throbber
IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`
`
`
`
`
`
`
`
`
`
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`
`
`
`
`
`
`
`
`
`
`PRAXAIR DISTRIBUTION, INC.
`Petitioner
`v.
`INO THERAPEUTICS, INC. d/b/a IKARIA, INC.
`Patent Owner
`
`DECLARATION OF DR. MAURICE BEGHETTI IN SUPPORT OF
`
`PETITION FOR INTER PARTES REVIEW OF U.S. PATENT NO.
`
`8,293,284
`
`I, Dr. Maurice Beghetti, declare that:
`
`QUALIFICATIONS
`
`1.
`
`I am the Head of the Paediatric Cardiology Unit and also am the
`
`Director of the Subspecialty Division at the University Hospital of Geneva, in
`
`Geneva, Switzerland. I hold several degrees from Genève, Université, Faculté de
`
`Médecine, including specialist degrees in paediatric cardiology. I have spent most
`
`of my professional career in Geneva, with a three-year fellowship at the Hospital
`
`1
`
`
`Ex. 2033-0001
`
`

`
`for Sick Children in Toronto, Canada with one year devoted specifically to cardiac
`
`intensive care focusing on pulmonary hypertension research.
`
`2.
`
`I have treated patients with inhaled nitric oxide (“NO,” “inhaled NO,”
`
`or “iNO”) since at least the early 1990s, when it was first shown to be efficacious.
`
`I have both extensively studied the drug and researched its potential uses since the
`
`early 1990s. I regularly speak and lecture about treatment of pulmonary
`
`hypertension,1 including how to treat patients with inhaled NO or how to assess the
`
`condition of a patient’s pulmonary vasculature using inhaled NO.
`
`3.
`
`I have been and currently am a full professor at Genève, University,
`
`Faculty of Medicine, where I have taught the uses and contraindications for inhaled
`
`NO within my lectures for cardiologists, neonatologists, and intensive care
`
`specialists, as well as for nurses specialized in intensive care. I have taught these
`
`subjects at the University since 1996, first as a senior fellow, and then as an
`
`associate professor since 2001, and as a full professor since 2010.
`
`4.
`
`I have received several awards throughout my career, including two
`
`directly related to my research on inhaled NO. In 1996, I received a clinical
`
`research award at the Hospital for Sick Children in Toronto, for my work entitled
`
`“A comparison of inhaled nitric oxide and mild metabolic alkalosis as acute
`
`1 Pulmonary hypertension is increased pressure in the pulmonary arteries—the
`
`arteries that carry blood from the heart to the lungs to pick up oxygen.
`
`2
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0002
`
`

`
`therapy for control of pulmonary hypertension following open-heart surgery.” I
`
`additionally received an award in 2000 for my research entitled “Inhaled Iloprost
`
`versus inhaled nitric oxide in secondary pulmonary hypertension: the vasodilator
`
`capacity and cellular mechanisms.” This award was presented by the third World
`
`Congress on Pediatric Intensive Care, held in June of 2000.
`
`5.
`
`During the last 12 years, I have been extensively involved with
`
`numerous international, standard-setting organizations. I am a Member of the
`
`Executive Board of the Association for Paediatric PH (“pulmonary hypertension”),
`
`which has generated the TOPP Registry (for Tracking Outcomes and Practice in
`
`Paediatric PH). I am the Paediatric Member of the European Society of
`
`Cardiology (“ESC”) Working Group on Pulmonary Circulation and Right
`
`Ventricular Function. I am also the Paediatric Member of the ESC Guidelines.
`
`The guidelines are endorsed by the European Respiratory Society (ERS), the
`
`European Association for Pediatric Cardiology (AEPC) (indeed, I represent AEPC
`
`in the guidelines) and the International Society for Heart and Lung Transplantation
`
`(ISHLT). I was the Co-Chair of the Paediatric Task Force at the last World
`
`Symposium on Pulmonary Hypertension in 2013, involving representatives from
`
`numerous countries, including the United States.
`
`6.
`
`I am a member of the editorial board of Cardiology in the Young and
`
`have authored numerous publications, book chapters and books on pulmonary
`
`3
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0003
`
`

`
`hypertension. I am the editor of what is currently the only book on paediatric
`
`pulmonary hypertension.
`
`7. My research interests are focused on pulmonary hypertension and
`
`congenital heart defects in paediatric patients. I also work with colleagues and
`
`pharmaceutical companies to design pediatric pulmonary hypertension and
`
`persistent pulmonary hypertension of the newborn (“PPHN”) studies with the
`
`European Medicines Agency (“EMA”) to develop alternative treatments for
`
`patients who do not respond to treatment with inhaled NO.
`
`8.
`
`As part of my involvement with international organizations, including
`
`the world symposia, and through consulting work where I have presented materials
`
`to the FDA as part of paediatric investigational programs for new compounds, I
`
`have been able to confirm that there are no material differences in the standards of
`
`care and clinical practice for treating patients with inhaled NO in the United States
`
`as compared to Europe. Additionally, as part of my work with the ESC guidelines,
`
`I regularly confer with practitioners in the United States, Europe, and other
`
`countries throughout the world.2
`
`2 Advisory boards involving experts in the US and Europe have been established
`
`to develop recommendations for the use of inhaled NO. See, e.g., Ex. 1010,
`
`Germann, et al., Inhaled Nitric Oxide Therapy in Adults: European Expert
`
`Recommendations, 31 Intensive Care Med, 1029-1041 at 1030 (2005)
`
`4
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0004
`
`

`
`9.
`
`A copy of my curriculum vitae is found in Exhibit 1003.
`
`10.
`
`I am not an employee of Praxair Distribution, Inc.; Praxair, Inc. or any
`
`affiliated company. Rather, I have been engaged in the present matter to provide
`
`my independent analysis of the issues raised in the above-mentioned inter partes
`
`review of U.S. Patent No. 8,293,284 (“the ʼ284 Patent”) (Ex. 1001). I have
`
`received no compensation for this declaration beyond my normal hourly
`
`compensation of $500/hr. for time actually spent studying the matter, and I will not
`
`receive any added compensation based on the outcome of any proceeding related
`
`to the ʼ284 Patent.
`
`(“Germann”); see also Ex. 1008, Macrae, et al., Inhaled Nitric Oxide Therapy
`
`in Neonates and Children: Reaching a European Consensus, 30 Intensive Care
`
`Medicine, 372-380 (2004) (“Macrae”); see also Ex. 1017, Ivy et al., Pediatric
`
`Pulmonary Hypertension, J Am Coll Cardiol. 62(25_S) (2013) (“Ivy”). As
`
`shown by the papers resulting from these Boards, there is no major
`
`disagreement on the paediatric guidelines among practitioners with regard to
`
`the treatment approach to be used for administration of inhaled NO. There
`
`may, however, be some differences in treatment selection due to the access and
`
`reimbursement availability of different therapies in different regions of the
`
`world. However, once a particular treatment is chosen, the approach from that
`
`point on is primarily consistent worldwide.
`
`5
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0005
`
`

`
`11. Based upon my extensive knowledge and years of experience in this
`
`field, I have an understanding of how inhaled NO was being used for medical
`
`treatment on or before June 30, 2009, as well as the risks and contraindications
`
`associated with its use. My analysis on this matter, as set forth below, is based on
`
`my personal experience and what was known, and in fact, considered to be
`
`standard, by one skilled in the art prior to June 30, 2009.
`
`12.
`
`I have reviewed and am familiar with the ʼ284 Patent. Additionally, I
`
`have reviewed the following documents: (1) Ex.1004, Bernasconi, et al., Inhaled
`
`Nitric Oxide Applications in Paediatric Practice, 4 Images in Paediatric
`
`Cardiology, 4-29 (2002) (“Bernasconi”); (2) Ex.1005, Davidson, et al., Inhaled
`
`Nitric Oxide for the Early Treatment of Persistent Pulmonary Hypertension of the
`
`Term Newborn: A Randomized, Double-Masked, Placebo-Controlled, Dose-
`
`Response, Multicenter Study, 101 Pediatrics, 325-334 (1998) (“Davidson”); (3)
`
`Ex.1006, Loh, et al., Cardiovascular Effects of Inhaled Nitric Oxide in Patients
`
`with Left Ventricular Dysfunction, 90 Circulation, 2780-2785 (1994) (“Loh”); (4)
`
`Ex.1007, P. Goyal, et al., Efficacy of Nitroglycerin Inhalation in Reducing
`
`Pulmonary Arterial Hypertension in Children with Congenital Heart Disease, 97
`
`British Journal of Anaesthesia, 208-214 (2006) (“Goyal”); (5) Ex.1008, Macrae, et
`
`al., Inhaled Nitric Oxide Therapy in Neonates and Children: Reaching a European
`
`Consensus, 30 Intensive Care Medicine, 372-380 (2004) (“Macrae”); (6) Ex.1009,
`
`6
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0006
`
`

`
`Ichinose, et al., Inhaled Nitric Oxide: A Selective Pulmonary Vasodilator: Current
`
`Uses and Therapeutic Potential, 109 Circulation, 3106-3111 (2004) (“Ichinose”);
`
`(7) Ex.1010, Germann, et al., Inhaled Nitric Oxide Therapy in Adults: European
`
`Expert Recommendations, 31 Intensive Care Med, 1029-1041 at 1030 (2005)
`
`(“Germann”); (8) Ex.1011, The Neonatal Inhaled Nitric Oxide Study Group,
`
`Inhaled Nitric Oxide in Full-Term and Nearly Full-Term Infants with Hypoxic
`
`Respiratory Failure, 336 The New England Journal of Medicine, 597-604 (1997)
`
`(“Neonatal Group”); and (9) Ex. 1014, Center for Drug Evaluation and Research,
`
`Application Number: NDA 20845, INOMAX, Final Printed Labeling, available at
`
`http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20845_inomax_prntlbl.pdf
`
`(August 9, 2000). (“INOMAX label”). I was already familiar with many of these
`
`references from having read them at the time they were first published, and I have
`
`also cited several of them in my own publications. I have also reviewed the
`
`documents cited elsewhere herein, as well as any documents cited in the
`
`declarations I have submitted or will submit in other inter partes review petitions
`
`arising out of my engagement in this matter.
`
`13. My opinions, explained below, are based on my education,
`
`experience, and background in the field discussed above as well as my review of
`
`the references cited above.
`
`7
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0007
`
`

`
`BACKGROUND KNOWLEDGE ONE OF SKILL IN THE ART WOULD
`
`HAVE HAD BEFORE THE PRIORITY DATE OF THE ʼ284 PATENT
`
`14. The ʼ284 patent is entitled “Methods of Reducing the Risk of
`
`Occurrence of Pulmonary Edema in Term or Near-Term Neonates in Need of
`
`Treatment with Inhaled Nitric Oxide.” The ʼ284 patent provides contraindications
`
`for treatment of neonates with inhaled NO. Specifically the ʼ284 patent provides a
`
`pre-screening protocol to determine whether a patient is at risk of a serious adverse
`
`event upon treatment with NO, such as pulmonary oedema.3 See ʼ284 patent at
`
`Abstract, 1:49-62. It essentially provides that if the patient demonstrates
`
`characteristics suggesting that he or she is at risk, then the patient should not be
`
`treated with inhaled NO. Id. The evaluation includes a determination that patients
`
`who have left ventricular dysfunction should be excluded from treatment if the risk
`
`of harm to the patient outweighs the therapeutic benefit of the inhaled NO
`
`treatment. Id.
`
`Claim 1 is representative:
`
`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:
`
`
`3 Pulmonary edema is a buildup of fluid in the lungs. “Oedema” is an alternative
`
`spelling for “edema.”
`
`8
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0008
`
`

`
`(a) performing echocardiography to identify a term or near-term
`neonate patient in need of 20 ppm inhaled nitric oxide treatment for
`pulmonary hypertension, wherein the patient is not dependent on
`right-to-left shunting of blood;
`(b) determining that the patient identified in (a) has a pulmonary
`capillary wedge pressure greater than or equal to 20 mm Hg and thus
`has left ventricular dysfunction, so is at particular risk of pulmonary
`edema upon treatment with inhaled nitric oxide; and
`(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.
`15.
`In practice, the determination that the patient has left ventricular
`
`dysfunction may be made in a variety of ways, such as by measuring pulmonary
`
`capillary wedge pressure (“wedge pressure”) or through echocardiography.4 Id. at
`
`1:58-61, 4:63-5:12 I am an expert in these protocols and treatments, and was an
`
`expert in this area prior to the priority date of the ʼ284 patent on June 30, 2009.
`
`This expertise comes from the field of paediatric cardiology and pulmonary
`
`hypertension where the difference between pre-capillary pulmonary hypertension
`
`that includes normal wedge pressure and post capillary pulmonary hypertension is
`
`a key discussion in this field. It is important in fact to differentiate these two
`
`entities as they react differently to therapies. This is indeed well described in the
`
`pulmonary hypertension field and many years ago led to the classification of these
`
`4 Echocardiography is the use of ultrasound waves to investigate the actions of
`
`the heart.
`
`9
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0009
`
`

`
`two types of pulmonary hypertension in two different groups of pulmonary
`
`hypertension classification. See e.g., Ex. 1018, Simonneau, et al., Clinical
`
`Classification of Pulmonary Hypertension, J. Am. Coll. Cardiol. 43(12 Suppl
`
`S):5S-12S (2004) (“Simonneau 2004”); Ex. 1019, Simonneau, et al., Updated
`
`Clinical Classification of Pulmonary Hypertension, J Am. Coll. Cardiol. 54(1
`
`Suppl):S43-54 (2009) (“Simonneau 2009”); Ex. 1020, Simonneau, et al., Updated
`
`Clinical Classification of Pulmonary Hypertension, J. Am. Coll. Cardiol. 62(25
`
`Suppl):D34-41 (2013) (“Simonneau 2013”). Although the clinical classifications
`
`apply to pulmonary hypertension generally, the teachings are equally applicable to
`
`the context of pulmonary hypertension treated with inhaled NO and the effect of
`
`left heart disease.
`
`16. Pulmonary arterial hypertension is characterized by an increased
`
`pulmonary artery pressure and increased pulmonary vascular resistance. See Ex.
`
`1021, Chemla, et al., Haemodynamic Evaluation of Pulmonary Hypertension 20
`
`Eur Respir J. 1314-1331 at 1314 (2002) (“Chemla”). One cause of pulmonary
`
`hypertension is vasoconstriction. Id. at 1314. Before June 30, 2009, it was known
`
`to doctors in the field of paediatric cardiology that nitric oxide may be used as a
`
`vasodilator.5 See Ex. 1010 at 1030, 1031. Inhaled nitric oxide is a selective
`
`5 Vasodilation is the widening of blood vessel that results from relaxation of
`
`smooth muscle cells within the vessel walls.
`
`10
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0010
`
`

`
`pulmonary vasodilator, and, as such, relaxes pulmonary vessels, which decreases
`
`pulmonary vascular resistance, pulmonary arterial pressure, and right ventricular
`
`afterload. See Ex. 1022, Griffiths, et al,. Inhaled Nitric Oxide Therapy in Adults,
`
`353 New England Journal of Medicine, 2683-2695 at 2685 (2005) (“Griffiths”).
`
`When nitric oxide is inhaled, it diffuses rapidly across the alveolar-capillary
`
`membrane and into the subjacent smooth muscle of pulmonary vessels to activate
`
`the soluble enzyme guanylate cyclase. See Ex. 1009 at 3106. This enzyme
`
`converts GTP to cGMP, and the increased intracellular concentrations of cGMP
`
`relax smooth muscle resulting in vasodilation. Id.
`
`17. Not all patients and not all conditions are responsive to treatment with
`
`inhaled NO. Pulmonary hypertension, specifically PPHN, is a condition that may
`
`be treated with inhaled NO. See, e.g. Ex. 1004 at 3. Twenty parts per million of
`
`inhaled NO is approved by the FDA to treat neonatal hypoxic respiratory failure6
`
`6 Hypoxic respiratory failure and hypoxaemic respiratory failure, conditions
`
`where the cells of the body do not have enough oxygen, may be caused by
`
`pulmonary hypertension. Therefore, treatment of pulmonary hypertension
`
`would also result in treatment of hypoxic respiratory failure caused by
`
`pulmonary hypertension. Sever hypoxic respiratory failure may lead to hypoxia
`
`(a condition characterized by low oxygen in all organs; where the tissue does
`
`not have enough oxygen). Treatment of hypoxia may be understood to include
`
`11
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0011
`
`

`
`and has been approved since 2000. Ex. 1004 at 3; see also Ex. 1014 at 6. It is
`
`indeed the only pathology for which inhaled nitric oxide has been approved in the
`
`United States. Id. Inhaled NO can be used to treat both hypoxic and hypoxaemic
`
`respiratory failure. However, such treatment is not suitable for all patients.
`
`Therefore, as is the case with many medications, doctors involved in the treatment
`
`of patients with inhaled NO will examine and evaluate patients before
`
`administering treatment. Such examinations are and have long been performed by
`
`doctors before administering any kind of treatment. These examinations were
`
`done for two main reasons: (1) to determine whether the treatment is likely to help
`
`the patient; and (2) to determine whether the patient is at particular risk of having a
`
`negative reaction. In the case of inhaled NO, one such well-known negative
`
`reaction is pulmonary oedema due to left ventricular dysfunction. See, e.g., Ex.
`
`1004 at 8. Such examinations were commonly done prior to June 30, 2009. Id.
`
`18. Before June 30, 2009, it was known that systolic and diastolic left
`
`ventricular dysfunction, any obstruction to the pulmonary venous flow, or lesions
`
`that may increase pulmonary venous pressure (such as obstructed pulmonary
`
`
`treatment of hypoxic respiratory failure, as the hypoxia is the condition that
`
`causes harm to the patient.
`
`12
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0012
`
`

`
`venous return, mitral stenosis7 or insufficiency, etc.) increase the risk of a patient
`
`suffering a serious adverse event upon treatment with inhaled NO. See, e.g. Ex.
`
`1004 at 8 (“However, in patients with elevated left atrial pressure due to left
`
`ventricular dysfunction, a decrease in pulmonary vascular resistance (induced by
`
`inhaled NO) will lead to an increase in pulmonary venous return and hence to an
`
`increase in left atrial and left ventricular filling pressures . . . This effect may lead
`
`to . . . left heart failure and pulmonary oedema”).
`
`19. As part of the general medical practice before June 30, 2009, doctors
`
`implemented a clinical diagnostic procedure to assess patient conditions, treatment
`
`options, and potential risks from any potential treatment. First, doctors would
`
`assess the condition of the patient to see if the patient had a condition likely to be
`
`helped by inhaled NO, such as pulmonary hypertension. Second, doctors would
`
`assess whether inhaled NO would likely trigger adverse events in the patient. This
`
`process was performed for all patients. As is clear from the studies which include
`
`numerous patients, one skilled in the art would have understood that a process for
`
`selecting a patient to be treated, or a method of treatment, could be applied to one
`
`
`7 Mitral stenosis is a condition where the mitral valve, which separates the upper
`
`and lower chambers on the left side of the heart, does not open fully, restricting
`
`blood flow.
`
`13
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0013
`
`

`
`patient, or to a plurality of patients. See generally Exs. 1004, 1005, 1006, and 1009
`
`(all disclosing studies treating multiple patients with inhaled NO).
`
`20. Doctors who were considering prescribing inhaled NO prior to June
`
`30, 2009, like today, would not do so for patients at risk of adverse events or
`
`serious adverse events. For example, in 2005, an Advisory Board was established
`
`under the auspices of the European Society of Intensive Care Medicine and
`
`European Association of Cardiothoracic Anesthesiologists to analyze the usage of
`
`inhaled NO. The Advisory Board was composed of experts with proven scientific
`
`or clinical expertise relevant to the clinical use of inhaled NO, including paediatric
`
`specialists, to prepare recommendations for NO use. See Ex. 1010 at 1030. The
`
`Advisory Board concluded in its written recommendations in 2005 that while
`
`inhaled NO is approved for use in neonates with hypoxic respiratory failure,8
`
`before administration it should be determined whether the patients had left heart
`
`dysfunction or other heart conditions that increase post capillary pressures. Once
`
`identified, these patients should not be treated with inhaled NO unless the heart
`
`condition is first addressed. See Ex. 1010 at 1030, 1033.
`
`21.
`
`In accordance with the recommendations, which conformed to
`
`industry practice even before the publications by the Advisory Board, the
`
`8 The Advisory Board also recognized that inhaled NO has significant off-label
`
`use. See Ex. 1010 at 1030.
`
`14
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0014
`
`

`
`diagnostic process for administering inhaled NO included assessing the patient
`
`condition and determining if there were any contraindications for use of inhaled
`
`NO, including, specifically, left ventricular dysfunction. The assessment included
`
`performing echocardiography before administering inhaled NO. See, e.g., Ex.
`
`1011 at Abstract; see also Ex. 1030, Henrichsen, et al., Inhaled Nitric Oxide can
`
`Cause Severe Systemic Hypotension, 129 The Journal of Pediatrics, 183, col. 1,
`
`par. 2 (1996) (“Henrichsen”) (disclosing echocardiography prior to treatment to
`
`examine the structure of the heart, diagnose left ventricular function, and identify
`
`patients dependent on right-to-left shunting of blood); Ex. 1016, Hoehn, Therapy
`
`of Pulmonary Hypertension
`
`in Neonates and Infants, Pharmacology &
`
`Therapeutics 2007 114:318-326 at 322. (“Hoehn”). It was a well-known clinical
`
`practice or before June 30, 2009, to suggest an echocardiogram before
`
`administering inhaled NO. Indeed, before June 30, 2009, my team followed this
`
`practice before starting nitric oxide, and the intensive care or neonatology
`
`specialists consistently confirmed that it was done before treatment. We even
`
`often assessed the efficacy by echocardiography through the evaluation of
`
`pulmonary pressure, right ventricular anatomy and function as well as shunt
`
`direction through the ductus arteriosus and the foramen ovale.
`
`22. Additionally, a wedge pressure of 20 mm Hg is a physiological
`
`indicator of conditions that increases risk for patients if they were to receive
`
`15
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0015
`
`

`
`treatment with inhaled NO, including left heart dysfunction.9 As was known in the
`
`art prior to June 30, 2009, wedge pressure can be measured by inserting a
`
`pulmonary catheter with an inflated balloon into a small pulmonary arterial branch
`
`(e.g., a Swan-Ganz catheter). See, e.g., Ex. 1023, Royster, et al., Differences in
`
`Pulmonary Artery Wedge Pressures Obtained by Balloon Inflation Versus
`
`Impaction Techniques, 61 Anesthesiology, 339 – 341 (1984) (“Royster”); see also,
`
`Ex. 1007 at p. 209, col. 1, lines 16-20 (showing measurement of wedge pressure in
`
`infants and other children); Ex. 1015, Klabunde, Pulmonary Capillary Wedge
`
`Pressure, Cardiovascular Physiology Concepts, 4/11/2007 available at
`
`http://www.cvphysiology.com/Heart%20Failure/HF008.htm (“Klabunde”). A rise
`
`in wedge pressure upon treatment with inhaled NO suggests left ventricular
`
`9 Wedge pressure is referred to in the literature as pulmonary capillary wedge
`
`pressure (“PCWP”), pulmonary arterial wedge pressure (“PAWP”), or merely
`
`“wedge.” See, e.g., Ex. 1025, M. Hoeper, et al., Definitions and Diagnosis of
`
`Pulmonary Hypertension 62:25 J. of the American College of Cardiology D44
`
`(2013) (“Hoeper”) (noting that pulmonary capillary wedge pressure, pulmonary
`
`arterial wedge pressure, wedge pressure, and wedge are all used to refer to the
`
`same concept and also noting that “wedge” and “wedge pressure” are
`
`commonly used in daily clinical practice, even in non-English speaking
`
`countries).
`
`16
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0016
`
`

`
`dysfunction. See, e.g. Ex. 1024, Ignarro, L.J., ed. Nitric Oxide Biology and
`
`Pathobiology, Academic Press, at 940–941 (2000) (“Ignarro”). One skilled in the
`
`art would have known prior to June 30, 2009, that older children and adults could
`
`have wedge pressure measured with a catheter. While not typically performed in
`
`neonates, one skilled in the art would have known to measure wedge pressure with
`
`a catheter in emergency situations.
`
`23. Before June 30, 2009, it was well-known that wedge pressure could
`
`also be determined through extrapolation based on information gained through
`
`echocardiography. See, e.g., Ex. 1012, Pozzoli, et al., Non-Invasive Estimation of
`
`Left Ventricular Filling Pressures by Doppler Echocardiography, 3 Eur J
`
`Echocardiogr., 75-79 (2002) (“Pozzoli”). Wedge pressure may be extrapolated by
`
`the physician in his or her mind from echocardiographic information to identify
`
`whether left heart dysfunction exists and, concomitantly, that physiologically a
`
`wedge pressure exists over a certain value. A paediatric cardiologist with skill and
`
`extensive experience with echocardiography would be able to extrapolate wedge
`
`pressure with accuracy to be of use in making a diagnosis or determining whether
`
`the patient in question has a condition such as left ventricular dysfunction that
`
`would require assessment of the risks of treatment and likely contraindicate
`
`treatment with inhaled NO. Even with such skill, a precisely accurate numerical
`
`value will not be reached, only an estimate.
`
`17
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0017
`
`

`
`24. As part of regular clinical practice before June 30, 2009, patients not
`
`at risk of adverse events such as pulmonary oedema were treated with inhaled NO,
`
`and patients that revealed risk factors during echocardiography, measurement of
`
`wedge pressure, blood gas level, or other clinical assessment were not treated,
`
`assuming that after evaluation, one skilled in the art determined that the risk of
`
`harm to the patient outweighed the potential benefits of treatment. If the
`
`diagnostic results were unclear, or if a potential benefit was expected, as part of the
`
`diagnostic process, one skilled in the art would have known to administer inhaled
`
`NO as a test to see how a patient would react to the drug and to determine whether
`
`a patient had left ventricular dysfunction. Such a patient would have been
`
`carefully evaluated through regular and repeated echocardiography and clinical
`
`evaluation while the test inhaled NO was administered. If the patient responded in
`
`such a way as to suggest that he or she had left ventricular dysfunction, full
`
`treatment with inhaled NO would not have been prescribed, and the test treatment
`
`would have been stopped. See, e.g., Ex. 1024 at 940-941. All physicians have a
`
`basic understanding of negative side effects, and one skilled in the art would have
`
`known not to administer inhaled NO if it would cause harm to the patient that
`
`outweighed the benefits of treatment. See, e.g., Ex. 1026, Kaldijian., et al., A
`
`Clinician’s Approach to Clinical Ethical Reasoning, J Gen Intern Med. 20(3):
`
`306–311 at 309 (Mar. 2005) (“Kaldijian”) (discussing the duty of nonmaleficence,
`
`18
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0018
`
`

`
`to avoid causing harm to a patient); see also Ex. 1027, Jonsen, A. et al., Clinical
`
`Ethics: A Practical Approach to Ethical Decisions in Clinical Medicine 4th ed.
`
`(1998) (discussing the Hippocratic Oath and the requirement to do no harm)
`
`(“Jonsen”).
`
`INTERPRETATIONS OF THE ʼ284 PATENT CLAIMS AT ISSUE
`
`
`
`Legal Principles Applicable to Claim Construction
`
`25.
`
`I understand that, for purposes of my analysis, the terms and phrases
`
`appearing in a patent claim should be interpreted according to their “broadest
`
`reasonable construction in light of the specification of the patent in which it
`
`appears.” 37 C.F.R. § 42.100(b). I further understand that the words of the claims
`
`should be given their plain meaning unless that meaning is inconsistent with the
`
`patent specification. I also understand that the words of the claims should be
`
`interpreted as they would have been interpreted by a person of ordinary skill in the
`
`art at the time of the invention was made (not today). For my analysis, I was
`
`instructed to use the priority date of the ʼ284 patent, June 30, 2009, as the point in
`
`time for claim interpretation purposes. In my opinion, all the terms in the ’284
`
`patent should be understood to have their plain and ordinary meaning as would
`
`have been known to one of ordinary skill in the art.
`
`
`
`19
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0019
`
`

`
`Level of Skill In The Art
`
`26.
`
`In my opinion, a person of ordinary skill in the art would be a
`
`paediatric cardiologist with experience prescribing inhaled NO before June 30,
`
`2009. I understand that a person of ordinary skill in the art is a hypothetical person
`
`who is presumed to be aware of all pertinent art, thinks along conventional wisdom
`
`in the art, and is a person of ordinary creativity. A person of ordinary skill in the
`
`art of the treatment of patients with inhaled NO would have had knowledge of the
`
`scientific
`
`literature concerning administration of
`
`inhaled NO,
`
`including
`
`contraindications and risks as of June 30, 2009. Such a person of ordinary skill in
`
`the art would have had knowledge of the scientific literature related to pulmonary
`
`hypertension and hypoxic respiratory failure. The person of ordinary skill in the
`
`art would also have had extensive knowledge and experience with
`
`echocardiography. A person of ordinary skill in the art would have known how to
`
`research the scientific literature regarding the use of inhaled NO. Typically, a
`
`person of ordinary skill in the art would be an experienced paediatric cardiologist.
`
`27. The person of ordinary skill in the art would have been familiar with
`
`all of the technical concepts set forth in this declaration.
`
`20
`
`
`
`
`Declaration of Dr. Maurice Beghetti Regarding U.S. Patent No. 8,293,284
`
`Ex. 2033-0020
`
`

`
`LEGAL PRINCIPLES
`
`Obviousness
`
`28.
`
`I have been informed that a patent claim is invalid as “obvious” under
`
`35 U.S.C. § 103 in light of one or more prior art references if it would have been
`
`obvious to one of skill in the art at the time the invention was made, taking into
`
`account (1) the scope and content of the prior art, (2) the differences between the
`
`prior art and the claims, (3) the level of ordinary skill in the art, and (4) any so
`
`called “secondary considerations” of non-obviousness, whic

This document is available on Docket Alarm but you must sign up to view it.


Or .

Accessing this document will incur an additional charge of $.

After purchase, you can access this document again without charge.

Accept $ Charge
throbber

Still Working On It

This document is taking longer than usual to download. This can happen if we need to contact the court directly to obtain the document and their servers are running slowly.

Give it another minute or two to complete, and then try the refresh button.

throbber

A few More Minutes ... Still Working

It can take up to 5 minutes for us to download a document if the court servers are running slowly.

Thank you for your continued patience.

This document could not be displayed.

We could not find this document within its docket. Please go back to the docket page and check the link. If that does not work, go back to the docket and refresh it to pull the newest information.

Your account does not support viewing this document.

You need a Paid Account to view this document. Click here to change your account type.

Your account does not support viewing this document.

Set your membership status to view this document.

With a Docket Alarm membership, you'll get a whole lot more, including:

  • Up-to-date information for this case.
  • Email alerts whenever there is an update.
  • Full text search for other cases.
  • Get email alerts whenever a new case matches your search.

Become a Member

One Moment Please

The filing “” is large (MB) and is being downloaded.

Please refresh this page in a few minutes to see if the filing has been downloaded. The filing will also be emailed to you when the download completes.

Your document is on its way!

If you do not receive the document in five minutes, contact support at support@docketalarm.com.

Sealed Document

We are unable to display this document, it may be under a court ordered seal.

If you have proper credentials to access the file, you may proceed directly to the court's system using your government issued username and password.


Access Government Site

We are redirecting you
to a mobile optimized page.





Document Unreadable or Corrupt

Refresh this Document
Go to the Docket

We are unable to display this document.

Refresh this Document
Go to the Docket