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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
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`DECLARATION OF DR. MAURICE BEGHETTI IN SUPPORT OF
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`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.
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`8,431,163
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`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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`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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`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. 8,431,163
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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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`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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`3
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,431,163
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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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`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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`4
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,431,163
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`9.
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`A copy of my curriculum vitae is found in 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. 8,431,163 (“the ʼ163 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 ʼ163 Patent.
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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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`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) (“Ivy”). As
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`shown by the papers resulting from these Boards, there is no major
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`disagreement on the paediatric guidelines among practitioners with regard to
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`the treatment approach to be used for administration of inhaled NO. There
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`may, however, be some differences in treatment selection due to the access and
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`reimbursement availability of different therapies in different regions of the
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`world. However, once a particular treatment is chosen, the approach from that
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`point on is primarily consistent worldwide.
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,431,163
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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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`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, as set forth below, is based on
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`my personal experience and what was known, and in fact, considered to be
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`standard, by one skilled in the art prior to June 30, 2009.
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`12.
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`I have reviewed and am familiar with the ʼ163 Patent. Additionally, I
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`have reviewed the following documents: (1) Ex. 1004, Bernasconi, et al., Inhaled
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`Nitric Oxide Applications in Paediatric Practice, 4 Images in Paediatric
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`Cardiology, 4-29 (2002) (“Bernasconi”); (2) Ex. 1005, Davidson, et al., Inhaled
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`Nitric Oxide for the Early Treatment of Persistent Pulmonary Hypertension of the
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`Term Newborn: A Randomized, Double-Masked, Placebo-Controlled, Dose-
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`Response, Multicenter Study, 101 Pediatrics, 325-334 (1998) (“Davidson”); (3) Ex.
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`1006, Loh, et al., Cardiovascular Effects of Inhaled Nitric Oxide in Patients with
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`Left Ventricular Dysfunction, 90 Circulation, 2780-2785 (1994) (“Loh”); (4) Ex.
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`1007, P. Goyal, et al., Efficacy of Nitroglycerin Inhalation in Reducing Pulmonary
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`Arterial Hypertension in Children with Congenital Heart Disease, 97 British
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`Journal of Anaesthesia, 208-214 (2006) (“Goyal”); (5) Ex. 1008, Macrae, et al.,
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`Inhaled Nitric Oxide Therapy in Neonates and Children: Reaching a European
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`Consensus, 30 Intensive Care Medicine, 372-380 (2004) (“Macrae”); (6) 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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`(7) Ex. 1010, Germann, et al., Inhaled Nitric Oxide Therapy in Adults: European
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`Expert Recommendations, 31 Intensive Care Med, 1029-1041 at 1030 (2005)
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`(“Germann”); (8) Ex. 1011, The Neonatal Inhaled Nitric Oxide Study Group,
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`Inhaled Nitric Oxide in Full-Term and Nearly Full-Term Infants with Hypoxic
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`Respiratory Failure, 336 The New England Journal of Medicine, 597-604 (1997)
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`(“Neonatal Group”); and (9) Ex. 1014, Center for Drug Evaluation and Research,
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`Application Number: NDA 20845, INOMAX, Final Printed Labeling, available at
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`http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20845_inomax_prntlbl.pdf
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`(August 9, 2000). (“INOMAX label”). I was already familiar with many of these
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`references from having read them at the time they were first published, and I have
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`also cited several of them in my own publications. I have also reviewed the
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`documents cited elsewhere herein, as well as any documents cited in the
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`declarations I have submitted or will submit in other inter partes review petitions
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`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
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`HAVE HAD BEFORE THE PRIORITY DATE OF THE ʼ163 PATENT
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`14. The ʼ163 patent is entitled “Methods of Reducing the Risk of
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`Occurrence of Pulmonary Edema Associated With Inhalation of Nitric Oxide Gas.”
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`The ’163 patent provides contraindications for treatment of neonates with inhaled
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`NO. Specifically the ʼ163 patent provides a pre-screening protocol to determine
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`whether a patient is at risk of an adverse event upon treatment with inhaled NO,
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`such as pulmonary oedema.3 Ex. 1001 at Abstract, 1:46–2:4. It essentially
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`provides that if the patient demonstrates characteristics suggesting that he or she is
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`at risk, then the patient should not be treated with inhaled NO. Id. The evaluation
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`includes a determination that patients who have left ventricular dysfunction
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`(“LVD”) should be excluded from treatment. Id. Claim 1 is representative:
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`A method of reducing the risk of occurrence of pulmonary edema
`associated with a medical treatment comprising inhalation of 20 ppm
`nitric oxide gas, said method comprising:
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`(a) performing echocardiography to identify a term or near-term
`neonate patient in need of 20 ppm inhaled nitric oxide treatment for
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`3 Pulmonary edema is a buildup of fluid in the lungs. “Oedema” is an alternative
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`spelling for “edema.”
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`hypoxic respiratory failure, wherein the patient is not dependent on
`right-to-left shunting of blood;
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`(b) determining that the patient identified in (a) has left ventricular
`dysfunction consistent with a pulmonary capillary wedge pressure
`greater than or equal to 20 mm Hg, so it at particular risk of
`pulmonary edema upon treatment with inhaled nitric oxide; and
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`(c) excluding the patient from inhaled nitric oxide treatment, based on
`the determination that the patient has left ventricular dysfunction and
`so is at particular risk of pulmonary edema upon treatment with
`inhaled nitric oxide.
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`15.
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`In practice, the determination that the patient has left ventricular
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`dysfunction may be made in a variety of ways, such as by measuring pulmonary
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`capillary wedge pressure (“wedge pressure”), or through echocardiography.4 I am
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`an expert in these protocols and treatments, and was an expert in this area prior to
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`the priority date of the ʼ163 patent on June 30, 2009. This expertise comes from
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`the field of paediatric cardiology and pulmonary hypertension where the difference
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`between pre-capillary pulmonary hypertension that includes normal pulmonary
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`wedge pressure and post-capillary pulmonary hypertension is a key discussion in
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`this field. 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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`4 Echocardiography is the use of ultrasound waves to investigate the actions of
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`the heart.
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`hypertension in two different groups of pulmonary hypertension classification. See
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`e.g., Exhibit 1018, Simonneau, et al., Clinical Classification of Pulmonary
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`Hypertension, J. Am. Coll. Cardiol. 43(12 Suppl S):5S-12S (2004) (“Simonneau
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`2004”); Exhibit 1019, Simonneau, et al., Updated Clinical Classification of
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`Pulmonary Hypertension, J Am. Coll. Cardiol. 54(1 Suppl):S43-54 (2009)
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`(“Simonneau 2009”); Exhibit 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) (“Simonneau 2013”). Although, the clinical classifications
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`apply to pulmonary hypertension generally, the teachings are equally applicable to
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`the context of pulmonary hypertension treated with inhaled NO and the effect of
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`left heart disease.
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`16. 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) (“Chemla”). One cause of pulmonary
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`hypertension is vasoconstriction. Id. at 1314. Before June 30, 2009, it was known
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`to doctors in the field of paediatric cardiology that nitric oxide may be used as a
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`vasodilator.5 Ex. 1010 at 1030, 1031. Inhaled nitric oxide is a selective pulmonary
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`5 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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`vasodilator, and, as such, relaxes pulmonary vessels, which decreases pulmonary
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`vascular resistance, pulmonary arterial pressure, and right ventricular afterload.
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`See Ex. 1022, Griffiths, et al,. Inhaled Nitric Oxide Therapy in Adults, 353 New
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`England Journal of Medicine 2683-2695 at 2685 (2005) (“Griffiths”). When nitric
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`oxide is inhaled, it diffuses rapidly across the alveolar-capillary membrane and into
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`the subjacent smooth muscle of pulmonary vessels to activate the soluble enzyme
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`guanylate cyclase. Ex. 1009 at 3106. This enzyme converts GTP to cGMP, and
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`the increased intracellular concentrations of cGMP relax smooth muscle resulting
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`in vasodilation. Id.
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`17. 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 at 3. Twenty parts per million of
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`inhaled NO is approved by the FDA to treat neonatal hypoxic respiratory failure6
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`6 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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`and has been approved since 2000. Ex. 1004 at 3; see also Ex. 1014 at 6. It is
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`indeed the only pathology for which inhaled nitric oxide has been approved in the
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`United States. Id. 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 will examine and evaluate patients before
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`administering treatment. Such examinations are and have long been performed by
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`doctors before administering any kind of treatment. These examinations were
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`done for two main reasons: (1) to determine whether the treatment is likely to help
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`the patient; and (2) to determine whether the patient is at particular risk of having a
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`negative reaction. In the case of inhaled NO, one such well-known negative
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`reaction is pulmonary oedema due to left ventricular dysfunction. See, e.g., Ex.
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`1004 at 8. Such examinations were commonly done prior to June 30, 2009. Id.
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`18. Before June 30, 2009, it was known that systolic and diastolic left
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`ventricular dysfunction, any obstruction to the pulmonary venous flow, or lesions
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`that may increase pulmonary venous pressure (such as obstructed pulmonary
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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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`venous return, mitral stenosis7 or insufficiency, etc.) increase the risk of a patient
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`suffering a serious adverse event upon treatment with inhaled NO. See, e.g. Ex.
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`1004 at 8 (“However, in patients with elevated left atrial pressure due to left
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`ventricular dysfunction, a decrease in pulmonary vascular resistance (induced by
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`inhaled NO) will lead to an increase in pulmonary venous return and hence to an
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`increase in left atrial and left ventricular filling pressures . . . This effect may lead
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`to . . . left heart failure and pulmonary oedema”).
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`19. 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 pulmonary hypertension. Second, doctors would
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`assess whether inhaled NO would likely trigger adverse events in the patient. This
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`process was performed for all patients. As is clear from the studies which include
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`numerous patients, one skilled in the art would have understood that a process for
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`selecting a patient to be treated, or a method of treatment, could be applied to one
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`7 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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`patient, or to a plurality of patients. See generally Ex. 1004, Ex. 1006, Ex. 1005,
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`Ex. 1009 (all disclosing studies treating multiple patients with inhaled NO).
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`20. Doctors who were considering prescribing inhaled NO prior to June
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`30, 2009, like today, would not do so for patients at risk of adverse events or
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`serious adverse events. For example, in 2005, an Advisory Board was established
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`under the auspices of the European Society of Intensive Care Medicine and
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`European Association of Cardiothoracic Anesthesiologists to analyze the usage of
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`inhaled NO. The Advisory Board was composed of experts with proven scientific
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`or clinical expertise relevant to the clinical use of inhaled NO, including paediatric
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`specialists, to prepare recommendations for NO use. Ex. 1010 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,8
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`before administration it should be determined whether the patients had 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. Ex. 1010 at 1030, 1033.
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`21.
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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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`8 The Advisory Board also recognized that inhaled NO has significant off-label
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`use. Ex. 1010 at 1030.
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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 at Abstract; see also Ex. 1030, Henrichsen, et al., Inhaled Nitric Oxide can
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`Cause Severe Systemic Hypotension, 129 The Journal of Pediatrics, 183, col. 1,
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`par. 2 (1996) (“Henrichsen”) (disclosing echocardiography prior to treatment to
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`examine the structure of the heart, diagnose left ventricular function, and identify
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`patients dependent on right-to-left shunting of blood); Ex. 1016, Hoehn, Therapy
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`of Pulmonary Hypertension
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`in Neonates and Infants, Pharmacology &
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`Therapeutics 2007 114:318-326 at 322. (“Hoehn”). It was a well-known clinical
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`practice or before June 30, 2009, to suggest an echocardiogram before
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`administering inhaled NO. Indeed, before June 30, 2009, my team followed this
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`practice before starting nitric oxide, and the intensive care or neonatology
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`specialists consistently confirmed that it was done before treatment. We even
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`often assessed the efficacy by echocardiography through the evaluation of
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`pulmonary pressure, right ventricular anatomy and function as well as shunt
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`direction through the ductus arteriosus and the foramen ovale.
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`22. Additionally, wedge pressure of 20 mm Hg is a physiological
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`indicator of conditions that increases risk for patients if they were to receive
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`treatment with inhaled NO, including left heart dysfunction.9 As was known in the
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`art prior to June 30, 2009, wedge pressure can be measured by inserting a
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`pulmonary catheter with an inflated balloon into a small pulmonary arterial branch
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`(e.g., a Swan-Ganz catheter). See, e.g., Ex. 1023, Royster, et al., Differences in
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`Pulmonary Artery Wedge Pressures Obtained by Balloon Inflation Versus
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`Impaction Techniques, 61 Anesthesiology, 339 – 341 (1984) (“Royster”); see also,
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`Ex. 1007 at p. 209 (showing measurement of wedge pressure in infants and other
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`children); Ex. 1015, Klabunde, Pulmonary Capillary Wedge Pressure,
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`Cardiovascular
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`Physiology
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`Concepts,
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`4/11/2007
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`available
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`at
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`http://www.cvphysiology.com/Heart%20Failure/HF008.htm (“Klabunde”). A rise
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`in wedge pressure upon treatment with inhaled NO suggests left ventricular
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`dysfunction. See, e.g. Ex. 1024, Ignarro, L.J., ed. Nitric Oxide Biology and
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`9 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, 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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`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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`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 children and adults could
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`have wedge pressure measured with a catheter. While not typically performed in
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`neonates, one skilled in the art would have known to measure wedge pressure with
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`a catheter in emergency situations.
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`23. 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, et al., Non-Invasive Estimation of
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`Left Ventricular Filling Pressures by Doppler Echocardiography, 3 Eur J
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`Echocardiogr., 75-79 (2002) (“Pozzoli”). Wedge pressure may be extrapolated by
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`the physician in his/her mind from echocardiographic information to identify
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`whether left heart dysfunction exists and, concomitantly, that physiologically a
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`wedge pressure exists over a certain value. A paediatric cardiologist with skill and
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`extensive experience with echocardiography would be able to extrapolate wedge
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`pressure with accuracy to be of use in making a diagnosis or determining whether
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`the patient in question has a condition such as left ventricular dysfunction that
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`would require assessment of the risks of treatment and likely contraindicate
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`treatment with inhaled NO. Even with such skill, a precisely accurate numerical
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`value will not be reached, only an estimate.
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`17
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,431,163
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`24. As part of regular clinical practice before June 30, 2009, patients not
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`at risk of adverse events such as pulmonary edema were treated with inhaled NO,
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`and patients that revealed risk factors during echocardiography, measurement of
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`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 at 940-941. All physicians have a basic understanding
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`of negative side effects, and one skilled in the art would have known not to
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`administer inhaled NO if it would cause harm to the patient that outweighed the
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`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) (“Kaldijian”) (discussing the duty of nonmaleficence, to avoid causing
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`harm to a patient); see also Ex. 1027, Jonsen, A. et al., Clinical Ethics: A Practical
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`18
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,431,163
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`Approach to Ethical Decisions in Clinical Medicine 4th ed. (1998) (discussing the
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`Hippocratic Oath and the requirement to do no harm) (“Jonsen”).
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`INTERPRETATIONS OF THE ʼ163 PATENT CLAIMS AT ISSUE
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`Legal Principles Applicable to Claim Construction
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`25.
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`I understand that, for purposes of my analysis, the terms and phrases
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`appearing in a patent claim should be interpreted according to their “broadest
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`reasonable construction in light of the specification of the patent in which it
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`appears.” 37 C.F.R. § 42.100(b). I further understand that the words of the claims
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`should be given their plain meaning unless that meaning is inconsistent with the
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`patent specification. I also understand that the words of the claims should be
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`interpreted as they would have been interpreted by a person of ordinary skill in the
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`art at the time of the invention was made (not today). For my analysis, I was
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`instructed to use the priority date of the ʼ163 patent, June 30, 2009, as the point in
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`time for claim interpretation purposes. In my opinion, all the terms in the ’163
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`patent should be understood to have their plain and ordinary meaning as would
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`have been known to one of ordinary skill in the art.
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`19
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,431,163
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`Level of Skill In The Art
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`26.
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`In my opinion, a person of ordinary skill in the art to be a paediatric
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`cardiologist with experience prescribing inhaled NO before June 30, 2009. I
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`understand that a person of ordinary skill in the art is a hypothetical person who is
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`presumed to be aware of all pertinent art, thinks along conventional wisdom in the
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`art, and is a person of ordinary creativity. A person of ordinary skill in the art of
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`treatment of patients with inhaled NO would have had knowledge of the scientific
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`literature concerning administration of inhaled NO, including contraindications and
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`risks as of June 30, 2009. Such a person of ordinary skill in the art would have had
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`knowledge of the scientific literature related to pulmonary hypertension and
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`hypoxic respiratory failure. The person of ordinary skill in the art would also have
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`extensive knowledge and experience with echocardiography. A person of ordinary
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`skill in the art would have known how to research the scientific literature regarding
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`the use of inhaled NO. Typically, a person of ordinary skill in the art would be an
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`experienced pediatric cardiologist.
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`27.
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` The person of ordinary skill in the art would have been familiar with
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`all of the technical concepts set forth in this declaration.
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`20
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`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,431,163
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`LEGAL PRINCIPLES
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`Obviousness
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`28.
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`I have been informed that a patent claim is invalid as “obvious” under
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`35 U.S.C. § 103 in light of one or more prior art references if it would have been
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`obvious to one of skill in the art at the time the invention was made, taking into
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`account (1) the scope and content of the prior art, (2) the differences between the
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`prior art and the claims, (3) the level of ordinary skill in the art, and (4) any so
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`called “secondary considerations” of non-obviousness, which include: (i) “long felt
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`need” for the claimed invention, (ii) commercial success attributable to the claimed
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`invention, (iii) unexpected results of the claimed invention, and (iv) “copying” of
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`the claimed invention by others.
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`29. For purposes of my analysis above, unless otherwise stated, I have
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`applied a date of June 30, 2009, as the date of invention, in my obviousness
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`analyses, although in many cases the same analysis would hold true even at an
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