throbber
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
`
`DECLARATION OF DR. MAURICE BEGHETTI IN SUPPORT OF
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.
`8,846,112
`I, Dr. Maurice Beghetti, declare that:
`
`QUALIFICATIONS
`
`1.
`
`I am the Head of the Paediatric Cardiology Unit and also am the
`
`Director of the Subspecialty Division at the University Hospital of Geneva, in
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`Geneva, Switzerland. I hold several degrees from Genève, Université, Faculté de
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`Médecine, including specialist degrees in paediatric cardiology. I have spent most
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`of my professional career in Geneva, with a three-year fellowship at the Hospital
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`for Sick Children in Toronto, Canada with one year devoted specifically to cardiac
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`intensive care focusing on pulmonary hypertension research.
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`1
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`
`
`Ex. 2033-0001
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`

`
`2.
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`I have treated patients with inhaled nitric oxide (“NO,” “inhaled NO,”
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`or “iNO”) since at least the early 1990s, when it was first shown to be efficacious.
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`I have both extensively studied the drug and researched its potential uses since the
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`early 1990s. I regularly speak and lecture about treatment of pulmonary
`
`hypertension,1 including how to treat patients with inhaled NO or how to assess the
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`condition of a patient’s pulmonary vasculature using inhaled NO.
`
`3.
`
`I have been and currently am a full professor at Genève, University,
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`Faculty of Medicine, where I have taught the uses and contraindications for inhaled
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`NO within my lectures for cardiologists, neonatologists, and intensive care
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`specialists, as well as for nurses specialized in intensive care. I have taught these
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`subjects at the University since 1996, first as a senior fellow, and then as an
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`associate professor since 2001, and as a full professor since 2010.
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`4.
`
`I have received several awards throughout my career, including two
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`directly related to my research on inhaled NO. In 1996, I received a clinical
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`research award at the Hospital for Sick Children in Toronto, for my work entitled
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`“A comparison of inhaled nitric oxide and mild metabolic alkalosis as acute
`
`therapy for control of pulmonary hypertension following open-heart surgery.” I
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`additionally received an award in 2000 for my research entitled “Inhaled Iloprost
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`1 Pulmonary hypertension is increased pressure in the pulmonary arteries—the
`
`arteries that carry blood from the heart to the lungs to pick up oxygen.
`
`2
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`Ex. 2033-0002
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`

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`versus inhaled nitric oxide in secondary pulmonary hypertension: the vasodilator
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`capacity and cellular mechanisms.” This award was presented by the third World
`
`Congress on Pediatric Intensive Care, held in June of 2000.
`
`5.
`
`During the last 12 years, I have been extensively involved with
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`numerous international, standard-setting organizations. I am a Member of the
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`Executive Board of the Association for Paediatric PH (“pulmonary hypertension”),
`
`which has generated the TOPP Registry (for Tracking Outcomes and Practice in
`
`Paediatric PH). I am the Paediatric Member of the European Society of
`
`Cardiology (“ESC”) Working Group on Pulmonary Circulation and Right
`
`Ventricular Function. I am also the Paediatric Member of the ESC Guidelines.
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`The guidelines are endorsed by the European Respiratory Society (ERS), the
`
`European Association for Pediatric Cardiology (AEPC) (indeed, I represent AEPC
`
`in the guidelines) and the International Society for Heart and Lung Transplantation
`
`(ISHLT). I was the Co-Chair of the Paediatric Task Force at the last World
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`Symposium on Pulmonary Hypertension in 2013, involving representatives from
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`numerous countries, including the United States.
`
`6.
`
`I am a member of the editorial board of Cardiology in the Young and
`
`have authored numerous publications, book chapters and books on pulmonary
`
`hypertension. I am the editor of what is currently the only book on paediatric
`
`pulmonary hypertension.
`
`3
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`Ex. 2033-0003
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`

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`7. My research interests are focused on pulmonary hypertension and
`
`congenital heart defects in paediatric patients. I also work with colleagues and
`
`pharmaceutical companies to design pediatric pulmonary hypertension and
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`persistent pulmonary hypertension of the newborn (“PPHN”) studies with the
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`European Medicines Agency (“EMA”) to develop alternative treatments for
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`patients who do not respond to treatment with inhaled NO.
`
`8.
`
`As part of my involvement with international organizations, including
`
`the world symposia, and through consulting work where I have presented materials
`
`to the FDA as part of paediatric investigational programs for new compounds, I
`
`have been able to confirm that there are no material differences in the standards of
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`care and clinical practice for treating patients with inhaled NO in the United States
`
`as compared to Europe. Additionally, as part of my work with the ESC guidelines,
`
`I regularly confer with practitioners in the United States, Europe, and other
`
`countries throughout the world.2
`
`2 Advisory boards involving experts in the US and Europe have been established
`
`to develop recommendations for the use of inhaled NO. See, e.g., Ex. 1010,
`
`Germann, et al., Inhaled Nitric Oxide Therapy in Adults: European Expert
`
`Recommendations, 31 Intensive Care Med, 1029-1041 at 1030 (2005)
`
`(“Germann”); see also Ex. 1008, Macrae et al., Inhaled Nitric Oxide Therapy
`
`in Neonates and Children: Reaching a European Consensus, 30 Intensive Care
`
`4
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0004
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`

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`9.
`
`A copy of my curriculum vitae is attached as Exhibit 1003.
`
`10.
`
`I am not an employee of Praxair Distribution, Inc.; Praxair, Inc. or any
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`affiliated company. Rather, I have been engaged in the present matter to provide
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`my independent analysis of the issues raised in the above-mentioned inter partes
`
`review of U.S. Patent No. 8,846,112 (“the ʼ112 Patent”) (Ex. 1001). I have
`
`received no compensation for this declaration beyond my normal hourly
`
`compensation of $500/hr. for time actually spent studying the matter, and I will not
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`receive any added compensation based on the outcome of any proceeding related
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`to the ʼ112 Patent.
`
`11. Based upon my extensive knowledge and years of experience in this
`
`field, I have an understanding of how inhaled NO was being used for medical
`
`Medicine, 372-380 (2004) (“Macrae”); see also Ex. 1017, Ivy et al., Pediatric
`
`Pulmonary Hypertension, J Am Coll Cardiol. 62(25_S) (2013). As shown by
`
`the papers resulting from these Boards, there is no major disagreement on the
`
`paediatric guidelines among practitioners with regard to the treatment approach
`
`to be used for administration of inhaled NO. There may, however, be some
`
`differences in treatment selection due to the access and reimbursement
`
`availability of different therapies in different regions of the world. However,
`
`once a particular treatment is chosen, the approach from that point on is
`
`primarily consistent worldwide.
`
`5
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`Ex. 2033-0005
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`

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`treatment on or before June 30, 2009, as well as the risks and contraindications
`
`associated with its use. My analysis on this matter, including my analysis of the
`
`prior art references as set forth below, is based on my personal experience and
`
`what was known, and in fact, considered to be standard, by one skilled in the art
`
`prior to June 30, 2009.
`
`12.
`
`I have reviewed and am familiar with the ʼ112 Patent. (Ex. 1001).
`
`Additionally, I have reviewed the following documents: (1) Ex. 1004, Bernasconi,
`
`et al., Inhaled Nitric Oxide Applications in Paediatric Practice, 4 Images in
`
`Paediatric Cardiology, 4-29 (2002) (“Bernasconi”); (2) Ex. 1006, Loh, et al.,
`
`Cardiovascular Effects of Inhaled Nitric Oxide in Patients with Left Ventricular
`
`Dysfunction, 90 Circulation, 2780-2785 (1994) (“Loh”); (3) 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”); (4) 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_inomax_prntlbl.pdf (August 9, 2000) (“INOMAX label”); (5) Ex. 1009,
`
`Ichinose, et al., Inhaled Nitric Oxide: A Selective Pulmonary Vasodilator: Current
`
`Uses and Therapeutic Potential, 109 Circulation, 3106-3111 (2004) (“Ichinose”);
`
`and (6) Ex. 1011, The Neonatal Inhaled Nitric Oxide Study Group, Inhaled Nitric
`
`6
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`Ex. 2033-0006
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`

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`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”). I have also reviewed the documents cited elsewhere herein, as well as
`
`any documents cited in the declarations I have submitted or will submit in other
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`inter partes review petitions arising out of my engagement in this matter.
`
`13. My opinions, explained below, are based on my education,
`
`experience, and background in the field discussed above as well as my review of
`
`the references cited above.
`
`BACKGROUND KNOWLEDGE ONE OF SKILL IN THE ART WOULD
`HAVE HAD BEFORE THE PRIORITY DATE OF THE ʼ112 PATENT
`14. The ʼ112 Patent is entitled “Methods of Distributing a Pharmaceutical
`
`Product Comprising Nitric Oxide Gas for Inhalation.” The ʼ112 Patent discusses
`
`supplying inhaled NO (for example, a cylinder of NO gas) to doctors along with
`
`information/instructions regarding dosage and contraindications for treatment. Ex.
`
`1001, Abstract. The ʼ112 Patent discusses a pre-screening protocol to determine
`
`whether a patient has a condition, such as left ventricular dysfunction (“LVD”),
`
`that could lead to an Adverse Event or Serious Adverse Event3 if the patient is
`
`
`3 Before June 30, 2009, the FDA had defined an “Adverse Event” as “any
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`undesirable experience associated with the use of a medical product in a
`
`patient.” See Ex. 1013, “What is a Serious Adverse Event?” available at
`
`7
`
`
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`Ex. 2033-0007
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`treated with inhaled NO. See, e.g., Ex. 1001 at 1:50-56; 9:24-33; 12:49-61. It also
`
`explains that if a patient is determined to have LVD, he or she is at risk of
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`suffering a Serious Adverse Event such as pulmonary oedema4 upon treatment
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`with iNO. Ex. 1001 at Abstract; 1:50-56. The ’112 Patent suggests that these
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`patients should be “possibly exclude[d] from treatment.” Ex. 1001 at 1:53-54.
`
`15. Claim 1 of the ’112 Patent is representative:
`
`A method of providing pharmaceutically acceptable nitric oxide
`gas, the method comprising:
`
`obtaining a cylinder containing compressed nitric oxide gas in
`the form of a gaseous blend of nitric oxide and nitrogen;
`supplying the cylinder containing compressed nitric oxide gas
`to a medical provider responsible for treating neonates who have
`
`
`http://web.archive.org/web/20090611022009/http://www.fda.gov/Safety/MedW
`
`atch/HowToReport/ucm053087.htm
`
`(June
`
`11,
`
`2009)
`
`(“FDA
`
`Safety
`
`Information”). An Adverse Event was considered to be a Serious Adverse
`
`Event when the patient outcome required intervention to prevent permanent
`
`impairment or damage, was a life-threatening outcome, was an outcome that
`
`required hospitalization (initiation or prolongation of stay), resulted in a
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`disability, resulted in a congenital anomaly (resulting from a treatment given to
`
`a pregnant patient), or resulted in death. Id.
`
`4 Pulmonary oedema is a buildup of fluid in the lungs.
`
`8
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`Ex. 2033-0008
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`hypoxic respiratory failure, including some who do not have left
`ventricular dysfunction;
`providing to the medical provider (i) information that a
`recommended dose of inhaled nitric oxide gas for treatment of
`neonates with hypoxic respiratory failure is 20 ppm nitric oxide
`and (ii) information that, in patients with pre-existing left
`ventricular dysfunction, inhaled nitric oxide may increase pulmonary
`capillary wedge pressure (PCWP), leading to pulmonary edema, the
`information of (ii) being sufficient to cause a medical provider
`considering inhaled nitric oxide treatment for a plurality of neonatal
`patients who (a) are suffering from a condition for which inhaled
`nitric oxide is indicated, and (b) have pre-existing left ventricular
`dysfunction, to elect to avoid treating one or more of the plurality of
`patients with inhaled nitric oxide in order to avoid putting the one or
`more patients at risk of pulmonary edema.
`Ex. 1001 at 14:28-52.
`16. The ’112 Patent discloses that the determination of whether the patient
`
`has LVD may be made in a variety of ways, such as by determining pulmonary
`
`capillary wedge pressure (“wedge pressure”)5 or through echocardiography.6 Ex.
`
`
`5 Wedge pressure is referred to in the literature as pulmonary capillary wedge
`
`pressure (“PCWP”), pulmonary arterial wedge pressure (“PAWP”), or merely
`
`“wedge.” See, e.g., Ex. 1025, S, M. Hoeper, et al., Definitions and Diagnosis of
`
`Pulmonary Hypertension 62:25 J. of the American College of Cardiology D44
`
`(2013) (noting that pulmonary capillary wedge pressure, pulmonary arterial
`
`wedge pressure, wedge pressure, and wedge are all used to refer to the same
`
`9
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0009
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`

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`1001 at 2:48-50; 5:15-19. The ’112 Patent characterizes these techniques for
`
`determining that patients have LVD as being “known to those skilled in the
`
`medicinal arts.” Ex. 1001 at 5:19-19.
`
`17.
`
`I am an expert in the protocols and treatments described in the ’112
`
`Patent, and was an expert in this area prior to the priority date of the ʼ112 Patent on
`
`June 30, 2009. This expertise comes from my involvement in the field of
`
`paediatric cardiology and pulmonary hypertension.
`
`18.
`
`In the field of paediatric cardiology and pulmonary hypertension, the
`
`difference between pre-capillary pulmonary hypertension that includes normal
`
`pulmonary wedge pressure and post-capillary pulmonary hypertension is a key
`
`distinction. It is important, in fact, to differentiate these two entities as they react
`
`differently to therapies. This is well described in the pulmonary hypertension field
`
`and many years ago led to the classification of these two types of pulmonary
`
`hypertension in two different classes of pulmonary hypertension. See e.g., Ex.
`
`1018, Simonneau, et al., Clinical Classification of Pulmonary Hypertension, J.
`
`Am. Coll. Cardiol. 43(12 Suppl S):5S-12S (2004); Ex. 1019, Simonneau, et al.,
`
`concept and also noting that “wedge” and “wedge pressure” are commonly used
`
`in daily clinical practice, even in non-English speaking countries).
`
`6 Echocardiography is the use of ultrasound waves to investigate the actions of
`
`the heart.
`
`10
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`Ex. 2033-0010
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`

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`Updated Clinical Classification of Pulmonary Hypertension, J Am. Coll. Cardiol.
`
`54(1 Suppl):S43-54 (2009); Ex. 1020, Simonneau, et al., Updated Clinical
`
`Classification of Pulmonary Hypertension, J. Am. Coll. Cardiol. 62 (25
`
`Suppl):D34-41 (2013). Although the clinical classifications apply to pulmonary
`
`hypertension generally, the teachings are equally applicable to the context of
`
`pulmonary hypertension treated with inhaled NO and the effect of left heart
`
`disease.
`
`19. Pulmonary arterial hypertension is characterized by an increased
`
`pulmonary artery pressure and increased pulmonary vascular resistance. See Ex.
`
`1021, Chemla, et al., Haemodynamic Evaluation of Pulmonary Hypertension 20
`
`Eur Respir J. 1314-1331 at 1314 (2002). One cause of pulmonary hypertension is
`
`vasoconstriction. Id. at 1314. Before June 30, 2009, it was known to doctors in
`
`the field of paediatric cardiology that nitric oxide may be used as a vasodilator.7
`
`See Germann at 1030, 1031. The INOMAX label reference specifically recognizes
`
`this usage, stating that “Nitric oxide, the active substance in INOmax, is a
`
`pulmonary vasodilator.” Ex. 1014 at 1.
`
`20.
`
`Inhaled nitric oxide is a selective pulmonary vasodilator, and, as such,
`
`relaxes pulmonary vessels, which decreases pulmonary vascular resistance,
`
`7 Vasodilation is the widening of blood vessel that results from relaxation of
`
`smooth muscle cells within the vessel walls.
`
`11
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`Ex. 2033-0011
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`

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`pulmonary arterial pressure, and right ventricular afterload. See Ex. 1022,
`
`Griffiths, et al., Inhaled Nitric Oxide Therapy in Adults, 353 New England Journal
`
`of Medicine 2683-2695 at 2685 (2005). When nitric oxide is inhaled, it diffuses
`
`rapidly across the alveolar-capillary membrane and into the subjacent smooth
`
`muscle of pulmonary vessels to activate the soluble enzyme guanylate cyclase. See
`
`Ex. 1009 (Ichinose) at 3106. This enzyme converts GTP to cGMP, and the
`
`increased intracellular concentrations of cGMP relax smooth muscle resulting in
`
`vasodilation. Id.
`
`21. Not all patients and not all conditions are responsive to treatment with
`
`inhaled NO. Pulmonary hypertension, specifically PPHN, is a condition that may
`
`be treated with inhaled NO. See, e.g. Ex. 1004 (Bernasconi) at 3; Ex. 1014
`
`(INOMAX label) at 1. Twenty parts per million of inhaled NO is approved by the
`
`FDA to treat neonatal hypoxic respiratory failure8 and has been approved since
`
`8 Hypoxic respiratory failure and hypoxemic respiratory failure, conditions where
`
`the cells of the body do not have enough oxygen, may be caused by pulmonary
`
`hypertension. Therefore, treatment of pulmonary hypertension would also
`
`result in treatment of hypoxic respiratory failure caused by pulmonary
`
`hypertension. Hypoxic respiratory failure may lead to hypoxia (a condition
`
`characterized by low oxygen in all organs; where the tissue does not have
`
`enough oxygen). Treatment of hypoxia may be understood to include treatment
`
`12
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0012
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`

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`2000. Id. This is the only pathology for which inhaled nitric oxide has been
`
`approved in the United States.
`
`22.
`
`Inhaled NO can be used to treat both hypoxic and hypoxemic
`
`respiratory failure. However, such treatment is not suitable for all patients.
`
`Therefore, as is the case with many medications, doctors involved in the treatment
`
`of patients with inhaled NO examine and evaluate patients before administering
`
`treatment. Such examinations are and have long been performed by doctors before
`
`administering any kind of treatment. These examinations are done for two main
`
`reasons: (1) to determine whether the treatment is likely to help the patient; and (2)
`
`to determine whether the patient is at particular risk of having a negative reaction.
`
`In the case of inhaled NO, one such well-known negative reaction is pulmonary
`
`oedema due to left ventricular dysfunction. See, e.g., Ex. 1004 at 8. Such
`
`examinations and evaluations were commonly done, and decisions were made
`
`based thereon, prior to June 30, 2009. Id.
`
`23. Before June 30, 2009, it was known that systolic and diastolic LVD,
`
`any obstruction to the pulmonary venous flow, or lesions that may increase
`
`pulmonary venous pressure (such as obstructed pulmonary venous return, mitral
`
`
`of hypoxic respiratory failure, as the hypoxia is the condition that causes harm
`
`to the patient.
`
`13
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0013
`
`

`
`stenosis9 or insufficiency, etc.) increase the risk of a patient suffering a Serious
`
`Adverse Event upon treatment with inhaled NO. See, e.g. Ex. 1004 at 8
`
`(“However, in patients with elevated left atrial pressure due to left ventricular
`
`dysfunction, a decrease in pulmonary vascular resistance (induced by inhaled NO)
`
`will lead to an increase in pulmonary venous return and hence to an increase in left
`
`atrial and left ventricular filling pressures . . . This effect may lead to . . . left heart
`
`failure and pulmonary oedema” 10).
`
`24. As part of the general medical practice before June 30, 2009, doctors
`
`implemented a clinical diagnostic procedure to assess patient conditions, treatment
`
`options, and potential risks from any potential treatment. First, doctors would
`
`assess the condition of the patient to see if the patient had a condition likely to be
`
`helped by inhaled NO, such as hypoxic respiratory failure or pulmonary
`
`hypertension. Second, doctors would assess whether inhaled NO would likely
`
`trigger Adverse Events in the patient. This process was performed for all patients.
`
`As is clear from the studies which include numerous patients, one skilled in the art
`
`would have understood that a process for selecting a patient to be treated, or a
`
`
`9 Mitral stenosis is a condition where the mitral valve, which separates the upper
`
`and lower chambers on the left side of the heart, does not open fully, restricting
`
`blood flow.
`
`10 “Oedema” is an alternate spelling to the word “edema.”
`14
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0014
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`

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`method of treatment, could be applied to one patient, or to a plurality of patients.
`
`See generally Ex. 1004, Ex. 1006, Ex. 1009 (discussing studies treating multiple
`
`patients with inhaled NO).
`
`25. Doctors considering prescribing inhaled NO prior to June 30, 2009,
`
`like today, would weigh the risk of Adverse Events or Serious Adverse Events.
`
`For example, in 2005, an Advisory Board was established under the auspices of the
`
`European Society of Intensive Care Medicine and European Association of
`
`Cardiothoracic Anesthesiologists to analyze the usage of inhaled NO. The
`
`Advisory Board was composed of experts with proven scientific or clinical
`
`expertise relevant to the clinical use of inhaled NO, including paediatric specialists,
`
`to prepare recommendations for NO use. See Ex. 1010 (Germann) at 1030. The
`
`Advisory Board concluded in its written recommendations in 2005 that while
`
`inhaled NO is approved for use in neonates with hypoxic respiratory failure,11
`
`before administration it should be determined whether the patients have left heart
`
`dysfunction or other heart conditions that increase post capillary pressures. Once
`
`identified, these patients should not be treated with inhaled NO unless the heart
`
`condition is first addressed. See Ex. 1010 (Germann) at 1030, 1033.
`
`
`11 The Advisory Board also recognized that inhaled NO has significant off-label
`
`use. See Ex. 1010 (Germann) at 1030.
`
`15
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0015
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`

`
`26.
`
`In accordance with the recommendations, which conformed to
`
`industry practice even before the publications by the Advisory Board, the
`
`diagnostic process for administering inhaled NO included assessing the patient
`
`condition and determining if there were any contraindications for use of inhaled
`
`NO, including, specifically, left ventricular dysfunction. The assessment included
`
`performing echocardiography before administering inhaled NO. See, e.g., Ex.
`
`1011 (Neonatal Group) at Abstract; see also Ex. 1030, Henrichsen, et al., Inhaled
`
`Nitric Oxide can Cause Severe Systemic Hypotension, 129 The Journal of
`
`Pediatrics, 183, col. 1, par. 2 (1996) (disclosing echocardiography prior to
`
`treatment to examine the structure of the heart, diagnose LVD, and identify
`
`patients dependent on right-to-left shunting of blood) (“Henrichsen”). These
`
`references reflect the well-known clinical practice before June 30, 2009 to suggest
`
`an echocardiogram before administering inhaled NO. Indeed, before June 30,
`
`2009, my team followed this practice before starting nitric oxide, and the intensive
`
`care or neonatology specialists consistently confirmed that it was done before
`
`treatment. We even often assessed the efficacy by echocardiography through the
`
`evaluation of pulmonary pressure, right ventricular anatomy and function as well
`
`as shunt direction through the ductus arteriosus and the foramen ovale.
`
`27. Additionally, a wedge pressure of 20 mm Hg is a physiological
`
`indicator of conditions that increases risk for patients if they were to receive
`
`16
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0016
`
`

`
`treatment with inhaled NO, including left heart dysfunction. As was known in the
`
`art prior to June 30, 2009, wedge pressure can be determined by inserting a
`
`pulmonary catheter with an inflated balloon (e.g., a Swan-Ganz catheter) into a
`
`small pulmonary arterial branch. See, e.g., Ex. 1023, Royster, et al., Differences in
`
`Pulmonary Artery Wedge Pressures Obtained by Balloon Inflation Versus
`
`Impaction Techniques, 61 Anesthesiology, 339 – 341 (1984); see also, Ex. 1007
`
`(Goyal) at p. 209, col. 1, lines 16-20 (showing measurement of wedge pressure in
`
`infants and other children). A rise in wedge pressure upon treatment with inhaled
`
`NO suggests LVD. See, e.g. Ex. 1024, Ignarro, L.J., ed. Nitric Oxide Biology and
`
`Pathobiology, Academic Press, at 940–941 (2000) (“Ignarro”). One skilled in
`
`the art would have known prior to June 30, 2009, that older children and adults
`
`could have wedge pressure measured with a catheter. While not typically
`
`performed in neonates, one skilled in the art would have known to measure wedge
`
`pressure with a catheter in neonates in emergency situations.
`
`28. Before June 30, 2009, it was well-known that wedge pressure could
`
`also be determined through extrapolation based on information gained through
`
`echocardiography. See, e.g., 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”). Wedge pressure may be extrapolated
`
`from echocardiographic information to identify whether left heart dysfunction
`
`17
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0017
`
`

`
`exists and, concomitantly, that physiologically a wedge pressure exists over a
`
`certain value. A paediatric cardiologist with skill and extensive experience with
`
`echocardiography would be able to extrapolate wedge pressure with accuracy to be
`
`of use in making a diagnosis or determining whether the patient in question has a
`
`condition such as left ventricular dysfunction that would require assessment of the
`
`risks of treatment and likely contraindicate treatment with inhaled NO.
`
`29. As part of regular clinical practice before June 30, 2009, patients not
`
`at risk of Adverse Events such as pulmonary oedema were treated with inhaled
`
`NO, and patients that revealed risk factors during echocardiography, measurement
`
`of wedge pressure, blood gas level, or other clinical assessment were not treated,
`
`assuming the risk of harm to the patient outweighed the benefits. If the diagnostic
`
`results were unclear, or if a potential benefit was expected, as part of the diagnostic
`
`process, one skilled in the art would have known to administer inhaled NO as a test
`
`to see how a patient would react to the drug and to determine whether a patient had
`
`left ventricular dysfunction. Such a patient would have been carefully evaluated
`
`through regular and repeated echocardiography and clinical evaluation while the
`
`test inhaled NO was administered. If the patient responded in such a way as to
`
`suggest that he or she had left ventricular dysfunction, full treatment with inhaled
`
`NO would not have been prescribed, and the test treatment would have been
`
`stopped. See, e.g., Ex. 1024 (Ignarro) at 940-941. All physicians have a basic
`
`18
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0018
`
`

`
`understanding of negative side effects, and one skilled in the art would have known
`
`not to administer inhaled NO if it would cause harm to the patient that outweighed
`
`the benefits of treatment. See, e.g., Ex. 1026, Kaldijian., et al., A Clinician’s
`
`Approach to Clinical Ethical Reasoning, J Gen Intern Med. 20(3): 306–311 at 309
`
`(Mar. 2005) (discussing the duty of nonmaleficence, to avoid causing harm to a
`
`patient); see also Ex. 1027, Jonsen, A. et al., Clinical Ethics: A Practical Approach
`
`to Ethical Decisions in Clinical Medicine 4th ed. (1998) (discussing the
`
`Hippocratic Oath and the requirement to do no harm).
`
`Introduction To Prior Art References
`
`30. The ‘112 Patent contains a discussion of the FDA approval for sale of
`
`a product called INOmax®. See generally Ex. 1001 at 3:34-4:22. As part of this
`
`FDA approval, the ’112 Patent discusses certain approved “prescribing information
`
`for INOmax®” that was “in effect in 2009.” Ex. 1001 at 3:45-47. The reference I
`
`refer to as the INOMAX label contains this prescribing information. See Ex. 1014.
`
`This reference was submitted to the FDA in 1999, and published in 2000. Thus,
`
`INOMAX label was published and available several years before the June 30, 2009
`
`earliest priority date of the ’112 Patent.
`
`31.
`
`In general,
`
`the INOMAX
`
`label reference contains prescribing
`
`information that was distributed to medical providers purchasing and using
`
`INOmax® branded iNO gas for therapy. It describes INOmax as “a drug
`19
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0019
`
`

`
`administered by inhalation” whose active substance is nitric oxide. Ex. 1014 at p.
`
`1. INOMAX label describes that “INOmax is a gaseous blend of nitric oxide
`
`(0.8%) and nitrogen (99.2%).” Ex. 1014 at p. 1. It also states that INOmax is
`
`“supplied in aluminum cylinders” of varying sizes and concentrations. Ex. 1014 at
`
`pp. 1, 6-7. Consistent with the discussion above, the INOMAX label informed
`
`medical providers that “nitric oxide produces pulmonary vasodilation” and can be
`
`used to treat neonates with PPHN to improve oxygenation. Ex. 1014 at p. 1.
`
`32. The INOMAX label reference contains “prescribing information” that
`
`was given to medical providers responsible for treating those individuals to whom
`
`INOMAX label is directed - that is, neonates who have hypoxic respiratory failure.
`
`See Ex. 1014 at p. 4 (iNO indicated for treatment of “neonates with hypoxic
`
`respiratory failure”). The INOMAX label does not indicate that a practitioner
`
`should determine if such neonates do or do not have LVD and therefore discloses
`
`treating neonates with hypoxic respiratory failure but without LVD. Ex. 1014 at 4.
`
`A person of skill in the art reading the INOMAX label reference understands that it
`
`discloses a protocol (or method) for administering nitric oxide gas, and that the
`
`protocol information contained in the INOMAX label is provided to medical
`
`providers along with cylinders of nitric oxide gas to educate the providers as to the
`
`use of the nitric oxide gas.
`
`20
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
`
`Ex. 2033-0020
`
`

`
`33. The INOMAX label reference therefore discloses providing cylinders
`
`of a gaseous blend of nitric oxide a

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