`
`
`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 IPR2015-00525
`U.S. Patent No. 8,431,163
`
`
`
`PRELIMINARY RESPONSE BY
`PATENT OWNER PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`

`

`
`
`
`I.
`
`II.
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 2
`
`BACKGROUND ............................................................................................. 6
`
`A.
`
`The Development of the ’163Patent ..................................................... 6
`
`1.
`
`2.
`
`3.
`
`The Original 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 ’163 Patent Prosecution History .................................................. 11
`
`1.
`
`2.
`
`The PTO Considered Many References ................................... 11
`
`Praxair Relies on the Same Statements Ikaria
`Overcame During Prosecution .................................................. 13
`
`a.
`
`b.
`
`References Relating to (1) Adult Studies or
`(2) Studies in Neonates Dependent on Right-
`to-Left Shunting Are Not Relevant to the
`Invention ......................................................................... 16
`
`Had It Been Known or Suggested that the
`Claimed Excluded Group Would Have Had
`Such SAEs, Including Death, It Would Have
`Been Negligent To Include Those Patients
`In The Initial INOT22 Study .......................................... 18
`
`C.
`
`The ’163 Patent Claims ....................................................................... 20
`
`III.
`
`PERSON OF ORDINARY SKILL ............................................................... 21
`
`IV. CLAIM CONSTRUCTION .......................................................................... 21
`
`i
`
`

`

`
`
`V.
`
`LEGAL STANDARD ................................................................................... 23
`
`VI. A SKILLED ARTISAN WOULD NOT HAVE BEEN
`MOTIVATED TO EXCLUDE NEONATES HAVING LVD
`AND NOT DEPENDENT ON RIGHT-TO-LEFT SHUNTING
`OR REASONABLY EXPECT THOSE NEONATES WOULD
`HAVE EXPERIENCED SAES ..................................................................... 27
`
`A.
`
`B.
`
`There was No Motivation to Implement the Claimed
`Exclusion Based on Studies with Adults Because Left
`Ventricular Dysfunction in Neonates is Much Different
`Than in Adults ..................................................................................... 29
`
`A Skilled Artisan Would Not Have Reasonably Expected
`that the Claimed 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 THE INOMAX®
`LABEL, LOH AND GOYAL .......................................................................... 35
`
`A.
`
`B.
`
`C.
`
`D.
`
`Praxiar Fails to Show that Bernasconi, the INOmax®
`label, Loh or Goyal Include the Claimed Exclusion
`Criteria ................................................................................................. 37
`
`Praxair’s Assertions that Warnings in the Prior Art are
`Applicable to the Claimed Exclusion Criteria are
`Unsupported. ....................................................................................... 45
`
`Praxair Fails to Raise Any New Arguments or
`Supplement the Record to Address Issues Overcome
`During Prosecution .............................................................................. 47
`
`Praxair Fails to Show that Elements in Dependent Claims
`4, 9, 15, 18 and 23 are Present in the Prior Art ................................... 50
`
`VIII. GROUND 2: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`BERNASCONI IN COMBINATION WITH THE INOMAX®
`LABEL, LOH, GOYAL AND MACRAE ........................................................ 51
`
`ii
`
`

`

`
`
`IX. GROUND 3: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`ICHINOSE IN COMBINATION WITH NEONATAL GROUP,
`MACRAE, LOH, GOYAL AND GERMANN ................................................. 53
`
`X.
`
`PRAXAIR FAILS TO DEMONSTRATE A REASONABLE
`LIKELIHOOD OF SUCCESS TO COUNTER THE
`OBJECTIVE EVIDENCE OF UNEXPECTED RESULTS ......................... 55
`
`XI. CONCLUSION .............................................................................................. 57
`
`
`
`iii
`
`

`

`
`
`
`
`Cases
`
`TABLE OF AUTHORITIES
`
`Apple, Inc. v. ITC,
`725 F.3d 1356 (Fed. Cir. 2013) .....................................................................55
`
`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) .....................................................................22
`
`Graham v. John Deere Co.,
`383 U.S. 1, 17 (1966).............................................................................. 23, 56
`
`In re Cuozzo Speed Tech. LLC,
`No. 14-1301, slip op. at 18-19 (Fed. Cir., 2015) .................................... 21, 22
`
`In re Dembiczak,
`175 F.3d 994 (Fed. Cir. 1999), abrogated on other grounds by
`In re Gartside, 203 F.3d 1305 (Fed. Cir. 2000) ............................................24
`
`Insite Vision Inc., et al. v. Sandoz, Inc.,
`2014-1065 (Fed. Cir. 2015) ...........................................................................46
`
`KSR Int’l Co. v. Teleflex Inc.,
`550 U.S. 398 (2007)................................................................................ 24, 56
`
`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) .....................................................................22
`
`Rohm and Haas Co. v. Brotech Corp.,
`127 F.3d 1089 (Fed. Cir. 1997) .....................................................................45
`
`Statutes
`
`35 U.S.C. § 103 ............................................................................... 23, 24, 35, 51, 53
`
`35 U.S.C. § 103(a) ............................................................................................ 23, 24
`
`iv
`
`

`

`
`
`
`35 U.S.C. § 314(a) ...............................................................................................2, 23
`
`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) ............................................................................. 25, 41, 42
`
`37 C.F.R. § 42.108(c) ...........................................................................................2, 23
`
`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, 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, 57
`
`Merial v. Virbac,
`IPR No. 2014-01279, Paper 13 (P.T.A.B. Jan. 22, 2015) . 5, 26, 42, 47-49, 57
`
`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, 26, 45
`
`Zetec,Inc. v. Westinghouse Elec. Co., LLC,
`IPR No. 2014-00384, Paper 10 (P.T.A.B. Jul. 23, 2014) ............. 4, 25, 41, 42
`
`
`
`
`
`
`
`v
`
`

`

`
`
`
`Ikaria Exhibit No.
`
`Description
`
`TABLE OF EXHIBITS
`
`
`2001
`
`Original INOT22 Protocol, Excerpt from prosecution
`
`history of U.S. Patent No. 8,795,741 (submitted as
`
`Appendix 1 to Dr. Baldassarre Declaration under 37
`
`C.F.R. § 1.131)
`
`2002
`
`Amended INOT22 Protocol, Excerpt from prosecution
`
`history of U.S. Patent No. 8,795,741 (submitted as
`
`Appendix 3 to Dr. Baldassarre Declaration under 37
`
`C.F.R. § 1.131)
`
`2003
`
`Adatia et al, “Inhaled nitric oxide and hemodynamic
`
`evaluation of patients with pulmonary hypertension
`
`before transplantation,” 25:1656-64, J. Am. Coll.
`
`Cardiol., 1995 (“Adatia”)
`
`2004
`
`Beghetti et al., “Inhaled nitric oxide can cause severe
`
`systemic hypotension,” 130:844, J. Pediatr., 1997
`
`(“Beghetti (1997)”)
`
`2005
`
`Rosales et al., “Adverse hemodynamic effects observed
`
`with inhaled nitric oxide after surgical repair of total
`
`anomalous pulmonary venous return,” 20:224-26,
`
`vi
`
`

`

`
`
`Ikaria Exhibit No.
`
`Description
`
`Pediatr. Cardiol., 1999 (“Rosales”)
`
`2006
`
`Lipshultz, “Ventricular dysfunction clinical research in
`
`infants, children and adolescents,” 12:1-28, Prog.
`
`Pediatr. Cardiol., 2000 (“Lipshultz”)
`
`2007
`
`Stedman’s Medical Dictionary at a Glance, 28th Ed,
`
`Lippincott Williams & Wilkins ©2006, pg. 359
`
`2008
`
`2009
`
`(“Stedman’s 2006”)
`
`Reserved
`
`Gidding, “The Importance of Randomized Controlled
`
`Trials in Pediatric Cardiology,” 298:1214-1216, JAMA.
`
`2007 (“Gidding”)
`
`2010
`
`Balaguru et al., “Management of Heart Failure in
`
`Children,” 30:5-30, Curr. Probl. Pediatr., 2000
`
`(“Balaguru”)
`
`2011
`
`Berger et al., “Clinical features of paediatric pulmonary
`
`hypertension: a registry study,” 379:537-46, Lancet,
`
`2012 (“Berger”)
`
`2012
`
`Rimensberger et al., “Inhaled nitric oxide versus
`
`vii
`
`

`

`
`
`Ikaria Exhibit No.
`
`Description
`
`aerosolized iloprost in secondary pulmonary
`
`hypertension in children with congenital heart disease:
`
`vasodilator capacity and cellular mechanisms”, 103:
`
`544-48, Circulation, 2001 (“Rimensberger”)
`
`2013
`
`Brief on Appeal filed Oct. 4, 2011, Excerpt from
`
`prosecution history of U.S. Patent Application No.
`
`12/820,866 (“’866 Appeal Brief”)
`
`viii
`
`

`

`
`
`
`Abbreviation
`
`TABLE OF ABBREVIATIONS
`
`
`Description
`
`’284 patent
`
`U.S. Patent No. 8,293,284
`
`’966 patent
`
`U.S. Patent No. 8,282,966
`
`’163 patent
`
`U.S. Patent No. 8,431,163
`
`’741 patent
`
`U.S. Patent No. 8,795,741
`
`’112 patent
`
`U.S. Patent No. 8,846,112
`
`’041 Application U.S. Patent Application No. 12/821,041
`
`’598 Application U.S. Patent Application No. 12/494,598
`
`’660 Application U.S. Patent Application No. 13/651,660
`
`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
`
`ix
`
`

`

`
`
`
`Abbreviation
`
`Description
`
`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]
`
`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]
`
`x
`
`

`

`
`
`
`Abbreviation
`
`Description
`
`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
`
`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]
`
`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]
`
`xi
`
`

`

`
`
`
`Abbreviation
`
`Description
`
`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]
`
`AE
`
`Adverse event
`
`xii
`
`

`

`
`
`
`Abbreviation
`
`Description
`
`Amended
`
`INOT22 Protocol after amendment of exclusion criteria
`
`INOT22 Protocol
`
`[Exh 2002]
`
`EPD
`
`FDA
`
`IEC
`
`iNO
`
`Earliest priority date
`
`The 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
`
`IRB
`
`LVD
`
`NO
`
`O2
`
`Study
`
`Institutional review board
`
`Left ventricular dysfunction
`
`Nitric oxide
`
`Oxygen
`
`xiii
`
`

`

`
`
`
`Abbreviation
`
`Description
`
`Original INOT22
`
`INOT22 Protocol prior to amendment of exclusion criteria
`
`Protocol
`
`[Exh. 2001]
`
`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
`
`
`
`
`
`xiv
`
`

`

`
`
`
`
`
`
`
`Case IPR2015-00525
`U.S. Patent No. 8,431,163
`
`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. 8,431,163 (“the ’163
`
`patent”).1
`
`
`
`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. 8,795,741
`
`(“the ’741 patent”), which is the subject of IPR2015-00526; and U.S. Patent
`
`No. 8,846,112 (“the ’112 patent”), which is the subject of IPR2015-00529.
`
`The ’966, ’284, ’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
`
`

`

`
`
`
`
`
`
`
`Case IPR2015-00525
`U.S. Patent No. 8,431,163
`
`I.
`
`INTRODUCTION
`
`Praxair seeks to institute an IPR on the basis of obviousness of all
`
`claims of the ’163 patent, which cover methods of safely administering
`
`inhaled nitric oxide (“iNO”) to neonates with life threatening heart
`
`conditions by excluding neonates with left ventricular dysfunction (“LVD”)
`
`from iNO treatment. 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, much less
`
`ordinary skill, in the art were unaware that neonates with LVD should be
`
`excluded from iNO therapy. 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 by experts in
`
`2
`
`

`

`
`
`
`
`
`
`
`Case IPR2015-00525
`U.S. Patent No. 8,431,163
`
`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. 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 with LVD
`
`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 that if it was so obvious to
`
`exclude those pediatric patients, 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.
`
`1052 at 585, ¶ 8).
`
`3
`
`

`

`
`
`
`
`
`
`
`Case IPR2015-00525
`U.S. Patent No. 8,431,163
`
`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 10 at 14 (P.T.A.B. Jul. 23, 2014). Here, Praxair fails to cite to
`
`any prior art stating that iNO therapy administered to “neonates” with LVD
`
`should be “excluded” or “discontinued” as recited in the ’163 patent’s
`
`claims. Instead, Praxair primarily relies on studies showing that adults with
`
`LVD should be excluded from iNO treatment. 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 conclusory expert opinion as to the key exclusion claim
`
`element. Neither Praxair, nor its medical expert, cite to any prior art
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`literature stating, or data showing, that neonates with LVD should be
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`excluded from iNO therapy.
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`Third, the Board has denied instituting IPRs where the petitioner does
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`not address arguments made during prosecution or fails to provide
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`arguments beyond those rejected during prosecution. Merial v. Virbac, IPR
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`No. 2014-01279, Paper 13 at 8-9 (P.T.A.B. Jan. 22, 2015). Here, Praxair
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`relies on the same cautionary statements relied on by the Examiner during
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`prosecution, which Ikaria successfully rebutted by submitting declarations
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`explaining such cautions were irrelevant because, for example, they applied
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`to adults, not 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 ’163 patent file history. (Exh. 1002 at 6-7, ¶12). As
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`the Board has ruled, Praxair should have addressed all of the evidence
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`provided during prosecution, and its failure to do so is not only a glaring
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`hole in its proofs, but 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 neonates, and not once did he state that
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`neonates with LVD should be excluded from iNO therapy.
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`Finally, objective evidence, including the undisputed fact that experts
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`in the field failed to recognize that pediatric patients with LVD would suffer
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`serious adverse events from the use of iNO therapy, shows that the claims
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`are not obvious. Those real-world facts, when considered as required,
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`eliminate any question that the claimed invention would not have been
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`obvious to those of ordinary skill in the art.
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`II. BACKGROUND
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`A. The Development of the ’163Patent
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`U.S. Patent No. 8,431,163, entitled “Methods of Reducing the Risk of
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`Occurrence of Pulmonary Edema Associated with Inhalation of Nitric Oxide
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`Gas,” is directed to methods of reducing the risk or preventing the
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`occurrence of an adverse event (“AE”) or a serious adverse event associated
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`with treatment using inhaled nitric oxide. (Exh. 1001, col. 1:61-65). The
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`invention was the result of a discovery that occurred during the INOT22
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`Study, which involved the administration of INOmax® (Ikaria’s inhaled
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`nitric oxide product) to pediatric patients.2 (Exh. 1001, col. 9:25-14:15).
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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. 3:39-42).
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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
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`INOT22 Steering Committee”), and Ikaria, the study sponsor.3 (Exh. 1052
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`at 912, ¶ 8). It was a randomized, multi-center study with approximately 18
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`clinical study sites. (Exh. 1001, col. 9:47-49; Exh. 1052 at 633, ¶ 5). The
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`study compared the utility and side effects of oxygen (O2), iNO and a
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`combination of iNO and O2 for determining pulmonary reactivity. (Exh.
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`1001, col. 9:28-36). The original INOT22 protocol (“Original INOT22
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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 (Exh. 1052 at 583-84, ¶¶1-4; 586-625);
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`Robyn J. Barst, M.D., Professor Emeritus of Pediatrics and Medicine,
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`Columbia University College of Physicians and Surgeons, New York; and
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`Duncan J. Macrae, M.D., Director, Children’s Services, Consultant in
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`Pediatric Critical Care at the Royal Brompton Hospital, London, U.K. (Exh.
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`1052 at 633-34, ¶8; Exh. 2001, (Original INOT22 Protocol) at 14.)
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`Protocol”) did not exclude pediatric patients with pre-existing left
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`ventricular dysfunction (“LVD”) who were not dependent on right-to-left
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`shunting of blood. (Exh. 1001, col. 9:47-56, 12:29-43; Exh. 2001 (Original
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`INOT22 Protocol) at 21-22).
`
`Prior to commencing the study, the Original INOT22 Protocol was
`
`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 Board (“IRB”) and/or Independent Ethics Committee (“IEC”) at
`
`each of the approximately 18 participating study institutions reviewed the
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`Original INOT22 Protocol. (Exh. 1052 at 645-6, ¶8). Those committees
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`include practicing physicians and other knowledgeable individuals whose
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`role is “the protection of the rights and welfare of human research subjects.”
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`(Id. at 646, ¶ 9). Additionally, the U.S. Food & Drug Administration
`
`(“FDA”) and four European National Health Authorities (United Kingdom,
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`France, Netherlands and Spain), the European equivalents to the FDA, had
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`the opportunity to review the Original INOT22 Protocol prior to study
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`initiation. (Id. at 645-46, ¶ 8). And, Ikaria regularly requested input and
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`scientific guidance on clinical trials from its own Scientific Advisory Board.
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`(Id.). In sum, “at least 115 individuals experienced in, and responsible for,
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`the review of clinical trial protocols for patient safety,” evaluated the
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`Original INOT22 Protocol prior to its commencement. (Id. at 647, ¶ 11).
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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 of the four European
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`National Health Authorities, or (v) any member of Ikaria’s own Scientific
`
`Advisory Board ever appreciate, recognize or suggest excluding pediatric
`
`patients with LVD from the Original INOT22 Protocol. (Id. at 914-15, ¶
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`12).
`
`2.
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`Unanticipated Serious Adverse Events Initially
`Occurred During the INOT22 Study
`
`After initiation of the first 24 pediatric patients in the INOT22 Study,
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`there were five SAEs, which was a rate much higher than the INOT22
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`Steering Committee and Ikaria expected. (Exh. 1052 at 915, ¶ 13). The
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`SAEs were all cardiovascular events, and included pulmonary edema,
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`cardiac arrest and hypotension (low blood pressure). (Id.). One baby who
`
`developed pulmonary edema died. (Exh. 1001 at col. 12:65-6).
`
`Analysis revealed some of the “patients suffering [SAEs] had severe
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`[LVD], largely due to viral cardiomyopathy, and exhibited, during their
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`right-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. 1052 at 968, ¶ 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. (Id. at 915-16, ¶ 14; Exh.
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`2002 (Amended INOT22 Protocol) at 20).
`
`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
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`[SAEs] associated with heart failure) was significantly reduced.” (Exh.
`
`1052 at 916, ¶ 15). Whereas five SAEs were reported in the first 24 patients
`
`before the amended exclusion criteria, only two SAEs were reported in the
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`last 80 patients after the amendment. (Id.). “As a result of the INOT22
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`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 . . .” (Id. at 561,
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`¶ 11). Given the significance of the difference in the pre- and post-protocol-
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`amendment SAE frequencies, on February 25, 2009, Ikaria submitted to the
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`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
`
`pulmonary edema. The FDA agreed and approved the labeling supplement
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`on August 28, 2009. (Id. at 961, ¶¶ 16-17).
`
`B.
`
`The ’163 Patent Prosecution History
`
`Based on this surprising discovery, on June 30, 2009, Ikaria filed U.S.
`
`Patent Application No. 12/494,598 (“the ’598 application”), which issued as
`
`the ’284 patent from continuation Application No. 12/821,041 (“the ’041
`
`Application”). On June 22, 2010, Ikaria filed U.S. Patent Application No.
`
`13/651,660 (“the ’660 application) as a continuation of the ’041 application,
`
`which issued as the ’163 patent. (Exh. 1001, col. 1:9-14).
`
`1.
`
`The PTO Considered Many References
`
`The claims of the ’163 patent were extensively reviewed. In addition
`
`to overcoming a double patenting rejection, the ’660 application
`
`incorporated by reference the contents of the ’041 application and the ’598
`
`application. The Examiner specifically addressed over 20 references, and
`
`considered over 150 references, prior to allowance of the claims. (See, e.g.
`
`Exh. 1054 at 146-202, 475-78, 487-94, 521-24; Exh. 1001 at 1-6). To the
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`extent that Praxair cites different references, they fail to add any new
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`information to that considered by the Examiner.
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`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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`• Exh. 1009 (“Ichinose”);
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`• Exh. 1014 (“INOmax® label”);
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`• Exh. 1005 (“Davidson”); and
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`• Exh. 1011 (“Neonatal Group”).
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`(See e.g., Exh. 1001 at 1-6; Exh. 1054 at 146-202, 475-78, 487-94, 521-24).
`
`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 Examiner (id. at 8, references 103-115): Exh. 1006
`
`(“Loh”), Exh. 2003 (“Adatia”); Kieler-Jensen et al., J. Heart Lung
`
`Transplant., 13:366-75, 1994 (“Kieler-Jensen”); Semigran et al., J. Am.
`
`Coll. Cardiol., 24:982-88, 1994 (“Semigran”); Hayward et al., J.
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`Cardiovasc. Pharmacol., 27:80-85, 19