Paper No. ____
`Date Filed: May 6, 2015
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`
`
`
`
`Filed on behalf of:
`
`INO Therapeutics LLC
`
`By:
`
`Dominick A. Conde
`dconde@fchs.com
`(212) 218-2100
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`________________
`
`Praxair Distribution, Inc.
`Petitioner,
`v.
`INO Therapeutics LLC
`Patent Owner.
`________________
`
`Case IPR2015-00526
`U.S. Patent No. 8,795,741
`________________
`
`
`
`PRELIMINARY RESPONSE BY
`PATENT OWNER PURSUANT TO 37 C.F.R. § 42.107
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`
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`Ex. 2019-0001
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`I.
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`TABLE OF CONTENTS
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`INTRODUCTION .................................................................................................... 1
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`II.
`
`BACKGROUND ....................................................................................................... 6
`
`A.
`
`The Development of the ’741 Patent ........................................................... 6
`
`1.
`
`2.
`
`3.
`
`The Original INOT22 Protocol Was Carefully
`Constructed and Reviewed, and Did Not Contain
`the Claimed Exclusion Criteria .......................................................... 6
`
`Unanticipated Serious Adverse Events Initially
`Occurred During the INOT22 Study ................................................ 9
`
`Based on the Unexpected Serious Adverse Events
`Early in the Trial the INOT22 Protocol Was
`Amended and the Rate of SAEs Was Significantly
`Reduced ............................................................................................... 10
`
`B.
`
`The ’741 Prosecution History ...................................................................... 11
`
`1.
`
`2.
`
`The PTO Considered Many References ......................................... 11
`
`Praxair Relies on the Same Statements Ikaria
`Overcame During Prosecution ........................................................ 13
`
`C.
`
`The ’741 Patent Claims ................................................................................. 19
`
`III. PERSON OF ORDINARY SKILL ...................................................................... 20
`
`IV. CLAIM CONSTRUCTION ................................................................................... 20
`
`V.
`
`LEGAL STANDARD ............................................................................................. 23
`
`VI. A SKILLED ARTISAN WOULD NOT HAVE BEEN
`MOTIVATED TO EXCLUDE CHILDREN OR NEONATES
`HAVING LVD OR REASONABLY EXPECT THOSE
`CHILDREN OR NEONATES WOULD HAVE
`EXPERIENCED SAES .......................................................................................... 27
`
`A.
`
`There was no motivation to implement the claimed
`exclusion based on studies with adults because left
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`i
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`Ex. 2019-0002
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`B.
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`ventricular dysfunction in children and neonates is much
`different than in adults .................................................................................. 29
`
`A skilled artisan would not have reasonably expected that
`the claimed excluded children or neonates would have
`SAEs as initially occurred in the INOT22 Study ...................................... 32
`
`VII. GROUND 1: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`BERNASCONI IN COMBINATION WITH LOH AND
`GOYAL...................................................................................................................... 35
`
`A.
`
`B.
`
`C.
`
`D.
`
`Praxiar fails to show that Bernasconi, Loh or Goyal include
`the claimed exclusion criteria ....................................................................... 37
`
`Praxair’s Assertions that warnings in the art are applicable
`to the claimed exclusion criteria are unsupported. .................................... 44
`
`Praxair fails to raise any new arguments or supplement the
`record to address issues overcome during prosecution ............................ 46
`
`Praxair fails to show that elements in dependent claims 4,
`17-21, 35, and 42-44 are present in the prior art ....................................... 49
`
`VIII. GROUND 2: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`BERNASCONI IN COMBINATION WITH LOH, INOMAX®
`LABEL, JULIANA, and GOYAL ......................................................................... 50
`
`IX. GROUND 3: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`BERNASCONI IN COMBINATION WITH LOH, MACRAE,
`AND GOYAL .......................................................................................................... 52
`
`X. GROUND 4: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`BERNASCONI IN COMBINATION WITH LOH, INOMAX®
`LABEL, JULIANA, MACRAE, AND GOYAL ................................................ 54
`
`XI. GROUND 5: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`ICHINOSE IN COMBINATION WITH NEONATAL
`GROUP, MACRAE, LOH, GERMANN, AND GOYAL ................................ 54
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`ii
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`Ex. 2019-0003
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`XII. GROUND 6: THE BOARD SHOULD NOT INSTITUTE
`XII. GROUND 6: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`ICHINOSE IN COMBINATION WITH NEONATAL
`ICHINOSE IN COMBINATION WITH NEONATAL
`GROUP, MACRAE, LOH, INOMAX® LABEL, GERMANN,
`GROUP, MACRAE, LOH, INOMAX® LABEL, GERMANN,
`AND GOYAL .......................................................................................................... 57
`AND GOYAL ........................................................................................................ .. 57
`
`XIII. PRAXAIR FAILS TO DEMONSTRATE A REASONABLE
`XIII. PRAXAIR FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD OF SUCCESS TO COUNTER THE
`LIKELIHOOD OF SUCCESS TO COUNTER THE
`OBJECTIVE EVIDENCE OF UNEXPECTED RESULTS .......................... 57
`OBJECTIVE EVIDENCE OF UNEXPECTED RESULTS ........................ .. 57
`
`XIV. CONCLUSION ...................................................................................................... .. 59
`XIV. CONCLUSION ........................................................................................................ 59
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`
`
`iii
`iii
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`Ex. 2019-0004
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`Ex. 2019-0004
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`Cases
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`
`
`
`
`TABLE OF AUTHORITIES
`
`Apple, Inc. v. ITC,
`725 F.3d 1356 (Fed. Cir. 2013) ................................................................................ 58
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) .................................................................................. 45
`
`CCS Fitness, Inc. v. Brunswick Corp.,
`288 F.3d 1359 (Fed. Cir. 2002) ................................................................................ 21
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) ................................................................................................. 24, 58
`
`In re Cuozzo Speed Tech. LLC,
`No. 14-1301, slip op. (Fed. Cir. Feb. 4, 2015) ....................................................... 20
`
`In re Dembiczak,
`175 F.3d 994 (Fed. Cir. 1999) .................................................................................. 25
`
`Insite Vision Inc. v. Sandoz, Inc.,
`2014-1065 (Fed.Cir. April 19, 2015) ....................................................................... 46
`
`KSR Int'l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007) ....................................................................................... 24, 25, 58
`
`Leo Pharmaceutical Products, Ltd v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .......................................................................... 24, 34
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .......................................................................... 20, 21
`
`Rohm and Haas Co. v. Brotech Corp.,
`127 F.3d 1089 (Fed. Cir. 1997) ................................................................................ 45
`
`Statutes
`
`35 U.S.C. § 103............................................................................................. 24, 51, 52, 54, 57
`
`35 U.S.C. § 314(a) ............................................................................................................. 2, 23
`
`35 U.S.C. § 325(d) ................................................................................................................. 46
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`iv
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`Ex. 2019-0005
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`
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`Regulations
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`
`
`
`
`21 C.F.R. Part 56 .................................................................................................................... 8
`
`37 C.F.R. § 42.1(b) ................................................................................................................ 48
`
`37 C.F.R. § 42.100(b) ........................................................................................................... 20
`
`37 C.F.R. § 42.104(b)(4) ................................................................................................. 25, 41
`
`37 C.F.R. § 42.108(c) ........................................................................................................ 2, 23
`
`37 C.F.R. § 42.6..................................................................................................................... 61
`
`37 C.F.R. § 42.65(a) .............................................................................................................. 45
`
`P.T.A.B.
`
`Int’l Securities Exchange, LLC v. Chicago Board Options Exchanges, Inc.,
`IPR No. 2014-00099, Paper 12 (P.T.A.B. May 22, 2014) ........................ 26, 41, 42
`
`Integrated Global Concepts, Inc., v. Advanced Messaging Tech., Inc.,
`IPR No. 2014-01027, Paper 16 (P.T.A.B. Dec. 22, 2014) ....................... 26, 42, 59
`
`Merial v. Virbac,
`IPR No. 2014-01279, Paper 13 (P.T.A.B. Jan. 22, 2015) . 4, 26, 42, 46, 48, 49, 59
`
`Mylan v. Gilead Sciences, Inc.,
`IPR No. 2014-00888, Paper 15 (P.T.A.B. Dec. 9, 2014) ........................... 4, 26, 45
`
`Mylan Pharma. Inc. v. Gilead Sciences, Inc.,
`IPR No. 2014-00885, Paper 15 (P.T.A.B. Dec. 9, 2014) ..................................... 45
`
`Zetec, Inc. v. Westinghouse Elec. Co., LLC,
`IPR No. 2014-00384, Paper 10 (P.T.A.B. Jul. 23, 2014) ..................... 3, 25, 41, 42
`
`
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`v
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`Ex. 2019-0006
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`TABLE OF ABBREVIATIONS
`
`
`Abbreviation
`
`Description
`
`’741 patent
`
`U.S. Patent No. 8,795,741
`
`’966 patent
`
`U.S. Patent No. 8,282,966
`
`’284 patent
`
`U.S. Patent No. 8,293,284
`
`’163 patent
`
`U.S. Patent No. 8,431,163
`
`’112 patent
`
`U.S. Patent No. 8,846,112
`
`’417 Application
`
`U.S. Patent Application No. 13/683,417
`
`Adatia
`
`Adatia et al, “Inhaled nitric oxide and hemodynamic evaluation of
`
`patients with pulmonary hypertension before transplantation,”
`
`25:1656-64, J. Am. Coll. Cardiol., 1995 [Exh. 2003]
`
`Balaguru
`
`Balaguru et al., “Management of Heart Failure in Children,” 30:5-
`
`30, Curr. Probl. Pediatr., 2000 [Exh. 2010]
`
`Beghetti (1997)
`
`Beghetti et al., “Inhaled nitric oxide can cause severe systemic
`
`hypotension,” 130:844, J. Pediatr., 1997 [Exh. 2004]
`
`Berger
`
`Berger et al., “Clinical features of paediatric pulmonary
`
`hypertension: a registry study,” 379:537-46, Lancet, 2012
`
`[Exh. 2011]
`
`Bernasconi
`
`Bernasconi et al., “Inhaled nitric oxide applications in paediatric
`
`practice”, 4: 4-29, Images Paediatr. Cardiol., 2002 [Exh. 1004]
`
`vi
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`Ex. 2019-0007
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`
`
`Abbreviation
`
`
`
`
`
`Description
`
`Davidson
`
`Davidson et al., “Inhaled nitric oxide for the early treatment of
`
`persistent pulmonary hypertension of the term newborn: a
`
`randomized, double-masked, placebo-controlled, dose-response,
`
`multicenter study, 101: 325-334, Pediatrics, 1998 [Exh. 1005]
`
`Germann
`
`Germann et al., “Inhaled nitric oxide therapy in adults: European
`
`expert recommendations,” 31:1029-41, Intensive Care Med., 2005
`
`[Exh. 1010]
`
`Gidding
`
`Gidding, “The Importance of Randomized Controlled Trials in
`
`Pediatric Cardiology,” 298:1214-1216, JAMA. 2007 [Exh. 2009]
`
`Goyal
`
`Goyal et al., “Efficacy of nitroglycerin inhalation in reducing
`
`pulmonary arterial hypertension in children with congenital heart
`
`disease, 97:208-14, Br. J. Anaesth., 2006 [Exh. 1007]
`
`Henrichsen
`
`Henrichsen et al., “Inhaled nitric oxide can cause Severe systemic
`
`hypotension, 129:183, J. Pediatr., 1996 [Exh. 1030]
`
`Ichinose
`
`Ichinose et al., “Inhaled nitric oxide: a selective pulmonary
`
`vasodilator: current uses and therapeutic potential,” 109: 3106-
`
`3111, Circulation, 2004 [Exh. 1009]
`
`INOmax® label
`
`Center for Drug Evaluation and Research, Application Number:
`
`NDA 20845, INOMAX, Final Printed Labeling, available at
`
`vii
`
`Ex. 2019-0008
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`

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`
`
`
`
`
`Abbreviation
`
`
`
`
`
`Description
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20845
`
`_inomax_prntlbl.pdf (August 9, 2000) [Exh. 1014]
`
`Ivy
`
`Ivy et al., “Pediatric Pulmonary Hypertension,” 62(25
`
`Suppl):D117-26, J. Am. Coll. Cardiol., 2013 [Exh. 1017]
`
`Juliana
`
`Juliana et al., “Severe persistent pulmonary hypertension of the
`
`newborn in a setting where limited resources exclude the use of
`
`inhaled nitric oxide: successful treatment with sildenafil,”
`
`164:626-9, Eur. J. Pediatr., 2005
`
`Lipshultz
`
`Lipshultz, “Ventricular dysfunction clinical research in infants,
`
`children and adolescents,” 12:1-28, Prog. Pediatr. Cardiol., 2000
`
`[Exh. 2006]
`
`Loh
`
`Loh, et al., “Cardiovascular effects of inhaled nitric oxide in
`
`patients with left ventricular dysfunction,” 90: 2780-2785,
`
`Circulation, 1994 [Exh. 1006]
`
`Macrae
`
`Macrae, et al., “Inhaled nitric oxide therapy in neonates and
`
`children: reaching a European consensus, 30: 372-380, Intensive
`
`Care Med., 2004 [Exh. 1008]
`
`Neonatal Group
`
`The Neonatal Inhaled Nitric Oxide Study Group, “Inhaled nitric
`
`oxide in full-term and nearly full-term infants with hypoxic
`
`viii
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`Ex. 2019-0009
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`Abbreviation
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`
`
`
`
`Description
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`respiratory failure,” 336: 597-604, N. Engl. J. Med., 1997
`
`[Exh. 1011]
`
`Rimensberger
`
`Rimensberger et al., “Inhaled nitric oxide versus aerosolized
`
`iloprost in secondary pulmonary hypertension in children with
`
`congenital heart disease: vasodilator capacity and cellular
`
`mechanisms”, 103: 544-48, Circulation, 2001 [Exh. 2012]
`
`Rosales
`
`Rosales et al., “Adverse hemodynamic effects observed with
`
`inhaled nitric oxide after surgical repair of total anomalous
`
`pulmonary venous return,” 20:224-26, Pediatr. Cardiol., 1999
`
`[Exh. 2005]
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`Stedman’s 2006
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`Stedman’s Medical Dictionary at a Glance, 28th Ed, Lippincott
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`Williams & Wilkins ©2006, pg. 359, 967-68, 1288 [Exh. 2007]
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`Webster 1995
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`Webster’s II New College Dictionary, Houghton Mifflin
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`Company, ©1995, pg. 194 [Exh. 2008]
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`Webster (2002)
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`Webster’s Third New International Dictionary of the English
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`Language Unabridged 388 (2002) [Exh. 1031]
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`AE
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`Adverse event
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`Amended
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`INOT22 Protocol after amendment of exclusion criteria
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`INOT22 Protocol
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`ix
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`Ex. 2019-0010
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`Abbreviation
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`EPD
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`FDA
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`IEC
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`iNO
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`
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`
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`Description
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`Earliest priority date
`
`U.S. Food & Drug Administration
`
`Independent Ethics Committee
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`Inhaled nitric oxide
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`INOT22 Study
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`A clinical trial, titled “Comparison of Supplemental Oxygen and
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`Nitric Oxide for Inhalation Plus Oxygen in the Evaluation of the
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`Reactivity of the Pulmonary Vasculature During Acute
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`Pulmonary Vasodilator Testing”
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`INOT22 Protocol Protocol for INOT22 Study
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`INOT22 Steering
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`A committee composed of “internationally recognized experts”
`
`Committee
`
`in pediatric heart and lung disease who designed the INOT22
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`IRB
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`LVD
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`NO
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`O2
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`Study
`
`Institutional review board
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`Left ventricular dysfunction
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`Nitric oxide
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`Oxygen
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`Original INOT22
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`INOT22 Protocol prior to amendment of exclusion criteria
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`Protocol
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`PCWP
`
`Pulmonary capillary wedge pressure
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`x
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`Ex. 2019-0011
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`Abbreviation
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`POSA
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`SAE
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`
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`
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`Description
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`Person of ordinary skill in the art
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`Serious adverse event
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`TAPVR
`
`Total anomalous pulmonary venous return
`
`Ikaria
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`Praxair
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`INO Therapeutics LLC, Patent Owner
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`Praxair Distribution, Inc., Petitioner
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`Exh. ___
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`This refers to the indicated exhibit
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`___:___
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`This refers to the indicated column or page and lines of the
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`patent or patent publication
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`xi
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`Ex. 2019-0012
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`Case IPR2015-00526
`U.S. Patent No. 8,795,741
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`INO Therapeutics LLC ( “Ikaria”) respectfully submits this Preliminary
`
`Response to the Petition of Praxair Distribution, Inc. (“Praxair”) seeking inter
`
`partes review (“IPR”) of U.S. Patent No. 8,795,741 (“the ’741 patent”).1
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`I.
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`INTRODUCTION
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`Praxair seeks to institute an IPR on the basis of obviousness of all claims
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`of the ’741 patent, which cover methods of safely administering inhaled nitric
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`oxide (“iNO”) to children or neonates with life threatening heart conditions by
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`excluding all children or neonates with left ventricular dysfunction (“LVD”)
`
`from iNO treatment. To institute an IPR, Praxair must show a reasonable
`
`
`
`1 Praxair has filed four other IPR petitions challenging Ikaria’s related patents,
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`including U.S. Patent No. 8,282,966 (“the ’966 patent”), which is the subject of
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`IPR2015-00522; U.S. Patent No. 8,293,284 (“the ’284 patent”), which is the
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`subject of IPR2015-00524; U.S. Patent No. 8,431,163 (“the ’163 patent”),
`
`which is the subject of IPR2015-00525; and U.S. Patent No. 8,846,112 (“the
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`’112 patent”), which is the subject of IPR2015-00529. The ’966, ’284, ’163,
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`’741, and ’112 patents issued from continuation or divisional applications
`
`claiming priority to U.S. Patent Application No. 12/494,598. Each was
`
`examined by the same examiner.
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`1
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`Ex. 2019-0013
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`Case IPR2015-00526
`U.S. Patent No. 8,795,741
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`likelihood of prevailing on invalidity. 35 U.S.C. § 314(a) (IPR may not be
`
`instituted absent “a reasonable likelihood that the petitioner would prevail”); see
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`also 37 C.F.R. § 42.108(c). Praxair’s petition does not establish even prima facie
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`obviousness, much less a likelihood of success.
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`Praxair’s petition wholly ignores the evidence submitted during
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`prosecution demonstrating that those of extraordinary skill in the art were
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`unaware that all children or neonates with LVD should be excluded from iNO
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`therapy, as required by the claims of the ’741 patent. As shown below, the
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`claimed invention was discovered in the course of a clinical trial, titled
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`“Comparison of Supplemental Oxygen and Nitric Oxide for Inhalation Plus
`
`Oxygen in the Evaluation of the Reactivity of the Pulmonary Vasculature
`
`During Acute Pulmonary Vasodilator Testing” (“INOT22 Study”). The
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`protocol for that clinical trial (“INOT22 Protocol”) was developed and
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`designed not by ordinary artisans, but by experts in the field. Additionally, the
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`INOT22 Protocol was reviewed by dozens of persons responsible for its safe
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`conduct. When it was commenced, an alarming portion of the pediatric
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`patients surprisingly developed serious adverse events (“SAE”), including
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`death, which caused a cessation of the trial. Based on an analysis of the
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`pediatric patients who had these SAEs, it was theorized that a reason some of
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`2
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`Ex. 2019-0014
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`U.S. Patent No. 8,795,741
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`them suffered SAEs was because they had LVD. The trial was reinitiated with
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`pediatric patients having LVD excluded, and the rate of SAEs was greatly
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`reduced. All of that evidence was before the Examiner.
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`Nowhere does Praxair discuss or address how the dozens of persons
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`involved with designing the trial – including leaders in the field – could have
`
`designed the trial without excluding those pediatric patients with LVD if it was
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`so obvious that they were at such serious risk. Indeed, a member of the
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`Steering Committee of the INOT22 Study stated that if it was so obvious to
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`exclude those patients, e.g., “babies,” then he would have had to act
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`“intentionally” to subject them to the serious harm they incurred in the study –
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`something he “most certainly” did not do and would not have done. (Exh.
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`1052 at 585, ¶8).
`
`Praxair’s Petition also fails as a matter of proof. First, the Board has
`
`denied petitions where the petitioner fails to identify prior art disclosing a claim
`
`limitation. Zetec, Inc. v. Westinghouse Elec. Co., LLC, IPR No. 2014-00384, Paper
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`10 at 14 (P.T.A.B. Jul. 23, 2014). Here, Praxair fails to cite to any prior art
`
`stating that all “children” or “neonates” having LVD should be “excluded” or
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`otherwise restricted from iNO therapy as recited by the claims of the ’741
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`patent. Instead, Praxair primarily relies on studies showing that adults with
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`3
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`Ex. 2019-0015
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`Case IPR2015-00526
`U.S. Patent No. 8,795,741
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`LVD should be excluded. But as the Examiner stated, iNO studies on adults
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`with LVD “cannot be generally extrapolated” to children or neonates with
`
`LVD. And as the prior art repeatedly states, “children should not be
`
`considered small adults.” (See, e.g., Exh. 1052 at 355; Exh. 2006 (Lipshultz) at 2).
`
`Second, the Board has denied petitions where the petitioner fails to
`
`support its assertions or relies on conclusory expert testimony. Mylan v. Gilead
`
`Sciences, Inc., IPR No. 2014-00888, Paper 15 at 11-12 (P.T.A.B. Dec. 9, 2014).
`
`Here, Praxair’s petition fails to support its assertions, and relies only on a
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`conclusory expert opinion as to the key exclusion claim element. Neither
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`Praxair nor its medical expert cite to any prior art literature stating or data
`
`showing that all children or neonates with LVD should have been excluded
`
`from iNO therapy.
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`Third, the Board has denied instituting IPRs where the petitioner does
`
`not address arguments made during prosecution or fails to provide arguments
`
`beyond those rejected during prosecution. Merial v. Virbac, IPR No. 2014-
`
`01279, Paper 13 at 8-9 (P.T.A.B. Jan. 22, 2015). Here, Praxair relies on the
`
`same cautionary statements relied on by the Examiner during prosecution,
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`which Ikaria successfully rebutted by submitting declarations explaining such
`
`cautions were irrelevant because, for example, they applied to adults, not
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`4
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`Ex. 2019-0016
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`Case IPR2015-00526
`U.S. Patent No. 8,795,741
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`children or neonates. Praxair’s petition, however, does not even mention
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`Ikaria’s evidence, let alone attempt to refute it. And, its expert admits that he
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`did not even review the ’741 file history (Exh. 1002 at 6-7, ¶12). As the Board
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`has ruled, Praxair should have addressed all of the evidence provided during
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`prosecution, and its failure to do so is not only a glaring hole in its proofs, but
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`also prejudicial to Ikaria.
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`Rather, Praxair’s petition is based on pure hindsight. This is
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`demonstrated by the fact that Praxair’s medical expert wrote prior art articles
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`regarding the use of iNO therapy in children or neonates, and not once did he
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`state that all children or neonates with LVD should be excluded from iNO
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`therapy.
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`Finally, objective evidence, including the undisputed fact that experts in
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`the field failed to recognize that children or neonates with LVD would suffer
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`serious adverse events from the use of iNO therapy, show that the claims are
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`not obvious. Those real-world facts, when considered as required, eliminate
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`any question that the claimed invention would not have been obvious to those
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`of ordinary skill in the art.
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`5
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`Ex. 2019-0017
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`Case IPR2015-00526
`U.S. Patent No. 8,795,741
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`II. BACKGROUND
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`A. The Development of the ’741 Patent
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`U.S. Patent No. 8,795,741, entitled “Methods for Treating Patients Who
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`are Candidates for Inhaled Nitric Oxide Treatment,” is directed to methods of
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`“reducing the risk that a medical treatment comprising inhalation of nitric
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`oxide gas will induce an increase in pulmonary capillary wedge pressure in the
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`patient, leading to pulmonary edema.” (Exh. 1001 at 1, Abstract). The
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`invention was the result of a discovery that occurred during the INOT22 Study,
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`which involved the administration of INOmax® (Ikaria’s inhaled nitric oxide
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`product) to pediatric patients between the ages of four weeks and 18 years.2
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`(Exh. 1001 at col. 9:35 -
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` 14:25; Exh. 1055 at 416, ¶5).
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`1.
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`The Original INOT22 Protocol Was Carefully
`Constructed and Reviewed, and Did Not Contain the
`Claimed Exclusion Criteria
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`The INOT22 Study was designed by a committee composed of
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`“internationally recognized experts” in pediatric heart and lung disease (“the
`
`
`2 INOmax® is an inhaled NO treatment that, among other things, improves
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`oxygenation, reduces the need for extracorporeal oxygenation and is indicated
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`for use with ventilatory support. (Exh. 1001, col. 3:42-45).
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`6
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`Ex. 2019-0018
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`Case IPR2015-00526
`U.S. Patent No. 8,795,741
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`INOT22 Steering Committee”), and Ikaria, the study sponsor.3 (Exh. 1052 at
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`912, ¶8). It was a randomized, multi-center study with approximately 18
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`clinical study sites. (Id. at 925, ¶5). The study compared the utility and side
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`effects of oxygen (O2), iNO and a combination of iNO and O2 for determining
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`pulmonary reactivity. (Id. at 912, ¶5; Exh. 1055 at 422). The original INOT22
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`protocol (“Original INOT22 Protocol”) (Exh. 1055 at 421-479) did not
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`exclude children with pre-existing LVD who were not dependent on right-to-
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`left shunting of blood. (Id. at 442; see also Exh. 1001 at col. 9:60 -
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` 10:5; Exh.
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`1052 at 913-14, ¶ 10).
`
`
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`3 The INOT22 Steering Committee included David L. Wessel, M.D., Professor
`
`of Anesthesiology and Critical Care Medicine and of Pediatrics at the George
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`Washington University (Exh. 1052 at 583-84, ¶¶1-4; 586-625); Robyn J. Barst,
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`M.D., Professor Emeritus of Pediatrics and Medicine, Columbia University
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`College of Physicians and Surgeons, New York; and Duncan J. Macrae, M.D.,
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`Director, Children’s Services, Consultant in Pediatric Critical Care at the Royal
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`Brompton Hospital, London, U.K. (Exh. 1052 at 633-34, ¶8; Exh. 1055 at
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`435).
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`7
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`Ex. 2019-0019
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`Case IPR2015-00526
`U.S. Patent No. 8,795,741
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`Prior to commencing the study, the Original INOT22 Protocol was
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`reviewed and approved by independent boards for each study site, as well as
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`U.S. and European regulatory agencies. In particular, the Institutional Review
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`Board (“IRB”) and/or Independent Ethics Committee (“IEC”) at each of the
`
`approximately 18 participating study institutions reviewed the Original
`
`INOT22 Protocol. (Exh. 1052 at 645-6, ¶8; Exh. 1055 at 557-58). Those
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`committees include practicing physicians and other knowledgeable individuals
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`whose role is “the protection of the rights and welfare of human research
`
`subjects.” (Exh. 1052 at 646, ¶9; 21 C.F.R. Part 56). Additionally, the U.S.
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`Food & Drug Administration (“FDA”) and four European National Health
`
`Authorities (United Kingdom, France, Netherlands and Spain), the European
`
`equivalents to the FDA, had the opportunity to review the Original INOT22
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`Protocol prior to study initiation. (Exh. 1052 at 645-46, ¶8). And, Ikaria
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`regularly requested input and scientific guidance on clinical trials from its own
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`Scientific Advisory Board. (Id.). In sum, more than a “hundred individuals
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`experienced in, and responsible for, the review of clinical trial protocols for
`
`patient safety,” evaluated the Original INOT22 protocol prior to its
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`commencement. (Exh. 1052 at 647, ¶11).
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`8
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`Ex. 2019-0020
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`Case IPR2015-00526
`U.S. Patent No. 8,795,741
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`Yet, at no time did: (i) any member of the INOT22 Steering Committee,
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`(ii) any member of an IRB, or IEC, (iii) any individual investigator, (iv) any
`
`representative of the FDA or the four European National Health Authorities,
`
`or (v) any member of Ikaria’s own Scientific Advisory Board ever appreciate,
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`recognize or suggest excluding subjects with LVD from the Original INOT22
`
`Protocol due to an increased risk of adverse events within such pediatric
`
`patients. (Exh. 1052 at 914-15, ¶12).
`
`2.
`
`Unanticipated Serious Adverse Events Initially
`Occurred During the INOT22 Study
`
`After initiation of the first 24 pediatric patients in the INOT22 Study,
`
`there were five SAEs, which was a rate much higher than the INOT22 Steering
`
`Committee and Ikaria expected. (Exh. 1052 at 915, ¶13). The SAEs were all
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`cardiovascular events, and included pulmonary edema, cardiac arrest and
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`hypotension (low blood pressure). (Id.). One baby who developed pulmonary
`
`edema died. (Exh. 1001 at col. 13:16-17).
`
`Analysis revealed some of the “patients suffering [SAEs] had severe
`
`[LVD], largely due to viral cardiomyopathy, and exhibited during their right-
`
`sided cardiac catheterizations an increased pulmonary capillary wedge pressure
`
`(“PCWP”) of greater than 20 mm Hg, indicative of elevated pressures in the
`
`upper chamber of the left side of the hear (the left atrium).” (Exh. 1052 at 968,
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`9
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`Ex. 2019-0021
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`U.S. Patent No. 8,795,741
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`¶21). After these unexpected SAEs occurred, the study protocol was amended
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`(“Amended INOT22 Protocol” (Exh. 1055 at 482-542)) to exclude patients
`
`who had pre-existing LVD, i.e., those having a PCWP greater than 20 mm Hg.
`
`(Exh. 1052 at 915-16, ¶14; Exh. 1055 at 502).
`
`3.
`
`Based on the Unexpected Serious Adverse Events
`Early in the Trial the INOT22 Protocol Was Amended
`and the Rate of SAEs Was Significantly Reduced
`
`Following the change in protocol, “the rate of SAEs (including SAEs
`
`associated with heart failure) was significantly reduced.” (Exh. 1052 at 916,
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`¶15). Whereas five SAEs were reported in the first 24 patients before the
`
`amended exclusion criteria, only two SAEs were reported in the last 80 patients
`
`after the amendment. (Id.). “As a result of the INOT22 study, it was
`
`recognized that a second population of neonates existed . . . that had an
`
`increased risk of adverse events when inhaled NO was administered, namely:
`
`pediatric patients with left ventricular dysfunction . . .” (Id. at 561, ¶11).
`
`Given the significance of the difference in the pre- and post-protocol-
`
`amendment SAE frequencies, on February 25, 2009, Ikaria submitted to the
`
`FDA a change to the INOmax® label, which included a warning that the use
`
`of iNO in patients with pre-existing LVD could cause SAEs, such as
`
`10
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`Ex. 2019-0022
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`Case IPR2015-00526
`U.S. Patent No. 8,795,741
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`pulmonary edema. The FDA agreed and approved the labeling supplement on
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`August 28, 2009. (Id. at 916, ¶¶16-17).
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`B. The ’741 Prosecution History
`
`Based on this surprising discovery, on June 30, 2009, Ikaria filed U.S.
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`Patent Application No. 12/494,598, which issued as the ’741 patent from a
`
`continuation Application No. 13/683,417 (“the ’417 Application”). (Exh.
`
`1001, col. 1:8-16).
`
`1.
`
`The PTO Considered Many References
`
`The claims of the ’741 patent were extensively reviewed. The Examiner
`
`specifically considered over 200 references and the file histories of the ’966 and
`
`’284 patents, prior to allowance of the claims. (See, e.g., Exh. 1055 at 225-265,
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`269-275, 278-280, 323-325, 327-333, 366, 645, 649-651, 655-659672). To the
`
`extent that Praxair cites different references, they fail to add any new
`
`information to that considered by the Examiner.
`
`Among the references considered by the Examiner, the following are
`
`also relied on explicitly by Praxair in its petition:
`
`• Exh. 1006 (“Loh”);
`
`• Exh. 1008 (“Macrae”)
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`• Exh. 1030 (“Henrichsen”);
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`11
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`Ex. 2019-0023
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`U.S. Patent No. 8,795,741
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`• Exh. 1009 (“Ichinose”);
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`• Exh. 1014 (“INOmax® label”);
`
`• Exh. 1005 (“Davidson”); and
`
`• Exh. 1011 (“Neonatal Group”).
`
`(See, e.g., Id. at 228, 235, 263, 330, 331, 670).
`
`Praxair also relies on Bernasconi (Exh. 1004) in its petition. Although the
`
`Examiner did not explicitly consider Bernasconi, ten of the thirteen references
`
`cited in Bernasconi’s LVD section relied on by Praxair were considered by the
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`Examiner (id. at 8, references 103-115): Exh. 1006 (“Loh”), Exh. 2003 (“Adatia
`
`”); Kieler-Jensen et al., J Heart Lung Transplant., 1994, 13, 366–75 (“Kieler-
`
`Jensen”); Semigran et al., J Am Coll Cardiol., 1994, 24,982–88 (“Semigran”);
`
`Hayward et al., J Cardiovasc Pharmacol., 1996, 27, 80–85 (“Hayward (1996)”);
`
`Exh. 2004 (“Beghetti (1997)”); Exh. 2005 (“Rosales”); Argenziano et al., J Thorac
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`Cardiovasc Surg., 1998, 115, 700–08 (“Argenziano”); Hayward et al., J Am Coll
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`Cardiol., 1997, 30, 49–56 (“Hayward (1997)”