IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
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`PRAXAIR DISTRIBUTION, INC.
`Petitioner
`v.
`INO THERAPEUTICS, INC. d/b/a IKARIA, INC.
`Patent Owner
`
`
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,293,284
`PURSUANT TO §§ 35 U.S.C. 311-319 AND 37 C.F.R. § 42
`
`
`
`Mail Stop PATENT BOARD
`Patent Trial and Appeal Board
`United States Patent and Trademark Office
`PO Box 1450
`Alexandria, Virginia 22313-1450
`
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`Ex. 2016-0001
`
`

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`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`Table of Contents
`
`Page
`
`I.
`II.
`
`INTRODUCTION ........................................................................................... 1
`OVERVIEW .................................................................................................... 1
`A.
`Summary of the ʼ284 Patent .................................................................. 1
`B.
`Summary of the Prosecution History of the ʼ284 Patent ...................... 2
`III. BACKGROUND ON PULMONARY HYPERTENSION, HYPOXIC
`RESPIRATORY FAILURE, AND DIAGNOSTIC STEPS USED IN
`TREATMENT ................................................................................................. 4
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a)) ................................. 6
`V.
`PAYMENT OF FEES (37 C.F.R. § 42.103) ................................................... 6
`VI. MANDATORY NOTICES (37 C.F.R. § 42.8) ............................................... 7
`A.
`Real-Parties-in-Interest .......................................................................... 7
`B.
`Related Matters ...................................................................................... 7
`C.
`Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4)) .................................................... 7
`VII. PERSON OF SKILL IN THE ART ................................................................ 8
`VIII. CLAIM CONSTRUCTION ............................................................................ 8
`IX. STATEMENTS OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. §§ 42.22(a) and 42.104(b)) ................ 9
`A. Ground 1: Independent Claims 1, 6, 13, and 23 and Dependent
`Claims 2-3, 5, 7-9, 11, 14, 16-18, 21, 24-27, and 29 Are
`Unpatentable Under 35 U.S.C. § 103(a) as Obvious Over
`Bernasconi, INOMAX label, Loh and Goyal ....................................... 12
`1.
`Overview of Prior Art Applied in Ground 1 ............................. 13
`2. Motivation to Combine Art Applied in Ground 1 .................... 15
`3.
`Independent Claims 1 and 6 ...................................................... 19
`(a)
`Part (a) of Independent Claims 1 and 6 .......................... 20
`(b)
`Part (b) of Independent Claims 1 and 6 .......................... 23
`(c)
`Part (c) of Independent Claims 1 and 6 .......................... 25
`
`i
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`Ex. 2016-0002
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`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`4.
`
`5.
`
`Independent Claims 13 and 23 .................................................. 26
`(a)
`Part (a) of Independent Claims 13 and 23 ...................... 26
`(b)
`Part (b) of Independent Claims 13 and 23 ...................... 27
`(c)
`Part (c) of Independent Claims 13 and 23 ...................... 28
`(d)
`Part (d) of Independent Claims 13 and 23 ...................... 29
`(e)
`Part (e) of Independent Claims 13 and 23 ...................... 30
`Dependent Claims 2-3, 5, 7-9, 11, 14, 16-18, 21, 24-27, and
`29 ............................................................................................... 30
`(a) Dependent Claims 2, 8, and 18 ....................................... 31
`(b) Dependent Claims 3, 9, 17, and 27 ................................. 32
`(c) Dependent Claims 5, 11, 21, and 29 ............................... 32
`(d) Dependent Claims 7 and 24 ............................................ 33
`(e) Dependent Claims 14 and 25 .......................................... 34
`(f) Dependent Claims 16 and 26 .......................................... 35
`Ground 2: Dependent Claims 4, 10, 12, 15, 19, 20, 22, 28, and 30
`Are Unpatentable Under 35 U.S.C. § 103(a) as Obvious Over
`Bernasconi, INOMAX label, Loh, Goyal, and Macrae ....................... 35
`Ground 3: Independent Claims 1, 6, 13, and 23 and Dependent
`Claims 2-5, 7-12, 14-22, and 24-30 Are Unpatentable Under 35
`U.S.C. § 103(a) as Obvious Over Ichinose, Macrae, Germann,
`Neonatal Group, Loh and Goyal ......................................................... 38
`1.
`Overview of Prior Art Applied in Ground 3 ............................. 38
`2. Motivation to Combine Art Applied In Ground 3 .................... 40
`3.
`Independent Claims 1 and 6 ...................................................... 41
`(a)
`Part (a) of Independent Claims 1 and 6 .......................... 42
`(b)
`Part (b) of Independent Claims 1 and 6 .......................... 45
`(c)
`Part (c) of Independent Claims 1 and 6 .......................... 46
`Independent Claims 13 and 23 .................................................. 47
`(a)
`Part (a) of Independent Claims 13 and 23 ...................... 47
`(b)
`Part (b) of Independent Claims 13 and 23 ...................... 48
`
`B.
`
`C.
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`4.
`
`ii
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`Ex. 2016-0003
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`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`5.
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`Part (c) of Independent Claims 13 and 23 ...................... 49
`(c)
`Part (d) of Independent Claims 13 and 23 ...................... 50
`(d)
`Part (e) of Independent Claims 13 and 23 ...................... 50
`(e)
`Dependent Claims 2-5, 7-12, 14-22, and 24-30 ........................ 51
`(a) Dependent Claims 2, 8, and 18 ....................................... 51
`(b) Dependent Claims 3, 9, 17, and 27 ................................. 52
`(c) Dependent Claims 5, 11, 21, and 29 ............................... 53
`(d) Dependent Claims 7 and 24 ............................................ 54
`(e) Dependent Claims 14 and 25 .......................................... 55
`(f) Dependent Claims 16 and 26 .......................................... 55
`CONCLUSION .............................................................................................. 56
`
`
`
`X.
`
`
`
`iii
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`Ex. 2016-0004
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`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`List of Exhibits
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`Ex. 1001: U.S. Patent No. 8,293,284 to Baldassarre et al. (“ʼ284 Patent), filed
`
`June 22, 2010, issued October 23, 2012.
`
`Ex. 1002: Declaration of Dr. Maurice Beghetti.
`
`Ex. 1003: Curriculum vitae of Dr. Maurice Beghetti.
`
`Ex. 1004: Bernasconi et al., Inhaled Nitric Oxide Applications in Paediatric
`
`Practice, 4
`
`Images
`
`in Paediatric Cardiology, 4-29
`
`(2002).
`
`(“Bernasconi”).
`
`Ex. 1005: 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 Pediatrics, 325-334 (1998). (“Davidson”).
`
`Ex. 1006: Loh, et al., Cardiovascular Effects of Inhaled Nitric Oxide in Patients
`
`with Left Ventricular Dysfunction, 90 Circulation, 2780-2785 (1994).
`
`(“Loh”).
`
`Ex. 1007: P. Goyal, et al., Efficacy of Nitroglycerin Inhalation in Reducing
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`Pulmonary Arterial Hypertension in Children with Congenital Heart
`
`Disease, 97 British Journal of Anaesthesia, 208-214 (2006).
`
`(“Goyal”).
`
`Ex. 1008: Macrae, et al., Inhaled Nitric Oxide Therapy in Neonates and
`
`iv
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`Ex. 2016-0005
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`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`Children: Reaching a European Consensus, 30 Intensive Care
`
`Medicine, 372-380 (2004). (“Macrae”).
`
`Ex. 1009:
`
`Ichinose, et al., Inhaled Nitric Oxide: A Selective Pulmonary
`
`Vasodilator: Current Uses and Therapeutic Potential, 109
`
`Circulation, 3106-3111 (2004). (“Ichinose”).
`
`Ex. 1010: Germann, et al., Inhaled Nitric Oxide Therapy in Adults: European
`
`Expert Recommendations, 31 Intensive Care Med, 1029-1041 (2005).
`
`(“Germann”).
`
`Ex. 1011: The Neonatal Inhaled Nitric Oxide Study Group, Inhaled Nitric Oxide
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`in Full-Term and Nearly Full-Term Infants with Hypoxic Respiratory
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`Failure, 336 The New England Journal of Medicine, 597-604 (1997).
`
`(“Neonatal Group”).
`
`Ex. 1012: Pozzoli, et al., Non-Invasive Estimation of Left Ventricular Filling
`
`Pressures by Doppler Echocardiography, 3 Eur J Echocardiogr.,
`
`75-79 (2002). (“Pozzoli”).
`
`Ex. 1013:
`
`“What
`
`is
`
`a
`
`Serious Adverse
`
`Event?”
`
`available
`
`at
`
`http://web.archive.org/web/20090611022009/http://www.fda.gov/Safe
`
`ty/MedWatch/HowToReport/ucm053087.htm
`
`(June
`
`11,
`
`2009).
`
`(“FDA Safety Information”).
`
`Ex. 1014: Center for Drug Evaluation and Research, Application Number: NDA
`
`v
`
`Ex. 2016-0006
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`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`20845,
`
`INOMAX, Final Printed Labeling,
`
`available
`
`at
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20845_inoma
`
`x_prntlbl.pdf (August 9, 2000). (“INOMAX label”).
`
`Ex. 1015:
`
` Richard E. Klabunde, Pulmonary Capillary Wedge Pressure,
`
`Cardiovascular Physiology Concepts, 4/11/2007 available at
`
`http://www.cvphysiology.com/Heart%20Failure/HF008.htm
`
`(“Klabunde”).
`
`Ex. 1016: Hoehn, Therapy of Pulmonary Hypertension in Neonates and Infants,
`
`Pharmacology & Therapeutics 2007 114:318-326. (“Hoehn”).
`
`Ex. 1017:
`
`Ivy et al., Pediatric Pulmonary Hypertension, J Am Coll Cardiol.
`
`62(25_S) (2013). (“Ivy”).
`
`Ex. 1018: Simonneau, et al., Clinical Classification of Pulmonary Hypertension,
`
`J. Am. Coll. Cardiol. 43(12 Suppl S):5S-12S (2004). (“Simonneau
`
`2004”).
`
`Ex. 1019: Simonneau, et al., Updated Clinical Classification of Pulmonary
`
`Hypertension, J Am. Coll. Cardiol. 54(1 Suppl):S43-54 (2009).
`
`(“Simonneau 2009”).
`
`Ex. 1020: Simonneau, et al., Updated Clinical Classification of Pulmonary
`
`Hypertension, J. Am. Coll. Cardiol. 62(25 Suppl):D34-41 (2013).
`
`(“Simonneau 2013”).
`
`vi
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`Ex. 2016-0007
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`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`Ex. 1021: Chemla,
`
`et al., Haemodynamic Evaluation of Pulmonary
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`Hypertension, 20 Eur Respir J., 1314-1331 (2002). (“Chemla”).
`
`Ex. 1022: Griffiths, et al. “Inhaled Nitric Oxide Therapy in Adults.” 353 New
`
`England Journal of Medicine, 2683-2695 (2005). (“Griffiths”).
`
`Ex. 1023: Royster, et al., Differences in Pulmonary Artery Wedge Pressures
`
`Obtained by Balloon Inflation Versus Impaction Techniques, 61
`
`Anesthesiology, (1984). (“Royster”).
`
`Ex. 1024:
`
`Ignarro, L.J., ed. Nitric Oxide Biology and Pathobiology, Academic
`
`Press, (2000). (“Ignarro”).
`
`Ex. 1025: M. Hoeper, et al., Definitions and Diagnosis of Pulmonary
`
`Hypertension 62:25 J. of the American College of Cardiology (2013).
`
`(“Hoeper”).
`
`Ex. 1026: Kaldijian, L., et al., A Clinician’s Approach to Clinical Ethical
`
`Reasoning, J Gen Intern Med. 20(3): 306–311 (Mar. 2005).
`
`(“Kaldijian”).
`
`Ex. 1027:
`
`Jonsen, A. et al., Clinical Ethics: A Practical Approach to Ethical
`
`Decisions in Clinical Medicine 4th ed. (1998). (“Jonsen”).
`
`Ex. 1028: Ware, L., Inhaled Nitric Oxide in Infants and Children, Crit Care
`
`Nurs Clin North Am. Mar;14(1):1-6 (2002). (“Ware”).
`
`Ex. 1029: Wessel, D.L., Commentary: Simple Gases and Complex Single
`
`vii
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`Ex. 2016-0008
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`

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`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`Ventricles, J. of Thoracic and Cardiovascular Surgery, 112:3 655–57
`
`(Sept. 1996). (“Wessel”).
`
`Ex. 1030: Henrichsen, et al., Inhaled Nitric Oxide can Cause Severe Systemic
`
`Hypotension, 129 The
`
`Journal of Pediatrics, 183
`
`(1996).
`
`(“Henrichsen”).
`
`Ex. 1031: Waldmann, et al., Oxford Desk Reference Critical Care, Oxford
`
`University Press (2008). (“Waldmann”).
`
`Ex. 1032: Reserved.
`
`Ex. 1033: Reserved.
`
`Ex. 1034: Reserved.
`
`Ex. 1035: Reserved.
`
`Ex. 1036: Claim Chart for Claims 1–3, 5–9, 11, 13–14, 16–18, 21, 23–27, and
`
`29.
`
`Ex. 1037: Claim Chart for Claims 4, 10, 12, 15, 19, 20, 22, 28, and 30.
`
`Ex. 1038: Claim Chart for Claims 1–30.
`
`Ex. 1039: Reserved.
`
`Ex. 1040: Reserved.
`
`Ex. 1041: Reserved.
`
`Ex. 1042: Reserved.
`
`Ex. 1043: Reserved.
`
`viii
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`Ex. 2016-0009
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`

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`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`Ex. 1044: Reserved.
`
`Ex. 1045: Reserved.
`
`Ex. 1046: Reserved.
`
`Ex. 1047: Reserved.
`
`Ex. 1048: Reserved.
`
`Ex. 1049: Reserved.
`
`Ex. 1050: Reserved.
`
`Ex. 1051: Reserved.
`
`Ex. 1052: Reserved.
`
`Ex. 1053: Prosecution History for U.S. Patent No. 8,293,284.
`
`
`
`ix
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`Ex. 2016-0010
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`I.
`
`INTRODUCTION
`Praxair Distribution, Inc. (“Petitioner” or “Praxair”) petitions for Inter
`
`Partes Review (“IPR”) under 35 U.S.C. §§ 311-319 and 37 C.F.R. § 42 of claims 1
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`to 30 of U.S. Patent No. 8,293,284 (“the ʼ284 Patent”). (Ex. 1001.)
`
`II. OVERVIEW
`Summary of the ʼ284 Patent
`A.
`Nitric oxide (“NO”) is a gaseous chemical compound used to treat patients
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`with severe breathing problems. In 2000, the U.S. Food and Drug Administration
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`(“FDA”) approved inhaled nitric oxide (“iNO”) to treat term and near-term infants
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`(born after the 33rd week of pregnancy) with respiratory failure. Patent Owner
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`iNO Therapeutics, Inc. d/b/a Ikaria, Inc. (“Patent Owner” or “Ikaria”) is the
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`exclusive supplier in the United States for iNO, which it sells under the brand
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`INOMAX®. Ikaria’s original patents covering this drug expired in 2013. Like
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`many pharmaceutical companies facing the loss of patent protection, Ikaria has
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`used later acquired patents like the ʼ284 Patent to impermissibly extend its patent
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`protection for INOMAX®.1
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`Indeed, Ikaria filed the application leading to the ʼ284 Patent nine years after
`
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`1 By adding the ʼ284 Patent to the FDA’s Orange Book, Ikaria is seeking to
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`extend its potential monopoly on INOMAX® until 2029—33 years after the
`
`original patents covering the drug product and method of use issued.
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`1
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`Ex. 2016-0011
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`

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`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`INOMAX® was approved. Yet the ʼ284 Patent does not relate to any inventive
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`method of treating a patient with iNO or using iNO. To the contrary, it discloses a
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`series of well-known diagnostic steps and analyses to determine whether the
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`patient is at risk of a Serious Adverse Event, such as pulmonary edema, if treated
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`with iNO and excluding such patients from treatment based on the assessed risk.2
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`(Ex. 1001 at Abstract; 1:46-60; Ex. 1002 ¶ 14.) Methods of evaluating and
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`excluding patients from treatment with iNO were known long before June 30,
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`2009, the earliest possible priority date (“EPD”) of the ʼ284 Patent.
`
`The claims of the ʼ284 Patent merely combine well-known methods and
`
`techniques (e.g., echocardiography, measuring wedge pressure, measuring blood
`
`oxygen, etc.) for determining who can or cannot be safely treated with iNO. (See,
`
`e.g. Ex. 1016 at 322; Ex. 1004 at 8; Ex. 1006 at 2781; Ex. 1014 at 2-3; Ex. 1011 at
`
`598.) The conventional practices are disclosed in the prior art references relied on
`
`in this Petition. Indeed, these references are not only from the same field, they all
`
`relate to addressing risks associated with using iNO. Accordingly, this Petition
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`should be granted and trial instituted on all of the challenged claims.
`
`Summary of the Prosecution History of the ʼ284 Patent
`
`B.
`The application leading to the ’284 Patent was filed on June 22, 2010. (Ex.
`
`
`2 “Serious Adverse Event” is a statutorily defined term of art. (See 21 C.F.R. §
`
`312.32; Ex. 1002 ¶ 37; Ex. 1013.)
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`2
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`Ex. 2016-0012
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`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`1001.) After extensive prosecution including four rejections, on August 15, 2012,
`
`Applicants amended all four independent claims to specify that the dosage of iNO
`
`should be 20 parts per million (“ppm”), and that a child identified as needing
`
`treatment has a pulmonary capillary wedge pressure greater than or equal to 20 mm
`
`Hg and thus has left ventricular dysfunction (“LVD”). (Ex. 1053 at 863, additions
`
`via amendment underlined.) Representative application Claim 38 (which issued as
`
`Claim 1) reproduced below illustrates this August 15, 2012 Amendment:
`
`
`On September 4, 2012, the Examiner issued a notice of allowance including
`
`the following reasons for allowance:
`
`the cited art of record does not teach or suggest, alone or in combination, the
`patient population of a term or near term neonate in need of the
`administration of 20 ppm iNO and determining the [pulmonary capillary
`wedge pressure] as greater than or equal to 20 mm Hg in the method as
`instantly claimed to reduce the risk of occurrence of pulmonary edema. (Ex.
`1053 at 965, emphasis added.)
`
`3
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`Ex. 2016-0013
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`

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`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`The next day, Applicants filed comments asserting that “the Examiner’s
`
`statement of reasons for allowance . . . describes just some of many reasons that
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`the present claims are allowable over the cited art of record.” (Ex. 1053 at 991.)
`
`III. BACKGROUND ON PULMONARY HYPERTENSION, HYPOXIC
`RESPIRATORY FAILURE, AND DIAGNOSTIC STEPS USED IN
`TREATMENT
`
`In 2000 (nine years before the EPD), the FDA approved 20 ppm of iNO to
`
`treat neonatal hypoxic respiratory failure, which is often associated with
`
`pulmonary hypertension. (Ex. 1004 at 3; Ex. 1014 at 6.) Pulmonary hypertension
`
`is characterized by an increased pulmonary artery pressure and increased
`
`pulmonary vascular resistance. (Ex. 1002 ¶ 16; Ex. 1004 at 8.) iNO may be used
`
`to treat pulmonary hypertension. (Ex. 1002 ¶ 17; See e.g. Ex. 1004 at 8; Ex. 1014
`
`at 2-3; Ex. 1011 at Abstract, 597.) iNO is a selective pulmonary vasodilator that
`
`relaxes pulmonary vessels, resulting in decreased pulmonary arterial pressure,
`
`pulmonary vascular resistance, and right ventricular afterload. (Ex. 1002 ¶ 16; Ex.
`
`1004 at 1, 2.)
`
`It was well known before the EPD that when a patient exhibited symptoms
`
`of pulmonary hypertension, including hypoxic respiratory failure, a pediatric
`
`cardiologist had to perform diagnostic tests to determine the best and safest method
`
`of treatment. (Ex. 1002 ¶¶ 17, 19; Ex. 1004 at 8; Ex. 1008 at 373-374.)
`
`Specifically, it was well known that pediatric cardiologists had to examine and
`
`4
`
`Ex. 2016-0014
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`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`evaluate patients before administering iNO to determine: (1) whether the treatment
`
`would likely benefit the patient; and (2) whether the patient would be at risk of
`
`reacting negatively to the treatment. (Ex. 1002 ¶ 17; Ex. 1004 at 8; Ex. 1009 at
`
`3109.)
`
`It was also known before the EPD that patients with either systolic or
`
`diastolic LVD should not be treated with iNO because they could have an
`
`increased risk of suffering a Serious Adverse Event, such as pulmonary edema.3
`
`(Ex. 1002 ¶ 18; Ex. 1004 at 8; Ex. 1013; Ex. 1009 at 3109; Ex. 1010 at 1033.)
`
`Thus, before prescribing iNO, pediatric cardiologists could have ordered various
`
`known diagnostic processes and tests, such as echocardiography4, to determine
`
`whether the patient had LVD, or any other condition contraindicating the use of
`
`iNO. (Ex. 1002 ¶¶ 15, 19-21; Ex. 1004 at 8.)
`
`Before the EPD, pediatric cardiologists also used wedge pressure to confirm
`
`whether the patient could be safely treated with iNO.5 (Ex. 1002 ¶¶ 15, 22; Ex.
`
`3 Pulmonary edema is a buildup of fluid in the lungs. (Ex. 1002 ¶ 14 FN 3.)
`
`4 Echocardiography is the use of ultrasound waves to image and investigate the
`
`heart. (See Ex. 1002 ¶ 15, FN 4.)
`
`5 “Wedge pressure” is also sometimes referred to as pulmonary capillary wedge
`
`pressure (“PCWP”), pulmonary arterial wedge pressure (“PAWP”), or merely
`
`“wedge.” (Ex. 1002 ¶ 22, FN 9.) Wedge pressure may be determined via
`
`5
`
`Ex. 2016-0015
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`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
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`1004 at 8; Ex. 1006 at 2781, 2782, Table 1.) As detailed in the literature, a high
`
`wedge pressure of, for example over 20 mm Hg, often indicated LVD, and the
`
`pediatric cardiologist thus knew not to treat the patient with iNO. (Ex. 1002 ¶ 22;
`
`Ex. 1004 at 8; Ex. 1006 at 2781, 2782, Table 1; Ex. 1015 at 1.) Indeed, pediatric
`
`cardiologists safely and effectively used iNO for at least nine years before the
`
`EPD. (Ex. 1002 ¶¶ 17, 24; Ex. 1004 at 3; Ex. 1014 at 2-3, 6.)
`
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`Petitioner certifies that (1) the ʼ284 Patent, issued on October 23, 2012, is
`
`available for IPR; (2) Petitioner is not barred or estopped from requesting an IPR
`
`on the grounds identified in this Petition; and (3) Petitioner has not filed any
`
`complaint relating to the ʼ284 Patent. This Petition is filed in accordance with 37
`
`C.F.R. § 42.106(a.) Concurrently filed herewith is a Power of Attorney and an
`
`Exhibit List per 37 C.F.R. § 42.10(b) and § 42.63(e), respectively.
`
`V.
`
`PAYMENT OF FEES (37 C.F.R. § 42.103)
`
`In accordance with 37 C.F.R. § 42.15 and § 42.103, Petitioner authorizes the
`
`USPTO to charge the required fees for IPR of 30 claims, and any additional fees,
`
`to Deposit Account 02-1818.
`
`measurement through cardiac catheterization or by extrapolation through
`
`echocardiography. (Ex. 1002 ¶ 22-23; Ex. 1006 at 2781; Ex. 1007 at 209; Ex.
`
`1012 at 75-79.)
`
`6
`
`Ex. 2016-0016
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`VI. MANDATORY NOTICES (37 C.F.R. § 42.8)
`A. Real-Parties-in-Interest
`Petitioner certifies that Praxair Distribution, Inc., with its head office at 28
`
`McCandless Ave, Pittsburgh, PA 15201, (“Praxair” or “Petitioner”) and Praxair,
`
`Inc., with its worldwide headquarters at 39 Old Ridgebury Rd., Danbury, CT
`
`06810 are the real parties-in-interest.
`
`B. Related Matters
`Petitioner is not aware of any current litigation involving the ʼ284 Patent.
`
`C. Lead and Backup Counsel (37 C.F.R. § 42.8(b)(3)) and Service
`Information (37 C.F.R. § 42.8(b)(4))
`
`Lead Counsel
`
`Backup Counsel
`
`Sanjay K. Murthy
`Reg. No. 45,976
`K&L GATES LLP
`70 W. Madison Street, Suite 3100
`Chicago, IL 60602
`sanjay.murthy@klgates.com
`T:(312) 807-4416
`F:(312) 827-8138
`
`Sara Kerrane
`Reg. No. 62,801
`K&L GATES LLP
`1 Park Plaza
`Twelfth Floor
`Irvine, CA 92614
`sara.kerrane@klgates.com
`T:(949) 623-3547
`F:(949) 623-4470
`
`Michael J. Abernathy
`Pro hac vice Authorization
`Requested
`K&L GATES LLP
`70 W. Madison Street, Suite 3100
`Chicago, IL 60602
`michael.abernathy@klgates.com
`T:(312) 807-4257
`F:(312) 827-8032
`
`
`
`7
`
`Ex. 2016-0017
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`Please address all correspondence and service to counsel listed above.
`
`Petitioner consents to service by email.
`
`VII. PERSON OF SKILL IN THE ART
`A person of ordinary skill in the art (“POSA”) is a hypothetical person who
`
`is presumed to know and be aware of the relevant prior art. (See IPR2013-00116
`
`at 9, 37.) A POSA is of ordinary creativity, not an automaton, and is capable of
`
`combining teachings of the prior art. (Id. (citing KSR Int’l Co. v. Teleflex Inc., 550
`
`U.S. 398, 420-421 (2007)).) With respect to the ʼ284 Patent, Petitioner submits
`
`that a POSA is a pediatric cardiologist with experience prescribing iNO before the
`
`EPD. (Ex. 1002 ¶¶ 26-27.) Such a POSA would have had knowledge of
`
`diagnostic techniques and scientific literature related to pediatric cardiology, and
`
`would have understood how to search the literature for relevant publications. (Id.)
`
`VIII. CLAIM CONSTRUCTION
`In accordance with 37 C.F.R. § 42.100(b), the challenged claims must be
`
`given their broadest reasonable interpretation in light of the specification of the
`
`ʼ284 Patent. (See Ex. 1002 ¶ 25.) The Patent Trial and Appeal Board (“Board”)
`
`interprets claims using the “broadest reasonable construction in light of the
`
`specification of the patent in which [they] appear[].” 37 C.F.R. § 42.100(b); Office
`
`Patent Trial Practice Guide, 77 Fed. Reg. 48756, 48766 (Aug. 14, 2012).
`
`Under this broadest reasonable interpretation standard, claim terms are
`
`8
`
`Ex. 2016-0018
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`generally given their ordinary and customary meaning, as would be understood by
`
`a POSA in the context of the disclosure, unless a special definition is clearly set for
`
`in the specification. In re Translogic Tech., Inc. 504 F.3d 1249, 1257 (Fed. Cir.
`
`2007); In re Paulsen, 30 F.3d 1475, 1480 (Fed. Cir. 1994). Here, a POSA would
`
`have understood all the terms of each of the claims of the ʼ284 Patent to have their
`
`plain and ordinary meaning.6
`
`IX. STATEMENTS OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. §§ 42.22(a) and 42.104(b))
`Petitioner requests inter partes review and cancellation of claims 1-30 on the
`
`grounds listed in the table below.
`
`Ground
`
`35 U.S.C.
`
`Index of References
`
`1
`
`2
`
`3
`
`§ 103
`
`§ 103
`
`§ 103
`
`Bernasconi, INOMAX label, Loh,
`and Goyal.
`
`Bernasconi, INOMAX label, Loh,
`Goyal, and Macrae.
`Ichinose, Neonatal Group, Macrae,
`Loh, Goyal, and Germann.
`
`ʼ284 Patent
`Claims
`1-3, 5-9, 11, 13,
`14, 16-18, 21, 23-
`27, and 29
`4, 10, 12, 15, 19,
`20, 22, 28, and 30
`1-30
`
`Per C.F.R. § 42.6(c), copies of the references are filed herewith.
`
`
`6 Any contention that terms should be construed to have a special meaning
`
`should be disregarded unless the Patent Owner amends the claims in
`
`compliance with 35 U.S.C. § 112 to make them expressly correspond to that
`
`meaning. See 77 Fed. Reg. 48764 at II.B.6 (Aug.14, 2012).
`
`9
`
`Ex. 2016-0019
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`Additionally, Petitioner provides the declaration of Dr. Maurice Beghetti in
`
`support of the grounds for challenging the claims. (Ex. 1002.)7
`
`Claims 1, 6, 13, and 23 are the four independent claims of the ʼ284 Patent.
`
`Independent claim 1 recites:
`
`A method of reducing the risk of occurrence of pulmonary edema associated
`with a medical treatment comprising inhalation of 20 ppm nitric oxide gas,
`said method comprising:
`(a) performing echocardiography to identify a term or near-term neonate
`patient in need of 20 ppm [iNO]8 treatment for pulmonary hypertension,
`wherein the patient is not dependent on right-to-left shunting of blood;
`(b) determining that the patient identified in (a) has a [wedge pressure]9
`greater than or equal to 20 mm Hg and thus has [LVD]10, so is at particular
`risk of pulmonary edema upon treatment with [iNO]; and
`
`7 Dr. Beghetti is the Head of Paediatric Cardiology at the University Hospital of
`
`Geneva in Geneva, Switzerland and is the lead author of the Bernasconi
`
`reference discussed below. He is a highly qualified expert in the field with
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`specific experience in pediatric cardiology and iNO. (Ex. 1002 ¶¶ 1-13, 28-32;
`
`Ex. 1003.)
`
`8 “Inhaled nitric oxide” is abbreviated as “iNO.”
`
`9 “Pulmonary capillary wedge pressure (PCWP)” abbreviated as “wedge
`
`pressure.” See FN 4.
`
`10 “Left ventricular dysfunction” is abbreviated as “LVD.”
`
`10
`
`Ex. 2016-0020
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`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`(c) excluding the patient from [iNO] treatment based on the determination
`that the patient has [LVD] and so is at particular risk of pulmonary edema
`upon treatment with [iNO].
`
`(Ex. 1001 at 14:7-25.) Independent claim 6 includes almost all of the same method
`
`steps as claim 1, except part (a) recites “carrying out a diagnostic process
`
`comprising measuring blood oxygen level, to identify a term or near-term neonate
`
`patient as being in need of 20 ppm [iNO] treatment for hypoxic respiratory failure,
`
`wherein the patient is not dependent on right-to-left shunting of blood.” (Ex. 1001
`
`at 14:44-49.)
`
`Independent claim 13 recites:
`
`A method of treatment comprising:
`(a) performing echocardiography to identify a plurality of term or near-term
`neonate patients who are in need of 20 ppm [iNO] treatment for pulmonary
`hypertension, wherein the patients are not dependent on right-to-left
`shunting of blood;
`(b) determining that a first patient of the plurality has a [wedge pressure]
`greater than or equal to 20 mm Hg and thus has [LVD], so is at particular
`risk of pulmonary edema upon treatment with [iNO];
`(c) determining that a second patient of the plurality does not have [LVD];
`(d) administering the 20 ppm [iNO] treatment to the second patient; and
`(e) excluding the first patient from treatment with [iNO], based on the
`determination that the first patient has [LVD], so is at particular risk of
`pulmonary edema upon treatment with [iNO].
`
`11
`
`Ex. 2016-0021
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`(Ex. 1001 at 15:11-30.) Independent claim 23 recites:
`
`A method of treatment comprising:
`(a) identifying a plurality of term or near-term neonate patients who are in
`need of 20 ppm [iNO] treatment, wherein the patients are not dependent on
`right-to-left shunting of blood;
`(b) in a first patient of the plurality, measuring [wedge pressure] to
`determine that the first patient of the plurality has a [wedge pressure] greater
`than or equal to 20 mm Hg and thus has [LVD], so is at particular risk of
`pulmonary edema upon treatment with [iNO];
`(c) in a second patient of the plurality, performing echocardiography and/or
`measurement of [wedge pressure] to determine that the second patient of the
`plurality does not have [LVD];
`(d) administering the 20 ppm [iNO] treatment to the second patient; and
`(e) excluding the first patient from treatment with [iNO], based on the
`determination that the first patient has [LVD], so is at particular risk of
`pulmonary edema upon treatment with [iNO].
`
`(Ex. 1001 at 16:7-29.)
`
`A. Ground 1: Independent Claims 1, 6, 13, and 23 and Dependent
`Claims 2-3, 5, 7-9, 11, 14, 16-18, 21, 24-27, and 29 Are
`Unpatentable Under 35 U.S.C. § 103(a) as Obvious Over
`Bernasconi, INOMAX label, Loh and Goyal
`As supported by Dr. Beghetti’s declaration, independent claims 1, 6, 13, and
`
`23, and dependent claims 2-3, 5, 7-9, 11, 14, 16-18, 21, 24-27, and 29 each would
`
`12
`
`Ex. 2016-0022
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`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`have been obvious to a POSA over Bernasconi, INOMAX label, Loh, and Goyal.11
`
`(Ex. 1002 ¶ 52-53.)
`
`1. Overview of Prior Art Applied in Ground 1
`Bernasconi (Ex. 1004), published in 2002, is a review of the delivery and
`
`monitoring aspects of iNO, including its applications in pediatric patients and
`
`potential risks with its use. (Ex. 1002 ¶ 33; Ex. 1004 at Abstract, 3, 8, 10, 12.)
`
`Bernasconi discloses that echocardiography is essential for identifying and treating
`
`pediatric patients with conditions that may be helped by iNO. (Ex. 1004 at 8; Ex.
`
`1002 ¶ 45.) Bernasconi further discloses a dosage of 20 ppm iNO to treat both
`
`hypoxic respiratory failure and pulmonary hypertension in neonates, and that the
`
`FDA recommended dose at the time of publication to treat neonatal hypoxic
`
`
`11 The preambles to independent claims 1 and 6 recite “[a] method of reducing the
`
`risk of occurrence of pulmonary edema associated with a medical treatment
`
`comprising inhalation of 20 ppm nitric oxide gas . . .” and claims 13 and 23
`
`recite a “[a] method of treatment . . .” (Ex. 1001 at 14:7-10, 40-43; 15:11;
`
`16:7.) These claims recite structurally complete methods without the preamble.
`
`See Catalina Mktg. Int'l, Inc. v. Coolsavings.com, Inc., 289 F.3d 801, 809 (Fed.
`
`Cir. 2002). Nonetheless, all the elements of the preamble are disclosed as
`
`described in Sections IX(A)(3)(a-c) and IX(A)(4)(a-e).
`
`13
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`Ex. 2016-0023
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`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,293,284
`
`respiratory failure was 20 ppm iNO. (Ex. 1004 at 3.) Additionally, Bernasconi
`
`discloses that iNO treatment may lead to pulmonary edema in patients with LVD.
`
`(Ex. 1004 at 8; Ex. 1002 ¶¶ 35-36.)
`
`INOMAX label (Ex. 1014) was submitted to the FDA in 1999 and was
`
`published before the end of 2000 when Ikaria’s New Drug Application was
`
`a