Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 1 of 54 PageID #: 4751
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`C. A. No. 14-1453-LPS
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`MEDA PHARMACEUTICALS INC. and
`CIPLA LTD.,
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`Plaintiffs,
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`v.
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`APOTEX INC. and APOTEX CORP.,
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`Defendants.
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`OF COUNSEL:
`
`Mark Fox Evens
`Uma N. Everett
`Dennies Varughese
`Adam C. LaRock
`Joshua I. Miller
`Josephine J. Kim
`STERNE, KESSLER, GOLDSTEIN & FOX
`P.L.L.C.
`1100 New York Ave., N.W., Suite 800
`Washington, DC 20005-3934
`(202) 371-2600
`
`Attorneys for Plaintiffs
`Meda Pharmaceuticals Inc. and Cipla Ltd.
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`Dated: January 10, 2017
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`PLAINTIFFS’ PROPOSED FINDINGS OF FACT
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`
`
`Frederick L. Cottrell, III (#2555)
`Selena E. Molina (#5936)
`Richards, Layton & Finger, P.A.
`One Rodney Square
`920 North King Street
`Wilmington, DE 19801
`(302) 651-7700
`cottrell@rlf.com
`molina@rlf.com
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`1
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`CIP2022
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 2 of 54 PageID #: 4752
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`TABLE OF CONTENTS
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`I. THE PARTIES. .......................................................................................................................... 1
`A. Meda. .................................................................................................................................. 1
`B. Cipla. .................................................................................................................................. 1
`C. Apotex. ............................................................................................................................... 1
`II. THE PATENTS-IN-SUIT. ........................................................................................................... 1
`III.
`THE PATENTS-IN-SUIT ISSUED OVER APOTEX’S REFERENCES. ....................................... 2
`IV. APOTEX ADMITS THAT IT INFRINGES THE ASSERTED CLAIMS. ...................................... 3
`V. EMBODIMENTS OF THE PATENTS-IN-SUIT. ........................................................................... 4
`A. Dymista®. ........................................................................................................................... 4
`B. Duonase. ............................................................................................................................. 4
`VI. APOTEX HAS FAILED TO PROVE BY CLEAR AND CONVINCING EVIDENCE THAT THE
`ASSERTED CLAIMS ARE INVALID AS HAVING BEEN OBVIOUS. ................................................... 5
`A. The Prior Art Would Not Have Motivated the POSA to Develop a Fixed-Dose Nasal
`Spray Formulation Comprising Azelastine and Fluticasone. ............................................... 5
`1. The POSA would not have been motivated to select azelastine and fluticasone from
`among the numerous treatment options that were available in 2002. .................................. 6
`2. The established standard of care in 2002 would not have motivated the POSA to
`combine azelastine and fluticasone. ..................................................................................... 10
`3. The significant drawbacks of a fixed-dose combination outweighed any modest
`clinical benefits. .................................................................................................................... 14
`4. None of the asserted prior art references would have motivated the POSA to combine
`azelastine and fluticasone into a fixed-dose combination. .................................................. 17
`B. The POSA would have had no reasonable expectation of successfully formulating an
`azelastine and fluticasone fixed-dose combination intranasal spray. ................................. 22
`1.
`Solubility concerns would have counseled against combining azelastine and
`fluticasone into a fixed-dose combination nasal spray. ...................................................... 22
`2. The POSA attempting to combine Astelin® and Flonase® faced formidable
`challenges in selecting the ingredients and other properties. ............................................. 25
`3. Even assuming the POSA could have successfully addressed the formulation
`challenges, nasal spray formulations require a narrow set of interrelated parameters. ... 27
`C. The Asserted Claims of the Patents-in-Suit Are Not Obvious in View of Apotex’s
`Asserted Prior Art. .................................................................................................................. 31
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 3 of 54 PageID #: 4753
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`VII. OBJECTIVE INDICIA SHOW THAT THE ASSERTED CLAIMS ARE NOT OBVIOUS. ........... 36
`A. Meda’s Skepticism in 2002 and Failure to Formulate an Azelastine and Fluticasone
`Combination Product in 2006 Supports Nonobviousness. .................................................. 36
`B. Licensing of Cipla’s Patent Applications Leading to the Patents-in-Suit Supports
`Nonobviousness........................................................................................................................ 38
`C. FDA Was Skeptical of the Claimed Invention. ............................................................ 39
`D. Dymista® Fulfills a Long-Felt Need and Is Unexpectedly More Effective with a
`Faster Onset of Action and Fewer Side Effects than Astelin® and Flonase®. .................... 41
`E. Dymista® Received Industry Praise. ............................................................................. 44
`F. Dymista® Is A Commercial Success in the United States. ........................................... 45
`1. No Patents Blocked the Commercialization of a Fixed-Dose Combination
`Fluticasone-Azelastine Nasal Spray. ................................................................................... 46
`2. Duonase and Its Imitators Are a Commercial Success in India. ............................... 48
`VIII. APOTEX HAS FAILED TO PROVE BY CLEAR AND CONVINCING EVIDENCE THAT THE
`ASSERTED CLAIMS ARE INVALID FOR LACK OF ENABLEMENT. ............................................... 49
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 4 of 54 PageID #: 4754
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`I.
`
`THE PARTIES.
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`A. Meda.
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`1. Meda Pharmaceuticals Inc. (“Meda”)1 is the exclusive licensee of the Patents-in-
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`Suit and is a corporation organized and existing under the laws of Delaware. D.I. 135, Ex. 1 at ¶¶
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`1, 20-21 (“Uncontested Facts”). On May 1, 2012, Meda received approval from the U.S. Food
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`and Drug Administration (“FDA”) to market Dymista®, a 137 mcg azelastine hydrochloride/50
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`mcg fluticasone propionate combination nasal spray, described in New Drug Application No.
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`202236. Uncontested Facts at ¶¶ 27-28.
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`B.
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`Cipla.
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`2. Cipla Ltd. (“Cipla”) is a publicly held company organized and existing under the
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`laws of India. Uncontested Facts at ¶ 2. Cipla is the owner of the Patents-in-Suit: U.S. Patent No.
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`8,168,620 B2 (“the ’620 patent”) and U.S. Patent No. 9,259,428 B2 (“the ’428 patent”)
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`(collectively, “Patents-in-Suit”). Uncontested Facts at ¶ 18.
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`C.
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`Apotex.
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`3. Apotex Inc. is a corporation organized and existing under the laws of Canada.
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`Uncontested Facts at ¶ 3. Apotex Corp. is a corporation organized and existing under the laws of
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`Delaware. Uncontested Facts at ¶ 4. Apotex Inc. and Apotex Corp. (collectively, “Apotex”) filed
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`ANDA No. 207712 seeking to make and market a generic version of Dymista®. D.I. 93, at ¶ 1.
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`II.
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`THE PATENTS-IN-SUIT.
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`4. On May 1, 2012, the U.S. Patent and Trademark Office (“Patent Office”) issued the
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`’620 patent, entitled “Combination of Azelastine and Steroids,” which expires on February 24,
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`2026. Uncontested Facts at ¶¶ 9, 12. The ’428 patent, entitled “Combination of Azelastine and
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`1 Meda had two predecessor companies, Carter-Wallace and MedPointe, but Plaintiffs will refer
`to each of these companies as “Meda” for convenience.
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 5 of 54 PageID #: 4755
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`Fluticasone for Nasal Administration,” issued on February 16, 2016 and expires on June 13,
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`2023. Uncontested Facts at ¶¶ 13, 16. The Patent Office issued a Certificate of Correction for the
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`’428 patent on May 3, 2016, which corrected typographical and other inadvertent errors made by
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`the Patent Office. Uncontested Facts at ¶ 17. The Patents-in-Suit have an earliest filing date of
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`June 14, 2002. Uncontested Facts at ¶ 19; Tr. 167:22-23 (Schleimer); Tr. 238:5-7 (Donovan).
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`5. Amar Lulla and Geena Malhotra are the named inventors of the Patents-in-Suit.
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`Uncontested Facts at ¶¶ 10, 14, 18.
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`6.
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`The Patents-in-Suit are directed to allergic rhinitis (“AR”), (Tr. 426:11-22
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`(Kaliner)), a common condition that afflicts millions of people in the United States that is
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`defined as inflammation of the membranes lining the nose, characterized by nasal congestion,
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`rhinorrhea (i.e., runny nose), sneezing, and itching of the nose. Tr. 148:18-149:7 (Schleimer); Tr.
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`427:22-428:1 (Kaliner); see PTX0022.00003-4; PTX0326.00017.
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`III. THE PATENTS-IN-SUIT ISSUED OVER APOTEX’S REFERENCES.
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`7.
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`The ’620 patent was filed with the Patent Office as Application No. 10/518,016,
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`which is a 35 U.S.C. § 371 national stage application of PCT/GB03/02557. PTX0001.00001.
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`During prosecution of the ’620 patent, the patent examiner issued three Office Actions.
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`PTX0005.09527-48; PTX0005.09850-69; PTX0005.10864-82.
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`8.
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`The Patent Office considered the disclosures of Cramer (PTX0062) to be the closest
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`prior art, (PTX0005.09866, 10050; PTX0007.09941, 09983), and therefore, every Office Action
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`issued by the Patent Office during prosecution of the ’620 patent identified Cramer as the
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`primary reference. PTX0005.09527-48; PTX0005.09850-69; PTX0005.10864-82. The Patent
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`Office thrice considered the Cramer reference, and dozens of other references Apotex re-asserts
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 6 of 54 PageID #: 4756
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`in this action despite their previous consideration by the Patent Office.2 Nevertheless, the Patent
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`Office allowed the claims to issue. PTX0005.18279-281; PTX0007.11219-226.
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`9. Cipla overcame these Office Actions by amending claims and providing a
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`declaration from co-inventor Geena Malhotra setting forth evidence of unexpected results,
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`licensing, and long-felt need. PTX0005.00288-306; PTX0005.00455-77; PTX0005.00609-29;
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`PTX0005.00654-82. Cipla overcame the last Office Action by amending claims, providing
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`another declaration from Ms. Malhotra explaining why the Cramer reference was inoperable, and
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`providing three additional declarations setting forth further evidence of unexpected results,
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`licensing, commercial
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`success, copying, and
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`long-felt need. PTX0005.00791-820;
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`PTX0005.01312-33; PTX0005.01334-1433; PTX0005.01434-53; PTX0005.01454-61.
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`10. The same and additional art was considered during prosecution of the ’428 patent.
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`See PTX0003.00002-10.
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`IV. APOTEX ADMITS THAT IT INFRINGES THE ASSERTED CLAIMS.
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`11. Plaintiffs assert that Apotex infringes claims 4, 29, 42, 43, and 44 of the ’620
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`patent, and claims 10, 11, 13, 15, 16, 23, 24, 26, 29, and 30 of the ’428 patent (collectively,
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`“Asserted Claims”). Uncontested Facts at ¶¶ 23-24.
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`12. Apotex has stipulated that the filing of its ANDA No. 207712 with FDA seeking
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`approval to market its generic 137 mcg strength azelastine hydrochloride and 50 mcg strength
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`2 The Flonase® reference (PTX0059), Astelin® reference (PTX0011), Hettche patent (PTX0343),
`Phillipps patent (PTX0104), Juniper reference (PTX0336), Segal reference (PTX0088), Barnes
`reference (PTX0012), Di Lorenzo reference (PTX0021), Dykewicz reference (PTX0022),
`Nielsen references (PTX0036; PTX0085; PTX0338), Simpson reference (PTX0039), Spector
`reference (PTX0041), Akerlund reference (PTX0053), Falser reference (PTX0066), Galant
`reference (PTX0099), Hampel reference (PTX0230), Berger reference (PTX0328), Ratner
`references (PTX0330; PTX0331), Brooks reference (PTX0332), Drouin reference (PTX0333),
`Howarth reference (PTX0337), Johnson reference (DTX-039), McNeely reference (DTX-043),
`Shenfield reference (DTX-048), and Cauwenberge reference (DTX-154) were all considered by
`the Patent Office. See PTX0001.00002-8; PTX0003.00002-10.
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 7 of 54 PageID #: 4757
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`fluticasone propionate combination nasal spray and the proposed generic product defined by its
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`ANDA infringes the Asserted Claims under 35 U.S.C. § 271(a) and § 271(e)(2)(A). D.I. 104 at ¶
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`1-2; D.I. 135, Joint Pretrial Order at ¶ 8. Thus, Apotex’s infringement is undisputed.
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`V.
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`EMBODIMENTS OF THE PATENTS-IN-SUIT.
`Dymista®.
`A.
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`13. Dymista® is a nasal spray that contains the active ingredients azelastine
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`hydrochloride (“azelastine”) and fluticasone propionate (“fluticasone”) and is indicated for the
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`relief of symptoms of seasonal AR in patients six years of age and older who require treatment
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`with both azelastine and fluticasone. Uncontested Facts at ¶¶ 29, 30. Dymista® also contains
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`glycerin, microcrystalline cellulose and carboxymethylcellulose sodium, phenylethyl alcohol,
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`edetate disodium, benzalkonium chloride, polysorbate 80, and purified water. Uncontested Facts
`
`at ¶ 31; PTX0138.00001. Dymista® delivers 137 mcg of azelastine and 50 mcg of fluticasone
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`(137 mcg/50 mcg) in each 0.137 mL spray. Uncontested Facts at ¶ 32; PTX0154.00001.
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`Dymista® is indicated for one spray per nostril twice daily. Uncontested Facts at ¶ 33;
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`PTX0154.00001.
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`14. Dymista®, and its use for the treatment of AR, is covered by the Asserted Claims of
`
`the Patents-in-Suit. Tr. 470:24-471:16 (Kaliner) (citing PTX0024, PTX0134, PTX0026); Tr.
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`642:4-22 (Smyth) (citing PTX0138, PTX0141, PTX0154); Uncontested Facts at ¶ 35.
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`15. Dymista® launched in the United States in September 2012. Tr. 690:17-694:2,
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`695:21-698:16 (Jarosz) (citing PTX0929).
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`B.
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`Duonase.
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`16. Cipla launched Duonase commercially in India in 2004, and a reformulated version
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`of Duonase in 2010. Uncontested Facts at ¶ 36. Duonase is an azelastine and fluticasone
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`combination nasal spray used for the treatment of symptoms of AR. Uncontested Facts at ¶ 37.
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 8 of 54 PageID #: 4758
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`Duonase also contains benzalkonium chloride, glycerin, polysorbate 80, microcrystalline
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`cellulose and carboxymethylcellulose sodium, phenylethyl alcohol, and purified water. The 2010
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`reformulation of Duonase includes the excipient sucralose. Uncontested Facts at ¶ 38.
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`17.
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`It is undisputed that Duonase, and its use for the treatment of symptoms of AR,
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`meets at least one Asserted Claim of each of the Patents-in-Suit. Tr. 470:24-471:16 (Kaliner)
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`(citing PTX0024, PTX0134, PTX0026); Tr. 642:4-22 (Smyth) (citing PTX0135; PTX0153;
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`PTX0145); Uncontested Facts at ¶ 39.
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`VI. APOTEX HAS FAILED TO PROVE BY CLEAR AND CONVINCING EVIDENCE THAT THE
`ASSERTED CLAIMS ARE INVALID AS HAVING BEEN OBVIOUS.
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`18. Apotex has failed to show by clear and convincing evidence that the Asserted
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`Claims of the Patents-in-Suit would have been obvious to the POSA at the time of invention.
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`Apotex has not shown that the POSA would have been motivated to develop a fixed-dose
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`combination of azelastine and fluticasone. Rather, the art and practices of all testifying clinicians
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`showed an overwhelming preference for flexibility in treatment that is inconsistent with a fixed-
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`dose combination. Further, Apotex has not shown that the POSA would have had any
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`expectation of successfully developing such a fixed-dose combination. Specifically, Apotex has
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`not explained its selection of the various excipients, concentrations, and physical characteristics
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`recited in the claims, but it admits that changing one component of the formulation would change
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`the overall characteristics of the formulation. In short, the evidence shows that the Asserted
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`Claims would not have been obvious to the POSA at the time of invention.
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`A.
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`The Prior Art Would Not Have Motivated the POSA to Develop a Fixed-
`Dose Nasal Spray Formulation Comprising Azelastine and Fluticasone.
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`19. Apotex has failed to identify any reference or combination of references that would
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 9 of 54 PageID #: 4759
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`have motivated the person of ordinary skill in the art at the time of invention in 2002 (“POSA”)3
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`to combine azelastine and fluticasone into a fixed-dose combination nasal spray.
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`1.
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`The POSA would not have been motivated to select azelastine and
`fluticasone from among the numerous treatment options that were
`available in 2002.
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`20. By 2002, six major drug classes were used to treat AR. See generally PTX0022 and
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`PTX0326. These classes
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`included
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`(1) decongestants,
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`(2) mast cell stabilizers,
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`(3)
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`anticholinergics, (4) leukotriene receptor antagonists, (5) corticosteroids, and (6) antihistamines
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`each of which was used at the time of invention to treat AR. See Tr. 434:7-13 (Kaliner); see
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`generally PTX0022 and PTX0326.
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`21. POSAs had a broad array of choices for the treatment of AR in 2002. No fewer than
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`49 options from among these drug classes were known at the time of invention. PTX0022.00029-
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`33; PTX0326.00092-138; Tr. 434:7-13 (Kaliner). They were predominantly available as oral
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`tablets, (Tr. 606:24-607:1 (Smyth); see also Tr. 442:5-7 (Kaliner) (citing PTX0098)), but were
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`also available as oral liquids, intranasal solutions, and intranasal suspensions. Tr. 607:2-5
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`(Smyth). Oral dosage forms were known to have systemic efficacy, such that they could treat
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`multiple organs. See Tr. 46:22-47:9 (Accetta); PTX0326.00091-92. Patients overwhelmingly
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`preferred oral dosage forms over other available modes of administration. See Tr. 224:6-9
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`(Schleimer); Tr. 444:10-15 (Kaliner); see also PTX00020.00005 (75.1% of patients preferred
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`3 Plaintiffs assert that the person of ordinary skill in the field of the invention of the Patents-in-
`Suit (“POSA”) would have education and experience in both (1) the treatment of patients
`suffering from AR and (2) the development of drug formulations. From the clinical perspective,
`the POSA would have the experience of a primary care physician with a medical degree and two
`to four years of experience. Tr. 426:13-427:1 (Kaliner). From the formulation perspective, the
`POSA would possess a bachelor’s of science in pharmaceutical sciences and four to five years of
`experience, or commensurate work experience. Tr. 426:11-427:1 (Kaliner); Tr. 605:14-21
`(Smyth). Apotex’s proposed definition differs in that the POSA need not have a medical degree.
`Tr. 173:16-22 (Schleimer). Nevertheless, because both Plaintiffs’ and Apotex’s proposed
`definitions include an M.D., the opinions offered by Plaintiffs’ experts would not differ under
`Apotex’s proposed definition. Tr. 429:23-430:4 (Kaliner); Tr. 605:22-606:3 (Smyth).
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 10 of 54 PageID #: 4760
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`oral dosage forms); PTX0099.00010.
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`22. Decongestants worked well on congestion. Tr. 179:21-24 (Schleimer); Tr. 433:1-6
`
`(Kaliner); see also DTX-312.0005. The Dykewicz (PTX0022) and Allergic Rhinits and its
`
`Impact on Asthma (“ARIA”) Guidelines (PTX0326) (collectively, “Guidelines”) were the
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`treatment guidelines for AR in the U.S. and Europe, respectively. Tr. 83:14-23 (Wedner). They
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`describe at least nine different oral and intranasal decongestants available for use at the time of
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`invention. See generally PTX0022.00028; PTX0326.00105. Intranasal decongestants were
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`known to work in minutes. PTX0326.00105.
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`23. Mast cell stabilizers worked well on all symptoms when used prophylactically. See
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`Tr. 80:7-10 (Wedner); Tr. 180:2-5 (Schleimer); PTX0022.00030; DTX-312.0005. The
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`Guidelines describe at least two mast cell stabilizers available for use at the time of invention.
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`PTX0326.00104; PTX0022.00030-31.
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`24. Anticholinergics were known to treat runny nose. Tr. 180:6-10 (Schleimer); Tr.
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`80:1-6 (Wedner); see PTX0326.00107; DTX-312.0005. The Guidelines describe at least four
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`oral and intranasal anticholinergics available for use at the time of invention. PTX0326.00106-7;
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`PTX0022.00031-32.
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`25. Leukotriene receptor antagonists, or antileukotrienes, worked on all symptoms,
`
`but were particularly effective in treating congestion in the late phase response.4 See
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`4 In a laboratory setting, a patient’s exposure to an allergen begins a biphasic response. Tr.
`149:8-17 (Schleimer); Tr. 430:22-25 (Kaliner). The immediate neurophysiological response, or
`“early-phase” response, occurs within minutes of exposure. Tr. 149:8-17 (Schleimer) (citing
`PTX0333.00002). The later inflammatory response, or “late-phase” response, may occur more
`than four to ten hours after allergen exposure. Id. This biphasic response is a useful experimental
`model to classify the mechanisms of an allergic reaction. Tr. 149:8-17 (Schleimer); Tr. 430:5-
`432:15 (Kaliner). But, in a clinical setting, outside of laboratory models, patients are
`continuously exposed to allergens. Tr. 431:18-24 (Kaliner). With this continuous exposure, the
`early- and late-phases of the allergic reaction overlap. Tr. 431:18-432:15 (Kaliner). In addition,
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`PTX0326.00107; PTX0022.00033. The Guidelines describe at least three oral antileukotrienes
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`known at the time of invention. PTX0326.00107; PTX0022.00033.
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`26. Corticosteroids were known to manage all four primary symptoms of AR. Tr.
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`433:13-19 (Kaliner); see PTX0326.00100; DTX-312.0005. Corticosteroids took several days to
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`achieve full effect. See PTX0059.00003; see also Tr. 212:14-17 (Schleimer). The Guidelines
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`describe at least seven intranasal corticosteroids available for use at the time of invention.
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`PTX0326.00099-103. After a few days of use, they were also known to minimize both the early-
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`and late-phase responses. PTX0322.00015. Many patients at the time of invention refused to take
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`corticosteroids for fear of severe side effects associated with other classes of steroid. Tr. 436:4-7,
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`444:16-23 (Kaliner).
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`27. Fluticasone propionate, an intranasal corticosteroid, was known to have an
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`unpleasant smell that some patients did not like. Tr. 437:20-438:4, 439:6-20 (Kaliner) (citing
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`PTX0058.00006-7). Although fluticasone was more potent than other corticosteroids in in vitro
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`and asthma studies, (Tr. 152:13-22 (Schleimer) (citing PTX0325; DTX-039)), it was known in
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`the art that the concentration of all commercially available corticosteroid products had been
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`normalized so that each product had the same efficacy in humans. Tr. 437:3-14 (Kaliner).
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`28. Antihistamines were generally known to treat itching, sneezing, and runny nose.
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`PTX0022.00024; see also Tr. 433:1-6 (Kaliner). The Guidelines described at least twenty-four
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`antihistamines that were known at the time of invention. Tr. 434:7-10 (Kaliner); see also
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`PTX0022.00024-27; PTX0326.00092-99, 00138. Antihistamines were generally divided into two
`
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`the symptoms of both early- and late-phases consist of the same symptoms–sneezing, itching,
`runny nose, and congestion. Tr. 430:5-432:15 (Kaliner). Due to the complexity of the condition
`in a clinical setting, treating clinicians focused their efforts on managing their patients’
`symptoms rather than basing their treatment analysis on which phase the patient presents. Tr.
`(Kaliner); see generally PTX0022.00024-33; PTX0326.00093-107
`430:5-433:19
`(both
`describing drug efficacy in terms of symptoms managed).
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 12 of 54 PageID #: 4762
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`classes: first-generation antihistamines, which often caused sedation, and second-generation
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`antihistamines, which generally caused less sedation. Tr. 82:24-83:4 (Wedner); PTX0326.00092.
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`Both classes were frequently used at the time of invention. Tr. 434:14-19 (Kaliner).
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`29. Antihistamines were predominantly available in oral dosage forms; only two of the
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`twenty-four antihistamines were topical. Tr. 606:24-607:1 (Smyth); Tr. 153:2-12 (Schleimer);
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`see also PTX0326; PTX0022. Patients showed a significant preference for oral dosage forms,
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`(see Tr. 224:6-9 (Schleimer); Tr. 444:10-15 (Kaliner)), and the market bore out this preference.
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`Tr. 441:14-444:15 (Kaliner) (citing PTX0098.00029). Indeed, the limited combination products
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`that existed in the art—Allegra D®, Claritin D®, and Zyrtec D®—were all oral combinations of
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`antihistamines and decongestants, (Tr. 607:10-18 (Smyth)), two drug classes that had completely
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`complementary activity on all of the symptoms of AR. Tr. 433:1-12 (Kaliner).
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`30. Although azelastine was an antihistamine useful for treatment of AR, (see DTX-
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`312.0005), there was no preference for azelastine at the time of invention. Tr. 224:4-23
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`(Schleimer); Tr. 476:16-477:5 (Kaliner). Given patient preference for oral dosage forms, the
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`POSA would not have preferred azelastine over the numerous other oral antihistamine options at
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`least because azelastine was no more effective than oral antihistamines, (see PTX0036.00007;
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`PTX0099.00009), and it exhibited undesirable side effects including sedation and bitter taste.
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`See, e.g., Tr. 440:4-441:1 (Kaliner); PTX0011.00014; PTX0103.00004; PTX0326.00099. These
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`issues, along with azelastine being administered in an intranasal dosage form, contributed to poor
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`patient compliance with azelastine treatment. Tr. 440:14-20 (Kaliner). For these reasons, at the
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`time of invention, azelastine was used extremely infrequently, particularly in comparison with
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`the popular oral antihistamines. Tr. 441:16-443:25 (Kaliner) (citing PTX0098.00029). Based on
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`these issues, the Guidelines recommended the use of azelastine only in one narrow circumstance:
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 13 of 54 PageID #: 4763
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`“for mild organ-limited disease, as an ‘on-demand’ medication in conjunction with a continuous
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`one.” PTX0326.00099.
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`31. Consistent with the patient preference for oral dosage forms, (see Tr. 224:6-9
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`(Schleimer); Tr. 444:10-15 (Kaliner)), and the limited use of azelastine in clinical practice, (Tr.
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`441:16-443:25 (Kaliner) (citing PTX0098.00029)), an assessment of the future of the
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`antihistamine market as it stood in 2003 “hardly mentioned” azelastine at all. Tr. 443:17-21
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`(Kaliner) (citing PTX0098.00029).5 This market assessment included a breakdown of all sales of
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`AR treatments, and it showed that oral antihistamines comprised 56% of the AR market, nasal
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`steroids comprised 25% of the market, while at least four other intranasal anti-allergic
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`compounds (including azelastine)
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`together comprised only 2% of
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`the
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`total market.
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`PTX0098.00029. Azelastine itself comprised less than 1% of the total market. See Tr. 441:16-
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`442:19 (Kaliner) (citing PTX0098.00029).
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`2.
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`The established standard of care in 2002 would not have motivated the
`POSA to combine azelastine and fluticasone.
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`32. Neither the published art nor clinical practices suggested any desire for a fixed-dose
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`formulation of azelastine and fluticasone. Tr. 69:11-70:11 (Accetta); Tr. 83:11-23 (Wedner); Tr.
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`435:14-15 (Kaliner). Neither of Apotex’s experts, Drs. Accetta and Wedner, prescribed a fixed-
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`dose combination of azelastine and fluticasone, nor did they prescribe azelastine and fluticasone
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`on a consistent, conjunctive-use regimen. Tr. 68:20-70:11 (Accetta); Tr. 77:18-22; 83:11-23
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`(Wedner). Both, however, confirmed their desire for flexible dosing regimens, e.g. to titrate
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`dosages up and down and to cycle through drugs to provide individualized treatment for their
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`patients. See, e.g., Tr. 69:11-70:11 (Accetta); Tr. 83:11-23 (Wedner); Tr. 435:14-15 (Kaliner).
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`33. By 2002, the treatment of AR was an iterative process. Tr. 100:16-18 (Wedner); see
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`5 2003 was the first year that IMS carved out azelastine and other nasal anti-allergic treatments.
`Tr. 441:21-25 (Kaliner).
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 14 of 54 PageID #: 4764
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`also PTX0326.00119-00120. The balance between efficacy and side effects was paramount in
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`the treatment of AR because patients often refused to comply with the recommended treatment if
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`the patient found the side effects unacceptable. See, e.g., Tr. 458:13-18 (Kaliner); see also
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`PTX0099.00010. To achieve control of a patient’s symptoms with minimal side effects,
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`clinicians at the time of invention engaged in at least three distinct practices, each of which was
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`recommended by Apotex’s cited art.
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`34. The first practice was known as stepwise therapy. See Tr. 181:16-23 (Schleimer)
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`(citing PTX0326.00119-120). Drs. Accetta, Wedner, and Kaliner all practiced this approach. Tr.
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`206:25-207:2 (Schleimer) (describing Dr. Accetta’s practice as stepwise); Tr. 83:11-23
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`(Wedner); Tr. 435:14-15 (Kaliner). Stepwise therapy involves starting a patient on one drug and
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`increasing dosages or adding other drugs only if the initial therapy is found to be inadequate. Tr.
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`445:23-446:2
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`(Kaliner); Tr. 69:11-70:2
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`(Accetta); Tr. 181:16-23
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`(Schleimer)
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`(citing
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`PTX0326.00119-120). It also involves reducing the dosage or number of drugs once a patient’s
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`symptoms are under control. Tr. 69:11-70:2 (Accetta); Tr. 445:23-446:2 (Kaliner); see
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`PTX0326.00120. When a patient’s symptoms were generally under control, but certain triggers
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`caused an increase in symptoms, clinicians would tell the patient to use a second drug “as
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`needed” to control or decrease symptoms. Tr. 52:16-22 (Accetta). Again, this practice was
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`intended to provide patients with the lowest effective dosage necessary to maintain control over
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`their symptoms. Tr. 70:3-11 (Accetta). And, of course, the “need” for a second drug varied
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`widely from patient to patient. Tr. 85:17-25 (Wedner).
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`35. The second practice was known as titration, which involved increasing or
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`decreasing a patient’s treatment dose to achieve, and then maintain, relief of symptoms while
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`minimizing drug exposure. Tr. 205:4-7 (Schleimer); Tr. 445:7-14 (Kaliner); Tr. 69:11-70:2
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`Case 1:14-cv-01453-LPS Document 155 Filed 01/10/17 Page 15 of 54 PageID #: 4765
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`(Accetta); Tr. 531:11-23 (Carr). Once a patient’s symptoms are well-controlled, the patient’s
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`drug regimen is titrated down, i.e., reduced, to the lowest dose that still controls the symptoms.
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`PTX0326.00120. According to Apotex’s expert Dr. Donald Accetta, all clinicians ascribe to the
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`practice of titration. Tr. 69:11-16 (Accetta); see Tr. 77:18-22 (Wedner).
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`36. The third practice was known as cycling. Because patients responded differently to
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`different drugs, some might have experienced undesirable side effects where others did not, e.g.
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`azelastine’s prohibitively bitter taste. See Tr. 94:14-19 (Wedner); Tr. 440:8-441:1 (Kaliner). In
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`order to address this patient-to-patient variability, clinicians often rotated through different drugs
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`within the same class until they arrived at a satisfactory therapy. See Tr. 460:2-17 (Kaliner); Tr.
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`85:17-25 (Wedner); see also DTX-001–DTX-010 (showing years between Dr. Accetta’s
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`diagnosis of AR and arrival at concurrent azelastine and fluticasone therapy).
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`37. Each of these practices required flexibility, which is a “good concept for any
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`medication,” (Tr. 70:3-8 (Accetta)), and the Guidelines recommended these approaches. The
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`Dykewicz Guidelines recommended, for example, that “[m]anagement of rhinitis should be
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`individualized,”
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`including “instruction
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`in and/or modifications of
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`the medication or
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`immunotherapy program.” PTX0022.00034.
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`38. The ARIA Guidelines explicitly recommended a stepwise approach
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`that
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`incorporated the other available drug classes, including decongestants, mast cell stabilizers
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`(chromones), and the anticholinergic ipratropium bromide. Tr. 181:16