Case 1:14-cv-01453-LPS Document 163 Filed 02/21/17 Page 1 of 33 PageID #: 5026
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`C.A. No. 14-01453-LPS
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`MEDA PHARMACEUTICALS INC. and
`CIPLA LTD.,
`
`
`Plaintiffs,
`
`
`v.
`
`APOTEX INC. and APOTEX CORP.,
`
`
`Defendants.
`
`PLAINTIFFS’ POST-TRIAL SUR-REPLY BRIEF
`ON OBJECTIVE INDICIA OF NONOBVIOUSNESS
`
`
`
`
`RICHARDS, LAYTON & FINGER, P.A.
`Frederick L. Cottrell, III (#2555)
`Selena E. Molina (#5936)
`920 North King Street,
`Wilmington, DE 19801
`(302) 651-7700
`cottrell@rlf.com
`molina@rlf.com
`
`
`
`
`
`
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`Dennies Varughese
`Mark Fox Evens
`Uma N. Everett
`Adam C. LaRock
`Joshua I. Miller
`Josephine J. Kim
`1100 New York Ave., N.W., Suite 800
`Washington, DC 20005-3934
`(202) 371-2600
`
`Attorneys for Plaintiffs
`Meda Pharmaceuticals Inc. and Cipla Ltd.
`
`
`
`
`Dated: February 21, 2017
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`Case 1:14-cv-01453-LPS Document 163 Filed 02/21/17 Page 2 of 33 PageID #: 5027
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`
`TABLE OF CONTENTS
`
`INTRODUCTION .......................................................................................................................... 1
`
`ARGUMENT .................................................................................................................................. 3
`
`I.
`
`THE PATENTS-IN-SUIT ARE VALID, AND EIGHT OBJECTIVE INDICIA ARE AN
`ADDITIONAL AND INDEPENDENT BASIS CONFIRMING VALIDITY. ................. 4
`
`A.
`
`UNEXPECTED RESULTS: A POSA in 2002 would not have
`expected Dymista®’s clinical benefits and successful formulation. ....................... 5
`
`1.
`
`2.
`
`3.
`
`Dymista®’s increased efficacy, accelerated onset, and reduced
`side effects were not expected in 2002. ...................................................... 5
`
`Dymista®’s benefits are differences in “kind.” ........................................... 8
`
`A POSA would not have expected that a single formulation
`like Dymista® could be made suitable for nasal administration. .............. 10
`
`FAILURE OF OTHERS: At least three sophisticated pharmaceutical
`companies failed to develop an antihistamine/steroid fixed-dose
`formulation. ........................................................................................................... 11
`
`ACQUIESCENCE: Meda took a license from Cipla for the Patents-in-
`Suit to market Dymista®. ...................................................................................... 15
`
`SKEPTICISM: Both Meda and FDA doubted whether a fixed-dose
`antihistamine/steroid combination would work. ................................................... 15
`
`1.
`
`2.
`
`Clinical skepticism, prior to and well after the invention date,
`confirms that a POSA would not have anticipated success. ..................... 16
`
`Industry participants were skeptical that an
`antihistamine/steroid combination could be formulated. .......................... 18
`
`UNMET NEED: Dymista® satisfied a long-felt but previously unmet
`need for better, faster, and safer treatment of AR. ................................................ 19
`
`COMMERCIAL SUCCESS: Apotex has failed to overcome evidence
`of Dymista®’s commercial success. ...................................................................... 19
`
`COPYING: Duonase (the version of Dymista® in India) was
`immediately and widely copied by multiple pharmaceutical
`companies. ............................................................................................................ 21
`
`PRAISE: Dymista® has been received by the medical community as
`best treatment for AR available. ........................................................................... 22
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
`
`G.
`
`H.
`
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`Case 1:14-cv-01453-LPS Document 163 Filed 02/21/17 Page 3 of 33 PageID #: 5028
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`II.
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`THERE WERE NO “BLOCKING PATENTS” TO NEGATE ANY OBJECTIVE
`INDICIA OF NONOBVIOUSNESS. ............................................................................... 23
`
`A.
`
`B.
`
`C.
`
`D.
`
`Cipla did not own any of the alleged “blocking patents.” .................................... 23
`
`Cipla, Cramer, Segal, and Meda were not blocked or dissuaded by the
`alleged “blocking patents.” ................................................................................... 24
`
`Hettche and Phillipps were not blocking patents because they expired
`before Dymista®’s launch. .................................................................................... 24
`
`Hettche recites a closed Markush group of active ingredients that
`cannot cover a product that includes fluticasone. ................................................. 25
`
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`Case 1:14-cv-01453-LPS Document 163 Filed 02/21/17 Page 4 of 33 PageID #: 5029
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`
`Cases
`
`TABLE OF AUTHORITIES
`
`Allergan, Inc. v. Sandoz Inc.
`726 F.3d 1286 (Fed. Cir. 2013)............................................................................................1, 16, 17
`
`Allergan, Inc. v. Sandoz Inc.,
`796 F.3d 1293 Fed. Cir. 2015) ...................................................................................................9, 10
`
`Apple Inc. v. Samsung Elecs. Co.,
`839 F.3d 1034 (Fed. Cir. 2016)....................................................................................................3, 4
`
`AstraZeneca LP v. Breath Ltd,
`88 F. Supp. 3d 326 (D.N.J. 2015) ..................................................................................................12
`
`Boehringer Ingelheim Vetmedica, Inc. v. Schering-Plough Corp.,
`320 F.3d 1339 (Fed. Cir. 2004)......................................................................................................12
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013)........................................................................................9, 17, 18, 21
`
`Hybritech Inc. v. Monoclonal Antibodies, Inc.,
`802 F.2d 1367 (Fed. Cir. 1986)......................................................................................................14
`
`In re Brimonidine Patent Litig.,
`643 F.3d 1366 (Fed. Cir. 2011)..................................................................................................1, 18
`
`In re Geiger,
`815 F.2d 686 (Fed. Cir. 1987)..........................................................................................................7
`
`In re GPAC Inc.,
`57 F.3d 1573 (Fed. Cir. 1995)........................................................................................................15
`
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.,
`688 F.3d 1342 (Fed. Cir. 2012)........................................................................................................4
`
`Knoll Pharm. Co. v. Teva Pharm. USA, Inc.,
`367 F.3d 1381 (Fed. Cir. 2004)......................................................................................................14
`
`Leo Pharm. Prods. Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013)..........................................................................................1, 3, 4, 18
`
`Multilayer Stretching Cling Film Holdings, Inc. v. Berry Plastics Corp.,
`831 F.3d 1350 (Fed. Cir. 2016)......................................................................................................25
`
`Otsuka Pharm. Co., Ltd. v. Sandoz, Inc.,
`
`
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`678 F.3d 1280 (Fed. Cir. 2012)......................................................................................................24
`
`Procter & Gamble Co. v. Teva Pharm. USA, Inc.,
`566 F.3d 989 (Fed. Cir. 2009)..........................................................................................................5
`
`Richardson-Vicks, Inc. v. Upjohn Co.,
`122 F.3d 1476 (Fed. Cir. 1997)............................................................................................1, 16, 17
`
`Shire Development, LLC v. Watson Pharms., Inc.,
`--- F.3d ----, 2017 WL 541013 (Fed. Cir. February 10, 2017) .......................................................25
`
`TriMed, Inc. v. Stryker Corp.,
`608 F.3d 1333 (Fed. Cir. 2010)......................................................................................................11
`
`Unigene Labs. Inc. v. Apotex Inc.,
`2009 WL 2762706 (S.D.N.Y. Aug. 31, 2009) ...............................................................................11
`
`Unigene Labs., Inc. v. Apotex, Inc.,
`2010 WL 2730471 (S.D.N.Y. July 7, 2010) ..................................................................................11
`
`Unigene Labs., Inc. v. Apotex Inc.,
`655 F.3d 1352 (Fed. Cir. 2011)......................................................................................................11
`
`ViiV Healthcare UK Ltd. v. Lupin Ltd.,
`6 F. Supp. 3d 461 (D. Del. 2013), aff’d, 594 F. App’x 686 (Fed. Cir. 2015) ....................20, 23, 25
`
`WBIP, LLC v. Kohler Co.,
`829 F.3d 1317 (Fed. Cir. 2016)................................................................................................15, 19
`
`Windsurfing Int’l, Inc. v. AMF, Inc.,
`782 F.2d 995 (Fed. Cir. 1986)........................................................................................................22
`
`
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`Case 1:14-cv-01453-LPS Document 163 Filed 02/21/17 Page 6 of 33 PageID #: 5031
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`TABLE OF ABBREVIATIONS
`
`“Apotex”
`
`“AR”
`
`“Asserted Claims”
`
`“Astelin®”
`
`“azelastine”
`
`“Cipla”
`
`“Cramer”
`
`“Dr. Accetta”
`
`“Dr. Carr”
`
`“Dr. D’Addio”
`
`“Dr. Kaliner”
`
`“Dr. Schleimer”
`
`“Dr. Smyth”
`
`“Dr. Wedner”
`
`“Duonase”
`
`Refers collectively to Defendants Apotex, Inc.
`and Apotex Corporation
`
`Means “allergic rhinitis”
`
`Refers collectively to claims 4, 29, and 42-44
`of U.S. Patent No. 8,168,620 and claims 10-11,
`13, 15-16, 23, 24, 26, 29, and 30 of U.S. Patent
`No. 9,259,428
`
`Refers to the branded azelastine hydrochloride
`product and its product label (PTX0011 &
`DTX-022)
`
`Means azelastine hydrochloride
`
`Refers to Plaintiff Cipla, Ltd.
`
`Refers to European Patent Application No.
`0780127 (1997) (PTX0062 & DTX-012)
`
`Donald Accetta, M.D., a fact witness for
`Defendants
`
`Warner W. Carr, M.D., a clinical expert
`witness for Plaintiffs
`
`Alexander Dominic D’Addio, Ph.D., a fact
`witness for Plaintiffs
`
`Michael A. Kaliner, M.D., a clinical expert
`witness for Plaintiffs
`
`Robert P. Schleimer, Ph.D., a clinical expert
`witness for Defendants
`
`Hugh David Charles Smyth, Ph.D., a
`formulation expert witness for Plaintiffs
`
`H. James Wedner, M.D., a clinical expert
`witness for Defendants
`
`Cipla’s fixed-dose azelastine and fluticasone
`combination product
`
`“Duonase imitators”
`
`Refers collectively to the fixed-dose azelastine
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`and fluticasone combination products launched
`in India, including Combinase AQ, Azeflo,
`Nazomac-AF, Floresp-AZ, Ezicas-AZ, and
`Nasocom-AZ (PTX0026)
`
`Meda’s fixed-dose azelastine and fluticasone
`combination product
`
`Means the U.S. Food and Drug Administration
`
`Refers to the branded fluticasone propionate
`product and its product label (PTX0059 &
`DTX-033)
`
`Means fluticasone propionate
`
`Refers collectively to the ARIA Guidelines
`(PTX0326 & DTX-081) and the Dykewicz
`Guidelines (PTX0022 & DTX-246)
`
`Refers to U.S. Patent No. 5,164,194 (PTX0343
`& DTX-016)
`
`Refers collectively to Plaintiff Meda
`Pharmaceuticals, Inc. and its predecessor
`companies, MedPointe, Inc. and Carter-
`Wallace, Inc.
`
`Refers collectively to U.S. Patent Nos.
`8,168,620 and 9,259,428
`
`Refers to U.S. Patent No. 4,335,121 (PTX0104
`& DTX-096)
`
`Means a person of ordinary skill in the art
`
`Means the U.S. Patent and Trademark Office
`
`Refers to Ratner, P., et al. “Combination
`Therapy with Azelastine Hydrochloride Nasal
`Spray and Fluticasone Propionate Nasal Spray
`in the Treatment of Patients with Seasonal
`Allergic Rhinitis.” Annals of Allergy, Asthma,
`& Immunology, 100:74-81; 2008 (PTX0330 &
`DTX-191)
`
`Refers to International Publication No. WO
`98/48839 (1998) (PTX0088 & DTX-021)
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`“Dymista®”
`
`“FDA”
`
`“Flonase®”
`
`“fluticasone”
`
`“Guidelines”
`
`“Hettche”
`
`“Meda”
`
`“Patents-in-Suit”
`
`“Phillipps”
`
`“POSA”
`
`“PTO”
`
`“Ratner 2008”
`
`“Segal”
`
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`INTRODUCTION
`
`Apotex’s failure at trial to present any clear and convincing evidence that the Patents-in-
`
`Suit are obvious is further confirmed by its inability to respond to Plaintiffs’ evidence of
`
`objective indicia. Apotex’s Reply Brief (D.I. 162, “Rep. Br.”) does not address the evidentiary
`
`failings from trial that Plaintiffs highlighted in their Answering Brief (D.I. 161, “Pltfs. Br.”).1
`
`Apotex cannot supplement and cure its trial defects through unsupported argument in post-trial
`
`briefing. Those omissions are significant. In any event, even if Apotex had put forth a more
`
`persuasive prima facie case at trial, Apotex has not overcome the powerful real-world objective
`
`indicia Plaintiffs presented. The objective indicia are particularly important here because of
`
`Apotex’s extensive and improper use of hindsight in its presentation of evidence and argument.
`
`Plaintiffs presented evidence of eight objective indicia which constitute independent
`
`evidence of nonobviousness:
`
`Unexpected results. Dymista® exhibits (1) significant improvement in efficacy over
`
`fluticasone; (2) much faster onset than azelastine; and (3) dramatically reduced side effects. Each
`
`of these effects was unexpected, as explained in detail below. To try to rebut these surprising
`
`results, Apotex relies only upon Ratner 2008, which was published six years after the invention
`
`date, is indisputably not prior art, and in any event lends no support to Apotex’s theories.
`
`Failure of others. Co-plaintiff Meda (separate and distinct from co-Plaintiff Cipla, who
`
`1 Apotex’s Reply fails to rebut, or even address, at least five points negating prima facie
`obviousness: (i) Apotex provides no reason why a POSA would have selected azelastine and
`fluticasone (Pltfs. Br. at 21-24); (ii) Apotex is silent regarding the multiple formulation
`difficulties that would have confronted a POSA (id. at 24-30); (iii) Apotex has identified no
`reason to select the claimed excipients, their concentrations, and the claimed pH (id. at 30-37);
`(iv) Apotex fails to rebut Plaintiffs’ distinguishing of its principal cases—Richardson-Vicks and
`Allergan I; and (v) Apotex offers no substantive response to the In re Brimonidine or Leo cases,
`in each of which the Federal Circuit found nonobviousness when presented with facts similar to
`those here.
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`owns the Patents-in-Suit) failed to formulate an azelastine/fluticasone combination formulation
`
`despite decades of experience with azelastine. Likewise, Proctor & Gamble and Warner-Lambert
`
`failed to market any antihistamine/steroid combination formulation despite public evidence of
`
`their investigation into the feasibility of a combination. Apotex’s only response is unsupported
`
`argument and speculation. Apotex has not met its burden.
`
`Acquiescence through licensing. Having failed to develop its own combination
`
`formulation, Meda took a license to Cipla’s patent application to bring Dymista® to market.
`
`Apotex has failed to offer any credible rebuttal to this fact.
`
`Skepticism by others. The trial record shows that (1) Meda was skeptical in 2002 that an
`
`azelastine/steroid combination formulation could be formulated, (2) Meda and FDA were both
`
`skeptical that an azelastine/fluticasone combination product would satisfy FDA’s combination
`
`rule, and (3) both were further skeptical whether Dymista® would provide meaningful clinical
`
`benefit over fluticasone alone. Apotex responds by taking issue with an unrelated 2005 Meda
`
`patent application which, as explained below, is factually and legally irrelevant to this case.
`
`Commercial success. Dymista®, and its India counterpart, Duonase, are commercial
`
`successes, and those successes have a direct nexus to the Asserted Claims because both are
`
`embodiments of those claims. Apotex has made no effort to rebut nexus, instead arguing that the
`
`sales are not sufficient to constitute “success.” But to make those claims, Apotex artificially
`
`expands the relevant market to include generic and over-the-counter (“OTC”) drugs as
`
`competitors. That methodology fails on the facts because (1) OTC drugs are not direct
`
`competitors, and (2) even if generic AR drugs are considered competitors, Dymista® is still a
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`commercial success. And, contrary to Apotex’s insistence, the law does not require Dymista® to
`
`be the most popular product.
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`Copying by others. At least 11 imitator products launched in India immediately after
`
`Duonase launched in 2004. In rebuttal, Apotex relies solely upon decisions that hold that copying
`
`by filing an ANDA carries less weight. But the Duonase copycats were not ANDA products
`
`seeking FDA approval. Thus, Apotex’s cited cases are irrelevant, and Apotex has not overcome
`
`Plaintiffs’ copying evidence.
`
`Unmet need. Dymista® satisfies an unmet need for a more effective and faster AR drug
`
`with fewer side effects. Apotex does not directly address Plaintiffs’ evidence on this
`
`consideration, but instead relies only on its insufficient rebuttal to Plaintiffs’ showing of
`
`unexpected results. Because Apotex’s arguments on that consideration lack merit, so too do its
`
`arguments regarding unmet need.
`
`Industry praise. The AR medical community praised Dymista®, calling it the “drug of
`
`choice” and a “breakthrough.” Apotex criticizes this praise as allegedly not being independent,
`
`but tellingly has not come forth with any evidence of bias or lack of independence. Thus, the
`
`evidence of praise stands in Plaintiffs’ favor.
`
`ARGUMENT
`
`All eight objective indicia of nonobviousness in this case provide significant real-world
`
`evidence of the validity of the Patents-in-Suit. As Plaintiffs’ Answering Brief explained based
`
`upon the evidence presented at trial, Apotex’s invalidity theory exhibits hindsight of the worst
`
`kind. The evidence of objective indicia here safeguards against that type of hindsight. See Apple
`
`Inc. v. Samsung Elecs., Co., 839 F.3d 1034, 1052 (Fed. Cir. 2016) (explaining that objective
`
`indicia “serve to guard against slipping into use of hindsight, and to resist the temptation to read
`
`into the prior art the teachings of the invention in issue”) (en banc); see also Leo Pharm. Prod.,
`
`Ltd. v. Rea, 726 F.3d 1346, 1358 (Fed. Cir. 2013) (objective indicia “enables the court to avert
`
`the trap of hindsight”). Indeed, solid objective evidence “may often establish that an invention
`
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`appearing to have been obvious in light of the prior art was not.” Apple, 839 F.3d at 1052-53.
`
`Additionally, the Court should always weigh objective indicia evidence. Id. (“It is to be
`
`considered as part of all the evidence, not just when the decision maker remains in doubt after
`
`reviewing the art.”). Indeed, “evidence of secondary considerations may often be the most
`
`probative and cogent evidence in the record.” Id. “At all times, the burden is on [Apotex] to
`
`establish by clear and convincing evidence that the patent[s are] obvious.” Kinetic Concepts, Inc.
`
`v. Smith & Nephew, Inc., 688 F.3d 1342, 1360 (Fed. Cir. 2012); see also In re Cyclobenzaprine
`
`Hydrochloride Extended-Release Capsule Patent Litig., 676 F.3d 1063, 1075 (Fed. Cir. 2012).
`
`Plaintiffs respectfully ask that the Court find the Asserted Claims valid.
`
`I.
`
`THE PATENTS-IN-SUIT ARE VALID, AND EIGHT OBJECTIVE INDICIA ARE
`AN ADDITIONAL AND INDEPENDENT BASIS CONFIRMING VALIDITY.
`
`Although Apotex has failed to show by clear and convincing evidence that the Asserted
`
`Claims are obvious,2 Plaintiffs presented substantial and unrebutted objective evidence which
`
`must be considered in the Court’s analysis. In re Cyclobenzaprine, 676 F.3d 1063 at 1075. This
`
`evidence is not “just a cumulative or confirmatory part of the obviousness calculus but
`
`constitute[s] independent evidence of nonobviousness.” Leo, 726 F.3d at 1358 (internal quotation
`
`omitted).
`
`
`2 Apotex has repeatedly, but wrongly, suggested that Cipla’s patents issued solely because of
`objective indicia evidence. Rep. Br. at 18; see also D.I. 158 (“Op. Br.”) at 39. Plaintiffs already
`explained that this is wrong. Pltfs. Br. at 37, n. 8. In response to the PTO’s final rejection before
`the claims issued, Cipla (1) submitted a declaration showing that the closest prior art was
`inoperable (PTX0005.02559-02562); (2) submitted evidence of objective indicia, (id.); and (3)
`amended the claims to reflect that the claimed invention was a “nasal spray” “suitable for nasal
`administration.” PTX0005.02570). That the PTO applied the appropriate legal standard and
`considered all relevant evidence before it—including objective indicia—does not mean that it
`found the claims obvious but for objective indicia. The PTO—like Apotex—was unable to find
`any evidence in the art that a fixed-dose combination nasal spray could be made suitable for
`nasal administration, so it issued the claims after finding them “unexpectedly and surprisingly
`unobvious over, different from, and superior to the prior art of record.” Rep. Br. at 18.
`
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`A.
`
`UNEXPECTED RESULTS: A POSA in 2002 would not have expected
`Dymista®’s clinical benefits and successful formulation.
`
`Nonobviousness may be shown “by demonstrating that the claimed invention exhibits
`
`some superior property or advantage that a person of ordinary skill in the relevant art would have
`
`found surprising or unexpected.” Procter & Gamble Co. v. Teva Pharm. USA, Inc., 566 F.3d
`
`989, 994 (Fed. Cir. 2009). Here, there are unexpected clinical and formulation results.
`
`1.
`
`Dymista®’s increased efficacy, accelerated onset, and reduced side
`effects were not expected in 2002.
`
`Apotex wrongly argues that Plaintiffs should have compared Dymista® to the prior art ad
`
`hoc co-administration of azelastine and fluticasone, such as Dr. Accetta’s treatment records. Rep.
`
`Br. at 23. But that is not the closest prior art. Dymista® is a fixed-dose combination of an
`
`antihistamine and a steroid. Apotex adduced no evidence at trial that Dr. Accetta’s patient
`
`records, or any other alleged prior art co-administration of these agents, followed a strict dosing
`
`regimen comparable to Dymista®’s fixed-dose formulation. And Apotex admits as much, stating
`
`“[p]erhaps that is true.” Rep. Br. at 23.
`
`Because no such product existed before Cipla’s invention (Tr. 199:5-200:2 (Schleimer)),
`
`the closest prior art is a fixed dosing regimen of the sort studied in the Juniper 1989, Simpson,
`
`Benincasa, Ratner 1998, Howarth, and Nielsen 2001 references, not Apotex’s alleged prior ad
`
`hoc co-administration. Tr. 564:1-3 (Carr). These references—particularly Benincasa and Ratner
`
`1998, which used fluticasone—consistently found no meaningful benefit over the steroid alone.
`
`Pltfs. Br. at 13-16; Plaintiffs’ Proposed Findings Of Fact (D.I. 155,” “PFOF”) ¶¶ 55-59.
`
`The evidence at trial showed that Dymista® exhibited significant improved clinical
`
`benefits that were unexpected in 2002. Dymista® is 90% more effective than fluticasone. See
`
`PTX0230.00003; Tr. 551:10-16 (Carr). This was unexpected over the closest prior art’s
`
`conclusion that there was no meaningful improvement in efficacy over the steroid alone. Pltfs.
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`Br. at 13-16; PFOF ¶¶ 55-59. And the figure to
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`the left, which Dr. Kaliner explained in detail at
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`trial, shows Dymista®’s clinical benefits that were
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`unexpected in 2002. First, Dymista® has an onset
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`of thirty minutes for all AR symptoms, whereas
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`azelastine’s (the faster-acting drug versus
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`fluticasone) onset is three hours for those same symptoms. PTX0024; PTX0011; PTX0059; Tr.
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`89:8-15 (Wedner). Nothing in the art suggested that the claimed combination would achieve a
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`much faster onset. Pltfs. Br. at 38-39. Second, Dymista®’s side effects are significantly less than
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`either agent alone, but a POSA would have expected increased side-effects from combining two
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`agents. Pltfs. Br. at 39; DTX-048.0013; PTX0024; PTX0011; PTX0059. And third, Dymista
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`had a statistically significant improvement in mean TNSS score over placebo compared to
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`Astelin and Flonase administered alone.
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`Unable to respond to Plaintiffs’ evidence of unexpected results with relevant prior art,
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`Apotex instead points to Ratner 2008, a reference published six years after the invention date.
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`Ratner 2008 was the first study to investigate any co-administration of azelastine and fluticasone
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`when used together in a strict fixed-dosing regimen, and showed, for the first time, a marked
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`improvement in efficacy over a steroid alone. PTX0330.00001. This treatment regimen was not
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`practiced in 2002 (Tr. 456:17-22 (Kaliner)), so even the authors of the study were surprised by
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`their findings: “the use of intranasal azelastine in combination with intranasal fluticasone
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`produced an unanticipated magnitude of improvement in rhinitis symptoms.” PTX0330.00007.
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`Failing to rebut Plaintiffs’ unexpected results based on prior art, Apotex seeks to leverage
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`Ratner 2008’s findings six years later to assert that Dymista®’s benefits would have been
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`expected in 2002. D.I. 158 (“Op. Br.”) at 46; Rep. Br. at 22-23. Aside from the fact that it is not
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`prior art, Apotex’s reliance on Ratner 2008 is misplaced because: (1) its dosing regimen was
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`starkly different from the loose ad hoc usage Apotex relies on as closest prior art (Pltfs. Br. at 9-
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`10, 13-16, 40; Rep. Br. at 23); and (2) Dymista®—a fixed-dose formulation—showed clinical
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`benefits that went beyond even the benefits observed in Ratner 2008’s strict fixed dosing
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`regimen. Pltfs. Br. at 39-40.
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`Remarkably, Apotex concedes that it has produced no evidence that azelastine and
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`fluticasone were used in a fixed-dosing regimen prior to 2002: “there’s no way to know that real-
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`world patients actually took Astelin® and Flonase® together as regularly as they did in the Ratner
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`study. Perhaps that is true.” Rep. Br. at 22-23 (emphasis added). Apotex’s admission
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`undermines its case. Without evidence of patients taking azelastine and fluticasone in a strict
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`dosing regimen, Apotex cannot credit Ratner 2008’s findings to the prior art. Indeed, given that
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`the closest prior art showed no meaningful benefit to adding an antihistamine to a steroid (Pltfs.
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`Br. at 13-16), a POSA would not have expected the (1) benefits of Ratner 2008’s fixed dosing
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`regimen, or (2) even greater benefits of Dymista®’s fixed-dose single formulation.
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`Apotex is wrong to suggest “a deficiency of [Plaintiffs’] proof,” accusing Plaintiffs of not
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`comparing Dymista® to Ratner 2008. As Apotex concedes, Ratner was a treatment regimen that
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`was nothing like how patients were being dosed in 2002. Rep. Br. at 23. Plaintiffs are not
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`obligated to compare the results of the invention to art that did not exist in 2002. In re Geiger,
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`815 F.2d 686, 690 (Fed. Cir. 1987) (Newman, J., concurring) (“It is not required that the claimed
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`invention be compared with subject matter that does not exist in the prior art.”) (emphasis
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`added). Instead, Drs. Kaliner and Carr compared Dymista®’s results to the numerous fixed-
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`dosing studies, which were the closest prior art available in 2002. Tr. 564:1-3 (Carr).
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`Regarding onset, the evidence shows that (1) the FDA-approved label for Astelin®
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`unambiguously states that azelastine has an onset of three hours for all four AR symptoms (Tr.
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`89:8-15 (Wedner); PTX0011.00008); (2) the FDA-approved label for Flonase® unambiguously
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`states that fluticasone has an onset of twelve hours for all symptoms (PTX0059.00003); and (3)
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`the FDA-approved label for Dymista® has an onset of thirty minutes for all symptoms.
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`PTX0024.00018. This data, subject to FDA’s “rigorous review,” (Tr. 827:23-828:17
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`(Schleimer)), confirms the unexpected result of faster onset. PFOF ¶ 123. Apotex’s response is
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`only: “there is not” evidence of faster onset. Rep. Br. at 23. That is not evidence, and it does not
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`overcome Plaintiffs’ trial evidence.
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`Finally, Dymista® has been proven to have reduced side effects as compared to either
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`drug alone. Pltfs. Br. at 39; PFOF ¶¶ 122-123. This is the opposite of what a POSA would have
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`expected in 2002: “[t]he use of 2 drugs will always increase the risk of adverse drug reactions.”
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`DTX-048.0013. For this unexpected benefit, Apotex retreats from Ratner 2008 because it
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`showed “synergistic” and “near additive” increases in side effects, as a POSA would have
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`expected. Pltfs. Br. at 40; see also PTX0330.00005; Tr. 457:18-458:7 (Kaliner); PDX2.17.
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`Instead, Apotex again ignores the trial record, stating only “there is no evidence.” Rep. Br. at 23.
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`The facts belie Apotex’s denial—Dymista®’s reduced side effects comes directly from FDA-
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`approved labels. PTX0011.00014; PTX0059.00003; PTX0024.00006.
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`2.
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`Dymista®’s benefits are differences in “kind.”
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`The evidence shows that Dymista®’s efficacy, onset, and safety are different in kind from
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`what was expected in the art. Apotex claims that Dr. Carr made “admissions” that Dymista®’s
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`efficacy benefits were of a “degree,” in a legal sense. Rep. Br. at 23. Dr. Carr admitted no such
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`thing, and noticeably absent from Apotex’s brief is Dr. Carr’s actual testimony. Dr. Carr actually
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`testified: “Look, when we saw the efficacy data, we were superexcited [sic], my coauthors and
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`myself. We were surprised that we saw this kind of robust data that was reproducible.” Tr.
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`543:21-25 (Carr) (emphasis added). Dr. Carr’s testimony taken as a whole shows that
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`Dymista®’s benefits were unexpected in the art (and he drew no legal conclusions whatsoever).
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`Moreover, Apotex has failed to meaningfully distinguish the decision in Allergan, Inc. v.
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`Sandoz Inc., where the Federal Circuit found “unexpected results” under similar circumstances.
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`796 F.3d 1293, 1306 (Fed. Cir. 2015) (“Allergan II”). There, an excipient “would either have no
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`impact on the permeability of bimatoprost or decrease it…. [whereas] Allergan’s inventors
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`surprisingly determined that the opposite was true, namely, that 200 ppm BAK enhanced the
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`permeability of bimatoprost.” Id. (emphases added). In Allergan II, because the invention
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`reversed a trend (invention resulted in an increase, where the art suggested a decrease), the
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`invention was found to have unexpected results. Id.
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`Allergan II is squarely on point here. The evidence shows that (1) the prior art taught no
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`meaningful clinical benefit to fixed dosing of antihistamines and steroids over steroids alone; (2)
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`there was no expectation that azelastine or fluticasone would obtain a faster onset when put into
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`a fixed-dose combination; and (3) the side effects of a fixed-dose combination were expected to
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`increase.3 Pltfs. Br. at 13-16, 38-40. In contrast, the invention here—as embodied in Dymista®—
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`surprisingly shows: (1) a significant improvement of 90% over fluticasone after accounting for
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`placebo4 (Tr. 551:10-16 (Carr)); (2) accelerated onset of action versus both drugs taken
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`3 Although a POSA expected an increase in side effects when using two drugs, Dymista®
`unexpectedly shows a decrease as compared to either monotherapy. That is i