Paper No. ____
`Date Filed: May 6, 2015
`
`
`
`
`
`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 IPR2015-00529
`U.S. Patent No. 8,846,112
`________________
`
`
`
`PRELIMINARY RESPONSE BY
`PATENT OWNER PURSUANT TO 37 C.F.R. § 42.107
`
`Ex. 2019-0001
`
`
`Date Filed: May 6, 2015
`
`
`
`
`
`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 IPR2015-00529
`U.S. Patent No. 8,846,112
`________________
`
`
`
`PRELIMINARY RESPONSE BY
`PATENT OWNER PURSUANT TO 37 C.F.R. § 42.107
`
`Ex. 2019-0001
`
`
`
`
`
`
`I.
`
`II.
`
`
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`BACKGROUND ............................................................................................. 6
`
`A.
`
`The Development of the ’112 Patent .................................................... 6
`
`1.
`
`2.
`
`3.
`
`The Initial INOT22 Protocol Was Carefully
`Constructed and Reviewed, and Did Not Contain
`the Claimed Exclusion Criteria ................................................... 7
`
`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 ’112 Patent Prosecution History .................................................. 11
`
`1.
`
`2.
`
`The PTO Considered Many References ................................... 11
`
`Praxair Relies on the Same Statements Ikaria
`Overcame During Prosecution .................................................. 13
`
`C.
`
`The ’112 Patent Claims ....................................................................... 19
`
`III.
`
`PERSON OF ORDINARY SKILL ............................................................... 20
`
`IV. CLAIM CONSTRUCTION .......................................................................... 20
`
`V.
`
`LEGAL STANDARD ................................................................................... 22
`
`VI. A SKILLED ARTISAN WOULD NOT HAVE BEEN
`MOTIVATED TO EXCLUDE NEONATES HAVING LVD
`OR REASONABLY EXPECT THOSE NEONATES WOULD
`HAVE EXPERIENCED SAES ..................................................................... 26
`
`A.
`
`There was no motivation to implement the claimed
`exclusion based on studies with adults because left
`
`i
`
`Ex. 2019-0002
`
`
`
`
`
`
`
`
`
`
`ventricular dysfunction in neonates is much different than
`in adults ............................................................................................... 28
`
`B.
`
`A skilled artisan would not have reasonably expected that
`the claimed excluded neonates would have SAEs as
`initially occurred in the INOT22 Study .............................................. 31
`
`VII. GROUND 1: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`BERNASCONI IN COMBINATION WITH INOMAX® LABEL,
`LOH AND GOYAL ........................................................................................ 34
`
`A.
`
`B.
`
`C.
`
`Praxiar fails to show that Bernasconi, the INOmax®
`label, Loh or Goyal teaches to avoid or discontinue iNO
`treatment in the neonates with LVD ................................................... 35
`
`Praxair’s Assertions that “warnings” in the art are
`applicable to the claimed exclusion criteria are
`unsupported ......................................................................................... 43
`
`Praxair fails to raise any new arguments or supplement
`the record to address issues overcome during prosecution ................. 46
`
`VIII. GROUND 2: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`ICHINOSE IN COMBINATION WITH INOMAX® LABEL¸
`NEONATAL GROUP, LOH, AND GOYAL .................................................. 49
`
`IX. PRAXAIR FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD OF SUCCESS TO COUNTER THE
`OBJECTIVE EVIDENCE OF UNEXPECTED RESULTS ......................... 51
`
`X.
`
`CONCLUSION .............................................................................................. 53
`
`
`
`ii
`
`Ex. 2019-0003
`
`
`
`
`
`
`Cases
`
`
`
`
`
`TABLE OF AUTHORITIES
`
`Apple, Inc. v. ITC,
`725 F.3d 13256 (Fed. Cir. 2013) ...................................................................53
`
`Ashland Oil, Inc. v. Delta Resins & Refractories, Inc.,
`776 F.2d 281 (Fed. Cir. 1985) .......................................................................46
`
`CCS Fitness, Inc. v. Brunswick Corp.,
`288 F.3d 1359 (Fed. Cir. 2002) .....................................................................21
`
`Graham v. John Deere Co.,
`383 U.S. 1 (1966) .................................................................................... 23, 53
`
`In re Cuozzo Speed Tech. LLC,
`No. 14-1301 (Fed. Cir. Feb. 4, 2015) ............................................................21
`
`In re Dembiczak,
`175 F.3d 994 (Fed. Cir. 1999) .......................................................................24
`
`Insite Vision Inc., et al. v. Sandoz, Inc.,
`2014-1065 (Fed. Cir. April 19, 2015) ............................................................47
`
`KSR Int'l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007).......................................................................... 23, 24, 53
`
`Leo Pharmaceutical Products, Ltd v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) .............................................................. 23, 34
`
`Phillips v. AWH Corp.,
`415 F.3d 1303 (Fed. Cir. 2005) .....................................................................21
`
`Rohm and Haas Co. v. Brotech Corp.,
`127 F.3d 1089 (Fed. Cir. 1997) .....................................................................46
`
`Statutes
`
`35 U.S.C. § 103 ........................................................................................... 24, 35, 50
`
`35 U.S.C. § 103(a) ...................................................................................................23
`
`35 U.S.C. § 314(a) ...............................................................................................2, 22
`
`iii
`
`Ex. 2019-0004
`
`
`
`
`
`35 U.S.C. § 325(d) ...................................................................................................47
`
`
`
`
`
`Regulations
`
`37 C.F.R. § 42.1(b) ..................................................................................................49
`
`37 C.F.R. § 42.100(b) ..............................................................................................21
`
`37 C.F.R. § 42.104(b)(4) ................................................................................... 24, 41
`
`37 C.F.R. § 42.108(c) ...........................................................................................2, 22
`
`37 C.F.R. § 42.6(a)(3) ..............................................................................................45
`
`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) ............... 25, 40, 41
`
`Integrated Global Concepts, Inc., v. Advanced Messaging Tech., Inc.,
`IPR No. 2014-01027, Paper 16 (P.T.A.B. Dec. 22, 2014) ............... 25, 42, 54
`
`Merial v. Virbac,
`IPR No. 2014-01279, Paper 13 at 8-9 (P.T.A.B. Jan. 22, 2015) ........... passim
`
`Mylan Pharma. Inc. v. Gilead Sciences, Inc.,
`IPR No. 2014-00885, Paper 15 (P.T.A.B. Dec. 9, 2014) ..............................45
`
`Mylan v. Gilead Sciences, Inc.,
`IPR No. 2014-00888, Paper 15 (P.T.A.B. Dec. 9, 2014) ..........................4, 25
`
`Tempur Sealy Int’l v. Select Comfort Corp.,
`IPR No. 2014-01419, Paper 7 (P.T.A.B. Feb. 17, 2015)...............................45
`
`Zetec, Inc. v. Westinghouse Elec. Co., LLC,
`IPR No. 2014-00384, Paper 10 (P.T.A.B. Jul. 23, 2014) ............. 4, 25, 40, 41
`
`
`
`iv
`
`
`
`Ex. 2019-0005
`
`
`
`
`
`
`
`
`
`
`Abbreviation
`
`TABLE OF ABBREVIATIONS
`
`
`Description
`
`’112 patent
`
`U.S. Patent No. 8,846,112
`
`’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
`
`’741 patent
`
`U.S. Patent No. 8,795,741
`
`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
`
`v
`
`Ex. 2019-0006
`
`
`
`
`
`
`
`
`
`
`Abbreviation
`
`Description
`
`paediatric practice”, 4: 4-29, Images Paediatr. Cardiol., 2002
`
`[Exh. 1004]
`
`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]
`
`vi
`
`Ex. 2019-0007
`
`
`
`
`
`
`
`
`
`
`Abbreviation
`
`Description
`
`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
`
`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,
`
`vii
`
`Ex. 2019-0008
`
`
`
`
`
`
`
`
`
`
`Abbreviation
`
`Description
`
`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 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]
`
`Stedman’s 2006
`
`Stedman’s Medical Dictionary at a Glance, 28th Ed, Lippincott
`
`Williams & Wilkins ©2006, pg. 359, 967-68, 1288
`
`[Exh. 2007]
`
`viii
`
`Ex. 2019-0009
`
`
`
`
`
`
`
`
`
`
`Abbreviation
`
`Description
`
`Webster 1995
`
`Webster’s II New College Dictionary, Houghton Mifflin
`
`Company, ©1995, pg. 194 [Exh. 2008]
`
`Webster (2002) Webster’s Third New International Dictionary of the English
`
`Language Unabridged 388 (2002) [Exh. 1031]
`
`AE
`
`Adverse event
`
`Amended
`
`INOT22 Protocol after amendment of exclusion criteria
`
`INOT22 Protocol
`
`EPD
`
`FDA
`
`IEC
`
`iNO
`
`Earliest priority date
`
`U.S. Food & Drug Administration
`
`Independent Ethics Committee
`
`Inhaled nitric oxide
`
`INOT22 Study
`
`A clinical trial, titled “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 Protocol Protocol for INOT22 Study
`
`INOT22 Steering
`
`A committee composed of “internationally recognized experts”
`
`Committee
`
`in pediatric heart and lung disease who designed the INOT22
`
`ix
`
`Ex. 2019-0010
`
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`
`
`
`
`
`
`
`
`Abbreviation
`
`Description
`
`IRB
`
`LVD
`
`NO
`
`O2
`
`Study
`
`Institutional review board
`
`Left ventricular dysfunction
`
`Nitric oxide
`
`Oxygen
`
`Original INOT22
`
`INOT22 Protocol prior to amendment of exclusion criteria
`
`Protocol
`
`PCWP
`
`POSA
`
`SAE
`
`Pulmonary capillary wedge pressure
`
`Person of ordinary skill in the art
`
`Serious adverse event
`
`TAPVR
`
`Total anomalous pulmonary venous return
`
`Ikaria
`
`Praxair
`
`INO Therapeutics LLC, Patent Owner
`
`Praxair Distribution, Inc., Petitioner
`
`Exh. ___
`
`This refers to the indicated exhibit
`
`___:___
`
`This refers to the indicated column or page and lines of the
`
`patent or patent publication
`
`
`
`
`
`x
`
`Ex. 2019-0011
`
`
`
`
`
`
` Case IPR2015-00529
`
` U.S. Patent No. 8,846,112
`
`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. 8,846,112 (“the ’112
`
`patent”).1
`
`I.
`
`INTRODUCTION
`
`Praxair seeks to institute an IPR on the basis of obviousness of all
`
`claims of the ’112 patent, which cover methods of safely administering
`
`inhaled nitric oxide (“iNO”) to neonates with life threatening heart
`
`conditions by avoiding or discontinuing iNO treatment of all neonates with
`
`
`
`1 Praxair has filed four other IPR petitions challenging Ikaria’s related
`
`patents, including U.S. Patent No. 8,282,966 (“the ’966 patent”), which is
`
`the subject of IPR2015-00522; U.S. Patent No. 8,293,284 (“the ’284
`
`patent”), which is the 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. 8,795,741 (“the ’741 patent”), which is the subject of IPR2015-00526.
`
`The ’112, ’284, ’966, ’163, ’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.
`
`1
`
`
`Ex. 2019-0012
`
`
`
`
`
`
` Case IPR2015-00529
`
` U.S. Patent No. 8,846,112
`
`left ventricular dysfunction (“LVD”). To institute an IPR, Praxair must
`
`show a reasonable 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 also 37 C.F.R. § 42.108(c). Praxair’s petition does not
`
`establish even prima facie obviousness, much less a likelihood of success.
`
`Praxair’s petition wholly ignores the evidence submitted during
`
`prosecution demonstrating that those of extraordinary skill in the art were
`
`unaware that iNO treatment should be avoided or discontinued in all
`
`neonates with LVD, as required by the claims of the ’112 patent. As shown
`
`below, the claimed invention was discovered in the course of a clinical trial,
`
`titled “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 protocol for that clinical trial (“INOT22 Protocol”) was
`
`developed and designed not by ordinary artisans, but by experts in the field.
`
`Additionally, the INOT22 Protocol was reviewed by dozens of persons
`
`responsible for its safe conduct. When it was commenced, an alarming
`
`portion of the pediatric patients surprisingly developed serious adverse
`
`events (“SAE”), including death, which caused a cessation of the trial.
`
`2
`
`
`Ex. 2019-0013
`
`
`
`
`
`
` Case IPR2015-00529
`
` U.S. Patent No. 8,846,112
`
`Based on an analysis of the pediatric patients who had these SAEs, it was
`
`theorized that a reason some of them suffered SAEs was because they had
`
`LVD. The trial was reinitiated with pediatric patients excluded, and the rate
`
`of SAEs was greatly reduced. All of that evidence was before the Examiner.
`
`Nowhere does Praxair discuss or address how the dozens of persons
`
`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 so obvious that they were at such serious risk. Indeed, a member of the
`
`Steering Committee of the INOT22 Study stated during prosecution that if it
`
`was so obvious to exclude those infant subjects, e.g., “babies,” then he
`
`would have had to act “intentionally” to subject them to the serious harm
`
`they incurred in the study – something he “most certainly” did not do and
`
`would not have done. (Exh. 2013 at 114, ¶ 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
`
`claim limitation. Zetec, Inc. v. Westinghouse Elec. Co., LLC, IPR No. 2014-
`
`00384, Paper 10 at 14 (P.T.A.B. Jul. 23, 2014). Here, Praxair fails to cite to
`
`any prior art stating that iNO treatment should be avoided or discontinued (if
`
`pulmonary edema occurs) in neonates with LVD. Instead, Praxair primarily
`
`3
`
`
`Ex. 2019-0014
`
`
`
`
`
`
` Case IPR2015-00529
`
` U.S. Patent No. 8,846,112
`
`relies on studies showing that adults with LVD should be excluded. But as
`
`the Examiner stated, iNO studies on adults with LVD “cannot be generally
`
`extrapolated” to neonates with LVD. And as the prior art repeatedly states,
`
`“children should not be considered small adults.” (See, e.g., 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 conclusory expert opinion as to the key claim element.
`
`Neither Praxair, nor its medical expert, cite to any prior art literature stating
`
`or data showing that iNO therapy should be avoided or discontinued in all
`
`neonates with LVD.
`
`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, which Ikaria successfully rebutted by submitting declarations
`
`4
`
`
`Ex. 2019-0015
`
`
`
`
`
`
` Case IPR2015-00529
`
` U.S. Patent No. 8,846,112
`
`explaining such “cautions” were irrelevant because, for example, they
`
`applied to adults, not neonates. Praxair’s petition, however, does not even
`
`mention Ikaria’s evidence, let alone attempt to refute it. And, its expert
`
`admits that he did not even review the ’112 file history or any of the file
`
`histories of the related patents. As the Board has ruled, Praxair should have
`
`addressed all of the evidence provided during prosecution, and its failure to
`
`do so is not only a glaring hole in its proofs, but also prejudicial to Ikaria.
`
`Rather, Praxair’s petition is based on pure hindsight. This is
`
`demonstrated by the fact that Praxair’s medical expert wrote prior art articles
`
`regarding the use of iNO therapy with neonates, and not once did he state
`
`that iNO therapy should be avoided or discontinued in all neonates with
`
`LVD.
`
`Finally, objective evidence, including the undisputed fact that experts
`
`in the field failed to recognize that neonates with LVD would suffer serious
`
`adverse events from the use of iNO therapy, shows that the claims are not
`
`obvious. Those real-world facts, when considered as required, eliminate any
`
`question that the claimed invention would not have been obvious to those of
`
`ordinary skill in the art.
`
`5
`
`
`Ex. 2019-0016
`
`
`
`
`
`
` Case IPR2015-00529
`
` U.S. Patent No. 8,846,112
`
`II. BACKGROUND
`
`A. The Development of the ’112 Patent
`
`U.S. Patent No. 8,846,112, entitled “Methods of Distributing a
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`Pharmaceutical Product Comprising Nitric Oxide Gas for Inhalation,” is
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`directed to methods of providing nitric oxide gas (or a device that delivers
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`nitric oxide gase) to a “medical provider responsible for treating neonates
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`who have hypoxic respiratory failure” comprising providing information
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`sufficient to cause a medical provider “to elect to avoid treating” neonates
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`with preexisting [LVD] with iNO or to discontinue such treatment based on
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`the risk of an adverse event (“AE”) or an SAE associated with the treatment.
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`(Exh. 1001 at col. 14:27-67; col. 15:43-67). The invention was the result of
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`a discovery that occurred during the INOT22 Study, which involved the
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`administration of INOmax® (Ikaria’s inhaled nitric oxide product) to
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`pediatric patients.2 (Exh. 1001 at col. 9:35-col. 14-25).
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`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
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`indicated for use with ventilatory support. (Exh. 1001, col. 3:42-45).
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`6
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`Ex. 2019-0017
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` Case IPR2015-00529
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` U.S. Patent No. 8,846,112
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`1.
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`The Initial 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
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`INOT22 Steering Committee”), and Ikaria, the study sponsor.3 (Exh. 1056
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`at 663, ¶ 8). It was a randomized, multi-center study with 18 clinical study
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`sites. (Exh. 1001 at col. 9:57-59; Exh. 1056 at 508). The study compared
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`the utility and side effects of oxygen (O2), iNO and a combination of iNO
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`and O2 for determining pulmonary reactivity. (Exh. 1001 at col. 10:14-16).
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`The Original INOT22 Protocol (“Original INOT22 Protocol”) did not
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`exclude pediatric patients with pre-existing LVD who were not dependent
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`
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`3 The INOT22 Steering Committee included David L. Wessel, M.D.,
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`Professor of Anesthesiology and Critical Care Medicine and of Pediatrics at
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`the George Washington University; Robyn J. Barst, M.D., Professor
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`Emeritus of Pediatrics and Medicine, Columbia University College of
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`Physicians and Surgeons, New York; and Duncan J. Macrae, M.D., Director,
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`Children’s Services, Consultant in Pediatric Critical Care at the Royal
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`Brompton Hospital, London, U.K. (Exh. 1056 at 663, ¶ 8; id. at 448).
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`7
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`Ex. 2019-0018
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` Case IPR2015-00529
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` U.S. Patent No. 8,846,112
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`on right-to-left shunting of blood. (Exh. 1001 at col. 9: 59-66; Exh. 1056 at
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`487).
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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
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`Review Board (“IRB”) and/or Independent Ethics Committee (“IEC”) at
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`each of the approximately 18 participating study institutions reviewed the
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`Original INOT22 Protocol. (Exh. 1056 at 446, 471, 664, ¶ 11). Those
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`committees include practicing physicians and other knowledgeable
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`individuals whose role is “the protection of the rights and welfare of human
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`research subjects.” (Id. at 665, ¶ 12). Additionally, the U.S. Food & Drug
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`Administration (“FDA”) and four European National Health Authorities
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`(United Kingdom, France, Netherlands and Spain), the European equivalents
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`to the FDA, had the opportunity to review the Original INOT22 Protocol
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`prior to study initiation. (Id. at 664-66, ¶¶ 11-14). And, Ikaria regularly
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`requested input and scientific guidance on clinical trials from its own
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`Scientific Advisory Board. (Id. at 664-65, ¶ 11). In sum, more than a
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`“hundred individuals experienced in, and responsible for, the review of
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`8
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`Ex. 2019-0019
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` Case IPR2015-00529
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` U.S. Patent No. 8,846,112
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`clinical trial protocols for patient safety,” evaluated the Original INOT22
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`Protocol prior to its commencement. (Id. at 665-66, ¶ 14).
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`Yet, at no time did: (i) any member of the INOT22 Steering
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`Committee, (ii) any member of an IRB or IEC, (iii) any individual
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`investigator, (iv) any representative of the FDA or the four European
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`National Health Authorities, or (v) any member of Ikaria’s own Scientific
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`Advisory Board ever appreciate, recognize or suggest avoiding or
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`discontinuing iNO treatment in pediatric patients with LVD due to an
`
`increased risk of adverse events. (Id.).
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`2.
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`Unanticipated Serious Adverse Events Initially
`Occurred During the INOT22 Study
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`After initiation of the first 24 subjects in the INOT22 Study, there
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`were five SAEs, which was a rate much higher than the INOT22 Steering
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`Committee and Ikaria expected. (Id. at 666, ¶ 15). 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
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`pulmonary edema died. (Exh. 1001, col. 13:5-26).
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`Analysis revealed some of the “patients suffering [SAEs] had severe
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`[LVD], largely due to viral cardiomyopathy, and exhibited during their right-
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`9
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`Ex. 2019-0020
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` Case IPR2015-00529
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` U.S. Patent No. 8,846,112
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`sided cardiac catheterizations an increased pulmonary capillary wedge
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`pressure (“PCWP”) of greater than 20 mm Hg, indicative of elevated
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`pressures in the upper chamber of the left side of the heart (the left atrium).”
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`(Exh. 2013 at 96, ¶ 21). After these unexpected SAEs occurred, the study
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`protocol was amended to exclude patients who had pre-existing LVD, i.e.,
`
`those having a PCWP greater than 20 mm Hg. (Exh. 1056 at 666, ¶¶ 15, 16).
`
`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. 1056 at 667,
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`¶ 17). Whereas five SAEs were reported in the first 24 patients before the
`
`amended exclusion criteria, only two SAEs were reported in the last 100
`
`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,
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`namely: pediatric patients with left ventricular dysfunction . . .” (Exh. 2013
`
`at 159, ¶ 11). Given the significance of the difference in the pre- and post-
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`protocol-amendment SAE frequencies, on February 25, 2009, Ikaria
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`10
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`Ex. 2019-0021
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` Case IPR2015-00529
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` U.S. Patent No. 8,846,112
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`submitted to the FDA a change to the INOmax® label, which included a
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`warning that the use of iNO in patients with pre-existing LVD could cause
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`SAEs, such as pulmonary edema. The FDA agreed and approved the
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`labeling supplement on August 28, 2009. (Exh. 1056 at 667-68, ¶18).
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`B.
`
`The ’112 Patent Prosecution History
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`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 ’112 patent from a
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`division Application No. 13/683,236. (Exh. 1001 at col. 1:9-17).
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`1.
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`The PTO Considered Many References
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`The claims of the ’112 patent were extensively reviewed. The
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`Examiner specifically addressed 10 references, and considered over 200
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`references, prior to allowance of the claims. (Exh. 1056 at 228-58, 266-74,
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`331-43, 695-731, 773-74). To the extent that Praxair cites different
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`references, they fail to add any new information to that considered by the
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`Examiner.
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`Among the references considered by the Examiner, the following are
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`also relied on by Praxair in its petition:
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`• Exh. 1004 (“Bernasconi”);
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`11
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`Ex. 2019-0022
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` Case IPR2015-00529
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` U.S. Patent No. 8,846,112
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`• Exh. 1005 (“Davidson”);
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`• Exh. 1006 (“Loh”);
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`• Exh. 1008 (“Macrae”);
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`• Exh. 1009 (“Ichinose”);
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`• Exh. 1014 (“INOmax® label”);
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`• Exh. 1011 (“Neonatal Group”); and
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`• Exh. 1030 (“Henrichsen”).
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`(See e.g., Exh. 1056 at 231-38, 271, 329-35, 698, 703-04, 707-09, 723, 727 ).
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`Praxair relies heavily on Bernasconi (Exh. 1004) in its petition.
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`Further, ten of the thirteen references cited in Bernasconi’s LVD section
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`explicitly relied on by Praxair were considered by the Examiner (Exh. 1004,
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`p. 8, references 103-115): Loh (Exh. 1006), Adatia et al, J Am Coll Cardiol.,
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`1995, 25, 1656-64 (“Adatia”); Kieler-Jensen et al., J Heart Lung Transplant.,
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`1994, 13, 366-75 (“Kieler-Jensen”); Semigran et al., J Am Coll Cardiol.,
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`1994, 24,982-88 (“Semigran”); Hayward et al., J Cardiovasc Pharmacol.,
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`1996, 27, 80-85 (“Hayward (1996)”); Beghetti et al., J Pediatr., 1997, 130,
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`844 (“Beghetti (1997)”); Rosales et al., Pediatr Cardiol., 1999, 20, 224-26
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`(“Rosales”); Argenziano et al., J Thorac Cardiovasc Surg., 1998, 115, 700-
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`08 (“Argenziano”); Hayward et al., J Am Coll Cardiol., 1997, 30, 49-56
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`12
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`Ex. 2019-0023
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` Case IPR2015-00529
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` U.S. Patent No. 8,846,112
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`(“Hayward (1997)”); and Hayward et al., J Cardiovasc Pharmacol., 1999,
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`34, 749-54 (“Hayward (1999)”). (See, e.g., Exh. 1056 at 230, 237, 245-46,
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`268-69, 728). And references cited in these references were also considered
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`by the Examiner, including, for instance, Bocchi et al., Am. J. Cardiol.,
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`1994, 74, 70-4 (“Bocchi”), cited in Adatia. (Id. at 269).4 Thus, Bernasconi,
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`which itself was considered by the Examiner during the prosecution of the
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`’112 patent, is merely cumulative of prior art considered by the Examiner.
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`2.
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`Praxair Relies on the Same Statements Ikaria
`Overcame During Prosecution
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`The Examiner considered the same cautionary statements regarding
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`use of iNO that are now relied on by Praxair. (See, e.g., Petition at 11, 14,
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`22, 24, 42, 48, 50, 51). For example, the Examiner stated: (1) Bernasconi
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`“warn[s] of the negative effects of [iNO] in patients with [LVD] leading to
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`4 The three references cited in the LVD section of Bernasconi that were not
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`cited during prosecution of the ’112 patent add nothing to Praxair’s
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`assertions. As discussed below (infra, Section VIIA), these references were
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`directed to adults or animal models.
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`13
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`Ex. 2019-0024
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` Case IPR2015-00529
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` U.S. Patent No. 8,846,112
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`pulmonary edema;” (2) VasoKINOX, which is a gas mixture composed of
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`450 ppm mol/mol, compressed nitric oxide and nitrogen and indicated for
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`use in adults, newborn infants, infants, toddlers, children and adolescents
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`ages 0-17 years, is contraindicated for LVD and “warns of the risk of
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`pulmonary edema;” and (3) Loh teaches that “[iNO] in patients with LVD
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`can increase [PCWP]” and “more severe [LVD] was present in the patients
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`who had the largest increases in [PCWP] with [iNO].” (Exh.
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