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.
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`Petitioner
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`v.
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`INO THERAPEUTICS, INC. d/b/a IKARIA, INC.
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`Patent Owner
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO. 8,431,163
`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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`
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`

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`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`Table of Contents
`
`Page
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`OVERVIEW .................................................................................................... 1
`
`Summary of the ʼ163 Patent .................................................................. 1
`A.
`Summary of the Prosecution History of the ʼ163 Patent ...................... 3
`B.
`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.
`B.
`C.
`
`Real-Parties-in-Interest .......................................................................... 7
`Related Matters ...................................................................................... 7
`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 ORDINARY 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, 12, and 20 and Dependent
`Claims 2, 4, 7, 9, 11, 13, 15, 18, 21, 23, and 25 Are Unpatentable
`Under 35 U.S.C. § 103(a) as Obvious Over Bernasconi in View of
`the 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 12 .................................................... 19
`(a)
`Part (a) of Independent Claims 1 and 12 ........................ 19
`
`i
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`

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`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
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`4.
`
`(b)
`Part (b) of Independent Claims 1 and 12 ........................ 21
`Part (c) of Independent Claims 1 and 12 ........................ 23
`(c)
`Independent Claims 6 and 20 .................................................... 24
`(a)
`Part (a) of Independent Claims 6 and 20 ........................ 24
`(b)
`Part (b) of Independent Claims 6 and 20 ........................ 25
`(c)
`Part (c) of Independent Claims 6 and 20 ........................ 25
`(d)
`Part (d) of Independent Claims 6 and 20 ........................ 27
`(e)
`Part (e) of Independent Claims 6 and 20 ........................ 27
`Dependent Claims 2, 4, 7, 9, 11, 13, 15, 18, 21, 23, and 25 ..... 28
`(a) Dependent Claims 2, 11, 13, and 25 ............................... 29
`(b) Dependent Claims 4, 9, 15, 18, and 23 ........................... 30
`(c) Dependent Claims 7 and 21 ............................................ 31
`Ground 2: Dependent Claims 3, 5, 8, 10, 14, 16, 17, 19, 22, and 24
`Are Unpatentable Under 35 U.S.C. § 103(a) as Obvious Over
`Bernasconi, the INOMAX label, Loh, Goyal, and Macrae ................. 31
`Ground 3: Independent Claims 1, 6, 12, and 20 and Dependent
`Claims 2-5, 7-11, 13-19, and 21-25 Are Unpatentable Under 35
`U.S.C. § 103(a) as Obvious Over Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal ........................................................ 33
`1.
`Overview of Prior Art Applied in Ground 3 ............................. 34
`2. Motivation to Combine Art Applied in Ground 3 .................... 35
`3.
`Independent Claims 1 and 12 .................................................... 37
`(a)
`Part (a) of Independent Claims 1 and 12 ........................ 37
`(b)
`Part (b) of Independent Claims 1 and 12. ....................... 39
`(c)
`Part (c) of Independent Claims 1 and 12 ........................ 40
`Independent Claims 6 and 20 .................................................... 41
`(a)
`Part (a) of Independent Claims 6 and 20 ........................ 42
`(b)
`Part (b) of Independent Claims 6 and 20 ........................ 42
`(c)
`Part (c) of Independent Claims 6 and 20 ........................ 43
`(d)
`Part (d) of Independent Claims 6 and 20 ........................ 44
`
`5.
`
`4.
`
`B.
`
`C.
`
`ii
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
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`5.
`
`(e)
`Part (e) of Independent Claims 6 and 20 ........................ 44
`Dependent Claims 2-5, 7-11, 13-19, and 21-25 ........................ 45
`(a) Dependent Claims 2, 11, 13, and 25 ............................... 46
`(b) Dependent Claims 3, 5, 8, 10, 14, 16, 17, 19, 22, and
`24 .................................................................................... 46
`(c) Dependent Claims 4, 9, 15, 18, and 23 ........................... 47
`(d) Dependent Claims 7 and 21 ............................................ 48
`CONCLUSION .............................................................................................. 48
`
`X.
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`
`
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`iii
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`List of Exhibits
`Ex. 1001: U.S. Patent No. 8,431,163 to Baldassarre et al. (“ʼ163 Patent), filed
`
`October 15, 2012, issued April 30, 2013.
`
`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
`
`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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`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
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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
`
`in Full-Term and Nearly Full-Term Infants with Hypoxic Respiratory
`
`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
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
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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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`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`Ex. 1021: Chemla,
`
`et al., Haemodynamic Evaluation of Pulmonary
`
`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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`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`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: Reserved.
`
`Ex. 1037: Reserved.
`
`Ex. 1038: Reserved.
`
`Ex. 1039: Claim Chart for Claims 1, 2, 4, 6, 7, 9, 11-13, 15, 18, 20, 21, 23, and
`
`25.
`
`Ex. 1040: Claim Chart for Claims 3, 5, 8, 10, 14, 16, 17, 19, 22, and 24.
`
`Ex. 1041: Claim Chart for Claims 1–25.
`
`Ex. 1042: Reserved.
`
`Ex. 1043: Reserved.
`
`viii
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`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`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: Prosecution History for U.S. Patent No. 8,282,966.
`
`Ex. 1053: Prosecution History for U.S. Patent No. 8,293,284.
`
`Ex. 1054: Prosecution History for U.S. Patent No. 8,431,163.
`
`
`
`
`
`ix
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`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 to 25 of U.S. Patent No. 8,431,163 (“the ʼ163 Patent”). (Ex. 1001.)
`
`II. OVERVIEW
`Summary of the ʼ163 Patent
`A.
`Nitric oxide (“NO”) is a gaseous chemical compound used to treat patients
`
`with severe breathing problems. In 2000, the U.S. Food and Drug Administration
`
`(“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
`
`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
`
`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 ʼ163 Patent to impermissibly extend its patent
`
`protection for INOMAX®.1
`
`
`1 By adding the ʼ163 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.
`
`1
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`Indeed, Ikaria filed the application leading to the ʼ163 Patent eleven years
`
`after INOMAX® was approved. Yet the ʼ163 Patent does not relate to any
`
`inventive method of treating a patient with iNO or using iNO. To the contrary, it
`
`discloses a series of well-known diagnostic steps and analyses to determine
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`whether the patient is at risk of a Serious Adverse Event2, such as pulmonary
`
`edema, if treated with iNO and excluding such patients from treatment based on
`
`the assessed risk. (Id. at Abstract; 1:47-60; Ex. 1002 ¶ 14.) Methods of evaluating
`
`and excluding patients from treatment with iNO were known long before June 30,
`
`2009, the earliest possible priority date (“EPD”) of the ʼ163 Patent.
`
`The claims of the ʼ163 Patent merely combine well-known methods and
`
`techniques (e.g., echocardiography3, 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 1-14; Ex. 1009 at 3108.) These conventional
`
`practices are described 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
`
`
`2 “Serious Adverse Event” is a statutorily defined term of art. (See 21 C.F.R.
`
`§ 312.32; Ex. 1002 ¶ 37; Ex. 1013.)
`
`3 Echocardiography is the use of ultrasound waves to investigate the actions of
`
`the heart. (See Ex. 1002 ¶ 15, FN 4.)
`
`2
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`associated with using iNO. Accordingly, this Petition should be granted and trial
`
`instituted on all of the challenged claims.
`
`Summary of the Prosecution History of the ʼ163 Patent
`
`B.
`The application leading to the ’163 Patent was filed on October 15, 2012.
`
`(Ex. 1001.) On January 11, 2013, the Examiner issued a double patenting rejection
`
`over (i) U.S. Patent No. 8,282,966; (ii) U.S. Patent No. 8,293,284; and (iii) co-
`
`pending U.S. Serial No. 13/683,417 (now U.S. Patent No. 8,795,741), all three of
`
`which were also examined by the same Examiner.4 (Ex. 1054 at 137.) The
`
`Examiner did not reject any of the claims over the prior art because, as discussed
`
`below, the claims of the application leading to the ’163 Patent already included
`
`elements (namely, 20 parts per million (“ppm”) iNO and determining the wedge
`
`pressure was greater than or equal to 20 mm Hg) that the Examiner (incorrectly)
`
`believed distinguished the claims over the prior art, as he had found in
`
`prosecutions for (i) U.S. Patent No. 8,282,966 (see Ex. 1052 at 986) and (ii) U.S.
`
`Patent No. 8,293,284 (see Ex. 1053 at 965). Applicants filed terminal disclaimers
`
`to overcome the double patenting rejections.
`
`On February 4, 2013, the Examiner issued a notice of allowance including
`
`the following Examiner’s statement of reasons for allowance:
`
`4 Petitioner has concurrently filed petitions for inter partes review of each of
`
`these three patents, as well as U.S. Patent No. 8,846,112, all owned by Ikaria.
`
`3
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`Applicant’s amendments have overcome the rejections of record. The
`instantly claimed subject matter is free of the art. See US Patents 8282966
`and 8293284 for a complete rationale. (Ex. 1054 at 466, emphasis added;
`see also Ex. 1052 and Ex. 1053.)
`On February 15, 2013, Applicants filed general comments that they did not
`
`concede that the rationale from the prosecutions of U.S. Patent Nos. 8,282,966 and
`
`8,293,284 fully applied to the present case. (Ex. 1054 at 501.)
`
`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, a condition that 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; Ex. 1004 at
`
`8.) iNO is a selective pulmonary vasodilator that relaxes pulmonary vessels,
`
`decreasing 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
`
`4
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
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`of treatment. (See Ex. 1004 at 8.) Specifically, it was well known that pediatric
`
`cardiologists had to examine and evaluate patients before administering iNO to
`
`determine: (1) whether the treatment would likely to benefit the patient and (2)
`
`whether the patient would be at risk of reacting negatively to the treatment. (Ex.
`
`1002 ¶¶ 17, FN 6, 19; Ex. 1004 at 8.)
`
`It was also known before the EPD that patients with either systolic or
`
`diastolic left ventricular dysfunction (“LVD”) should not be treated with iNO
`
`because they could have an increased risk of suffering a Serious Adverse Event,
`
`such as pulmonary edema.5 (Ex. 1002 ¶¶ 17-18; 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
`
`echocardiography, to determine whether the patient had LVD, or any other
`
`condition contraindicating use of iNO. (Ex. 1002 ¶¶ 15, 19-21; Ex. 1004 at 8; Ex.
`
`1008 at 373-374.)
`
`Before the EPD, pediatric cardiologists also used wedge pressure to confirm
`
`whether the patient could be safely treated with iNO.6 (Ex. 1002 ¶¶ 15, 22; Ex.
`
`5 Pulmonary edema is a buildup of fluid in the lungs. (Ex. 1002 ¶ 14, FN 3.)
`
`6 “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
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`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. 1022 ¶ 22;
`
`Ex. 1004 at 8; Ex. 1006 at 2781, 2782, Table 1; Ex. 1015 at 1.) Indeed, pediatric
`
`cardiologists had been safely and effectively using iNO for at least nine years
`
`before the EPD. (Ex. 1002 ¶ 17, 24; Ex. 1004 at 3.)
`
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`Petitioner certifies that (1) the ʼ163 Patent, issued on April 30, 2013, 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 ʼ163 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 25 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
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`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 ʼ163 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
`
`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`Please address all correspondence and service to counsel listed above.
`
`Petitioner consents to service by email.
`
`VII. PERSON OF ORDINARY 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
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`combining teachings of the prior art. (Id. (citing KSR Int’l Co. v. Teleflex Inc., 550
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`U.S. 398, 420-421 (2007)).) With respect to the ’163 Patent, Petitioner submits
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`that a POSA is a pediatric cardiologist with experience prescribing iNO before the
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`EPD. (Ex. 1002 ¶¶ 26-27.) Such a POSA would have had knowledge of
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`diagnostic techniques and scientific literature related to pediatric cardiology, and
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`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
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`‘163 Patent. (See Ex. 1002 ¶ 25.) The Patent Trial and Appeal Board (“Board”)
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`interprets claims using the “broadest reasonable construction in light of the
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`specification of the patent in which [they] appear[].” 37 C.F.R. § 42.100(b); Office
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`Patent Trial Practice Guide, 77 Fed. Reg. 48756, 48766 (Aug. 14, 2012).
`
`8
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`A POSA would have understood all the terms of each of the claims of the
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`‘163 Patent to have their plain and ordinary meaning.7
`
`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 1-25 on the
`
`grounds listed in the table below.
`
`
`
`Ground
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`35 U.S.C.
`
`Index of References
`
`1
`
`2
`
`3
`
`§ 103
`
`§ 103
`
`§ 103
`
`Bernasconi in view of INOMAX
`label, Loh, and Goyal.
`
`Bernasconi in view of INOMAX
`label, Loh, Goyal and Macrae.
`Ichinose in view of Macrae,
`Germann, Neonatal Group, Loh,
`and Goyal.
`
`ʼ163 Patent
`Claims
`1, 2, 4, 6, 7, 9, 11-
`13, 15, 18, 20, 21,
`23, and 25
`3, 5, 8, 10, 14, 16,
`17, 19, 22, and 24
`1-25
`
`
`
`Per C.F.R. § 42.6(c), copies of the references are filed herewith.
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`Additionally, Petitioner provides the declaration of Dr. Maurice Beghetti in
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`support of the grounds for challenging the claims. (Ex. 1002.)8
`
`
`7 Any contention that terms should be construed to have a special meaning
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`should be disregarded unless the Patent Owner amends the claims in
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`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
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`Claims 1, 6, 12, and 20 are the four independent claims of the ʼ163 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] 9 treatment for hypoxic respiratory failure,
`wherein the patient is not dependent on right-to-left shunting of blood;
`(b) determining that the patient identified in (a) has [LVD] 10 consistent with
`a [wedge pressure]11 greater than or equal to 20 mm Hg, so is at particular
`risk of pulmonary edema upon treatment with [iNO]; and
`
`
`8 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
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`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;
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`Ex. 1003.)
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`9 “Inhaled nitric oxide” is abbreviated as “iNO.”
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`10 “Left ventricular dysfunction” is abbreviated as “LVD.”
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`11 “Pulmonary capillary wedge pressure (PCWP)” abbreviated as “wedge
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`pressure.” (See Ex. 1002 ¶ 22 FN 9.)
`
`10
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
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`(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 14:18-36.)
`
`Independent claim 12 includes almost all of the same method steps as claim
`
`1, except part (c) recites “excluding the patient from [iNO] treatment, or, despite
`
`the patient’s ongoing need for treatment for hypoxic respiratory failure,
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`discontinuing the treatment after it has begun, the exclusion or discontinuation
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`being based on the determination that the patient has [LVD] and so is at particular
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`risk of pulmonary edema upon treatment with [iNO].” (Ex. 1001 at 15:26-46.)
`
`Independent claim 6 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 hypoxic
`respiratory failure, wherein the patients are not dependent on right-to-left
`shunting of blood;
`(b) determining that a first patient of the plurality has [LVD] consistent with
`a [wedge pressure] greater than or equal to 20 mm Hg, 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 [iNO] treatment, based on the
`determination that the first patient has [LVD], so is at particular risk of
`pulmonary edema upon treatment with [iNO].
`
`11
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`(Ex. 1001 at 14:51-15:3.)
`
`Independent claim 20 includes almost all of the same method steps as claim
`
`6 except part (e) recites “excluding the first patient from [iNO] treatment, or,
`
`despite the first patient’s ongoing need for treatment for hypoxic respiratory
`
`failure, discontinuing the first patient’s treatment with [iNO] after it was begun, the
`
`exclusion or discontinuation being based on the determination that the first patient
`
`has [LVD] and so is at particular risk of pulmonary edema upon treatment with
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`[iNO].” (Ex. 1001 at 16:19-42.)
`
`A. Ground 1: Independent Claims 1, 6, 12, and 20 and Dependent
`Claims 2, 4, 7, 9, 11, 13, 15, 18, 21, 23, and 25 Are Unpatentable
`Under 35 U.S.C. § 103(a) as Obvious Over Bernasconi in View of
`the INOMAX label, Loh, and Goyal
`As supported by Dr. Beghetti’s declaration, independent claims 1, 6, 12, and
`
`20, and dependent claims 2, 4, 7, 9, 11, 13, 15, 18, 21, 23, and 25 each would have
`
`been obvious to a POSA in view of Bernasconi, the INOMAX label, Loh, and
`
`Goyal.12 (Ex. 1002 ¶ 52-54; Ex. 1039.)
`
`
`12 The preambles to independent claims 1 and 12 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 the preamble to
`
`claims 6 and 20 recite “[a] method of treatment . . . ” (Ex. 1001 at 14:18-21, 51;
`
`15:26-29; 16:17.) These claims recite structurally complete methods without
`
`12
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`

`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
`
`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 ¶¶ 34, 46-47.) 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
`
`respiratory failure was 20 ppm iNO. (Ex. 1004 at 3.) Additionally, Bernasconi
`
`warns that iNO treatment may lead to pulmonary edema in patients with LVD.
`
`(Ex. 1004 at 8; Ex. 1002 ¶¶ 35-36.)
`
`The 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
`
`approved. (See Ex. 1014; see also Ex. 1001 at 3:31-42.) The INOMAX label
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`discloses the uses and contraindications for iNO treatment. (Ex. 1014 at 2-6.) It
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`discloses the use of echocardiography to identify patients with pulmonary
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`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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`

`Petition for Inter Partes Review of U.S. Patent No. 8,431,163
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`hypertension and/or hypoxic respiratory failure in need of iNO treatment, and the
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`FDA recommended dosage of iNO for treatment is 20 ppm. (Id.) It also discloses
`
`contraindications for iNO treatment, such as dependency on right-to-left shunting
`
`of blood. (Id. at 4.)
`
`Loh (Ex. 1006), published in 1994 and a seminal work in the field of iNO,
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`studied the hemodynamic effects of iNO in patients with severe heart failure
`
`associated with LVD. (Ex. 1002 ¶¶ 40, 50; Ex. 1006 at Abstract, 2780.) Loh
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`discloses that (i) a catheter was placed in each patient and a baseline wedge
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`pressure wa