Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 1 of 55 PageID #: 4805
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`
`
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`
`
`MEDA PHARMACEUTICALS, INC. and
`CIPLA LTD.
`
`
`Plaintiffs,
`
`
`v.
`
`APOTEX, INC. and APOTEX CORP.
`
`
`Defendants.
`
`
`OF COUNSEL:
`
`WINSTON & STRAWN LLP
`Charles B. Klein
`Ilan Wurman
`1700 K Street, N.W.
`Washington, DC 20006
`(202) 282-5000
`cklein@winston.com
`iwurman@winston.com
`
`WINSTON & STRAWN LLP
`George C. Lombardi
`Samuel S. Park
`Kevin E. Warner
`Ryan B. Hauer
`35 W. Wacker Drive
`Chicago, Illinois 60601-9703
`(312) 558-5600
`glombardi@winston.com
`spark@winston.com
`kwarner@winston.com
`rhauer@winston.com
`
`
`
`Dated: January 10, 2017
`
`
`DEFENDANTS’ PROPOSED FINDINGS OF FACT
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`
`
`
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`
`
`Civil Action No. 14-1453 (LPS)
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`)
`)
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`)
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`)
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`
`
`
`Dominick T. Gattuso
`HEYMAN ENERIO
`Gattuso & HIRZEL LLP
`300 Delaware Avenue, Suite 200
`Wilmington, DE 19801
`(302) 472-7300
`dgattuso@hegh.law
`
`Attorneys for Defendants Apotex Inc. and
`Apotex Corp.
`
`
`1
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`CIP2023
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 2 of 55 PageID #: 4806
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`
`
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`TABLE OF CONTENTS
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`Page
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`I.
`
`II.
`
`III.
`
`IV.
`
`V.
`
`VI.
`
`VII.
`
`INTRODUCTION .............................................................................................................. 1
`
`PARTIES ............................................................................................................................ 2
`
`THE PATENTS-IN-SUIT .................................................................................................. 3
`
`THE ASSERTED CLAIMS AND PATENT SPECIFICATION. ...................................... 3
`
`THE PARTIES’ WITNESSES ........................................................................................... 4
`
`PERSON OF ORDINARY SKILL IN THE ART. ............................................................. 6
`
`IT WAS OBVIOUS TO COMBINE FLUTICASONE PROPIONATE AND
`AZELASTINE HYDROCHLORIDE INTO A SINGLE NASAL SPRAY
`FORMULATION TO TREAT ALLERGIC RHINITIS. ................................................... 7
`
`A.
`
`B.
`C.
`
`Physicians used fluticasone propionate and azelastine hydrochloride nasal
`sprays together in the prior art to treat allergic rhinitis. .......................................... 8
`1.
`Dr. Accetta (fact witness) ........................................................................... 8
`2.
`Physician expert witnesses .......................................................................... 9
`The prior art discloses azelastine and fluticasone co-formulations. ....................... 9
`The prior art motivated skilled artisans to combine azelastine and
`fluticasone to treat allergic rhinitis. ...................................................................... 10
`1.
`Corticosteroids and antihistamines were known to have different
`and complementary mechanisms of action. .............................................. 10
`Fluticasone was a preferred nasal corticosteroid because of its
`potency. ..................................................................................................... 13
`Azelastine was the preferred nasal antihistamine because of its
`efficacy. ..................................................................................................... 14
`Oral antihistamines and nasal steroids were regularly, and
`successfully, combined with nasal steroids before the critical date. ......... 14
`The prior art recommended administration of a nasal antihistamine
`and a nasal steroid to treat AR. ................................................................. 15
`A co-formulation of fluticasone and azelastine would have been
`thought to increase patient compliance. .................................................... 18
`Fluticasone was already co-formulated with another drug to
`remedy compliance issues......................................................................... 19
`
`2.
`
`3.
`
`4.
`
`5.
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`6.
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`7.
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`i
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`2
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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 3 of 55 PageID #: 4807
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`8.
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`Combinations studies showed a benefit to combining
`antihistamines and corticosteroids. ........................................................... 19
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`VIII.
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`IT WAS OBVIOUS HOW TO FORMULATE A NASAL SPRAY THAT
`COMBINES FLUTICASONE AND AZELASTINE FOR THE TREATMENT OF
`ALLERGIC RHINITIS. .................................................................................................... 21
`
`A.
`B.
`C.
`
`D.
`
`Flonase® Formulation ........................................................................................... 23
`Astelin® Formulation ............................................................................................ 25
`It was obvious to an ordinarily skilled formulator how to co-formulate an
`Azelastine and Fluticasone Nasal Spray. .............................................................. 26
`The patents-in-suit contain no information about how to formulate or use a
`combination product. ............................................................................................ 36
`
`IX.
`
`THERE ARE NO SECONDARY CONSIDERATIONS THAT INDICATE THE
`ASSERTED CLAIMS ARE NOT OBVIOUS. ................................................................ 37
`
`A.
`
`B.
`
`C.
`
`D.
`
`E.
`
`F.
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`There was simultaneous independent invention that confirms it was
`obvious to co-formulate fluticasone and azelastine. ............................................. 37
`Meda has failed to produce any persuasive evidence of failure of others to
`make the invention. ............................................................................................... 38
`Meda has failed to produce any persuasive evidence of unexpected results. ....... 40
`Meda has not shown that Dymista®’s efficacy is unexpectedly
`1.
`superior to the closest prior art.................................................................. 40
`Dymista®’s onset of action was expected. ................................................ 41
`2.
`Dymista®’s side effects were expected. .................................................... 42
`3.
`Two blocking patents belie other secondary considerations of non-
`obviousness. .......................................................................................................... 42
`Meda has failed to produce any evidence of commercial successes that
`rebuts the strong showing of obviousness. ........................................................... 43
`1.
`Blocking patents make evidence of commercial success weak. ............... 44
`2.
`Competitive factors make evidence of commercial success weak. .......... 44
`Dymista®’s performance is not indicative of nonobviousness. ................ 45
`3.
`4.
`There is no nexus between sales and the alleged invention. ..................... 46
`5.
`The Meda/Cipla License is not relevant. .................................................. 47
`6.
`Meda has failed to produce any persuasive evidence of copying. ............ 47
`Meda has failed to produce evidence that Dymista® satisfied a long-felt
`but unmet need for the alleged invention. ............................................................. 48
`
`ii
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`3
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`G.
`
`H.
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`Meda has failed to produce any evidence of independent praise for
`Dymista®. .............................................................................................................. 48
`Meda has failed to produce evidence that the FDA was skeptical about
`Dymista®’s safety or efficacy. .............................................................................. 49
`
`
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`iii
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`4
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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 5 of 55 PageID #: 4809
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`
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`Defendants Apotex Corp. and Apotex Inc. (together, “Apotex”), respectfully submit the
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`following proposed Findings of Fact. The clear and convincing evidence at trial showed that all
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`asserted claims from the two patents-in-suit held by Cipla Ltd. (“Cipla”) and exclusively licensed
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`to Meda Pharmaceuticals Inc. (“Meda”), are obvious. Alternatively, they are invalid under 35
`
`U.S.C. § 112.
`
`I.
`
`INTRODUCTION
`
`1.
`
`The patents-in-suit cover nasal sprays that treat allergic rhinitis (i.e., “hay fever”)
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`with two long-known active ingredients: a steroid called fluticasone propionate (“fluticasone”),
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`and an antihistamine called azelastine hydrochloride (“azelastine”), both of which were FDA-
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`approved before the priority date. PTX 1. The claimed co-formulation also included known
`
`excipients for known uses. Tr. (Smyth) at 652:1–654:4; Tr. (Smyth) at 670:1-6. As every single
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`physician who testified at trial—including Plaintiffs’ experts—conceded, doctors prescribed
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`azelastine (branded as Astelin®) with fluticasone (branded as Flonase®) to treat allergic rhinitis
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`(“AR”) before the time of the alleged invention in June 2002. Tr. (Accetta) at 46:12-14; Tr.
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`(Wedner) at 76:20-77:6; Tr. (Kaliner) at 433:20-434:6; Tr. (Carr) at 574:10-13. There can be no
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`question that combining these drugs was obvious.
`
`2.
`
`Combining fluticasone and azelastine in a single nasal spray was also expressly
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`disclosed and taught in the prior art. Two pharmaceutical companies expressly disclosed co-
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`formulations with these two drugs in prior art patent applications. DTX 12 (“Cramer”); DTX 21
`
`(“Segal”). Meda itself described combination fluticasone/azelastine nasal sprays in great detail
`
`before it knew anything about the work of its co-Plaintiff, Cipla, that led to the patents-in-suit—
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`and even described this combination as “obvious” because “Fluticasone was the then best selling
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`steroid, and Azelastine was the best antihistamine.” Tr. (Fuge) at 137:4-8, 138:19-25; DTX 313.
`
`Even Plaintiffs’ own expert conceded (through deposition testimony when impeached) that “a
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`1
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`5
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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 6 of 55 PageID #: 4810
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`person of skill in the art” as of 2002 would have thought that they “would have improved
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`compliance” by putting the two separate drugs “in one spray bottle.” Tr. (Kaliner) at 508:9-14.
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`This establishes a motivation to co-formulate azelastine and fluticasone.
`
`3.
`
`Nor was there anything inventive in co-formulating these two active ingredients
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`with the claimed excipients. A skilled artisan before 2002 was well aware of the ingredients and
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`manufacturing processes needed to make such a combination nasal spray work. It was obvious
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`for an ordinarily skilled formulator to start with the excipients from the FDA-approved products
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`and their formulation patents. Through nothing more than routine experimentation and
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`optimization, they would have arrived at a finite number of obvious combination formulations
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`that render all asserted claims of both patents-in-suit obvious. Tr. (Donovan) at 239:7-22.
`
`Although Plaintiffs highlighted in their opening that there would be a “solution suspension
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`problem” because azelastine dissolves and fluticasone is suspended, the evidence showed that
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`these ingredients behave in the patented formulation just as they did in the prior art—with
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`azelastine dissolving and fluticasone remaining suspended. Tr. (Smyth) at 669:4-20; 670:1-6.
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`Indeed, Plaintiffs’ formulator testified that an ordinarily skilled formulator would have been able
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`to create the formulation of one active in solution and another in suspension using “a finite
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`number of ways of mixing [the ingredients] together.” Tr. (Smyth) at 675:19–676:11.
`
`II.
`
`PARTIES
`
`4.
`
`Meda is a Delaware corporation with its principal place of business in New
`
`Jersey. Cipla is an Indian company. Meda obtained an exclusive license to the patents-in-suit
`
`from Cipla pursuant to a license agreement executed on November 13, 2006. D.I. 135 Ex. 1 at 1.
`
`Meda was recently acquired by Mylan N.V. Tr. 7:24–8:1.
`
`5.
`
`Defendant Apotex Inc. is a Canadian corporation, and Defendant Apotex Corp. is
`
`a Delaware corporation with its principal place of business in Florida. Id.
`
`2
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`6
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`III. THE PATENTS-IN-SUIT
`On May 1, 2012, the USPTO issued U.S. Patent No. 8,168,620 B2 (“the ’620
`6.
`
`patent”), titled “Combination of Azelastine and Steroids.” The expiration date of the ’620 patent
`
`is February 24, 2026. On February 16, 2016, the USPTO issued U.S. Patent No. 9,259,428 B2
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`(“the ’428 patent”), titled “Combination of Azelastine and Fluticasone for Nasal
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`Administration.” The expiration date of the ’428 patent is June 13, 2023. The ’620 and ’428
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`patents have an earliest claimed priority date of June 14, 2002. D.I. 135 Ex. 1 at 1-2.
`
`7.
`
`The named inventors of the patents-in-suit are Amar Lulla and Geena Malhotra.
`
`Mr. Lulla is deceased. Ms. Malhotra is a current employee of Plaintiff Cipla and under its
`
`control. Plaintiffs, however, did not call Ms. Malhotra to testify at trial. Id.
`
`IV.
`
`THE ASSERTED CLAIMS AND PATENT SPECIFICATION.
`
`8.
`
`Plaintiffs asserted 15 claims at trial: claims 4, 29, and 42-44 of the ’620 patent,
`
`and claims 10, 11, 13, 15, 16, 23, 24, 26, 29, and 30 of the ’428 patent (collectively, “asserted
`
`claims”). PTX 1; PTX 3; D.I. 135 Ex. 1 at 3-7. The ’620 patent claims cover pharmaceutical
`
`formulations suitable for nasal administration that contain azelastine hydrochloride and
`
`fluticasone propionate, along with various excipient ingredients and/or other characteristics such
`
`as particle size. The ’428 patent claims cover methods of using such formulations to treat
`
`allergic rhinitis. Claim 11 of the ’428 patent is illustrative of the claims. It depends from claim
`
`1 and recites:
`
`Claim 1: A method for the treatment of seasonal allergic rhinitis, comprising
`administration of a therapeutically effective amount of nasal spray formulation
`comprising: from 0.001% (weight/weight) to 1% (weight/weight) of azelastine
`hydrochloride; from 0.0357% (weight/weight) to 1.5% (weight/weight) of fluticasone
`propionate; one or more preservatives; one or more thickening agents; one or more
`surfactants; and one or more isotonization agents.
`
`Claim 11: The method of claim 1, wherein the formulation comprises: 0.1%
`(weight/weight) azelastine hydrochloride; from 0.0357% (weight/weight) to 1.5%
`
`3
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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 8 of 55 PageID #: 4812
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`(weight/weight) of fluticasone propionate; from 0.002% (weight/weight) to 0.05%
`(weight/weight) of edetate disodium; from 0.002% (weight/weight) to 0.02%
`(weight/weight) of benzalkonium chloride; from 0.65% (weight/weight) to 3%
`(weight/weight) of a combination of microcrystalline and carboxymethyl cellulose
`sodium; polysorbate 80; 2.3% (weight/weight) of glycerine; and 0.25% (weight/weight)
`of phenyl ethyl alcohol.
`
`
`PTX 3.
`
`V.
`
`THE PARTIES’ WITNESSES
`
`9.
`
`Defendants called Dr. Donald Accetta as their only live fact witness at trial. Dr.
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`Accetta is a practicing physician at Allergy and Asthma Care in Taunton, Massachusetts. Tr.
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`(Accetta) at 42:1-5. Notably, the Plaintiffs did not call the only living inventor of the patents, Ms.
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`Maholtra, to testify at trial despite her being an employee of Cipla’s and under its control.
`
`10.
`
`Defendants called by deposition Dennis Fuge, Patsy Jeffery, and Jeffrey Hostler
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`as fact witnesses. Mr. Fuge is the Vice President of Technical Operations at Meda. Tr. 131:2-3.
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`Ms. Jeffery is an employee of Plaintiff Cipla Ltd. Tr. 753:1-2. Mr. Hostler is Chief Financial
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`Officer of Plaintiff Meda Pharmaceuticals. Tr. 759:2-3.
`
`11.
`
`Defendants called live Dr. H. James Wedner, Dr. Robert Schleimer, Dr. Maureen
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`Donovan, and Mr. Jeffrey Press as expert witnesses. Dr. Wedner is professor of medicine and
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`chief of the division of allergy and clinical immunology at Washington University of Medicine
`
`in St. Louis. Tr. (Wedner) at 72:6-10. He was offered and accepted as an expert in the treatment
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`of patients suffering from allergic rhinitis. Tr. 75:8-13. Dr. Schleimer is the Roy and Elaine
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`Patterson Professor, professor of medicine, and the Chief of the Division of Allergy-Immunology
`
`at Northwestern University’s School of Medicine. Tr. (Schleimer) at 142:3-6. He was offered
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`and accepted as an expert in the areas of allergy, immunology, pharmacology, and drug
`
`development. Tr. 147:13-18. Dr. Donovan is a professor at the University of Iowa’s college of
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`pharmacy. Tr. (Donovan) at 230:5-17. She was offered and accepted as an expert in the
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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 9 of 55 PageID #: 4813
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`formulation of pharmaceuticals, and specifically nasal formulations. Tr. 234:21–235:1. Mr.
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`Press is a Director in the Forensic, Litigation & Valuation Services Group at Baker Tilly in
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`Philadelphia. Tr. (Press) at 760:25–761:1. He was offered and accepted as an expert in the
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`financial and economic analysis of commercial success. Tr. 764:10-15.
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`12.
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`Plaintiffs called Dr. Alexander D’Addio as their only live fact witness at trial. Dr.
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`D’Addio is a Vice President of Scientific Affairs and Medical Communications at Meda
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`Pharmaceuticals. Tr. (D’Addio) at 352:12-16. Plaintiffs called live Dr. Michael Kaliner, Dr.
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`Warner Carr, Dr. Hugh Smyth, and Mr. John Jarosz as experts. Plaintiffs also called by
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`deposition Dr. Ram Govindarajan as an expert.
`
`13.
`
`Dr. Kaliner was a practicing physician with the Institute for Asthma and Allergy.
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`Tr. (Kaliner) at 416:7-13. He was offered and accepted as an expert in the fields of allergy and
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`immunology and particularly in the treatment of allergic rhinitis. Tr. 419:6-11. Dr. Kaliner
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`testified that he had a sense of loyalty to Meda, which has paid him hundreds of thousands of
`
`dollars, and that he “felt very uncomfortable and even unethical doing anything adverse to
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`Meda.” Tr. (Kaliner) at 482:13-19; 485:4-6; 486:18–487:3. Between August 2013 and
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`December 2015, Dr. Kaliner was the third most highly paid consultant on Meda’s Speakers’
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`Bureau. Tr. (Kaliner) at 482:13-19.
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`14.
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`Dr. Warner Carr is a practicing physician at Allergy and Asthma Associates of
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`Southern California. Tr. (Carr) at 516:11-18. He was offered and accepted as an expert in the
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`treatment of allergic rhinitis and the development and conduct of clinical trials for allergic
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`rhinitis. Tr. 517:22–5:18:2. Dr. Carr was also on Meda’s Speakers’ Bureau and was a principal
`
`investigator on the Dymista® trials, and estimates that he was paid by Meda approximately
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`$125,000 for these roles. Tr. (Carr) at 568:11-21; 570:1-4; 571:3-8.
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`15.
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`Dr. Hugh Smyth is an associate professor of pharmacy at the University of Texas
`
`at Austin. Tr. (Smyth) at 601:20–602:2. He was offered and accepted as an expert in the field of
`
`drug formulation and drug delivery. Tr. 603:24–604:3. Mr. John Jarosz is a practicing
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`economist with Analysis Group. Tr. (Jarosz) at 687:22–688:20. He was offered and accepted as
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`an expert in the area of intellectual property protection. Tr. 689:5-7. Dr. Ramprakash
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`Govindarajan is a Clinical Assistant Professor at the University of Iowa College of Pharmacy.
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`PTX 1664 at 2. He testified by deposition regarding his formulation of a prior art example for
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`Defendants in this case.
`
`VI.
`
`PERSON OF ORDINARY SKILL IN THE ART.
`
`16.
`
`The parties offer different definitions of a person of ordinary skill in the art from
`
`the perspective of using pharmaceutical compositions in the treatment of allergic rhinitis.
`
`Apotex’s expert on this subject matter, Robert Schleimer, testified that his opinions would be the
`
`same if his understanding of a POSA or Meda’s expert’s understanding of a POSA were
`
`ultimately adopted. See Tr. (Schleimer) at 173:16-22; Tr. (Kaliner) at 501:21-502:1.
`
`17.
`
`Dr. Schleimer opined that a clinical person of ordinary skill has an M.D., Ph.D. or
`
`Pharm.D. in the field of allergy/immunology and/or pharmacology (or the equivalent), and at
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`least three additional years of experience in the treatment, or research for treatments, of allergic
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`rhinitis, including with nasally administered steroids and antihistamines. D.I. 135 Ex. 3 at ¶ 21;
`
`Tr. (Schleimer) at 171:18-25. Meda’s definition limits the POSA to only having an M.D. D.I.
`
`135 Ex. 2 at ¶¶ 84-85; Tr. (Kaliner) at 426:11–427:1. However, Ms. Malhotra did not have an
`
`M.D., and there is no suggestion that the deceased inventor, Mr. Lulla, had an M.D. DTX 114
`
`(Malhotra Declaration); Tr. (Kaliner) at 503:3-8.
`
`18.
`
`Dr. Schleimer explained that he regularly supervises and teaches M.D.s and has
`
`also been intimately involved in the drug development process with M.D.s. Tr. (Schleimer) at
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`6
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`10
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`172:8–173:22. Dr. Kaliner also testified that Dr. Schleimer is “brilliant” and agreed that he is
`
`“qualified to offer an expert opinion in this case.” Tr. (Kaliner) at 502:2-11.
`
`19.
`
`The parties offer different definitions of a person of ordinary skill in the art from
`
`the perspective of formulating the claimed pharmaceutical compositions. Apotex’s expert on this
`
`subject matter, Dr. Donovan, testified that her opinions would be the same if her understanding
`
`of a POSA or Meda’s expert’s understanding of a POSA were ultimately adopted. Tr.
`
`(Donovan) at 237:24–238:3.
`
`20.
`
`Dr. Donovan opined that a person of ordinary skill in the art with respect to
`
`formulating the claimed composition would have been a pharmaceutical formulator with at least
`
`a bachelor’s degree in chemistry, biology, chemical engineering or pharmaceutical science and
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`3-5 years of experience in formulation development of nasal dosage forms, although the
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`formulator could have more advanced degrees with fewer years of experience; and would have
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`had familiarity with pharmaceutical excipients and their uses. Tr. (Donovan) at 237:5-23.
`
`VII.
`
`IT WAS OBVIOUS TO COMBINE FLUTICASONE PROPIONATE AND
`AZELASTINE HYDROCHLORIDE
`INTO A SINGLE NASAL SPRAY
`FORMULATION TO TREAT ALLERGIC RHINITIS.
`
`21.
`
`It was obvious to co-formulate fluticasone and azelastine because such a
`
`combination was actually practiced by doctors, disclosed in the prior art, and also encouraged by
`
`the prior art. Indeed, Dennis Fuge, Meda’s Vice President of Technical Operations and who was
`
`one of the first Meda representatives to visit Cipla to discuss a license for the patents-in-suit,
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`testified that Cipla’s motive to co-formulate azelastine and fluticasone was “obvious,” because
`
`“Fluticasone was the then best selling steroid, and Azelastine was the best antihistamine.” Tr.
`
`(Fuge) at 134:3-8, 135:2-10, 138:19-25. He testified further that Meda (then called MedPointe)
`
`had also—and independently—“selected [azelastine and fluticasone] as the best two compounds
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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 12 of 55 PageID #: 4816
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`to utilize.” Tr. (Fuge) at 139:7-17. The prior art confirms Mr. Fuge’s impression that co-
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`formulating fluticasone and azelastine was “obvious.”
`
`A.
`
`Physicians used fluticasone propionate and azelastine hydrochloride nasal
`sprays together in the prior art to treat allergic rhinitis.
`
`22.
`
`There is no dispute that physicians in the United States and elsewhere co-
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`prescribed azelastine hydrochloride in a nasal spray formulation and fluticasone propionate in a
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`nasal spray formulation before June 2002. Tr. (Kaliner) at 497:1-8. As described in further
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`detail below, each testifying physician in this case, including Meda’s experts, co-prescribed the
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`combination prior to 2002.
`
`Dr. Accetta (fact witness)
`
`1.
`Dr. Accetta co-prescribed Astelin® and Flonase® to treat allergic rhinitis before
`
`23.
`
`June 2002. Tr. (Accetta) at 46:12-14. He supported his testimony with ten patient records. See
`
`DTX 1-10; Tr. (Accetta) at 53:23-54:6. He co-prescribed the drugs as early as April 28, 1997.
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`DTX 5; see also Tr. (Accetta) at 46:15-21. Dr. Accetta testified that he actually prescribed the
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`combination for about a third of patients who were on combination therapy. Tr. (Accetta) at
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`54:20-24.
`
`24.
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`Azelastine was the only intranasal antihistamine that Dr. Accetta prescribed. Tr.
`
`(Accetta) at 47:10-12. He prescribed a handful of nasal steroids in the combination therapy, but
`
`referred to Flonase® as “one of the major ones.” Tr. (Accetta) at 46:10-21. In some cases, Dr.
`
`Accetta would prescribe the Astelin® on an “as needed” basis. See, e.g., DTX 4 (patient record).
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`He explained that he would prescribe the drug “as needed” for a patient with some seasonal
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`symptoms, so the patient would supplement their steroid therapy in the months of allergen
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`exposure. Tr. (Accetta) at 52:13-22.
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`8
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`12
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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 13 of 55 PageID #: 4817
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`25.
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`Dr. Accetta generally used the FDA prescribed doses when co-prescribing
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`Astelin® and Flonase® together. Tr. (Accetta) at 52:13-53:19. But he would also instruct patients
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`to tailor their combination regimen to the lowest effective dose of the drugs. Id.
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`Physician expert witnesses
`
`2.
`Apotex’s testifying expert physician, Dr. Wedner, co-prescribed the combination
`
`26.
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`as two nasal sprays for “those patients who didn’t have complete relief with [Flonase®
`
`monotherapy].” Tr. (Wedner) at 76:20-77:6. For dosing, he would often instruct patients to
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`modify the dose “depending on the patient’s response to the therapy.” Tr. (Wedner) at 77:18-22.
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`For example, he would often start with the “conventional dose” of Astelin® (two sprays, twice a
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`day), but would also instruct patients to take two sprays once a day or one spray twice a day,
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`both of which were effective. Tr. (Wedner) at 78:24–79:12.
`
`27. Meda’s first testifying physician, Dr. Kaliner, testified that physicians, including
`
`himself, combined azelastine and fluticasone nasal sprays prior to 2002. Tr. (Kaliner) at 433:20–
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`434:6. He further testified that his azelastine prescribing practices mirrored Dr. Accetta’s and
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`that this was the way he instructed other physicians to treat patients with AR before 2002. Tr.
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`(Kaliner) at 454:15-17; 493:10-23; see also DTX 312. And similar to Drs. Wedner and Accetta,
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`Dr. Kaliner would “try to use the lowest dose of [azelastine or fluticasone] that worked.” Tr.
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`(Kaliner) at 460:9-18.
`
`28.
`
`Finally, Meda’s other expert physician, Dr. Carr, testified that he co-prescribed
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`the combination of azelastine and fluticasone before June 2002. Tr. (Carr) at 574:10-13.
`
`B.
`29.
`
`The prior art discloses azelastine and fluticasone co-formulations.
`
`Two prior art references, Cramer and Segal, specifically disclosed putting
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`azelastine and fluticasone into a single nasal spray formulation and administering it to treat
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`allergic rhinitis. See DTX 12; DTX 21.
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`9
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`13
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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 14 of 55 PageID #: 4818
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`30.
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`Cramer is a European Patent application filed by the Procter & Gamble Company.
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`It published on June 25, 1997. DTX 12. Cramer discloses a pharmaceutical composition for
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`nasal administration comprising a glucocorticoid and a leukotriene inhibiting antihistamine.
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`Cramer discloses fluticasone as a nasal steroid that can be used in its co-formulation. Id. Dr.
`
`Schleimer testified that a POSA would have been drawn to either fluticasone or mometasone
`
`because of their superior potency. Tr. (Schleimer) at 176:16-19.
`
`31.
`
`Cramer disclosed azelastine as an acceptable leukotriene inhibiting antihistamine,
`
`which are antihistamines that, when used in the nose, can exert anti-inflammatory effects that are
`
`not found with oral versions. Tr. (Schleimer) at 175:17-24. Of the three antihistamines listed,
`
`azelastine was the only one already formulated for nasal administration and FDA approved as of
`
`the critical date. Tr. (Schleimer) at 176:20-24. Dr. Schleimer testified that a POSA viewing
`
`Cramer would have been drawn to a fluticasone/azelastine combination or a
`
`mometasone/azelastine combination for a co-formulation. Tr. (Schleimer) at 176:18–177:12.
`
`32.
`
`Segal is an International Application filed by Warner Lambert published on
`
`November 5, 1998. DTX 21. It similarly disclosed a co-formulation of azelastine and
`
`fluticasone. Id. It disclosed a co-formulation containing a “topical anti-inflammatory agent” and
`
`an antihistamine. Segal lists fluticasone among its preferred anti-inflammatory steroids, and it
`
`lists azelastine among its preferred antihistamines. Id.; Tr. (Schleimer) at 178:1-18.
`
`C.
`
`The prior art motivated skilled artisans to combine azelastine and fluticasone
`to treat allergic rhinitis.
`
`1.
`
`Corticosteroids and antihistamines were known to have different and
`complementary mechanisms of action.
`
`33.
`
`The evidence explains why physicians co-prescribed azelastine and fluticasone,
`
`and why references like Cramer and Segal disclosed co-formulations with those two drugs, prior
`
`to June 2002.
`
`10
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`14
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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 15 of 55 PageID #: 4819
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`34.
`
`Prior to that date, it was well known that allergic rhinitis occurred in two phases:
`
`an early phase and a late phase. Tr. (Schleimer) at 149:8-17; Tr. (Carr) at 573:10-22; Tr.
`
`(Kaliner) at 430:13-25; see also PTX 333 (Drouin 1995).
`
`35.
`
`The early phase occurs “within minutes” after an allergy sufferer is exposed to
`
`allergen. Tr. (Schleimer) at 149:8-17; see also DTX 34 (Galant & Wilkinson 2001); PTX 333
`
`(Drouin 1995). Upon allergen exposure, mast cells in the nose release inflammatory mediators,
`
`including histamine. Tr. (Schleimer) at 149:23-150:5. These mediators are what cause early
`
`phase symptoms. Tr. (Schleimer) at 149:23-150:5.
`
`36.
`
`The late phase is characterized as a “chronic inflammatory-type response.” Tr.
`
`(Schleimer) at 150:8-14. The mast cells release inflammatory mediators into the blood creating a
`
`more prolonged response. Tr. (Schleimer) at 150:8-14.
`
`37.
`
`Corticosteroids were known to treat the late phase response and were also known
`
`to be the first-line therapy to treat allergic rhinitis. Tr. (Schleimer) at 150:17-23; PTX 326
`
`(ARIA Guidelines 2001); DTX 34 (Galant & Wilkinson 2001). Meda’s expert, Dr. Carr, also
`
`testified that “steroids treat the late phase better than antihistamines.” Tr. (Carr) at 573:10-22.
`
`However, steroids were known to have a deficiency in that they had a slow onset of action. Tr.
`
`(Schleimer) at 151:14-18. That slow onset caused patients to stop using the drugs because they
`
`perceived them as not working well. Tr. (Schleimer) at 151:14–152:1.
`
`38.
`
`Antihistamines, also referred to as H1 receptor antagonists, were known as the top
`
`therapy to treat the early phase response. Tr. (Schleimer) at 152:25–153:22; PTX 333 (Drouin
`
`1995). Meda’s expert, Dr. Carr, explained that it was “medical dogma” that “antihistamines
`
`predominantly treat the early phase of allergic rhinitis more effectively than steroids.” Tr. (Carr)
`
`at 573:2-14. Unlike nasal steroids, antihistamines, and nasal antihistamines in particular, were
`
`11
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`15
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`Case 1:14-cv-01453-LPS Document 156 Filed 01/10/17 Page 16 of 55 PageID #: 4820
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`known to have a rapid onset of action that occurred as quickly as 15 minutes after administration.
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`Tr. (Schleimer) at 78:3-9; Tr. (Wedner) at 84:8-19; PTX 326 (ARIA Guidelines 2001). Dr. Carr
`
`also confirmed that “antihistamines generally have a faster onset of action than steroids.” Tr.
`
`(Carr) at 573:23–574:1.
`
`39.
`
`At the 2002 priority date, there were two formulations of antihistamines available
`
`on the market: oral and intranasal (meaning administered through the nose in a spray or
`
`solution). Intranasal antihistamines were known to have advantages over their oral counterparts.
`
`In addition to inhibiting histamine, intranasal (sometimes referred to as “topical”) antihistamines
`
`were known to have some effect on the release of inflammatory mediators, thus having some
`
`effect on the late phase in addition to the early phase. Tr. (Schleimer) at 155:3-20; DTX 26
`
`(Berger 1999). However, these anti-inflammatory effects did not compare to a nasal steroid’s
`
`pronounced effect on the late phase. Tr. (Sch