`
`
`Paper No. ____
`Date Filed: May 4, 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 IPR2015-00522
`U.S. Patent No. 8,282,966
`________________
`
`
`
`PRELIMINARY RESPONSE BY
`PATENT OWNERS PURSUANT TO 37 C.F.R. § 42.107
`
`
`
`
`
`
`
`
`I.
`
`II.
`
`
`
`
`
`TABLE OF CONTENTS
`
`INTRODUCTION ........................................................................................... 1
`
`BACKGROUND ............................................................................................. 6
`
`A.
`
`The Development of the ’966 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 ’966 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 ......................................................................... 15
`
`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 .......................................... 17
`
`C.
`
`The ’966 Patent Claims ....................................................................... 19
`
`III. PERSON OF ORDINARY SKILL ............................................................... 20
`
`IV. CLAIM CONSTRUCTION .......................................................................... 20
`
`i
`
`
`
`
`
`V.
`
`
`
`
`
`LEGAL STANDARD ................................................................................... 23
`
`VI. A SKILLED ARTISAN WOULD NOT HAVE BEEN
`MOTIVATED TO EXCLUDE CHILDREN HAVING LVD
`AND NOT DEPENDENT ON RIGHT-TO-LEFT SHUNTING
`OR REASONABLY EXPECT THOSE CHILDREN WOULD
`HAVE EXPERIENCED SAES ..................................................................... 27
`
`A.
`
`There was no motivation to implement the claimed
`exclusion based on studies with adults because left
`ventricular dysfunction in children is much different than
`in adults ............................................................................................... 29
`
`B. A skilled artisan would not have reasonably expected that
`the claimed excluded children 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 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 ................ 36
`
`Praxair’s Assertions that warnings in the 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 5,
`11, 20 and 28 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 INOMAX®
`LABEL, LOH, GOYAL AND MACRAE .................................................... 51
`
`IX. GROUND 3: THE BOARD SHOULD NOT INSTITUTE
`REVIEW BASED ON ALLEGED OBVIOUSNESS OVER
`
`ii
`
`
`
`
`
`
`X.
`
`
`
`
`
`ICHINOSE IN COMBINATION WITH NEONATAL
`GROUP, MACRAE, LOH, GOYAL AND GERMANN ............................. 53
`
`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) .....................................................................56
`
`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, 56
`
`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) .......................................................................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, 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) ........................................................ 20, 21, 22
`
`Rohm and Haas Co. v. Brotech Corp.,
`127 F.3d 1089 (Fed. Cir. 1997) .....................................................................46
`
`Statutes
`
`35 U.S.C. § 103 ..................................................................................... 23, 35, 51, 53
`
`35 U.S.C. § 314(a) ...............................................................................................2, 23
`
`35 U.S.C. § 325(d) ............................................................................................ 47, 50
`
`iv
`
`
`
`
`
`37 C.F.R. § 42.1(b) ..................................................................................................49
`
`
`
`
`
`37 C.F.R. § 42.100(b) ..............................................................................................20
`
`37 C.F.R. § 42.108(c) ...........................................................................................2, 23
`
`37 C.F.R. § 42.65(a) .................................................................................................48
`
`37 C.F.R. § 42.104(b)(4) ................................................................................... 25, 41
`
`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
`
`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) 4, 26, 42, 47, 49, 57
`
`Mylan v. Gilead Sciences, Inc.,
`IPR No. 2014-00888, Paper 15 (P.T.A.B. Dec. 9, 2014) ..........................4, 26
`
`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
`
`
`
`
`
`
`
`v
`
`
`
`
`
`
`
`
`
`
`Abbreviation
`
`TABLE OF ABBREVIATIONS
`
`
`Description
`
`’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
`
`’112 patent
`
`U.S. Patent No. 8,846,112
`
`’020 Application U.S. Patent Application No. 12/821,020
`
`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]
`
`vi
`
`
`
`
`
`
`
`
`
`
`Abbreviation
`
`Description
`
`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]
`
`Henrichsen
`
`Henrichsen et al., “Inhaled nitric oxide can cause Severe
`
`systemic hypotension, 129:183, J. Pediatr., 1996 [Exh. 1030]
`
`vii
`
`
`
`
`
`
`
`
`
`
`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]
`
`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]
`
`viii
`
`
`
`
`
`
`
`
`
`
`Abbreviation
`
`Description
`
`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]
`
`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]
`
`ix
`
`
`
`
`
`
`
`
`
`
`Abbreviation
`
`Description
`
`Wood
`
`Wood et al., “The effect of acetylcholine on pulmonary
`
`vascular resistance and left atrial pressure in mitral stenosis,”
`
`19:279–286, Br. Heart J., 1957
`
`AE
`
`Adverse event
`
`Amended
`
`INOT22 Protocol after amendment of exclusion criteria
`
`INOT22 Protocol
`
`[Exh 2002]
`
`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
`
`Study
`
`x
`
`
`
`
`
`
`
`
`
`
`Abbreviation
`
`Description
`
`IRB
`
`LVD
`
`NO
`
`O2
`
`Institutional review board
`
`Left ventricular dysfunction
`
`Nitric oxide
`
`Oxygen
`
`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
`
`
`
`
`
`xi
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`Case IPR2015-00522
`U.S. Patent No. 8,282,966
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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. 8,282,966 (“the ’966
`
`patent”).1
`
`I.
`
`INTRODUCTION
`
`Praxair seeks to institute an IPR on the basis of obviousness of all
`
`claims of the ’966 patent, which cover methods of safely administering
`
`
`
`1
`
`Praxair has filed four other IPR petitions challenging Ikaria’s related
`
`patents, including 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; 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.
`
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`1
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`Case IPR2015-00522
`U.S. Patent No. 8,282,966
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`inhaled nitric oxide (“iNO”) to children with life threatening heart
`
`conditions by excluding all children 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 in the art were
`
`unaware that all children with LVD should be excluded from iNO therapy,
`
`as required by the claims of the ’966 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 subjects surprisingly
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`U.S. Patent No. 8,282,966
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`developed serious adverse events (“SAE”), including death, which caused a
`
`cessation of the trial. Based on an analysis of the subjects 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 LVD subjects
`
`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 subjects 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 subjects, 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).
`
`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
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`3
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`U.S. Patent No. 8,282,966
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`any prior art stating that all “children” having LVD should be “excluded”
`
`from iNO therapy as recited in the ’966 claims. Instead, Praxair primarily
`
`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 children or 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 exclusion claim
`
`element. Neither 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.
`
`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 8-10 (P.T.A.B. Jan. 22, 2015). Here, Praxair
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`4
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`Case IPR2015-00522
`U.S. Patent No. 8,282,966
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`relies on the same cautionary statements relied on by the Examiner during
`
`prosecution, which Ikaria successfully rebutted by submitting declarations
`
`explaining such cautions were irrelevant because, for example, they applied
`
`to adults not children or 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 ’966 file history. 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 in children or neonates, and not once did
`
`he state that all children or neonates with LVD should be excluded from iNO
`
`therapy.
`
`Finally, objective evidence, including the undisputed fact that experts
`
`in the field failed to recognize that children or neonates with LVD would
`
`suffer serious adverse events from the use of iNO therapy, show that the
`
`claims are not obvious. Those real-world facts, when considered as
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`5
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`U.S. Patent No. 8,282,966
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`required, eliminate any question that the claimed invention would not have
`
`been obvious to those of ordinary skill in the art.
`
`II. BACKGROUND
`
`A. The Development of the ’966 Patent
`
`U.S. Patent No. 8,282,966, entitled “Methods of Reducing the Risk of
`
`Occurrence of Pulmonary Edema in Children in Need of Treatment with
`
`Inhaled Nitric Oxide,” is directed to methods of reducing the risk of an SAE
`
`associated with treating children with iNO. (Exh. 1001 at col. 1:61-2:34).
`
`The invention was the result of a discovery that occurred during the INOT22
`
`Study, which involved the administration of INOmax® (Ikaria’s inhaled
`
`nitric oxide product) to children.2 (Exh. 1001 at col. 9:20-14:3).
`
`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. (Exh. 1052 at
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`INOmax® is an inhaled NO treatment that, among other things,
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`improves oxygenation, reduces the need for extracorporeal oxygenation and
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`is indicated for use with ventilatory support. (Exh. 1001 at col. 3:39-42).
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`912, ¶ 8).3 It was a randomized, multi-center study with approximately 18
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`clinical study sites. (Id. at 912, ¶ 6). The study compared the utility and
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`side effects of oxygen (“O2”), iNO and a combination of iNO and O2 for
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`determining pulmonary reactivity. (Id. at 912, ¶ 5). The Original INOT22
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`Protocol (“Original INOT22 Protocol”) did not exclude subjects with pre-
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`existing LVD who were not dependent on right-to-left shunting of blood.
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`(Exh. 1001 at col. 9:41-55; Exh. 1052 at 913-14, ¶ 10; Exh. 2001 (Original
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`INOT22 Protocol) at 21).
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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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`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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`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. 1052 at 926, ¶ 9). 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 927, ¶ 10) Additionally, the U.S. Food & Drug Administration
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`(“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 926-27, ¶ 9). And, Ikaria regularly requested input and
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`scientific guidance on the clinical trial from its own Scientific Advisory
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`Board. (Id.). In sum, more than a hundred “individuals experienced in, and
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`responsible for, the review of clinical trial protocols for patient safety,”
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`evaluated the Original INOT22 Protocol prior to its commencement. (Id. at
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`928, ¶ 12).
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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
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`Advisory Board ever appreciate, recognize or suggest excluding subjects
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`with LVD from the Original INOT22 Protocol, as claimed in the ’966
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`patent, due to an increased risk of adverse events within such pediatric
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`patients. (Id.).
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`2.
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`Unanticipated Serious Adverse Events Initially
`Occurred During the INOT22 Study
`
`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 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
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`pulmonary edema died. (Exh. 1001 at col. 12:60-61).
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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
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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.,
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`children having a PCWP greater than 20 mm Hg. (Exh. 1052 at 915-16, ¶
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`14; Exh. 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 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 subjects before the
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`amended exclusion criteria, only two SAEs were reported in the last 80
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`subjects after the amendment. (Id.). “As a result of the INOT22 study, it
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`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).
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`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
`
`FDA a change to the INOmax® label, which included a warning that the use
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`of iNO in patients with pre-existing LVD could cause SAEs, such as
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`pulmonary edema. The FDA agreed and approved the labeling supplement
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`on August 28, 2009. (Id. at 916, ¶¶ 16-17).
`
`B.
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`The ’966 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 ’966 patent from
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`continuation Application No. 12/821,020 (“the ’020 Application”). (Exh.
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`1001, col. 1:9-14).
`
`1.
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`The PTO Considered Many References
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`The claims of the ’966 patent were extensively reviewed. The
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`Examiner specifically addressed 24 references, and considered over 150
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`references, prior to allowance of the claims. (Exh. 1052 at 344-51, 486-97,
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`720-28, 860-77; Exh. 1001 at 1-5). 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 explicitly by Praxair in its petition:
`
`• Exh. 1006 (“Loh”);
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`• 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. 1052 at 347-349, 493, 723, 991-92).
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`Praxair also relies on Exh. 1004 (“Bernasconi”) in its petition.
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`Although the Examiner did not explicitly consider Bernasconi, ten of the
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`thirteen references cited in Bernasconi’s LVD section relied on by Praxair
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`were considered by the Examiner (id. at 8, references 103-115): Exh. 1006
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`(“Loh”), Exh. 2003 (“Adatia”); Kieler-Jensen et al., J. Heart Lung
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`Transplant., 13:366-75, 1994 (“Kieler-Jensen”); Semigran et al., J Am Coll
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`Cardiol., 24:982-88, 1994 (“Semigran”); Hayward et al., J. Cardiovasc.
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`Pharmacol., 27:80-85, 1996 (“Hayward (1996)”); Exh. 2004 (Beghetti
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`(1997)); Exh. 2005 (Rosales); Argenziano et al., J. Thorac. Cardiovasc.
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`Surg., 115:700-08, 1998 (“Argenziano”); Hayward et al., J. Am. Coll.
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`Cardiol., 30:49-56, 1997 (“Hayward (1997)”); and Hayward et al., J.
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`Cardiovasc. Pharmacol., 34:749-54, 1999 (“Hayward (1999)”). (See, e.g.,
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`Exh. 1052 at 317, 346, 348-49, 709, 861-62, 718, 991).4 And references
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`cited in these references were also considered by the Examiner, including,
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`for instance, Bocchi et al., Am. J. Cardiol., 74:70-4, 1994 (“Bocchi”), cited
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`in Exh. 2003 (Adatia). Thus, Bernasconi is merely cumulative of prior art
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`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 15
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`(“Bernasconi warns that iNO treatment may lead to pulmonary edema in
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`patients with LVD. Ex. 1004 at 8; Ex. 1002 ¶¶ 35-36.”) (emphasis added).
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`For example, the Examiner stated: (1) that Atz and Wessel, Semin.
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`Perinatol., 21:441-5, 1997 (“Atz”) teaches that “[c]aution should be
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`4
`The three references cited in the LVD section of Bernasconi that were
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`not cited during prosecution of the ’966 patent add nothing to Praxair’s
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`assertions. As discussed below (infra at 37), these references were directed
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`to adults or animal models.
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`exercised when administering NO to patients with severe left ventricular
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`dysfunction and pulmonary hypertension,” (2) that Beghetti (1997) says
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`“[i]nhaled nitric oxide should be administered with caution to babies with
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`LV dysfunction,” and (3) that Ichinose teaches “inhalation of NO can
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`increase left ventricle filling pressure in patients with severe left ventricle
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`dysfunction and that it is important to be aware of the possibility that inhaled
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`NO can produce pulmonary vasodilation and may overwhelm a failing left
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`ventricle thereby producing pulmonary edema.” (Exh. 1052 at 317, 473,
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`709-10). From these references (like Praxair does here), the Examiner
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`initially concluded that “the ordinary artisan would . . . exclude any patient
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`with any form of LVD from iNO therapy to avoid the risk of adverse and
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`serious adverse events.” (Id. at 477-78).
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`In response, Ikaria submitted declarations from Dr. James S.
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`Baldassarre, Vice President of Clinical Research at Ikaria, Inc., Dr. David L.
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`Wessel, and Dr. Douglas A. Greene, Executive Vice P
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