UNITED STATES PATENT AND TRADEMARK OFFICE
`_____________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_____________________
`
`
`ARGENTUM PHARMACEUTICALS LLC
`
`Petitioner
`
`v.
`
`CIPLA LIMITED
`
`Patent Owner
`
`_____________________
`
`Case No. IPR2017-00807
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`U.S. Patent No. 8,168,620
`_____________________
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`PATENT OWNER RESPONSE
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`Mail Stop “PATENT BOARD”
`Patent Trial and Appeal Board
`U.S. Patent and Trademark Office
`P.O. Box 1450
`Alexandria, VA 22313-1450
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`Patent Owner's Response
` IPR2017-00807
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`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION .......................................................................................... 1
`
`BACKGROUND ............................................................................................ 5
`
`A.
`
`
`B.
`
`
`C.
`
`
`The ’620 patent and its commercial embodiments ............................... 5
`
`Background of related litigation ............................................................ 6
`
`Person of ordinary skill in the art .......................................................... 6
`
`III.
`
`PETITIONER FAILS TO CONSIDER THE “SUITABLE FOR
`NASAL ADMINISTRATION” AND “NASAL SPRAY” CLAIM
`LIMITATIONS. .............................................................................................. 7
`
`IV. PETITIONER’S MOTIVATION-TO-COMBINE ARGUMENTS
`REFLECT PURE HINDSIGHT. .................................................................. 10
`
`A.
`
`
`B.
`
`
`C.
`
`
`D.
`
`
`The prior clinical use of antihistamines and steroids would
`not have been a motivation to pursue a combination
`formulation. .........................................................................................11
`
`A POSA would have understood that azelastine and
`fluticasone had redundant mechanisms of action in vivo,
`further negating any motivation to combine into a single
`formulation. .........................................................................................18
`
`There is no factual support for Petitioner’s assertion that
`combining azelastine and fluticasone would increase
`treatment compliance. .........................................................................20
`
`Petitioner’s “anti-inflammatory properties” justification for
`selecting azelastine is based on improper hindsight. ..........................23
`
`V. A POSA WOULD NOT HAVE HAD A REASONABLE
`EXPECTATION OF SUCCESSFULLY COMBINING
`AZELASTINE AND FLUTICASONE INTO A SINGLE DOSAGE
`FORM THAT WAS “SUITABLE FOR NASAL
`ADMINISTRATION.” ................................................................................. 27
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`Patent Owner's Response
` IPR2017-00807
`
`
` A POSA would have been dissuaded by fluticasone’s A.
`propensity to aggregate when co-formulated with other
`drugs in liquid formulations. ...............................................................29
`
`B.
`
`
`C.
`
`
`D.
`
`
`Azelastine was known to be incompatible with MCC and
`CMC, the thickening agents used in Flonase®. ...................................30
`Cramer and Segal underscore the lack of reasonable
`expectation of success. ........................................................................32
`
`Petitioner’s remaining assertions of reasonable expectation
`of success equally fail. ........................................................................36
`
`VI. CLAIMS 42-44 WOULD NOT HAVE BEEN OBVIOUS IN VIEW
`OF SEGAL, HETTCHE, PHILLIPPS, AND THE FLONASE®
`LABEL.......................................................................................................... 38
`
`
` MCC and CMC were incompatible with cationic drugs and A.
`electrolytes like azelastine salts...........................................................40
`
`B.
`
`
`C.
`
`
`There was no design need or market pressure to use the
`claimed three preservative combination. .............................................41
`
`It would not have been obvious to try the claimed glycerine
`as an isotonicity agent. ........................................................................44
`
`VII. UNEXPECTED RESULTS CONFIRM NON-OBVIOUSNESS OF
`THE CHALLENGED CLAIMS. ................................................................. 46
`
`VIII. OTHER OBJECTIVE INDICIA COMPEL NON-OBVIOUSNESS
`OF THE CHALLENGED CLAIMS. ........................................................... 53
`
`A.
`
`
`B.
`
`
`C.
`
`
`Commercial embodiments of the claimed invention
`Dymista® and Duonase have a nexus to the challenged
`claims. ..................................................................................................55
`Dymista® meets long-felt but unmet medical needs for more
`effective, faster, and safer treatment of AR. .......................................56
`Dymista® faced industry skepticism from both Meda and
`FDA. ....................................................................................................57
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`Patent Owner's Response
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` Dymista® has enjoyed industry praise as the new “gold D.
`standard” for treatment of AR. ............................................................59
`
`E.
`
`
`Failure by Cramer, Segal, and Meda to develop a
`combination nasal spray confirms nonobviousness. ...........................60
`
`
` Meda’s royalty-bearing license to the ’620 patent supports F.
`patentability. ........................................................................................62
` Dymista® and Duonase were subject to widespread copying. ............63 G.
`
`
` Dymista® and Duonase are commercially successful. ........................63 H.
`No alleged “blocking patents” undercut Cipla’s commercial
`success and long-felt need evidence. ..................................................65
`
`I.
`
`
`IX. CONCLUSION ............................................................................................. 67
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` IPR2017-00807
`Patent No. 8,168,620
`
`I.
`
`INTRODUCTION
`
`The challenged claims cover a combination nasal spray formulation with
`
`two active ingredients: azelastine hydrochloride (“azelastine”) and fluticasone
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`propionate (“fluticasone”). Cipla’s successful combination formulation of these
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`two ingredients was a breakthrough: the world’s first combination of an intranasal
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`antihistamine (azelastine) with an intranasal corticosteroid (fluticasone). Indeed,
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`Cipla’s invention was the first time any of the myriad available allergic rhinitis
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`(“AR”) treatments were ever combined into a nasal spray formulation, by anyone,
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`anywhere. As a result, Dymista®, the U.S. commercial embodiment of Cipla’s
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`invention remains, more than fifteen years later, the only fixed-dose nasal spray
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`combination approved by the Food and Drug Administration (“FDA”) for the
`
`treatment of AR. Faced with the groundbreaking nature of Cipla’s invention,
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`Petitioner resorts to hindsight, relying either on art that was already considered—
`
`and overcome—during prosecution to build its case, or art that contradicts
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`Petitioner’s obviousness theories.
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`Petitioner has failed to prove that Hettche, Phillipps, and Segal render claims
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`1, 4-6, 24-26, and 29 obviousness. First, Petitioner’s evidence falls far short of
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`demonstrating that a person of ordinary skill in the art (“POSA”) would have been
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`motivated by the prior art to select azelastine, or to combine azelastine and
`
`fluticasone into a combination formulation. Instead, Petitioner and its clinical
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`Patent Owner's Response
` IPR2017-00807
`expert—Dr. Robert Schleimer—rely on stray statements in the art to claim a
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`motivation to combine these drugs, yet these same references provide teachings
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`that are squarely at odds with a combination formulation as claimed in the ’620
`
`patent, and in particular with the use of azelastine.
`
`Petitioner’s hindsight-driven analysis also fails to demonstrate that a POSA
`
`in 2002, looking forward, would have had a reasonable expectation of success in
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`combining azelastine and fluticasone into a combination “nasal spray” that was
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`“suitable for nasal administration.” Petitioner and its formulation expert—Dr.
`
`Maureen Donovan—fail to address the incompatibilities between (i) fluticasone
`
`and other active ingredients in liquid formulations and (ii) azelastine and the
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`claimed thickening agents carboxymethyl cellulose (“CMC”) and microcrystalline
`
`cellulose (“MCC”). Petitioner side-steps the inconvenient fact that multiple
`
`attempts to recreate the closest prior art formulation resulted in a formulation that
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`was not suitable for nasal administration because it was: (i) unacceptably acidic;
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`(ii) unacceptably unstable with significant settling and caking; and (iii)
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`unacceptably hypertonic.
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`Petitioner next stitches together four prior art references—Hettche, Phillipps,
`
`Segal, and the Flonase® label—to argue that the specific excipients recited in
`
`claims 42-44 would have been obvious. Petitioner continues its hindsight approach
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`by cherry-picking from the disclosures of those references. Petitioner, however,
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`provides no justification for why a POSA would have deviated from the
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`successfully employed excipients in either the prior art commercial azelastine
`
`product (Astelin®) or the prior art commercial fluticasone product (Flonase®), or
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`why a POSA would have ignored the known incompatibilities with the claimed
`
`excipients. Indeed, hundreds of possibilities are identified for the claimed
`
`excipients. Further exposing its hindsight, Petitioner then argues that a POSA
`
`would have selected glycerine as an excipient, but ignores that many other
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`isotonicity agents are known, and that Astelin® and Flonase® already successfully
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`employed isotonicity agents different than glycerine. Using the claims as a
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`blueprint, as Petitioner does here, is hindsight pure and simple.
`
`Additionally, Petitioner and its declarants failed to address the publicly-
`
`available objective indicia of nonobviousness of which they were aware before the
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`Petition was filed. Petitioner’s representative attended trial on the ’620 patent in a
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`related district court proceeding less than seven weeks before this Petition was
`
`filed. And both of Petitioner’s declarants addressed objective indicia of
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`nonobviousness applicable to the ’620 patent at that trial, but failed to
`
`acknowledge, much less, address it here. These compelling objective indicia of
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`nonobviousness further confirm the non-obviousness of the challenged claims.
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`Unexpected results. Dymista®—the U.S. commercial embodiment—
`
`exhibits surprising improvements in efficacy, onset, and safety as compared to the
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`Patent Owner's Response
` IPR2017-00807
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`closest prior art.
`
`Long-felt need. Because Dymista® exhibits improved efficacy, onset, and
`
`safety, Dymista® satisfies a long-felt but unmet need for a safer, more effective
`
`treatment of AR.
`
`Industry skepticism. Meda (the exclusive licensee of the ’620 patent)
`
`considered developing an azelastine/steroid combination formulation in 2002 but,
`
`before licensing the ’620 patent, abandoned the project because of the expected
`
`difficulties. FDA was also skeptical. Years after the invention date, FDA did not
`
`have any approval pathway in place for combination products like the one claimed,
`
`and its concerns mirrored many of the problems a POSA would have seen in 2002.
`
`Industry praise. Dymista® was hailed as the “drug of choice” for the
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`treatment of AR.
`
`Failure by others. When Meda ultimately attempted to make an
`
`azelastine/fluticasone combination formulation in 2006, Meda confirmed its initial
`
`skepticism, finding that significant precipitation occurred when azelastine was
`
`added to the Flonase® excipients. And, other companies investigated
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`antihistamine/steroid combination formulations but failed to bring a product to
`
`market. Only with the ’620 patent was Meda able to succeed.
`
`Licensing. Unable to develop its own azelastine/fluticasone formulation,
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`Meda licensed the ’620 patent from Cipla.
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`Patent Owner's Response
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`Copying. Duonase—the commercial embodiment in India—was subject to
`
`widespread copying within two years of market entry.
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`Commercial success. Since its introduction into the market, Dymista® has
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`consistently gained market share and is currently the most prescribed branded nasal
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`spray for the treatment of AR.
`
`The Board should affirm the patentability of the challenged claims.
`
`II. BACKGROUND
` The ’620 patent and its commercial embodiments A.
`
`The ’620 patent is directed to intranasal pharmaceutical formulations
`
`containing azelastine and fluticasone, along with specific pharmaceutical
`
`excipients. CIP2150, ¶19. The application that matured into the ’620 patent was
`
`filed on June 13, 2003 as PCT/GB03/02557 and claims priority to GB 0213739.6,
`
`filed June 14, 2002, under 35 U.S.C. § 119. Cipla is the assignee of the ’620 patent.
`
`EX1001, 1. Duonase was not only the first-ever nasal spray combination of an
`
`antihistamine and a steroid, but it was also the first-ever nasal spray combination
`
`of any type, anywhere in the world. As a result, soon after its introduction into the
`
`market, several azelastine/fluticasone copycat products (“Duonase copycats”) also
`
`entered the market.
`
`Meda Pharmaceuticals, Inc. (“Meda”, now part of Mylan Pharmaceuticals,
`
`Inc.) licensed the ’620 patent from Cipla, and developed and received FDA
`
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`Patent Owner's Response
` IPR2017-00807
`approval to market Dymista®—a commercial embodiment in the U.S. and the first
`
`and still only FDA-approved fixed-dose nasal spray combination formulation.
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`Background of related litigation
`
`B.
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`The ’620 patent is listed in the FDA Orange Book in connection with
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`Dymista®, which is approved for the treatment of seasonal AR. Apotex Inc. and
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`Apotex Corp. (“Apotex”) filed an Abbreviated New Drug Application (“ANDA”)
`
`seeking approval to introduce a generic copy of Dymista®. In response, Cipla
`
`(along with its exclusive licensee, Meda) sued Apotex in the District of Delaware
`
`in December 2014 asserting infringement of the ’620 patent. Meda Pharm., Inc. v.
`
`Apotex, Inc., Civ. No. 14-1453 (D. Del.). There was a bench trial December 13-16,
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`2016, with closing arguments in March 2017.1
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` All trial and hearing transcripts, and
`
`all post-trial submissions were publicly available to Petitioner from the Court’s
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`docket. Petitioner’s declarants in this IPR—Drs. Robert Schleimer and Maureen
`
`Donovan—served as testifying experts on Apotex’s behalf at trial on the issue of
`
`the ’620 patent’s validity. Finally, Petitioner admitted that “[it] attended the public
`
`portions of the trial.” CIP2127, 1. No part of trial was closed to the public.
`
`Person of ordinary skill in the art
`
`C.
`
`The hypothetical POSA in the field of the ’620 patent would have education
`
`and experience in both (1) the treatment of patients suffering from AR and (2) the
`
`
`1 The parties settled the district court dispute in May 2017.
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`Patent Owner's Response
` IPR2017-00807
`development of drug formulations. From the clinical perspective, a POSA would
`
`have the experience of a primary care physician with a medical degree and 2-4
`
`years of experience. CIP2147, ¶18. From the formulation perspective, a POSA
`
`would possess a bachelor of science degree in pharmaceutical sciences and 4-5
`
`years of experience as a formulator, although the POSA could also be a person
`
`with a higher level of formal education and fewer years of experience. CIP2150,
`
`¶¶17-18.
`
`Petitioner’s proposed definition differs in that it incorrectly renders optional
`
`clinical experience in treating patients. Pet. 11.2 By omitting the critical clinical
`
`experience of a POSA, Petitioner’s arguments seek to rely only on laboratory
`
`models. But the challenged claims are directed to pharmaceutical formulations,
`
`which indicates use in patients. CIP2147, ¶19. Petitioner’s limited view is
`
`problematic because it overlooks the significant body of clinical literature in 2002,
`
`discussed below, showing that (1) the addition of an antihistamine to a steroid
`
`treatment regimen conferred no meaningful benefit, and (2) antihistamines and
`
`steroids had redundant activity.
`
`III. PETITIONER FAILS TO CONSIDER THE “SUITABLE FOR
`NASAL ADMINISTRATION” AND “NASAL SPRAY” CLAIM
`LIMITATIONS.
`
`Petitioner’s obviousness grounds fail because they do not address every
`
`
`2 As used herein, “Pet.” refers to Petitioner’s Petition, Paper 1.
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`Patent Owner's Response
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`limitation of the claims. Namely, Petitioner has not demonstrated that the asserted
`
`prior art teaches the “nasal spray” or “suitable for nasal administration”
`
`elements required by each and every challenged claim. These terms, properly
`
`construed, mean “pharmaceutical formulations that are tolerable to patients,
`
`that are homogeneous, and that can be suitably deposited onto the nasal
`
`mucosa.” CIP2150, ¶¶20-21. But Petitioner’s references do not teach such
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`azelastine and fluticasone combined pharmaceutical formulations.
`
`The Board construes claim terms under a “broadest reasonable
`
`interpretation” standard. 37 C.F.R. § 42.1000(b); Cuozzo Speed Techs., LLC v. Lee,
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`136 S. Ct. 2131, 2144-46 (2016). And, the Board “must consult the patent’s
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`prosecution history in proceedings in which the patent has been brought back to the
`
`agency for a second review.” Hospira, Inc. v. Genentech, Inc., IPR2017-00731,
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`Paper 29, 8 (Oct. 26, 2017) (Yang, APJ) (quoting Microsoft Corp. v. Proxyconn,
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`Inc., 789 F.3d 1292, 1298 (Fed. Cir. 2015)). See also Hulu, LLC v. Intertainer,
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`Inc., CBM2014-00052, Paper 35, 8 (June 12, 2015) (Murphy, APJ) (citing Tempo
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`Lighting, Inc. v. Tivoli, LLC, 742 F.3d 973, 977-78 (Fed. Cir. 2014)).
`
`During prosecution, the terms “nasal spray” or “suitable for nasal
`
`administration” were construed to have a special meaning. The Examiner believed
`
`that the initial pending claims were broad enough to encompass formulations that
`
`would not have been tolerable, homogeneous, or suitable for deposition on the
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`Patent Owner's Response
` IPR2017-00807
`nasal mucosa, but the inventors explicitly disclaimed those formulations. For
`
`example, the Examiner rejected the pending claims over Cramer’s Example III,
`
`which disclosed a combination of azelastine hydrochloride and triamcinolone
`
`acetonide, as the closet prior art. CIP2147, ¶27; CIP2150, ¶22; EX1002, 507-522.
`
`However, attempts to recreate, and testing of, Cramer Example III revealed that the
`
`formulation exhibited: (1) unacceptable osmolality, which would have caused
`
`irritation to patients; (2) unacceptable spray quality, which would not have suitably
`
`deposited onto the nasal mucosa; and (3) unacceptable settling, which would have
`
`adversely affected homogeneity of the formulation. CIP2150, ¶23; EX1002, 284-
`
`87, 220-21. These problems rendered Cramer Example III unsuitable for use as
`
`either a “nasal spray” or a “pharmaceutical formulation in a dosage form suitable
`
`for nasal administration.” CIP2147, ¶28; CIP2150, ¶23; EX1002, 220-24, 286-87.
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`Accordingly, Cipla amended several claims to include the “suitable for nasal
`
`administration” limitation and explained that a “nasal spray,” within the meaning
`
`of its claims, must meet the same suitability requirements, which ultimately led to
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`allowance. CIP2150, ¶¶22-23; EX1002, 203-231. These amendments and
`
`arguments demonstrate that the term “nasal spray,” as used in the challenged
`
`claims, is specific and materially different from the meaning of that term in Cramer
`
`and Segal. CIP2150, ¶23; EX1011, 1; EX1012, 1. Indeed, neither teaches how to
`
`make two-drug “pharmaceutical formulations that are tolerable to patients, that are
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`Patent Owner's Response
` IPR2017-00807
`homogeneous, and that can be suitably deposited onto the nasal mucosa.”
`
`Based on the arguments and amendments made during prosecution, a POSA
`
`would have understood “nasal spray” or “suitable for nasal administration” to
`
`mean “pharmaceutical formulations that are tolerable to patients, that are
`
`homogeneous, and that can be suitably deposited onto the nasal mucosa.”
`
`CIP2150, ¶¶21-23. This construction is the broadest reasonable construction in
`
`light of the intrinsic record, and should apply here.
`
`Petitioner has not even attempted to show that the art taught the “suitable for
`
`nasal administration” and “nasal spray” limitations. In fact, Petitioner’s
`
`formulation expert, Dr. Maureen Donovan, actually wrote the limitation out of the
`
`claims: according to her claim 1 of the ’620 patent recites azelastine, fluticasone,
`
`“and not much more.” EX1004, ¶42. This mistake underscores Petitioner’s overall
`
`failure to consider and address all claim limitations in the art.
`
`IV. PETITIONER’S MOTIVATION-TO-COMBINE ARGUMENTS
`REFLECT PURE HINDSIGHT.
`
`Petitioner’s obviousness grounds are built on the faulty premise that a POSA
`
`would have been motivated to select azelastine and fluticasone for use in a
`
`combined formulation. But each of Petitioner’s alleged reasons for selecting
`
`azelastine and fluticasone for use in a combination formulation are all either absent
`
`in the prior art or are squarely contradicted by it.
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`Patent Owner's Response
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`
` The prior clinical use of antihistamines and steroids would not A.
`have been a motivation to pursue a combination formulation.
`
`Petitioner’s reliance on the clinical co-administration of antihistamines and
`
`steroids prior to 2002 is both legally incorrect and factually misguided. Pet. 35-36.
`
`At most, all Petitioner has shown is that both azelastine and fluticasone were
`
`known in the art, and that those drugs might have been co-prescribed to some
`
`patients at some times. But the mere possibility that azelastine and fluticasone
`
`could be co-administered is not enough. The Federal Circuit has repeatedly found
`
`non-obvious combined formulations even in cases where the record showed that
`
`individual constituent drugs were regularly prescribed together. See, e.g., Leo
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`Pharm. Prods. Ltd. v. Rea, 726 F.3d 1346, 1358 (Fed. Cir. 2013); In re
`
`Brimonidine Patent Lit., 643 F.3d 1366, 1374 (Fed. Cir. 2011) (the fact that two
`
`drugs “were routinely prescribed together … does not establish that it would have
`
`been obvious to combine the two in a single formulation.”).
`
`Accordingly, Petitioner was required to demonstrate that a POSA would
`
`have had reason, looking at the art as of 2002, to proactively combine azelastine
`
`and fluticasone in a combination formulation. Petitioner has not met its burden. In
`
`fact, Petitioner has not demonstrated that the two agents were even used routinely
`
`or in any fixed regimen, as in the Leo Pharma and Brimonidine cases that
`
`nevertheless fell short of obviousness. Thus, Petitioner’s “clinical use” motivation
`
`is insufficient as a matter of law, and reveals a textbook case of improper
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`hindsight.
`
`Next, Petitioner’s argument that the AR treatment guidelines recommend the
`
`use of azelastine and fluticasone is equally unpersuasive. Pet. 35-36 (citing
`
`Dykewicz (EX1019); Berger (EX1021); Cauwenberge (EX1022) (collectively,
`
`“AR treatment guidelines”); and Kusters (EX1016)). Those guidelines actually
`
`demonstrate that: (i) there was no clinical benefit to co-administration of steroids
`
`and antihistamines compared to steroids alone; and (ii) physicians treating AR
`
`required a flexible approach to treating patients that allowed for dose titration and
`
`combination of different therapies. Nothing in the guidelines suggest, even
`
`remotely, that azelastine and fluticasone should be administered in a combined
`
`formulation.
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`In contrast, the art as of 2002 showed that there was no clinical benefit to co-
`
`administration of steroids and antihistamines compared to steroids alone. Indeed,
`
`the guidelines and prevailing clinical practice all taught a flexible approach, where
`
`an antihistamine could be added to a steroid in an “as needed” or “intermittent”
`
`basis. CIP2147, ¶¶66-71, 84. Second, a POSA would have read the AR treatment
`
`guidelines in view of other teachings in the art that the fixed co-administration of
`
`steroids and antihistamines were no more effective than steroids alone, further
`
`negating any alleged “motivation” to pursue a combination formulation. CIP2147,
`
`¶85.
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`Patent Owner's Response
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`No less than six studies had published by 2002 to evaluate whether the co-
`
`administration of antihistamines and steroids would yield any additive benefit.
`
`Several included data that showed increased side effects, and none showed a
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`reduction in side effects from the co-administration of two agents. CIP2147, ¶¶ 52,
`
`55-56, 59; EX1039, 6; EX1036, 6; EX1040, 6; EX1035, 8. Of those, four
`
`concluded that:
`
`• Beclomethasone (a steroid) when used with astemizole (an
`
`antihistamine) “provided no better control of rhinitis than
`
`beclomethasone alone.” EX1039, 627 (emphasis added).
`
`• Fluticasone when used with cetirizine (an antihistamine) showed “no
`
`significant difference in efficacy” compared to fluticasone. EX1040,
`
`225 (emphasis added).
`
`• Budesonide (a steroid) when used with terfenadine (an antihistamine)
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`“produced a similar effect to treatment with budesonide alone.”
`
`EX1036, 497 (emphasis added).
`
`• Adding loratadine (an antihistamine) to fluticasone “does not confer
`
`meaningful additional benefit.” EX1034, 118 (emphasis added).
`
`A POSA would have understood these studies to teach no additional benefit
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`to co-administration of antihistamines and steroids than steroids alone. CIP2147,
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`¶¶52, 55-57.
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`Patent Owner's Response
` IPR2017-00807
`Petitioner relies on the remaining two studies, but they too do not establish
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`any meaningful clinical benefit. For example, Drouin (EX1035) reported data
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`across the four primary AR symptoms—itching, sneezing, runny nose, and
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`congestion (individually and collectively)—showing purported clinical
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`improvements from co-administering beclomethasone (a steroid) and loratadine
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`(an antihistamine) ranging from 2% to 13%. EX1035, 5; CIP2147, ¶59. But, these
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`“improvements” are less than that shown by the typical placebo group—a standard
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`control group used to eliminate bias in clinical studies. CIP2147, ¶59, n.3. This
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`result would not have motivated a POSA to pursue a combination formulation of
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`azelastine and fluticasone.
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`Brooks (EX1038) fares no better. In fact, a POSA, as Dr. Carr explains,
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`would have viewed Brooks’ results to be unreliable. For example, Petitioner
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`repeatedly asserts that steroids were well-known to be substantially more effective
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`than antihistamines in treating AR. EX1003, ¶¶52, 54. Yet Brooks reports the
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`opposite—that beclomethasone (a steroid) was no more effective than loratadine
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`(an antihistamine) alone. EX1038, 195. That outcome is contrary to clinical
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`knowledge as of 2002, as even Petitioner concedes. CIP2147, ¶60; EX1003, ¶52.
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`These findings come nowhere close to motivating a POSA to pursue a
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`steroid/antihistamine combination. CIP2147, ¶85.
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`After Drouin and Brooks, researchers in 2000-2002 reviewed the available
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`Patent Owner's Response
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`literature in retrospective analyses. CIP2147, ¶¶61-63; CIP2041; CIP2042). The
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`unanimously concluded that using a steroid with an antihistamine conferred no
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`meaningful benefit. In 2000, Howarth taught that the available co-administration
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`studies “do not support a superior effect” with co-administration versus the steroid
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`alone. CIP2041, 10. And then, in 2001, Nielsen stated that “[c]ombining
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`antihistamines and steroids in the treatment of [AR] does not provide any
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`additional effect to intranasal corticosteroids alone.” CIP2042, 1564. In 2002,
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`Andy stated that “[c]ombination nasal steroids and nonsedating antihistamines
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`yields no additional benefits,” and further assigned the grade of “A” to the strength
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`of the evidence supporting this conclusion. CIP2147, ¶63; CIP2162, 1.
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`Nielsen and Andy explicitly considered several of the references that
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`Petitioner and Dr. Schleimer now use to argue that a clinical benefit existed:
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`Juniper 1989 (EX1039); Ratner (EX1034); Benincasa (EX1040); Simpson
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`(EX1036); Brooks (EX1038); and Juniper 1997 (EX1031). See CIP2042, 1572.
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`Howarth, Nielsen, and Andy reflect the total weight of clinical evidence in 2002
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`and confirm what a POSA would have understood—that there was no reason to
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`combine an antihistamine and a steroid in the same formulation for treating AR.
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`CIP2147, ¶64. Further, this knowledge, in conjunction with Shenfield’s teaching
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`that “[i]n some circumstances patients may be exposed to additional ingredients
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`with little therapeutic benefit and major potential side effects,” would have
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`Patent Owner's Response
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`dissuaded a POSA from pursuing a combination of an antihistamine and a steroid.
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`CIP2147, ¶85; CIP2043, 13.
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`In addition, based on these teachings, a POSA would have recognized that
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`the statements in the art regarding co-administration were guided by benefits other
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`than clinical efficacy—things like patient compliance and reduced side-effects—
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`that inure specifically from the selection of an oral antihistamine (not an intranasal
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`antihistamine like azelastine). CIP2147, ¶¶74-79, 86-87. Thus, the statements
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`identified in the Petition would have guided a POSA to one of several oral
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`antihistamines, which dominated the AR market, and away from the claimed
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`invention that uses intranasal azelastine.
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`Next, Petitioner’s assertions of motivation are further belied by the realities
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`of clinical practice, where physicians treating AR required a flexible approach to
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`treating patients. CIP2147, ¶¶65-72, 84. The treatment guidelines recommended a
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`stepwise approach starting with intranasal steroids and, if that did not work,
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`attempting any of the following: (1) adding oral steroids, (2) adding nasal
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`decongestants, (3) doubling the dose of intranasal steroid, (4) adding an
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`antihistamine, (5) adding an anticholinergic, and (6) adding an oral
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`antihistamine/decongestant. EX1024, 110-111. Once symptoms were controlled,
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`these treatments were to be reduced in stepwise fashion. EX1024, 111. And other
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`guidelines recommended a flexible approach of titrating drug doses or cycling
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`Patent Owner's Response
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`through therapies, which is further consistent with the clinical trial-and-error
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`treatment approach. CIP2147, ¶¶66-67.
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`A combined formulation would cause physicians to act against the AR
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`guidelines and prevailing clinical practice, and relinquish the long-practiced
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`flexible approach to treating patients with AR. Indeed, Shenfield taught “[o]ne of
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`the major problems [with fixed dose combination] is that the prescribing doctor
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`loses flexibility in patent management.” EX2043, 12. Consequently, a POSA
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`would not have been motivated to combine a steroid with an antihistamine in a
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`dosage form for treating AR. On its face, these reasons demonstrate why, before
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`Cipla’s invention, no one else had previously brought to market a combined
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`steroid/antihistamine nasal spray formulation despite these drugs being known for
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`decades. CIP2167, 1 (antihistamines known since 1950s); EX1024, 90 (nasal
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`steroids introduced in 1973). Indeed, the motivation was to have them separate so
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`as to preserve clinical flexibility to titrate as needed. CIP2147, ¶69.
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`In sum, the weight of clinical evidence by 2002 confirmed that no
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`meaningful clinical benefit resulted from using an antihistamine with a steroid, the
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`treatment guidelines recommended a trial-and-error approach, and physicians
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`needed flexibility in dose titration and choice of therapy. The prevailing
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`knowledge and clinical practice in 2002 gave a POSA no motivation to combine
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`azelastine and fluticasone into a combination formulation; it did just the opposite.
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`Patent Owner's Response
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`
` A POSA would have understood that azelastine and fluticasone B.
`had redundant mechanisms of action in vivo, further negating any
`motivation to combine into a single formulation.
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`Petitioner’s assertion that alleged “complementary mechanisms of action” of
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`azelastine and fluticasone would have motivated a POSA to pursue a combined
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`formulation is not supported. Pet. 36-38. As of 2002, the art had rejecte