the child applications contain any working examples with
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`azelastine and ciclesonide, yet Cipla obtained claims covering this combination,
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`Patent No. 8,168,620
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`thus showing that Cipla was perfectly willing to rely on the general understanding
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`of a POSA in formulating solution-suspensions when convenient. EX1145, ¶¶56-
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`58. Lampi Corp. v. Am. Power Prods., Inc., 228 F.3d 1365, 1377 (Fed. Cir. 2000)
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`(applying judicial estoppel where party sought to repudiate arguments relied upon
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`to obtain a favorable result in earlier administrative proceedings).
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`C. Cipla misleadingly cites GlaxoSmithKline’s research
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`Cipla claims that a POSA knew fluticasone would cake when co-formulated
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`in a “liquid formulation” with a second active ingredient. POR, 29 (citing
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`CIP2111 and CIP2044).
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` However,
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`this “liquid”
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`is a non-aqueous
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`chlorofluorocarbon—a far different solvent than water. EX1145, ¶¶12-13.
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`CIP2044 itself highlights that different solvents provide different behavior (in one
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`of the chlorofluorocarbons the particles could be easily resuspended), and that
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`aqueous formulations yielded even better suspension properties. CIP2044,
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`Abstract, 5-10; CIP2111, 9-10; EX1145, ¶¶13-16. Cipla’s own references thus
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`encourage a POSA to combine fluticasone with another active using an aqueous
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`system. EX1145, ¶¶15-17.
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`D. Dr. Govindarajan successfully recreated a suitable nasal spray
`from Cramer’s Example
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`Dr. Govindarajan was an expert for Apotex in its litigation against Cipla
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`tasked with recreating and testing Cramer’s Example III. EX2030, 2-3. Using the
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`same criteria as Cipla for assessing whether a nasal suspension is acceptable
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`(EX2150, ¶35; EX2113, 5; EX2103, 12; EX2104, 6-7; cf. POR, 35 (equating
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`settling with caking)), he concluded that Cramer’s suspensions were physically
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`stable, and yielded pharmaceutically-acceptable products that “could be delivered
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`as a fine spray using a nasal spray pump.” EX2030, 4, 39; EX1145, ¶¶35-40.
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`Contrary to Cipla’s misstatements, Dr. Govindarajan had no formulation problems
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`nor did his recreations “fail.” EX1145, ¶¶31-49; cf. POR, 34-35. Nor does
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`Cramer, Segal, or even the ’620 patent refer to any formulation difficulties,
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`refuting Cipla’s argument that formulation was key to the invention. In re Epstein,
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`32 F.3d 1559, 1658 (Fed. Cir. 1994) (refusing to accept after-the-fact arguments in
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`favor of patentability where the specification lacked such detail).
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`Tellingly, Cipla’s experts never made or tested any of Dr. Govindarajan’s
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`recreations; instead, they used a different HPMC and avoided generating Dr.
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`Govindarajan’s spray-tested batch.2 EX2030, 27; EX2029, 2-3; EX1145, ¶¶41-45.
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`
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`2 During prosecution, Cipla submitted a declaration by one of the co-inventors, Dr.
`Malhotra, allegedly testing Cramer’s Example III formulation. EX1002, 284-87.
`However, Cipla refused to make Dr. Malhotra available for deposition in this
`proceeding, and therefore Dr. Malhotra’s declaration should not be considered for
`its truth. Further, Dr. Malhotra’s formulation did not reproduce those created and
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`Cipla’s experts also
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`ignored early
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`indications of erroneous reproduction,
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`apparently having predetermined failure. EX1145, ¶43.
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`Yet even Cipla’s flawed attempt at Dr. Govindarajan’s example produced a
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`pH within the range the ’620 patent states is “suitable for nasal administration.”
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`EX1001, claim 45; EX1143, 79:9-16; EX1145, ¶46. Further, the osmolality of all
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`the recreations fall within art-accepted osmolality values for nasal sprays.
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`EX1145, ¶¶47-49. There is no basis in the art for Cipla’s conclusory position that
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`these examples show unacceptable osmolality. EX2150, ¶38; EX1145, ¶¶47-48.
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`Thus, Cramer’s Example III supports rather than undercuts a POSA’s reasonable
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`expectation of success. EX1145, ¶¶30-33.
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`V. CLAIMS 42-44 ARE OBVIOUS OVER SEGAL, HETTCHE,
`PHILLIPPS, AND THE FLONASE® LABEL
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`A POSA would have been motivated to look to and employ the excipients
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`described in Hettche (EX1007) and Phillipps (EX1009) and listed in Flonase®
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`(EX1010). EX1004, ¶¶21-39, 52-64. The excipients were well known in the art
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`and used for the exact same functions as in the individual nasal formulations. Id.
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`Thus, a POSA would have had a reasonable expectation of success in co-
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`tested by Dr. Govindarajan, and therefore suffer from the same shortcomings as
`Dr. Herpin’s alleged tests. EX1002, 285; EX2029, 3, 20; Ex. 1145, ¶¶42-45.
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`formulating azelastine and fluticasone into a single nasal spray.
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`Id., 111165-67;
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`EX1145, 1112-58.
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`While Cipla concocts an “obvious-to-try” argument
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`in an attempt
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`to
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`circumvent the obviousness of claims 42-44 (POR, 38-40), even in this fictitious
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`scenario Cipla’s assertions are still wrong. As evidenced by the Table below,
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`Flonase® and Hettche (Example I) include the same active ingredients, same
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`vehicle, and all of the same excipients listed in claims 42-44 except glycerin(e).
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`EX1145, 1160; EX1007, 6:6-18; EX1010, 1:3.
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`Fluticasone
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`Azelastine HCl
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`Fluticasone
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`Ingredient(s)
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`propionate
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`Preservatives
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`(1) BKC;
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`(2) Phenyl ethyl
`alcohol
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`(1) BKC;
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`(2) EDTA
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`Propionate
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`Azelastine HCL
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`(1)BKC
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`(2) Phenyl ethyl
`alcohol
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`(3)EDTA
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`
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`Thickening
`Agents
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`Tonicity Adj.
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`Polysorbate80
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`Polysorbate80
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`MCC/CMC
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`HPMC
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`MCC/CMC
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`Sodium chloride
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`Glycerin(e)
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`l6
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` POSA would have reasonably expected successful combination of
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` A
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`azelastine and fluticasone with MCC and CMC in a suspension suitable for nasal
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`administration. Supra, §V. All components would be regarded as compatible and
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`adjustment of parameters was well within a POSA’s skill. EX1145, ¶¶12-29, 50-
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`55, 67-72.
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`In another attempt to misstate a reference’s teachings, Cipla asserts “Segal
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`teaches minimizing the use and amount of preservatives.” POR, 42. However, the
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`passage of Segal cited is directed to unit-dose formulations and special
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`systems―not typical multi-dose formulations. POR, 42; EX1012, 6:15-20;
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`EX1045 ¶66.
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`It is well known that multi-dose nasal spray formulations must be preserved
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`against microbial contamination. EX1145, ¶59. It was obvious to preserve a co-
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`formulation of azelastine and fluticasone using the preservatives taught by Hettche
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`and Flonase®―edetate disodium (“EDTA”), benzalkonium chloride (“BKC”), and
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`phenylethyl alcohol. EX1145, ¶¶60-65; EX1010, 1:3; EX1007, 6:6-18. A POSA
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`would reasonably expect using all three preservatives together with azelastine and
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`fluticasone would result in passing a preservative challenge test, because the
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`preservatives were already successfully used in the individual formulas. Id. A
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`POSA would understand a combination of preservatives with multiple synergies
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`means a greater chance of passing a preservative challenge test (synergy 1:
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`phenylethyl alcohol/BKC; synergy 2: BKC/EDTA). Id., ¶64; EX1033, 5 and 27.
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`The substitution of glycerin as a tonicity adjustor was nothing more than
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`routine optimization and an obvious substitution among known interchangeable
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`components, because:
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`• it was listed by Hettche for such purposes;
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`• it is known for its useful functions as a solvent and humectant;
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`• a POSA would avoid using sodium chloride with MCC/CMC;
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`• a POSA would avoid using dextrose because it aids bacterial growth;
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`• at low concentration its viscosity is similar to water;
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`• there was no reason to believe it is incompatible with fluticasone.
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`EX1007, 4:31-34; EX1145, ¶¶67-72.
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`VI. DYMISTA® SHOWS NO UNEXPECTED EFFICACY OR SIDE-
`EFFECTS
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`Evidence of unexpected results must stem from a comparison to the closest
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`prior art. Bristol-Myers Squibb v. Teva Pharm. USA, 752 F.3d 967, 977 (Fed. Cir.
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`2014). Here, the closest prior art is Segal, Cramer, and the clinical art of co-
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`administering Astelin® and Flonase®. Supra, §III. Thus, to establish unexpected
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`results, the proper comparison is not to the individual monotherapies, but to the co-
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`administration of azelastine and fluticasone (“conjunctive-use”).
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`Cipla is silent as to this closest prior art, and instead only considers the
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`combination of INS with oral antihistamines (not azelastine), or azelastine and
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`flu