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`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:
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`QUALIFICATIONS
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`1.
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`I am the Head of the Paediatric Cardiology Unit and also am the
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`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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`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
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`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.
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`3.
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`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.
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`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
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`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
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`arteries that carry blood from the heart to the lungs to pick up oxygen.
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`2
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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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
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`Congress on Pediatric Intensive Care, held in June of 2000.
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`5.
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`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”),
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`which has generated the TOPP Registry (for Tracking Outcomes and Practice in
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`Paediatric PH). I am the Paediatric Member of the European Society of
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`Cardiology (“ESC”) Working Group on Pulmonary Circulation and Right
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`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
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`European Association for Pediatric Cardiology (AEPC) (indeed, I represent AEPC
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`in the guidelines) and the International Society for Heart and Lung Transplantation
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`(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.
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`6.
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`I am a member of the editorial board of Cardiology in the Young and
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`have authored numerous publications, book chapters and books on pulmonary
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`hypertension. I am the editor of what is currently the only book on paediatric
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`pulmonary hypertension.
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`3
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`7. My research interests are focused on pulmonary hypertension and
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`congenital heart defects in paediatric patients. I also work with colleagues and
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`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.
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`8.
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`As part of my involvement with international organizations, including
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`the world symposia, and through consulting work where I have presented materials
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`to the FDA as part of paediatric investigational programs for new compounds, I
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`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
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`as compared to Europe. Additionally, as part of my work with the ESC guidelines,
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`I regularly confer with practitioners in the United States, Europe, and other
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`countries throughout the world.2
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`2 Advisory boards involving experts in the US and Europe have been established
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`to develop recommendations for the use of inhaled NO. See, e.g., Ex. 1010,
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`Germann, et al., Inhaled Nitric Oxide Therapy in Adults: European Expert
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`Recommendations, 31 Intensive Care Med, 1029-1041 at 1030 (2005)
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`(“Germann”); see also Ex. 1008, Macrae et al., Inhaled Nitric Oxide Therapy
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`in Neonates and Children: Reaching a European Consensus, 30 Intensive Care
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`4
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`9.
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`A copy of my curriculum vitae is attached as Exhibit 1003.
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`10.
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`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
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`review of U.S. Patent No. 8,846,112 (“the ʼ112 Patent”) (Ex. 1001). I have
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`received no compensation for this declaration beyond my normal hourly
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`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.
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`11. Based upon my extensive knowledge and years of experience in this
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`field, I have an understanding of how inhaled NO was being used for medical
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`Medicine, 372-380 (2004) (“Macrae”); see also Ex. 1017, Ivy et al., Pediatric
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`Pulmonary Hypertension, J Am Coll Cardiol. 62(25_S) (2013). As shown by
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`the papers resulting from these Boards, there is no major disagreement on the
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`paediatric guidelines among practitioners with regard to the treatment approach
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`to be used for administration of inhaled NO. There may, however, be some
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`differences in treatment selection due to the access and reimbursement
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`availability of different therapies in different regions of the world. However,
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`once a particular treatment is chosen, the approach from that point on is
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`primarily consistent worldwide.
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`5
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`treatment on or before June 30, 2009, as well as the risks and contraindications
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`associated with its use. My analysis on this matter, including my analysis of the
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`prior art references as set forth below, is based on my personal experience and
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`what was known, and in fact, considered to be standard, by one skilled in the art
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`prior to June 30, 2009.
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`12.
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`I have reviewed and am familiar with the ʼ112 Patent. (Ex. 1001).
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`Additionally, I have reviewed the following documents: (1) Ex. 1004, Bernasconi,
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`et al., Inhaled Nitric Oxide Applications in Paediatric Practice, 4 Images in
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`Paediatric Cardiology, 4-29 (2002) (“Bernasconi”); (2) Ex. 1006, Loh, et al.,
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`Cardiovascular Effects of Inhaled Nitric Oxide in Patients with Left Ventricular
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`Dysfunction, 90 Circulation, 2780-2785 (1994) (“Loh”); (3) Ex. 1007, P. Goyal, et
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`al., Efficacy of Nitroglycerin Inhalation in Reducing Pulmonary Arterial
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`Hypertension in Children with Congenital Heart Disease, 97 British Journal of
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`Anaesthesia, 208-214 (2006) (“Goyal”); (4) Ex. 1014, Center for Drug Evaluation
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`and Research, Application Number: NDA 20845, INOMAX, Final Printed
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`Labeling,
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`available
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`at
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`http://www.accessdata.fda.gov/drugsatfda_docs/nda/
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`99/20845_inomax_prntlbl.pdf (August 9, 2000) (“INOMAX label”); (5) Ex. 1009,
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`Ichinose, et al., Inhaled Nitric Oxide: A Selective Pulmonary Vasodilator: Current
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`Uses and Therapeutic Potential, 109 Circulation, 3106-3111 (2004) (“Ichinose”);
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`and (6) Ex. 1011, The Neonatal Inhaled Nitric Oxide Study Group, Inhaled Nitric
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`6
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`Oxide in Full-Term and Nearly Full-Term Infants with Hypoxic Respiratory
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`Failure, 336 The New England Journal of Medicine, 597-604 (1997) (“Neonatal
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`Group”). I have also reviewed the documents cited elsewhere herein, as well as
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`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.
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`13. My opinions, explained below, are based on my education,
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`experience, and background in the field discussed above as well as my review of
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`the references cited above.
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`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
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`Product Comprising Nitric Oxide Gas for Inhalation.” The ʼ112 Patent discusses
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`supplying inhaled NO (for example, a cylinder of NO gas) to doctors along with
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`information/instructions regarding dosage and contraindications for treatment. Ex.
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`1001, Abstract. The ʼ112 Patent discusses a pre-screening protocol to determine
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`whether a patient has a condition, such as left ventricular dysfunction (“LVD”),
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`that could lead to an Adverse Event or Serious Adverse Event3 if the patient is
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`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
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`patient.” See Ex. 1013, “What is a Serious Adverse Event?” available at
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`7
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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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
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`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.
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`15. Claim 1 of the ’112 Patent is representative:
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`A method of providing pharmaceutically acceptable nitric oxide
`gas, the method comprising:
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`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
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`http://web.archive.org/web/20090611022009/http://www.fda.gov/Safety/MedW
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`atch/HowToReport/ucm053087.htm
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`(June
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`11,
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`2009)
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`(“FDA
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`Safety
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`Information”). An Adverse Event was considered to be a Serious Adverse
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`Event when the patient outcome required intervention to prevent permanent
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`impairment or damage, was a life-threatening outcome, was an outcome that
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`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
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`a pregnant patient), or resulted in death. Id.
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`4 Pulmonary oedema is a buildup of fluid in the lungs.
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`8
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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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
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`has LVD may be made in a variety of ways, such as by determining pulmonary
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`capillary wedge pressure (“wedge pressure”)5 or through echocardiography.6 Ex.
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`5 Wedge pressure is referred to in the literature as pulmonary capillary wedge
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`pressure (“PCWP”), pulmonary arterial wedge pressure (“PAWP”), or merely
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`“wedge.” See, e.g., Ex. 1025, S, M. Hoeper, et al., Definitions and Diagnosis of
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`Pulmonary Hypertension 62:25 J. of the American College of Cardiology D44
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`(2013) (noting that pulmonary capillary wedge pressure, pulmonary arterial
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`wedge pressure, wedge pressure, and wedge are all used to refer to the same
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`9
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`1001 at 2:48-50; 5:15-19. The ’112 Patent characterizes these techniques for
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`determining that patients have LVD as being “known to those skilled in the
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`medicinal arts.” Ex. 1001 at 5:19-19.
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`17.
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`I am an expert in the protocols and treatments described in the ’112
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`Patent, and was an expert in this area prior to the priority date of the ʼ112 Patent on
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`June 30, 2009. This expertise comes from my involvement in the field of
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`paediatric cardiology and pulmonary hypertension.
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`18.
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`In the field of paediatric cardiology and pulmonary hypertension, the
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`difference between pre-capillary pulmonary hypertension that includes normal
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`pulmonary wedge pressure and post-capillary pulmonary hypertension is a key
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`distinction. It is important, in fact, to differentiate these two entities as they react
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`differently to therapies. This is well described in the pulmonary hypertension field
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`and many years ago led to the classification of these two types of pulmonary
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`hypertension in two different classes of pulmonary hypertension. See e.g., Ex.
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`1018, Simonneau, et al., Clinical Classification of Pulmonary Hypertension, J.
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`Am. Coll. Cardiol. 43(12 Suppl S):5S-12S (2004); Ex. 1019, Simonneau, et al.,
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`concept and also noting that “wedge” and “wedge pressure” are commonly used
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`in daily clinical practice, even in non-English speaking countries).
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`6 Echocardiography is the use of ultrasound waves to investigate the actions of
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`the heart.
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`10
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`Updated Clinical Classification of Pulmonary Hypertension, J Am. Coll. Cardiol.
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`54(1 Suppl):S43-54 (2009); Ex. 1020, Simonneau, et al., Updated Clinical
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`Classification of Pulmonary Hypertension, J. Am. Coll. Cardiol. 62 (25
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`Suppl):D34-41 (2013). Although the clinical classifications apply to pulmonary
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`hypertension generally, the teachings are equally applicable to the context of
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`pulmonary hypertension treated with inhaled NO and the effect of left heart
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`disease.
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`19. Pulmonary arterial hypertension is characterized by an increased
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`pulmonary artery pressure and increased pulmonary vascular resistance. See Ex.
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`1021, Chemla, et al., Haemodynamic Evaluation of Pulmonary Hypertension 20
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`Eur Respir J. 1314-1331 at 1314 (2002). One cause of pulmonary hypertension is
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`vasoconstriction. Id. at 1314. Before June 30, 2009, it was known to doctors in
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`the field of paediatric cardiology that nitric oxide may be used as a vasodilator.7
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`See Germann at 1030, 1031. The INOMAX label reference specifically recognizes
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`this usage, stating that “Nitric oxide, the active substance in INOmax, is a
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`pulmonary vasodilator.” Ex. 1014 at 1.
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`20.
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`Inhaled nitric oxide is a selective pulmonary vasodilator, and, as such,
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`relaxes pulmonary vessels, which decreases pulmonary vascular resistance,
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`7 Vasodilation is the widening of blood vessel that results from relaxation of
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`smooth muscle cells within the vessel walls.
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`11
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`pulmonary arterial pressure, and right ventricular afterload. See Ex. 1022,
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`Griffiths, et al., Inhaled Nitric Oxide Therapy in Adults, 353 New England Journal
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`of Medicine 2683-2695 at 2685 (2005). When nitric oxide is inhaled, it diffuses
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`rapidly across the alveolar-capillary membrane and into the subjacent smooth
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`muscle of pulmonary vessels to activate the soluble enzyme guanylate cyclase. See
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`Ex. 1009 (Ichinose) at 3106. This enzyme converts GTP to cGMP, and the
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`increased intracellular concentrations of cGMP relax smooth muscle resulting in
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`vasodilation. Id.
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`21. Not all patients and not all conditions are responsive to treatment with
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`inhaled NO. Pulmonary hypertension, specifically PPHN, is a condition that may
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`be treated with inhaled NO. See, e.g. Ex. 1004 (Bernasconi) at 3; Ex. 1014
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`(INOMAX label) at 1. Twenty parts per million of inhaled NO is approved by the
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`FDA to treat neonatal hypoxic respiratory failure8 and has been approved since
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`8 Hypoxic respiratory failure and hypoxemic respiratory failure, conditions where
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`the cells of the body do not have enough oxygen, may be caused by pulmonary
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`hypertension. Therefore, treatment of pulmonary hypertension would also
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`result in treatment of hypoxic respiratory failure caused by pulmonary
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`hypertension. Hypoxic respiratory failure may lead to hypoxia (a condition
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`characterized by low oxygen in all organs; where the tissue does not have
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`enough oxygen). Treatment of hypoxia may be understood to include treatment
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`12
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`2000. Id. This is the only pathology for which inhaled nitric oxide has been
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`approved in the United States.
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`22.
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`Inhaled NO can be used to treat both hypoxic and hypoxemic
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`respiratory failure. However, such treatment is not suitable for all patients.
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`Therefore, as is the case with many medications, doctors involved in the treatment
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`of patients with inhaled NO examine and evaluate patients before administering
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`treatment. Such examinations are and have long been performed by doctors before
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`administering any kind of treatment. These examinations are done for two main
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`reasons: (1) to determine whether the treatment is likely to help the patient; and (2)
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`to determine whether the patient is at particular risk of having a negative reaction.
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`In the case of inhaled NO, one such well-known negative reaction is pulmonary
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`oedema due to left ventricular dysfunction. See, e.g., Ex. 1004 at 8. Such
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`examinations and evaluations were commonly done, and decisions were made
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`based thereon, prior to June 30, 2009. Id.
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`23. Before June 30, 2009, it was known that systolic and diastolic LVD,
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`any obstruction to the pulmonary venous flow, or lesions that may increase
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`pulmonary venous pressure (such as obstructed pulmonary venous return, mitral
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`of hypoxic respiratory failure, as the hypoxia is the condition that causes harm
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`to the patient.
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`13
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`stenosis9 or insufficiency, etc.) increase the risk of a patient suffering a Serious
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`Adverse Event upon treatment with inhaled NO. See, e.g. Ex. 1004 at 8
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`(“However, in patients with elevated left atrial pressure due to left ventricular
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`dysfunction, a decrease in pulmonary vascular resistance (induced by inhaled NO)
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`will lead to an increase in pulmonary venous return and hence to an increase in left
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`atrial and left ventricular filling pressures . . . This effect may lead to . . . left heart
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`failure and pulmonary oedema” 10).
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`24. As part of the general medical practice before June 30, 2009, doctors
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`implemented a clinical diagnostic procedure to assess patient conditions, treatment
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`options, and potential risks from any potential treatment. First, doctors would
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`assess the condition of the patient to see if the patient had a condition likely to be
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`helped by inhaled NO, such as hypoxic respiratory failure or pulmonary
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`hypertension. Second, doctors would assess whether inhaled NO would likely
`
`trigger Adverse Events in the patient. This process was performed for all patients.
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`As is clear from the studies which include numerous patients, one skilled in the art
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`would have understood that a process for selecting a patient to be treated, or a
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`9 Mitral stenosis is a condition where the mitral valve, which separates the upper
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`and lower chambers on the left side of the heart, does not open fully, restricting
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`blood flow.
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`10 “Oedema” is an alternate spelling to the word “edema.”
`14
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`method of treatment, could be applied to one patient, or to a plurality of patients.
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`See generally Ex. 1004, Ex. 1006, Ex. 1009 (discussing studies treating multiple
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`patients with inhaled NO).
`
`25. Doctors considering prescribing inhaled NO prior to June 30, 2009,
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`like today, would weigh the risk of Adverse Events or Serious Adverse Events.
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`For example, in 2005, an Advisory Board was established under the auspices of the
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`European Society of Intensive Care Medicine and European Association of
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`Cardiothoracic Anesthesiologists to analyze the usage of inhaled NO. The
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`Advisory Board was composed of experts with proven scientific or clinical
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`expertise relevant to the clinical use of inhaled NO, including paediatric specialists,
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`to prepare recommendations for NO use. See Ex. 1010 (Germann) at 1030. The
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`Advisory Board concluded in its written recommendations in 2005 that while
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`inhaled NO is approved for use in neonates with hypoxic respiratory failure,11
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`before administration it should be determined whether the patients have left heart
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`dysfunction or other heart conditions that increase post capillary pressures. Once
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`identified, these patients should not be treated with inhaled NO unless the heart
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`condition is first addressed. See Ex. 1010 (Germann) at 1030, 1033.
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`11 The Advisory Board also recognized that inhaled NO has significant off-label
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`use. See Ex. 1010 (Germann) at 1030.
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`26.
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`In accordance with the recommendations, which conformed to
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`industry practice even before the publications by the Advisory Board, the
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`diagnostic process for administering inhaled NO included assessing the patient
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`condition and determining if there were any contraindications for use of inhaled
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`NO, including, specifically, left ventricular dysfunction. The assessment included
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`performing echocardiography before administering inhaled NO. See, e.g., Ex.
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`1011 (Neonatal Group) at Abstract; see also Ex. 1030, Henrichsen, et al., Inhaled
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`Nitric Oxide can Cause Severe Systemic Hypotension, 129 The Journal of
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`Pediatrics, 183, col. 1, par. 2 (1996) (disclosing echocardiography prior to
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`treatment to examine the structure of the heart, diagnose LVD, and identify
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`patients dependent on right-to-left shunting of blood) (“Henrichsen”). These
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`references reflect the well-known clinical practice before June 30, 2009 to suggest
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`an echocardiogram before administering inhaled NO. Indeed, before June 30,
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`2009, my team followed this practice before starting nitric oxide, and the intensive
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`care or neonatology specialists consistently confirmed that it was done before
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`treatment. We even often assessed the efficacy by echocardiography through the
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`evaluation of pulmonary pressure, right ventricular anatomy and function as well
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`as shunt direction through the ductus arteriosus and the foramen ovale.
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`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
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`16
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,846,112
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`treatment with inhaled NO, including left heart dysfunction. As was known in the
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`art prior to June 30, 2009, wedge pressure can be determined by inserting a
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`pulmonary catheter with an inflated balloon (e.g., a Swan-Ganz catheter) into a
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`small pulmonary arterial branch. See, e.g., Ex. 1023, Royster, et al., Differences in
`
`Pulmonary Artery Wedge Pressures Obtained by Balloon Inflation Versus
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`Impaction Techniques, 61 Anesthesiology, 339 – 341 (1984); see also, Ex. 1007
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`(Goyal) at p. 209, col. 1, lines 16-20 (showing measurement of wedge pressure in
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`infants and other children). A rise in wedge pressure upon treatment with inhaled
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`NO suggests LVD. See, e.g. Ex. 1024, Ignarro, L.J., ed. Nitric Oxide Biology and
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`Pathobiology, Academic Press, at 940–941 (2000) (“Ignarro”). One skilled in
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`the art would have known prior to June 30, 2009, that older children and adults
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`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
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`pressure with a catheter in neonates in emergency situations.
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`28. Before June 30, 2009, it was well-known that wedge pressure could
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`also be determined through extrapolation based on information gained through
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`echocardiography. See, e.g., Ex. 1012, Pozzoli, M. et al. Non-Invasive Estimation
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`of Left Ventricular Filling Pressures by Doppler Echocardiography. Eur J
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`Echocardiogr. 3:75–9 (2002) (“Pozzoli”). Wedge pressure may be extrapolated
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`from echocardiographic information to identify whether left heart dysfunction
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`exists and, concomitantly, that physiologically a wedge pressure exists over a
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`certain value. A paediatric cardiologist with skill and extensive experience with
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`echocardiography would be able to extrapolate wedge pressure with accuracy to be
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`of use in making a diagnosis or determining whether the patient in question has a
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`condition such as left ventricular dysfunction that would require assessment of the
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`risks of treatment and likely contraindicate treatment with inhaled NO.
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`29. As part of regular clinical practice before June 30, 2009, patients not
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`at risk of Adverse Events such as pulmonary oedema were treated with inhaled
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`NO, and patients that revealed risk factors during echocardiography, measurement
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`of wedge pressure, blood gas level, or other clinical assessment were not treated,
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`assuming the risk of harm to the patient outweighed the benefits. If the diagnostic
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`results were unclear, or if a potential benefit was expected, as part of the diagnostic
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`process, one skilled in the art would have known to administer inhaled NO as a test
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`to see how a patient would react to the drug and to determine whether a patient had
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`left ventricular dysfunction. Such a patient would have been carefully evaluated
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`through regular and repeated echocardiography and clinical evaluation while the
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`test inhaled NO was administered. If the patient responded in such a way as to
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`suggest that he or she had left ventricular dysfunction, full treatment with inhaled
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`NO would not have been prescribed, and the test treatment would have been
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`stopped. See, e.g., Ex. 1024 (Ignarro) at 940-941. All physicians have a basic
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`understanding of negative side effects, and one skilled in the art would have known
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`not to administer inhaled NO if it would cause harm to the patient that outweighed
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`the benefits of treatment. See, e.g., Ex. 1026, Kaldijian., et al., A Clinician’s
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`Approach to Clinical Ethical Reasoning, J Gen Intern Med. 20(3): 306–311 at 309
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`(Mar. 2005) (discussing the duty of nonmaleficence, to avoid causing harm to a
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`patient); see also Ex. 1027, Jonsen, A. et al., Clinical Ethics: A Practical Approach
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`to Ethical Decisions in Clinical Medicine 4th ed. (1998) (discussing the
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`Hippocratic Oath and the requirement to do no harm).
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`Introduction To Prior Art References
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`30. The ‘112 Patent contains a discussion of the FDA approval for sale of
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`a product called INOmax®. See generally Ex. 1001 at 3:34-4:22. As part of this
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`FDA approval, the ’112 Patent discusses certain approved “prescribing information
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`for INOmax®” that was “in effect in 2009.” Ex. 1001 at 3:45-47. The reference I
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`refer to as the INOMAX label contains this prescribing information. See Ex. 1014.
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`This reference was submitted to the FDA in 1999, and published in 2000. Thus,
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`INOMAX label was published and available several years before the June 30, 2009
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`earliest priority date of the ’112 Patent.
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`31.
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`In general,
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`the INOMAX
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`label reference contains prescribing
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`information that was distributed to medical providers purchasing and using
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`INOmax® branded iNO gas for therapy. It describes INOmax as “a drug
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`administered by inhalation” whose active substance is nitric oxide. Ex. 1014 at p.
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`1. INOMAX label describes that “INOmax is a gaseous blend of nitric oxide
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`(0.8%) and nitrogen (99.2%).” Ex. 1014 at p. 1. It also states that INOmax is
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`“supplied in aluminum cylinders” of varying sizes and concentrations. Ex. 1014 at
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`pp. 1, 6-7. Consistent with the discussion above, the INOMAX label informed
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`medical providers that “nitric oxide produces pulmonary vasodilation” and can be
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`used to treat neonates with PPHN to improve oxygenation. Ex. 1014 at p. 1.
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`32. The INOMAX label reference contains “prescribing information” that
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`was given to medical providers responsible for treating those individuals to whom
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`INOMAX label is directed - that is, neonates who have hypoxic respiratory failure.
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`See Ex. 1014 at p. 4 (iNO indicated for treatment of “neonates with hypoxic
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`respiratory failure”). The INOMAX label does not indicate that a practitioner
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`should determine if such neonates do or do not have LVD and therefore discloses
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`treating neonates with hypoxic respiratory failure but without LVD. Ex. 1014 at 4.
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`A person of skill in the art reading the INOMAX label reference understands that it
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`discloses a protocol (or method) for administering nitric oxide gas, and that the
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`protocol information contained in the INOMAX label is provided to medical
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`providers along with cylinders of nitric oxide gas to educate the providers as to the
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`use of the nitric oxide gas.
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`33. The INOMAX label reference therefore discloses providing cylinders
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`of a gaseous blend of nitric oxide and nitrogen to medical providers who will be
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`treating patients with the drug. Ex. 1014 at p. 1. Further, the INOMAX label
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`reference discloses that iNO is indicated for treatment of term and near-term
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`neonates with hypoxic respiratory failure, meaning that the informat