Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 1 of 57 PageID #: 4861
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
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`Civil Action 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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`
`DEFENDANTS’ OPENING POST-TRIAL BRIEF
`
`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.
`
`
`OF COUNSEL:
`
`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
`
`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
`
`
`
`Dated: January 24, 2017
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`
`
`1
`
`CIP2024
`Argentum Pharmaceuticals LLC v. Cipla Ltd.
`IPR2017-00807
`
`

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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 2 of 57 PageID #: 4862
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`TABLE OF CONTENTS
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`INTRODUCTION .......................................................................................................................... 1
`
`ARGUMENT .................................................................................................................................. 5
`
`I.
`
`II.
`
`Legal Framework ................................................................................................................ 5
`
`It was obvious to combine fluticasone propionate and azelastine hydrochloride in a
`single nasal spray to treat allergic rhinitis. .......................................................................... 7
`
`Page
`
`A.
`B.
`
`C.
`
`D.
`
`E.
`
`2.
`
`Persons of ordinary skill in the art .......................................................................... 7
`It was obvious to combine fluticasone with azelastine to treat AR. ....................... 7
`1.
`Doctors prescribed fluticasone (Flonase®) with azelastine
`(Astelin®) in clinical practice. .................................................................... 7
`The prior art explains the clinical practice of combining fluticasone
`and azelastine to treat AR. .......................................................................... 9
`It was obvious to make the clinical practice of combining fluticasone and
`azelastine more convenient for patients by co-formulating these drugs in a
`single nasal spray. ................................................................................................. 11
`1.
`Other pharmaceutical companies expressly disclosed co-
`formulating fluticasone and azelastine in a single nasal spray. ................ 11
`There were several motivations to co-formulate fluticasone and
`azelastine in a single nasal spray. ............................................................. 13
`Federal Circuit authorities compel a finding that it was obvious to co-
`formulate fluticasone and azelastine into a single nasal spray to treat AR. .......... 15
`Plaintiffs’ contrary arguments misstate the facts and otherwise fail as a
`matter of law. ........................................................................................................ 16
`
`2.
`
`III.
`
`It was obvious how to formulate a nasal spray that combines fluticasone and
`azelastine. .......................................................................................................................... 23
`
`A.
`B.
`
`Person of ordinary skill in the art. ......................................................................... 23
`The prior art disclosed a finite number of obvious possible combination
`formulations. ......................................................................................................... 23
`1.
`Flonase® label .......................................................................................... 24
`2.
`Astelin® label and formulation patent ...................................................... 25
`3.
`A POSA would have arrived at a finite number of obvious possible
`combination formulations. ........................................................................ 26
`
`
`
`2
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`

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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 3 of 57 PageID #: 4863
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`C.
`
`D.
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`The obvious possible combination formulations render all asserted claims
`obvious. ................................................................................................................. 28
`1.
`’428 Claim 11 ........................................................................................... 28
`2.
`’428 Claim 10 ........................................................................................... 31
`3.
`’428 Claim 13 ........................................................................................... 33
`4.
`’428 Claim 15 ........................................................................................... 33
`5.
`’428 Claim 16 ........................................................................................... 34
`6.
`’428 Claim 29 ........................................................................................... 34
`7.
`’428 Claims 23, 24, 26, and 30 ................................................................. 34
`8.
`’620 Claim 43 ........................................................................................... 34
`9.
`’620 Claim 44 ........................................................................................... 35
`10.
`’620 Claim 4 ............................................................................................. 35
`11.
`’620 Claim 29 and 42 ................................................................................ 35
`Plaintiffs’ theories about potential incompatibilities would not have
`deterred a POSA from formulating the claimed combination product. ................ 35
`
`IV.
`
`There are no secondary considerations sufficient to rebut the strong prima facie
`showing of obviousness. ................................................................................................... 39
`
`A.
`
`B.
`
`C.
`
`D.
`E.
`
`F.
`G.
`
`H.
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`Three simultaneous inventions indicate that co-formulating azelastine and
`fluticasone was within the level of ordinary skill in the art. ................................. 40
`Two blocking patents render remaining secondary considerations weak at
`best. ....................................................................................................................... 41
`Meda has failed to produce any evidence of commercial success or unmet
`need that rebuts the strong showing of obviousness. ............................................ 43
`There is no evidence of copying. .......................................................................... 45
`There are no superior results over the closest prior art, and any
`improvement over individual monotherapies was expected. ................................ 45
`There was no industry skepticism. ........................................................................ 46
`Meda has failed to produce any evidence of independent praise for
`Dymista®. .............................................................................................................. 48
`MedPointe’s single experiment does not constitute failure of others. .................. 48
`
`V.
`
`Alternatively, the claims are not enabled. ......................................................................... 50
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`
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`ii
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`3
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`

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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 4 of 57 PageID #: 4864
`
`TABLE OF AUTHORITIES
`
`
`
`Page(s)
`
`Cases
`
`Abbott Labs. v. Andrx Pharms., Inc.,
`452 F.3d 1331 (Fed. Cir. 2006)................................................................................................45
`
`Agrizap, Inc. v. Woodstream Corp.,
`520 F.3d 1337 (Fed. Cir. 2008)..........................................................................................40, 44
`
`Allergan, Inc. v. Sandoz Inc.,
`726 F.3d 1286 (Fed. Cir. 2013)........................................................................................ passim
`
`In re Applied Materials, Inc.,
`692 F.3d 1289 (Fed. Cir. 2012)................................................................................................43
`
`AstraZeneca LP v. Breath Ltd.,
`88 F. Supp. 3d 326 (D.N.J.), aff’d, 603 F. App’x 999 (Fed. Cir. 2015) ..................................49
`
`In re Baxter Travenol Labs.,
`952 F.2d 388 (Fed. Cir. 1991)..................................................................................................45
`
`Bayer Healthcare Pharms., Inc. v. Watson Pharms, Inc.,
`713 F.3d 1369 (Fed. Cir. 2013)................................................................................................48
`
`Cross Med. Prods., Inc. v. Medtronic Sofamor Danek, Inc.,
`424 F.3d 1293 (Fed. Cir. 2005)..................................................................................................8
`
`Duramed Pharm., Inc. v. Watson Labs., Inc.,
`413 F. App’x 289 (Fed. Cir. 2011) ..........................................................................................39
`
`Ecolochem, Inc. v. S. Cal. Edison Co.,
`227 F.3d 1361 (Fed. Cir. 2000)....................................................................................13, 40, 41
`
`In re Fulton,
`391 F.3d 1195 (Fed. Cir. 2004)..................................................................................................6
`
`Galderma Labs., L.P. v. Tolmar, Inc.,
`737 F.3d 731 (Fed. Cir. 2013)................................................................................21, 42, 45, 46
`
`Geo. M. Martin Co. v. All. Mach. Sys. Int’l LLC,
`618 F.3d 1294 (Fed. Cir. 2010)................................................................................................48
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .................................................................................................................5, 22
`
`iii
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`4
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`

`

`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 5 of 57 PageID #: 4865
`
`Great Atl. & Pac. Tea Co. v. Supermarket Equip. Corp.,
`340 U.S. 147 (1950) .....................................................................................................27, 28, 38
`
`In re Haase,
`542 F. App’x 962 (Fed. Cir. 2013) .................................................................................. passim
`
`Insight Tech. Inc. v. SureFire, LLC,
`447 F. Supp. 2d 120 (D.N.H. 2006) .........................................................................................41
`
`INVISTA N. Am. S.a.r.l. v. M & G USA Corp.,
`951 F. Supp. 2d 604 (D. Del. 2013) .........................................................................................43
`
`In re Kahn,
`441 F.3d 977 (Fed. Cir. 2006).......................................................................................... passim
`
`In re Kao,
`639 F.3d 1057 (Fed. Cir. 2011)................................................................................................33
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ......................................................................................................... passim
`
`Lincoln Eng’g Co. of Illinois v. Stewart-Warner Corp.,
`303 U.S. 545 (1938) .................................................................................................................27
`
`Merck & Co. v. Teva Pharm. USA, Inc.,
`395 F.3d 1364 (Fed. Cir. 2005)................................................................................................42
`
`In re Mouttet,
`686 F.3d 1322 (Fed. Cir. 2012)................................................................................................17
`
`Novo Nordisk A/S v. Caraco Pharm. Labs., Ltd.,
`719 F.3d 1346 (Fed. Cir. 2013)........................................................................................ passim
`
`In re O’Farrell,
`853 F.2d 894 (Fed. Cir. 1988)................................................................................................4, 6
`
`Ormco Corp. v. Align Tech., Inc.,
`463 F.3d 1299 (Fed. Cir. 2006)................................................................................................44
`
`PAR Pharm., Inc. v. TWI Pharm., Inc.,
`773 F.3d 1186 (Fed. Cir. 2014)..........................................................................................33, 34
`
`Pfizer, Inc. v. Apotex, Inc.,
`480 F.3d 1348 (Fed. Cir. 2007)......................................................................................3, 36, 38
`
`Rasmusson v. SmithKline Beecham Corp.,
`413 F.3d 1318 (Fed. Cir. 2005)................................................................................................50
`
`iv
`
`5
`
`

`

`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 6 of 57 PageID #: 4866
`
`Richardson-Vicks, Inc. v. Upjohn Co.,
`122 F.3d 1476 (Fed. Cir. 1997)........................................................................................ passim
`
`Senju Pharm. Co. Ltd. v. Apotex, Inc.,
`717 F. Supp. 2d 404 (D. Del. 2010), aff’d, 485 F. App’x 433 (Fed. Cir. 2012) ......6, 28, 30, 31
`
`SightSound Techs., LLC v. Apple Inc.,
`809 F.3d 1307 (Fed. Cir. 2015)........................................................................................ passim
`
`Sundance, Inc. v. Demonte Fabricating Ltd.,
`550 F.3d 1356 (Fed. Cir. 2008)................................................................................................40
`
`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) ....................47, 48
`
`Warner Chilcott Co, LLC v. Teva Pharm. USA, Inc.,
`37 F. Supp. 3d 731 (D. Del. 2014), aff’d, 594 F. App’x 630 (Fed. Cir. 2014) ........................42
`
`In re Woodruff,
`919 F.2d at 1578 ..........................................................................................................30, 32, 33
`
`Statutes
`
`35 U.S.C. § 103 ................................................................................................................................5
`
`35 U.S.C. § 103(a) ...........................................................................................................................5
`
`35 U.S.C. § 112 ..........................................................................................................................5, 50
`
`Other Authorities
`
`MPEP § 2111.03 ............................................................................................................................43
`
`MPEP § 2164.02 ............................................................................................................................49
`
`
`
`v
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`6
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`

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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 7 of 57 PageID #: 4867
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`INTRODUCTION
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`The trial record presents clear and convincing evidence that the asserted claims of U.S.
`
`Patent No. 8,168,620 (“the ’620 patent”) and U.S. Patent No. 9,259,428 (“the ’428 patent”) are
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`invalid as obvious. Before the priority date, each and every testifying physician had personally
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`used Flonase® (fluticasone propionate) in combination with Astelin® (azelastine hydrochloride)
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`to treat seasonal allergic rhinitis (“AR”). The patents-in-suit merely claim the co-formulation of
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`these two known, FDA-approved drugs for this known use—with known excipients. All asserted
`
`claims
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`are
`
`thus
`
`obvious
`
`because
`
`they
`
`represent
`
`nothing more
`
`than
`
`the
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`“predictable use of prior art elements according to their established functions.” KSR Int’l Co. v.
`
`Teleflex Inc., 550 U.S. 398, 417 (2007). There is, in short, nothing inventive about them.
`
`The trial focused on two questions: (1) was it obvious to treat AR using a nasal spray with
`
`both fluticasone and azelastine as active ingredients; and, if so, (2) was it obvious how to co-
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`formulate those drugs with pharmaceutical excipients? Defendants presented clear and convincing
`
`evidence that the answer to both questions is yes.
`
`First, using fluticasone and azelastine together to treat AR was the epitome of an obvious
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`clinical practice as of the June 2002 priority date—indeed, it was part of clinical practice. Both
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`ingredients were marketed in the prior art as FDA-approved nasal sprays branded as Flonase®
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`(fluticasone) and Astelin® (azelastine). D.I. 156 ¶ 1. Every physician who testified at trial—
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`including Plaintiffs’ two clinician experts—prescribed Flonase® together with Astelin® to treat
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`AR before June 2002. Id.; Tr. (Accetta) at 46:12-14; Tr. (Wedner) at 76:20-77:6; Tr. (Kaliner) at
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`433:20-434:6; Tr. (Carr) at 574:10-13. The rationale for such combination therapy was
`
`straightforward: the drugs had complementary mechanisms of action and, therefore, using two
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`drugs was more effective than using either one alone. D.I. 156 ¶¶ 35-38.
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`
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`7
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`

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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 8 of 57 PageID #: 4868
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`The next logical and obvious step in this therapy was to combine the active ingredients
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`from these FDA-approved drugs into a single nasal spray. Again, the rationale for doing so was
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`so obvious that Plaintiffs’ own expert conceded (through impeachment testimony) that “a person
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`of skill in the art” as of 2002 would have thought that they “would have improved compliance” by
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`putting the two separate drugs “in one spray bottle.” D.I. 156 ¶ 2; Tr. (Kaliner) at 508:9-14.
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`But the Court need not rely only on the Plaintiffs’ expert—because two pharmaceutical
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`companies expressly disclosed using the two drugs in a single combination nasal spray, just like
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`the one claimed in the patents-in-suit. Id. ¶ 2, DTX 12 (“Cramer”); DTX 21 (“Segal”). The first,
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`referred to at trial as “Cramer,” is a European Patent application published on June 25, 1997, five
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`years before the priority date in this case. D.I. 156 ¶ 30. It discloses an AR treatment for nasal
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`administration comprising a steroid and an antihistamine, and it discloses fluticasone as a useful
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`steroid and azelastine as a useful antihistamine. DTX 12. The second reference, “Segal,”
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`published in 1998, likewise discloses a combination nasal spray containing a “topical anti-
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`inflammatory agent” such as fluticasone, with an antihistamine such azelastine, to treat AR. D.I.
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`156 ¶ 32.
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`Driving this point home, Meda—which marketed Astelin and is not the patentee but,
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`instead, took a license to Cipla’s patent later in time—found it obvious to co-formulate its drug,
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`azelastine, with fluticasone. As Meda employee Dennis Fuge aptly put it in his testimony,
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`combining the two drugs was “obvious” at the time, because “Fluticasone was the then best selling
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`steroid, and Azelastine was the best antihistamine.” D.I. 156 ¶ 2. Plaintiffs’ efforts to distort the
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`prior art teachings—including teachings by their own clinical expert, Dr. Kaliner—are not
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`credible.
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`2
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`8
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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 9 of 57 PageID #: 4869
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`Second, the only question left is whether it was obvious to use the excipients claimed in
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`the patents-in-suit. Indeed it was. All claimed excipients and their functions were all known in
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`the art—and even disclosed as potential excipients for fluticasone, azelastine, or both. Indeed,
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`Meda itself filed a U.S. patent application in 2005, before it had knowledge of the patents-in-suit,
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`that claimed a combination of azelastine and fluticasone and disclosed as suitable each of the
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`excipients in the claims asserted here. D.I. 156 ¶¶ 128-30.
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`The person of ordinary skill in the art (“POSA”) in 2002 was well aware of how to make a
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`combination fluticasone/azelastine nasal spray, and the patents-in-suit merely claim some of the
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`most obvious formulations. The prior art Flonase® and Astelin® labels, along with their
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`associated public patents and basic formulation texts, disclosed all the ingredients that made these
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`prior art drugs work in nasal sprays. This included detailed information about suitable thickening
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`agents, preservatives, surfactants, and tonicity adjustors for fluticasone and azelastine
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`formulations, just like the claims cover. D.I. 156 ¶¶ 76-84; D.I. 156 ¶¶ 85-92. By consulting
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`nothing more than the most basic formulation information, a POSA would have arrived at a finite
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`number of obvious combination formulations.
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`Because a formulator would have had a “reasonable probability of success” using those
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`known excipients for known purposes, that renders all asserted claims of both patents-in-suit
`
`obvious. Pfizer, Inc. v. Apotex, Inc., 480 F.3d 1348, 1364 (Fed. Cir. 2007); see also KSR, 550 U.S.
`
`at 417, 421. That conclusion is consistent with the patents’ specification, which confirms that the
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`product can be “prepared by techniques well known in the art,” and gives no new information
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`showing that the claimed combination safely and effectively treats AR. D.I. 156 ¶ 116; PTX 1 at
`
`col. 8, l. 67–col. 9, l. 2.
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`3
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`9
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`

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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 10 of 57 PageID #: 4870
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`Time and again, the Federal Circuit has held similar types of patent claims obvious. For
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`example, in Allergan, Inc. v. Sandoz Inc., the Federal Circuit found claims covering a co-
`
`formulation of two eye drop drugs to treat glaucoma obvious, because key prior art taught “fixed
`
`combinations” of similar drugs “for the treatment of glaucoma,” and such a co-formulation could
`
`improve “patient compliance,” which was a “clear motivation to combine.” 726 F.3d 1286, 1289-
`
`90, 1293 (Fed. Cir. 2013). And in Richardson-Vicks, Inc. v. Upjohn Co., the Federal Circuit
`
`affirmed the district court’s decision to overturn a jury verdict that a combination pain
`
`relief/decongestant tablet was valid, because “[t]he only difference between the prescribed
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`combination [of ibuprofen and pseudoephedrine] and the patented invention is that the prescription
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`was not contained in a single tablet”—and “[s]uch a combination was clearly suggested by the
`
`prior art.” 122 F.3d 1476, 1483-84 (Fed. Cir. 1997).
`
`The asserted claims here are no different. They cover the obvious combination of two
`
`known drugs for a known use with known pharmaceutical excipients. Plaintiffs’ efforts to rely on
`
`purported formulation difficulties and multiple formulation options all conflict with controlling
`
`precedent. The mere “general unpredictability of the formulation arts” cannot support a showing
`
`of non-obviousness. Allergan, 726 F.3d at 1292-93. Nor does the existence of more than one
`
`obvious formulation make any of those particular formulations non-obvious, because “mere
`
`disclosure of more than one alternative does not amount to teaching away from” the invention.
`
`SightSound Techs., LLC v. Apple Inc., 809 F.3d 1307, 1320 (Fed. Cir. 2015) (internal quote marks
`
`omitted). And, of course, obviousness does not require an “absolute predictability of success.” In
`
`re O’Farrell, 853 F.2d 894, 903-04 (Fed. Cir. 1988). Try as they might, Plaintiffs cannot posit a
`
`viable theory of non-obviousness in light of these and other relevant legal standards.
`
`4
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`10
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`

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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 11 of 57 PageID #: 4871
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`The record thus provides clear and convincing evidence that Plaintiffs’ are not entitled to
`
`a monopoly on combining azelastine and fluticasone into a single nasal spray. The claimed
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`invention is nothing more than the obvious formulation of a drug combination that had been taught
`
`years before the work of the inventors. The asserted secondary considerations of non-obviousness
`
`all fail for both legal and factual reasons.
`
`Therefore, the Court should enter a judgment of obviousness under 35 U.S.C. § 103 in
`
`favor of Apotex. Alternatively, if the Court were to credit Plaintiffs’ arguments, the patent
`
`disclosure is inadequate to satisfy the enablement requirement of 35 U.S.C. § 112.
`
`I.
`
`LEGAL FRAMEWORK
`
`ARGUMENT
`
`The asserted claims in this case are invalid as obvious because one cannot patent a
`
`combination pharmaceutical product when all of the claimed elements were known in the prior art,
`
`combined in ways the prior art suggested, and then resulted in an expected form of treatment.
`
`A patent claim is invalid for obviousness under 35 U.S.C. § 103(a) if the differences
`
`between the subject matter of the claim and the prior art are “such that the subject matter as a
`
`whole would have been obvious at the time the invention was made to a person having ordinary
`
`skill in the pertinent art.” In re Kahn, 441 F.3d 977, 985 (Fed. Cir. 2006) (citing Graham v. John
`
`Deere Co., 383 U.S. 1, 13-14 (1966)). To determine if a patent claim is obvious, “the scope and
`
`content of the prior art are to be determined; differences between the prior art and the claims at
`
`issue are to be ascertained; and the level or ordinary skill in the pertinent art are resolved.” Graham
`
`v. John Deere Co., 383 U.S. 1, 17 (1966). And “[s]uch secondary considerations as commercial
`
`success, long felt by unsolved needs, failure of others, etc., might be utilized to give light to the
`
`circumstances surrounding the origin of the subject matter sought to be patented.” Id. at 17-18.
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`5
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`11
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`

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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 12 of 57 PageID #: 4872
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`Obviousness does not require an “absolute predictability of success,” only a “reasonable
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`expectation” that the combination will succeed. See In re O’Farrell, 853 F.2d 894, 903-04 (Fed.
`
`Cir. 1988). The mere existence of unpredictability is insufficient for a finding of nonobviousness.
`
`The Federal Circuit has even reversed a district court finding “that there was no reasonable
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`expectation of success in view of the general unpredictability of the formulation arts and
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`particularized, yet irrelevant, difficulties associated with the development of [the drug product].”
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`Allergan, Inc. v. Sandoz Inc., 726 F.3d 1286, 1292-93 (Fed. Cir. 2013). Similarly, the mere
`
`existence of alternatives is also insufficient for a finding of nonobviousness. “‘[M]ere disclosure
`
`of more than one alternative’ does not amount to teaching away from one of the alternatives where
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`the reference does not ‘criticize, discredit, or otherwise discourage the solution claimed.’”
`
`SightSound Techs., LLC v. Apple Inc., 809 F.3d 1307, 1320 (Fed. Cir. 2015) (quoting In re Fulton,
`
`391 F.3d 1195, 1201 (Fed. Cir. 2004)).
`
`Even if “a combination was” merely “obvious to try,” that “might show that it was obvious
`
`under § 103.” KSR Int’l Co. v. Teleflex, Inc., 550 U.S. 398, 421 (2007). For example, in the
`
`context of claims to pharmaceutical products that include excipients, courts in this district have
`
`held that “within the finite range of excipients disclosed to be suitable . . . , it would be obvious to
`
`try one such excipient characterized by the prior art” as having the desired property. Senju Pharm.
`
`Co. Ltd. v. Apotex, Inc., 717 F. Supp. 2d 404, 422-23 (D. Del. 2010) (Robinson, J.), aff’d, 485 F.
`
`App’x 433 (Fed. Cir. 2012).
`
`In light of these standards, the asserted claims are obvious over the Flonase® label, the
`
`Astelin® label and Astelin®’s formulation patent, in combination with standard formulation
`
`references such as the Handbook of Pharmaceutical Excipients.
`
`6
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`12
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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 13 of 57 PageID #: 4873
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`II.
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`IT WAS OBVIOUS TO COMBINE FLUTICASONE PROPIONATE AND
`AZELASTINE HYDROCHLORIDE IN A SINGLE NASAL SPRAY TO TREAT
`ALLERGIC RHINITIS.
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`The concept of using azelastine and fluticasone together to treat AR was undisputedly
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`recommended and, in fact, practiced in the prior art. That alone is enough to make their co-
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`formulation obvious. Beyond the prescribing habits of physicians and the teachings of the
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`guidelines they followed, however, the prior art also provided significant motivations to make that
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`combination.
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`Persons of ordinary skill in the art
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`A.
`The parties offer different definitions of a person of ordinary skill in the art from the
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`perspective of using pharmaceutical compositions in the treatment of allergic rhinitis. Dr.
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`Schleimer opined that a clinical person of ordinary skill has an M.D., Ph.D. or Pharm.D. in the
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`field of allergy/immunology and/or pharmacology (or the equivalent), and at least three additional
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`years of experience in the treatment, or research for treatments, of allergic rhinitis, including with
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`nasally administered steroids and antihistamines. D.I. 135 Ex. 3 ¶ 21; Tr. (Schleimer) at 171:18-
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`25. Meda’s definition limits the POSA to only having an M.D. D.I. 135 Ex. 2 ¶¶ 84-85; Tr.
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`(Kaliner) at 426:11–427:1. Regardless of which of these definitions the Court adopts, the claimed
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`invention is obvious.
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`B.
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`It was obvious to combine fluticasone with azelastine to treat AR.
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`1.
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`Doctors prescribed fluticasone (Flonase®) with azelastine (Astelin®) in
`clinical practice.
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`There is no dispute that physicians in the United States and elsewhere co-prescribed
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`azelastine in a nasal spray formulation and fluticasone in a nasal spray formulation before June
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`2002, for AR patients inadequately controlled by either drug alone. Each testifying clinician in
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`this case, including Meda’s own experts, did so. D.I. 156 ¶¶ 22-28. This practice was thus part of
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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 14 of 57 PageID #: 4874
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`the knowledge of a POSA. See In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006) (“the
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`understandings and knowledge of persons having ordinary skill in the art at the time of the
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`invention” are relevant to obviousness); Cross Med. Prods., Inc. v. Medtronic Sofamor Danek,
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`Inc., 424 F.3d 1293, 1322 (Fed. Cir. 2005) (“It has long been the law that the motivation to combine
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`need not be found in prior art references, but equally can be found in the knowledge generally
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`available to one of ordinary skill in the art.”) (citations and quote marks omitted).
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`This practice was not surprising given that it was recommended by prior art references and
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`AR treatment guidelines. The 2001 ARIA Guidelines recommended a “stepwise approach” for
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`treating “moderate/severe persistent disease.” D.I. 156 ¶ 56; PTX 326 at S251. It recommended
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`an intranasal glucocorticosteroid like fluticasone “as a first line treatment” and to “add” an “H1
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`antihistamine” like azelastine if the symptoms were inadequately controlled. D.I. 156 ¶ 56. The
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`1998 Dykewicz Guidelines taught that intranasal antihistamines “are appropriate for use as a first
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`line treatment for the symptoms of allergic rhinitis, or as part of combination therapy with nasal
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`corticosteroids.” D.I. 156 ¶ 57; DTX 246 at 28. Right after giving this recommendation, the
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`Dykewicz guidelines noted that “Astelin . . . is the first intranasal antihistamine preparation
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`approved for use in the US.” D.I. 156 ¶ 57.
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`The 2000 Cauwenberge “consensus statement on the treatment of allergic rhinitis” taught
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`that “[i]f that patient presents with severe symptoms or if the treatment with nasal steroids in the
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`case of moderate disease does not have an adequate effect, a combination of nasal steroids and
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`antihistamines (oral and/or topical [i.e., nasal]) is recommended.” D.I. 156 ¶ 58; DTX 154 at 10.
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`The 1999 Berger reference similarly taught that “[a]zelastine nasal spray can be used either in
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`place of oral antihistamines or in combination with intranasal corticosteroids.” D.I. 156 ¶ 59; DTX
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`26 at 6.
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`Case 1:14-cv-01453-LPS Document 158 Filed 01/24/17 Page 15 of 57 PageID #: 4875
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`Plaintiffs’ own expert, Dr. Kaliner, agreed that he made a presentation before the June 2002
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`priority to allergists where he “told those skilled in the art in May 2002 that symptoms typical of
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`allergic rhinitis; primarily sneezing, nasal itching and rhinorrhea; benefit most from an intranasal
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`corticosteroid combined with an oral antihistamine to which a topical antihistamine can be added
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`for additional symptomatic control.” D.I. 156 ¶ 60; Tr. (Kaliner) 490:1-8; DTX 312 at 8. Dr.
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`Kaliner also agreed that he taught that the ARIA guidelines “suggested the combined use of an
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`oral antihistamine with an intranasal corticosteroid” and “residual symptoms can be treated by
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`adding the topical antihistamine azelastine to the regimen.” D.I. 156 ¶ 60.
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`2.
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`The prior art explains the clinical practice of combining fluticasone and