IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`
`
`
`
`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. 8,846,112
`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
`
`Ex. 2016-0001
`
`

`
`Table of Contents
`
`I.
`
`II.
`
`INTRODUCTION ........................................................................................... 1
`
`OVERVIEW OF THE ’112 PATENT ............................................................ 1
`
`A.
`
`B.
`
`Summary of the ’112 Patent .................................................................. 1
`
`Summary of the Prosecution History of the ’112 Patent ...................... 2
`
`III. BACKGROUND OF THE TECHNOLOGY .................................................. 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) ............................................... 6
`
`A.
`
`B.
`
`C.
`
`Real Parties-In-Interest .......................................................................... 6
`
`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 SKILL IN THE ART AND STATE OF THE ART ................. 7
`
`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)) .................. 8
`
`A. Ground 1: Claims 1-19 Are Unpatentable Under 35 U.S.C. §
`103(a) As Obvious Over Bernasconi in View of INOMAX label,
`Loh, and Goyal ....................................................................................11
`
`1.
`
`Overview of the Prior Art .........................................................11
`
`2. Motivation to Combine .............................................................14
`
`3.
`
`Independent Claims 1, 7, 12 and 14 ..........................................19
`
`
`
`
`
`(a)
`
`Part (a) of Independent Claims 1, 7, 12 and 14 ..............19
`
`
`
`(i)
`
`Part (a) of Independent Claims 1 and 7 ................19
`
`i
`
`Ex. 2016-0002
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(ii) Part (a) of Independent Claim 12 .........................19
`
`(iii) Part (a) of Independent Claim 14 .........................19
`
`(b)
`
`Part (b) of Independent Claims 1, 7, 12 and 14 ..............20
`
`
`
`
`
`(c)
`
`(d)
`
`
`
`
`
`(i)
`
`Part (b) of Independent Claims 1 and 7 ...............20
`
`(ii) Part (b) of Independent Claims 12 and 14 ...........21
`
`Part (c) of Independent Claims 1, 7, 12 and 14 ..............21
`
`Part (d) of Independent Claims 1, 7, 12 and 14 ..............21
`
`(i)
`
`Part (d) of Independent Claims 1, 12 and 14 .......21
`
`(ii) Part (d) of Independent Claim 7 ...........................24
`
`4.
`
`Dependent Claims 2-6, 8-11, 13, 15-19 ....................................25
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(a) Dependent Claims 2, 5, 6, 13 and 15 ..............................25
`
`(b) Dependent Claim 8 .........................................................27
`
`(c) Dependent Claims 3, 9, 16 and 18 ..................................28
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(i) Dependent Claim 3 ...............................................28
`
`
`
`
`
`
`
`
`
`1. Part (a) of Dependent Claim 3 ......................29
`
`2. Part (b) of Dependent Claim 3......................30
`
`3. Part (c) of Dependent Claim 3 ......................30
`
`4. Parts (d) and (3) of Dependent Claim 3 .......31
`
`(ii) Dependent Claims 16 and 18 ...............................31
`
`(iii) Dependent Claim 9 ...............................................33
`
`
`
`
`
`
`
`1. Part (a) of Dependent Claim 9 ......................33
`
`2. Part (b) of Dependent Claim 9......................34
`
`3. Part (c) of Dependent Claim 9 ......................34
`
`ii
`
`Ex. 2016-0003
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`4. Part (d) of Dependent Claim 9......................34
`
`(d) Dependent Claims 4, 17 and 19 ......................................35
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(i) Dependent Claim 4 ...............................................35
`
`
`
`
`
`
`
`1. Parts (a)-(d) of Dependent Claim 4 ..............35
`
`2. Parts (e) and (f) of Dependent Claim 4 ........36
`
`3. Parts (g) and (h) of Dependent Claim 4 .......37
`
`(ii) Dependent Claims 17 and 19 ...............................38
`
`
`
`
`
`
`
`1. Parts (a)-(c) of Claims 17 and 19 .................39
`
`2. Parts (d) and (e) of Claims 17 and 19 ...........39
`
`3. Parts (f) and (g) of Claims 17 and 19 ...........40
`
`(e) Dependent Claims 10 and 11 ..........................................41
`
`B.
`
`Ground 2: Independent Claims 1-19 Are Unpatentable Under 35
`U.S.C. § 103(a) As Obvious Over Ichinose in View of INOMAX
`label, Neonatal Group, Loh, and Goyal ..............................................42
`
`1.
`
`Overview of Prior Art ...............................................................42
`
`2. Motivation to Combine .............................................................43
`
`3.
`
`Independent Claims 1, 7, 12 and 14 ..........................................46
`
`
`
`
`
`
`
`
`
`(a)
`
`(b)
`
`
`
`
`
`Parts (a)-(c) of Independent Claims 1, 7, 12 and 14.......46
`
`Part (d) of Independent Claims 1, 7, 12 and 14 ..............47
`
`(i)
`
`Part (d) of Independent Claims 1, 12 and 14 .......47
`
`(ii) Part (d) of Independent Claim 7 ...........................48
`
`4.
`
`Dependent Claims 2-6, 8-11, 13, 15-19 ....................................49
`
`
`
`
`
`(a) Dependent Claims 2, 5, 6, 13 and 15 ..............................49
`
`(b) Dependent Claim 8 .........................................................50
`
`iii
`
`Ex. 2016-0004
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(c) Dependent Claims 3, 9, 16 and 18 ..................................51
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(i) Dependent Claim 3 ...............................................51
`
`
`
`
`
`
`
`
`
`1. Part (a) of Claim 3 ........................................51
`
`2. Part (b) of Claim 3 ........................................51
`
`3. Part (c) of Claim 3 ........................................52
`
`4. Parts (d) and (e) of Claim 3 ..........................52
`
`(ii) Dependent Claims 16 and 18 ...............................53
`
`(iii) Dependent Claim 9 ...............................................54
`
`
`
`
`
`
`
`
`
`1. Part (a) of Claim 9 ........................................54
`
`2. Part (b) of Claim 9 ........................................54
`
`3. Part (c) of Claim 9 ........................................55
`
`4. Part (d) of Claim 9 ........................................55
`
`(d) Dependent Claims 4, 17 and 19 ......................................56
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(i) Dependent Claim 4 ...............................................56
`
`
`
`
`
`
`
`1. Parts (a) through (d) of Claim 4 ...................56
`
`2. Parts (e) and (f) of Claim 4 ...........................57
`
`3. Parts (g) and (h) of Claim 4 ..........................58
`
`(ii) Dependent Claims 17 and 19 ...............................58
`
`
`
`
`
`
`
`1. Parts (a) through (c) of Claims 17 and 19 ....58
`
`2. Parts (d) and (e) of Claims 17 and 19 ...........59
`
`3. Parts (f) and (g) of Claims 17 and 19 ...........59
`
`(e) Dependent Claims 10 and 11 ..........................................59
`
`X.
`
`CONCLUSION ..............................................................................................60
`
`iv
`
`Ex. 2016-0005
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`
`
`List of Exhibits
`
`Ex. 1001: U.S. Patent No. 8,846,112 to Baldassarre et al. (“ʼ112 patent), filed
`
`November 21, 2012, issued September 30, 2014.
`
`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: Reserved
`
`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
`
`Children: Reaching a European Consensus, 30 Intensive Care
`
`Medicine, 372-380 (2004). (“Macrae”).
`
`v
`
`Ex. 2016-0006
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`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 at 1030
`
`(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, M. et al. Non-Invasive Estimation of Left Ventricular Filling
`
`Pressures by Doppler Echocardiography. Eur J Echocardiogr. 3:75–9
`
`(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
`
`20845,
`
`INOMAX, Final Printed Labeling,
`
`available
`
`at
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20845_inoma
`
`vi
`
`Ex. 2016-0007
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`x_prntlbl.pdf (August 9, 2000). (“INOMAX label”).
`
`Ex. 1015: Reserved
`
`Ex. 1016: Reserved
`
`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”).
`
`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
`
`vii
`
`Ex. 2016-0008
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`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: Reserved
`
`Ex. 1029: Reserved
`
`Ex. 1030: Henrichsen, et al., Inhaled Nitric Oxide can Cause Severe Systemic
`
`Hypotension, 129 The
`
`Journal of Pediatrics, 183
`
`(1996).
`
`(“Henrichsen”).
`
`Ex. 1031: Reserved
`
`Ex. 1032: Reserved
`
`Ex. 1033: Reserved
`
`Ex. 1034: Reserved
`
`viii
`
`Ex. 2016-0009
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`Ex. 1035: Reserved
`
`Ex. 1036: Reserved
`
`Ex. 1037: Reserved
`
`Ex. 1038: Reserved
`
`Ex. 1039: Reserved
`
`Ex. 1040: Reserved
`
`Ex. 1041: Reserved
`
`Ex. 1042: Reserved
`
`Ex. 1043: Reserved
`
`Ex. 1044: Reserved
`
`Ex. 1045: Reserved
`
`Ex. 1046: Reserved
`
`Ex. 1047: Reserved
`
`Ex. 1048: Claim Chart demonstrating how Bernasconi in view of INOMAX
`
`label, Loh, and Goyal disclose each and every element of claims 1-19.
`
`Ex. 1049: Claim Chart demonstrating how Ichinose in view of INOMAX label,
`
`Neonatal Group, Loh, and Goyal discloses each and every element of
`
`claims 1-19.
`
`Ex. 1050: Reserved
`
`Ex. 1051: Reserved
`
`ix
`
`Ex. 2016-0010
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`Ex. 1052: Reserved
`
`Ex. 1053: Reserved
`
`Ex. 1054: Reserved
`
`Ex. 1055: Reserved
`
`Ex. 1056: Prosecution History of U.S. Patent No. 8,846,112.
`
`
`
`x
`
`Ex. 2016-0011
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`I.
`
`INTRODUCTION
`Praxair Distribution, Inc. (“Petitioner”) petitions for inter partes Review
`
`(“IPR”) under 35 U.S.C. §§ 311–319 and 37 C.F.R. § 42 of Claims 1 to 19 of U.S.
`
`Patent No. 8,846,112 (“the ʼ112 patent”). (Ex. 1001.)
`
`II. OVERVIEW OF THE ’112 PATENT
`Summary of the ’112 Patent
`A.
`Nitric oxide (“NO”) is a gaseous compound used, among other things, to
`
`treat infants 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 (born after the 33rd week of pregnancy) with respiratory failure.
`
`(See Ex. 1002 ¶¶ 18-20.) Patent Owner INO Therapeutics, LLC d/b/a Ikaria, Inc.
`
`(“PO”) is the exclusive iNO supplier in the U.S.; it sells iNO under the brand
`
`INOMAX®. PO’s original patents covering iNO expired in 2013. PO has tried to
`
`use the ʼ112 patent to impermissibly extend its patent protection for INOMAX®.1
`
`PO filed the application that issued as the ʼ112 patent nine years after it
`
`released INOMAX® into the market. The ʼ112 patent, however, does not relate to
`
`
`1 By adding the ʼ112 patent to the Orange Book, PO seeks to extend its monopoly
`
`until 2029—33 years after issue of the original INOMAX® patents. Petitioner is
`
`filing petitions for inter partes review of four other such patents concurrently
`
`herewith: U.S. Patent Nos. 8,292,966; 8,293,284; 8,431,163; and 8,795,741.
`
`1
`
`Ex. 2016-0012
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`an inventive method of using iNO. The ʼ112 patent instead claims methods of
`
`providing information about potential contraindications for iNO therapy and
`
`instructions for the potential exclusion of patients from therapy based thereon.
`
`(See, e.g., Ex. 1001 at 14:28-52 and 14:57-15:7; 15:8-33; Ex. 1002 ¶¶ 14-16.) It
`
`claims methods of potentially excluding patients determined to have left
`
`ventricular dysfunction (“LVD”) from treatment with iNO. (See, e.g., Ex. 1001 at
`
`14:41-52, 14:57-15:7; Ex. 1002 ¶¶ 14-16.) Yet methods for warning healthcare
`
`providers of contraindications of iNO and excluding patients contraindicated for
`
`treatment with iNO were known by those skilled in the art long before June 30,
`
`2009, the earliest potential priority date (“EPD”) of the ʼ112 patent.
`
`As described below, the claims of the ʼ112 patent are nothing more than a
`
`combination of well-known knowledge, methods, and techniques for determining
`
`whether patients can be safely treated with iNO. These conventional practices are
`
`described in the literature, including the prior art references relied on herein.
`
`Summary of the Prosecution History of the ’112 Patent
`
`B.
`The application leading to the ’112 patent was filed on November 21, 2012.
`
`(See generally Ex. 1056.) On January 3, 2013, the Examiner rejected the claims
`
`under 35 U.S.C. § 101, stating that the claims were “directed to mental processes
`
`which are non-statutory subject matter.” (Ex. 1056 at 222-27.) The Examiner
`
`stated that “[t]he Examiner cannot see how a method of: ‘Here, take this nitric
`
`2
`
`Ex. 2016-0013
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`oxide gas source, but do not do anything with it’ is patent eligible.” (Id. at 542.)
`
`PO amended the claims on April 2, 2013, and argued that its claims required active
`
`steps and thus were not patent ineligible. (Id. at 285-307.) Not satisfied, the
`
`Examiner issued a final rejection on April 24, 2013, finding that the parent
`
`applications did not disclose a “method of distributing a pharmaceutical product,”
`
`and thus finding that Applicant would be afforded a filing date of November 21,
`
`2012. (Id. at 325.) The Examiner also maintained the previous rejection under 35
`
`U.S.C. § 101. (Id. at 326-29.) Finally, the Examiner rejected the claims as
`
`obvious. (Id. at 329-38.) In response, PO filed for a correction of inventorship (id.
`
`at 354) and filed a response with
`
`three affidavits from
`
`two different
`
`employees/partial owners of PO in support of the alleged patentability of the
`
`claims (id. at 378-686). The affidavits allegedly supported arguments for non-
`
`obviousness and that a prior art reference that pre-dated the EPD by more than 11
`
`months should not be prior art because the sole inventor conceived and reduced to
`
`practice 11 months before filing the patent application. (See id.) The Examiner
`
`issued another rejection, again asserting that the priority claim was improper and
`
`that the claims were invalid as obvious. (Id. at 690-721.) PO again amended the
`
`claims and argued that its priority claim supported the pending claims, and
`
`therefore that the primary reference involved in the rejection under 35 U.S.C. §
`
`103 should be disqualified as prior art. (Id. at 735-51.) After a final rejection
`
`3
`
`Ex. 2016-0014
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`containing non-statutory obviousness-type double patenting rejections, PO filed the
`
`necessary terminal disclaimers and the ’112 patent issued on September 30, 2014.
`
`III. BACKGROUND OF THE TECHNOLOGY
`A condition called hypoxic respiratory failure can occur when cells receive
`
`insufficient oxygen. (Ex. 1002 ¶ 21.) Hypoxic respiratory failure can lead to
`
`hypoxia, a condition characterized by low oxygen in organs and thus the tissues do
`
`not to have enough oxygen to function normally. (Ex. 1002 ¶ 21.) Nine years
`
`before the EPD of the ’112 patent, the Food and Drug Administration (“FDA”)
`
`approved the use 20 parts per million (“ppm”) iNO to treat neonatal hypoxic
`
`respiratory failure; INOMAX label reference (Ex. 1014 hereto) is an early version
`
`of the FDA approved label for iNO. (Ex. 1002 ¶ 30.)
`
`Before the EPD, providers of nitric oxide (“NO”) gas for iNO therapy
`
`provided administering instructions and contraindications. (See generally Ex.
`
`1014; Ex. 1002 ¶ 30.) Based on these instructions and contraindications, medical
`
`providers evaluated patients before administering iNO to determine: (1) whether
`
`treatment was likely to benefit the patient; and (2) whether the patient was at risk
`
`of negative reaction to the treatment. (Ex. 1002 ¶ 29.)
`
`Beyond the FDA approved information in INOMAX label, it was well
`
`known before the EPD that when a neonatal patient exhibited symptoms of
`
`hypoxic respiratory failure, the pediatric cardiologist would initiate diagnostic tests
`
`4
`
`Ex. 2016-0015
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`to assess treatment options. (See Ex. 1004 at 8-9; Ex. 1002 ¶¶ 22-29.) It was also
`
`well known before the EPD that patients with LVD may have an increased risk of
`
`harm from events such as pulmonary edema upon treatment with iNO.2 (Ex. 1004
`
`at 8; Ex. 1009 at 3109; Ex. 1002 ¶ 22.) Thus, before prescribing iNO prior to the
`
`EPD, pediatric cardiologists knew
`
`to order diagnostic
`
`tests, such as
`
`echocardiography3, to determine whether the patient had LVD or other conditions
`
`contraindicating the use of iNO. (Ex. 1004 at 8; Ex. 1002 ¶ 26.)
`
`Prior to the EPD, pediatric cardiologists also knew that wedge pressure4
`
`could indicate whether the patient could safely be treated with iNO. (Ex. 1004 at 8;
`
`Ex. 1006 at 2781, 2782, Table 1; Ex. 1002 ¶ 27.) It was known prior to the EPD
`
`that a wedge pressure of >20 mm Hg could indicate LVD; pediatric cardiologist
`
`determining a wedge pressure of >20 mm Hg thus knew that the patient would be
`
`at risk of Adverse Events if treated with iNO. (See Ex. 1004 at 8; Ex. 1006 at
`
`2 Pulmonary edema is a buildup of fluid in the lungs. (Ex. 1002 ¶ 14.)
`
`3 Echocardiography is the use of ultrasound waves to image and investigate the
`
`heart. (See Ex. 1002 ¶ 16, FN 6.)
`
`4 “Wedge pressure” can be referred to as pulmonary capillary wedge pressure
`
`(“PCWP”), pulmonary arterial wedge pressure (“PAWP”), or “wedge.” (Ex. 1002
`
`¶ 16 FN 5.) It may be determined by measuring through cardiac catheterization or
`
`by extrapolation through echocardiography. (Ex. 1002 ¶¶ 27-28.)
`
`5
`
`Ex. 2016-0016
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`2781, 2782, Table 1; Ex. 1002 ¶ 27.)
`
`Written prior art describing pediatric cardiologists’ safe, effective use of
`
`iNO for at least nine years before the EPD, in combination with the early FDA
`
`approved label for iNO treatment in neonates with hypoxic respiratory failure,
`
`renders the claims of the ’112 patent obvious as discussed in more detail below.
`
`IV. GROUNDS FOR STANDING (37 C.F.R. § 42.104(a))
`Petitioner certifies that (1) the ʼ112 patent, issued on September 30, 2014, is
`
`available for IPR; (2) Petitioner is not barred or estopped from requesting inter
`
`partes review of the ʼ112 patent on the grounds identified herein; and (3) Petitioner
`
`has not filed any complaint relating to the ʼ112 patent. This Petition is filed in
`
`accordance with 37 C.F.R. § 42.106(a).
`
`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 inter partes review of 19 claims, and any
`
`additional fees, to Deposit Account 02–1818.
`
`VI. MANDATORY NOTICES (37 C.F.R. § 42.8)
`A. Real Parties-In-Interest
`Praxair Distribution, Inc., head office at 28 McCandless Ave, Pittsburgh, PA
`
`15201, Praxair, Inc., worldwide headquarters at 39 Old Ridgebury Rd., Danbury,
`
`CT 06810 are the real parties-in-interest.
`
`6
`
`Ex. 2016-0017
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`B. Related Matters
`Petitioner is not aware of any current litigation involving the ʼ112 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
`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
`
`Backup Counsel
`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
`
`Petitioner consents to electronic service by email.
`
`VII. PERSON OF SKILL IN THE ART AND STATE OF THE ART
`A person of ordinary skill in the art (“POSA”) is a hypothetical person
`
`presumed to know the relevant prior art. (IPR2013-00116, Final Written Decision,
`
`Paper 68 at 9.) A POSA is of ordinary creativity, not merely 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, 420-21 (2007).) Petitioner submits that a POSA
`
`7
`
`Ex. 2016-0018
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`related to the ’112 patent is a pediatric cardiologist with experience prescribing
`
`iNO. (Ex. 1002 ¶¶ 54-55.) 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 claims of the ’112 patent
`
`should be given their “broadest reasonable construction in light of the
`
`specification” of the ’112 patent. 37 C.F.R. § 42.100(b). A POSA would have
`
`understood each term of each claim to have its plain and ordinary meaning.5
`
`IX. STATEMENTS OF THE PRECISE RELIEF REQUESTED AND THE
`REASONS THEREFORE (37 C.F.R. § 42.22(a) and 42.104(b))
`
`Petitioner requests review of claims 1-19 of the ’112 patent based on the
`
`following Grounds:
`
`Ground
`1
`
`35 U.S.C. Section
`§ 103
`
`2
`
`§ 103
`
`Relied-On Reference
`Bernasconi (Ex. 1004) in view of
`INOMAX label (Ex. 1014), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`Ichinose (Ex. 1009)
`in view of
`INOMAX label (Ex. 1014), Loh (Ex.
`1006), Neonatal Group (Ex. 1011),
`and Goyal (Ex. 1007)
`
`Claims
`1-19
`
`1-19
`
`
`5 Any contention by PO that claim terms should have a special meaning should be
`
`disregarded unless PO also moves to amend its claims as permitted to expressly
`
`recite that meaning. See 77 Fed. Reg. 48764 at II.B.6 (August 14, 2012).
`
`8
`
`Ex. 2016-0019
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`Per 37 C.F.R. § 42.6(c), copies of the relied-on references are marked as exhibits
`
`filed herewith. Petitioner also provides the declaration of Dr. Maurice Beghetti6
`
`(Ex. 1002) in support of its proposed Grounds of unpatentability.
`
`Claims 1, 7, 12, and 14 are independent claims. Claim 1 recites:
`
`A method of providing pharmaceutically acceptable nitric oxide gas, the
`method comprising:
`[(a)] obtaining a cylinder containing compressed nitric oxide gas in the form
`of a gaseous blend of nitric oxide and nitrogen;
`[(b)] supplying the cylinder containing compressed nitric oxide gas to a
`medical provider responsible for treating neonates who have hypoxic
`respiratory failure, including some who do not have [LVD]7;
`[(c)] providing to the medical provider (i) information that a recommended
`dose of [iNO]8 gas for treatment of neonates with hypoxic respiratory failure
`is 20 ppm nitric oxide
`[(d)] and (ii) information that, in patients with pre-existing [LVD], [iNO]
`may increase pulmonary capillary wedge pressure (PCWP), leading to
`pulmonary edema, the information of (ii) being sufficient to cause a medical
`
`6 Dr. Beghetti is the Head of Paediatric Cardiology at the University Hospital of
`
`Geneva in Geneva, Switzerland. He is a co-author of Bernasconi (Ex. 1004). Dr.
`
`Beghetti is a qualified expert with experience in pediatric cardiology and iNO
`
`therapy. (See Ex. 1002 ¶¶ 1-13, 17, 54-55; see generally Ex. 1003.)
`
`7 “Left ventricular dysfunction” is abbreviated in the claims as “[LVD]”.
`
`8 “Inhaled nitric oxide” is abbreviated in the claims as “[iNO]”.
`
`9
`
`Ex. 2016-0020
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`provider considering [iNO] treatment for a plurality of neonatal patients who
`(a) are suffering from a condition for which [iNO] is indicated, and (b) have
`pre-existing [LVD], to elect to avoid treating one or more of the plurality of
`patients with [iNO] in order to avoid putting the one or more patients at risk
`of pulmonary edema.9
`(Ex. 1001 at 14:28-52.) Claim 7 is a method that differs from claim 1 in that the
`
`LVD must be “pre-existing” and the information required to be provided is:
`
`(i) information that a recommended dose of [iNO] for treatment of neonates
`with hypoxic respiratory failure is 20 ppm nitric oxide, (ii) information that
`patients who have pre-existing [LVD] and are treated with [iNO] may
`experience pulmonary edema, and (iii) a recommendation that, if pulmonary
`edema occurs in a patient who has pre-existing [LVD] and is treated with
`[iNO], the treatment with [iNO] should be discontinued.
`
`(Id. at 15:43-63) (emphasis added).
`
`Independent claim 12 includes the same steps as claim 1 except the
`
`preamble recites “[a] method comprising,” part (a) requires “obtaining a source of
`
`nitric oxide gas comprising a cylinder of compressed gas and/or a device that
`
`delivers nitric oxide gas into an inspiratory limb of a breathing circuit, for
`
`inhalation by a patient,” and part (b) replaces “supplying the cylinder containing
`
`compressed nitric oxide gas” with “supplying the source of nitric oxide gas.” (Id.
`
`
`9 The preamble is not limiting. Nonetheless, all the elements of the preamble are
`
`disclosed for each claim as described in sections IX(A)(3) and IX(B)(3) below.
`
`10
`
`Ex. 2016-0021
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`at 16:22-45.) Claim 14 mirrors claim 1 except the preamble recites “[a] method,”
`
`part (a) requires “obtaining a device that delivers nitric oxide gas into an
`
`inspiratory limb of a breathing circuit, for inhalation by a patient;” part (b) requires
`
`“supplying the device,” and the LVD must be “pre-existing.” (Id. at 16:50-57.)
`
`Part (d) of claim 14 also requires the information of (ii) to be “sufficient to cause a
`
`medical provider considering [iNO] treatment for multiple neonate patients who
`
`(a) are suffering from hypoxic respiratory failure…” (Id. at 16:62-17:5.)
`
`A. Ground 1: Claims 1-19 Are Unpatentable Under 35 U.S.C. §
`103(a) As Obvious Over Bernasconi in View of INOMAX label,
`Loh, and Goyal
`1. Overview of the Prior Art
`Bernasconi (Ex. 1004) was published in 2002 and contains a review of the
`
`delivery and monitoring aspects of iNO, including its applications in pediatric
`
`patients and potential risks with its use. (See Ex. 1004 at Abstract, 3, 8, 10, 12; Ex.
`
`1002 ¶¶ 39-45.) Bernasconi discloses that echocardiography is “essential” and
`
`should be used to confirm whether a pediatric patient has a condition that could be
`
`helped by iNO treatment. (Ex. 1004 at 8; Ex. 1002 ¶¶ 41, 45.) It discloses that the
`
`FDA approved dose to treat neonatal hypoxic respiratory failure was 20 ppm iNO
`
`in 2002. (Ex. 1004 at 3.) Bernasconi discloses that iNO can lead to pulmonary
`
`edema in neonates with LVD. (Ex. 1004 at 8; Ex. 1002 ¶¶ 42, 44.) Bernasconi
`
`discloses that risk assessment is important in patients with LVD, noting a “need for
`
`11
`
`Ex. 2016-0022
`
`

`
`Petition for Inter Partes Review of U.S. Patent No. 8,846,112
`
`careful observation and intensive monitoring during NO inhalation” in patients
`
`with LVD. (Ex. 1004 at 8; Ex. 1002 ¶ 43.) The disclosure that treatment of LVD
`
`patients can be performed with proper monitoring despite the risk of pulmonary
`
`edema applies to neonates and non-neonates. (Ex. 1004 at 8-9; Ex. 1002 ¶ 44.)
`
`INOMAX label (Ex. 1014) published before the end of 2000 when PO’s New
`
`Drug Application was approved. (See Ex. 1014; see also Ex. 1001 at 3:34-45; Ex.
`
`1002 ¶ 30.) INOMAX label contains information provided to medical providers
`
`(Ex. 1014 at i) regarding approved iNO uses and contraindications (id. at 4, 6; Ex.
`
`1002 ¶¶ 31-38). It teaches providing cylinders of gas (Ex. 1014 at 6-7; Ex. 1002 ¶¶
`
`31-33) and other delivery devices (Ex. 1014 at 6; Ex. 1002 ¶ 34), the advisability
`
`of echocardiography to identify patients with hypoxic respiratory failure (Ex. 1014
`
`at 4; Ex. 1002 ¶38), and a recommended dose of 20 ppm iNO for neonatal patients
`
`with hypoxic respiratory failure (Ex. 1014 at 1, 7; Ex.) INOMAX label also
`
`discloses discontinuing iNO treatment, or not treating in the first place, when
`
`treatment is contraindicated. (Ex. 1014 at 4-5; Ex. 1002 ¶¶ 35-36.)
`
`Loh (Ex. 1006), published in 1994, d