Filed on behalf of: Mallinckrodt Hosp. Prods. IP Ltd.
`
`
`
`
`
`
`Entered: June 30, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`PRAXAIR DISTRIBUTION, INC. AND NOxBOX LIMITED,
`Petitioner
`
`v.
`
`MALLINCKRODT HOSPITAL PRODUCTS IP LTD.,
`Patent Owner
`_______________________
`
`Case IPR2016-00778
`U.S. Patent No. 8,431,163
`_______________________
`
`
`Before STEVEN AMITRANI, Trial Paralegal.
`
`DECLARATION OF GEOFFREY L. ROSENTHAL, M.D., PH.D.
`IN SUPPORT OF PATENT OWNER’S PRELIMINARY RESPONSE
`TO PRAXAIR’S PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,431,163
`
`
`
`Ex. 2001-0001
`
`
`
`
`
`
`
`
`Entered: June 30, 2016
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`PRAXAIR DISTRIBUTION, INC. AND NOxBOX LIMITED,
`Petitioner
`
`v.
`
`MALLINCKRODT HOSPITAL PRODUCTS IP LTD.,
`Patent Owner
`_______________________
`
`Case IPR2016-00778
`U.S. Patent No. 8,431,163
`_______________________
`
`
`Before STEVEN AMITRANI, Trial Paralegal.
`
`DECLARATION OF GEOFFREY L. ROSENTHAL, M.D., PH.D.
`IN SUPPORT OF PATENT OWNER’S PRELIMINARY RESPONSE
`TO PRAXAIR’S PETITION FOR INTER PARTES REVIEW OF
`U.S. PATENT NO. 8,431,163
`
`
`
`Ex. 2001-0001
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No 8,431,163
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`QUALIFICATIONS ........................................................................................ 1
`
`SCOPE OF ASSIGNMENT AND APPROACH ............................................ 6
`
`III. APPLICABLE STANDARDS AND CONTROLLING PRINCIPLES ......... 7
`
`A. Obviousness ........................................................................................... 7
`B.
`Person of Ordinary Skill in the Art ....................................................... 8
`
`IV. GENERAL TECHNOLOGY BACKGROUND ........................................... 11
`
`V. DEVELOPMENT OF THE INVENTIONS OF THE ’163 PATENT .......... 17
`
`VI. A PERSON OF ORDINARY SKILL WOULD NOT HAVE RELIED
`UPON THE DISCLOSURE IN GREENOUGH OR JAYPEE ...................... 22
`
`B.
`
`A. A Person of Ordinary Skill Would Have Understood that There
`Are Different Categories of Medical Evidence ................................... 23
`A Person of Ordinary Skill Would Have Rejected the
`Disclosure in Greenough as Unreliable .............................................. 25
`A Person of Ordinary Skill Would Have Similarly Rejected the
`Disclosure in Jaypee as Unreliable ..................................................... 33
`
`C.
`
`i
`
`Ex. 2001-0002
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`I, Geoffrey L. Rosenthal, M.D., Ph.D., resident of Millersville, Maryland,
`
`hereby declare as follows:
`
`I.
`
`QUALIFICATIONS
`1.
`
`I am a Professor of Pediatrics and Epidemiology at the University of
`
`Maryland School of Medicine in Baltimore, Maryland. I have been at the
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`University of Maryland since July 2009. I have had both academic and hospital-
`
`based roles at the University of Maryland School of Medicine and the University
`
`of Maryland Children’s Hospital. The academic roles include Chair of the
`
`Division of Pediatric Cardiology (2009-present), and Chair of Pediatric Critical
`
`Care Medicine (2009-2014). In these roles I have had responsibility for faculty
`
`development, research, and training in several content areas, including training
`
`pediatric cardiologists and pediatric critical care physicians and nurses in the
`
`management of pulmonary hypertension in neonates, infants, older children, and
`
`certain categories of adults (specifically, adults with congenital heart disease).
`
`2.
`
`I am also the Co-Director of the Children’s Heart Program (2009-
`
`present) and the Co-Director of the University of Maryland Heart and Vascular
`
`Center (2015-present). I was the Executive Director of Pediatric Critical Care
`
`Services (2009-2016). In these hospital-based roles, I oversee quality of care,
`
`enhance collaboration across specialties, and assure efficient use of certain
`
`1
`
`Ex. 2001-0003
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`resources within the University of Maryland Medical Center and across the
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`University of Maryland Medical System.
`
`3.
`
`I have been a practicing pediatric cardiologist since 1998. Since
`
`1998, I have cared for over 7,000 children. My clinical area of expertise is
`
`Pediatric Cardiac Intensive Care, so my experience has been enriched over the arc
`
`of my career with neonates and children who are critically ill due to conditions
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`related to their hearts and blood vessels. Neonates and children with critical illness
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`due to the heart and blood vessels often have elevated resistance in the blood
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`vessels which carry blood to the lungs, and they often have pulmonary
`
`hypertension. I am very familiar with the use of inhaled Nitric Oxide (“iNO”) and
`
`other vasodilators in the neonatal and pediatric population.
`
`4.
`
`Prior to joining the University of Maryland School of Medicine, I
`
`served as the Director of Inpatient Medicine for Pediatric Cardiovascular Services
`
`and Director of Pediatric Cardiovascular Research at the Cleveland Clinic. While
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`at the Cleveland Clinic, I developed inpatient services for the Pediatric and
`
`Congenital Heart Center and started the Pediatric Cardiology Fellow’s Clinic. In
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`these roles I both recommended use of iNO and other vasodilators for neonates,
`
`infants, and children in need of these therapies, and I taught both Pediatric
`
`Cardiology and Pediatric Critical Care physicians to use these agents properly.
`
`Before joining the Cleveland Clinic, I served at Seattle Children’s Hospital where I
`
`2
`
`Ex. 2001-0004
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`started the Pediatric Cardiac Intensive Care Program. In this role I prescribed iNO
`
`and other vasodilators for neonates, infants, and children in need of these therapies,
`
`and I taught Pediatric Critical Care physicians to use these agents properly.
`
`5.
`
`I received my undergraduate degree in psychology from Boston
`
`University, a master’s degree in biostatistics and epidemiology from Georgetown
`
`University, a medical degree from the University of Maryland School of Medicine
`
`and a doctor of philosophy degree in epidemiology from the University of
`
`Maryland Graduate School. I completed my pediatric residency, neonatology chief
`
`residency, pediatric cardiology fellowship, and perioperative fellowship in
`
`pediatric cardiology at Baylor College of Medicine/Texas Children’s Hospital. I
`
`am licensed to practice medicine in Maryland, and am certified by the American
`
`Board of Pediatrics in General Pediatrics and Pediatric Cardiology. I am board
`
`certified through the American Board of Internal Medicine in Adult Congenital
`
`Heart Disease.
`
`6.
`
`I have been active in various professional committees. For instance, I
`
`was the Chair of the Pediatric Advisory Committee to the U.S. Food and Drug
`
`Administration (2009-2012) and have been a member or consultant to that
`
`committee since 2006. The Pediatric Advisory Committee advises the Food and
`
`Drug Administration (“FDA”) on matters of drug and other product safety and
`
`labeling as they pertain to use in neonates and children. For example, I
`
`3
`
`Ex. 2001-0005
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`participated on the last product safety review, including review of deaths and
`
`serious adverse events, for iNO that came before the Pediatric Advisory
`
`Committee (March 14, 2013).
`
`7.
`
`I have participated in several meetings of the Pediatric Ethics Sub-
`
`Committee (of the Pediatric Advisory Committee to the FDA). This committee
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`has performed protocol reviews under 45 C.F.R. § 46.407 to discuss the ethics of
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`specific research proposals when pediatric subject participation would involve
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`greater than minimal risk to the subject and no prospect of direct benefit to the
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`individual child (but would likely yield generalizable knowledge about the
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`subject’s disorder or condition). This highest category of research ethics review is
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`required when the potential risk of participation in a research study outweighs the
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`potential benefit to the subject.
`
`8.
`
`I served as the Co-Chair, and then the Chair of the Congenital Heart
`
`Public Health Consortium (2009-2014) and the Co-Chair of the Quality Metrics
`
`Working Group of the American College of Cardiology (2009-2013). In addition,
`
`I served on the Executive Committee for the Section of Cardiology and Cardiac
`
`Surgery of the American Academy of Pediatrics (2008-2014).
`
`9.
`
`I am also a founding member and former governing council member
`
`of the National Pediatric Cardiology Quality Improvement Collaborative of the
`
`Joint Council on Congenital Heart Disease (2006-2015). The goal of this
`
`4
`
`Ex. 2001-0006
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`collaborative is to reduce mortality and morbidity in neonates and infants with
`
`hypoplastic left heart syndrome. I was also a member of the National Program to
`
`Reduce Cardiovascular Risk Coordinating Committee of the National Heart, Lung
`
`and Blood Institute, representing the American Academy of Pediatrics (2011-
`
`2013).
`
`10. My training in epidemiology and biostatistics fostered expertise in
`
`fundamental aspects of biomedical research design, analysis, and interpretation.
`
`This includes expertise in teaching and adjudicating research concepts such as
`
`validity, precision, reliability, and generalizability. It also includes weighing
`
`clinical observations, observational studies, and clinical trials in the process of
`
`causal inference. I have participated in the design and analysis of many research
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`studies, including clinical trials, prospective observational studies, retrospective
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`observational studies, and case series.
`
`11.
`
`I have authored 55 peer reviewed articles, 2 books, 4 book chapters,
`
`and numerous scientific abstracts. I have also been an invited speaker at various
`
`symposia and professional conferences, at both national and international
`
`meetings. The topics most represented in the body of my research include
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`assessment of anthropometry
`
`in neonates with congenital heart disease,
`
`management of and outcomes following various surgical approaches in congenital
`
`heart disease, assessment of neonates and children with cardiomyopathy for viral
`
`5
`
`Ex. 2001-0007
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`etiologies, assessment of transplant rejection patients, and risk reduction among
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`infants with hypoplastic left heart syndrome.
`
`12. A copy of my current curriculum vitae is attached as Exhibit 2002.
`
`II.
`
`SCOPE OF ASSIGNMENT AND APPROACH
`13.
`
`I have been retained as an expert on behalf of the Patent Owner to
`
`provide information and opinions to the Board and to assist in responding to this
`
`petition for inter partes review (“Petition”) challenging the validity of claims 1-25
`
`of U.S. Patent No. 8,431,163. Specifically, counsel for Patent Owner asked me to
`
`provide opinions regarding the validity of claims 1-25 of the ’163 Patent (Ex.
`
`1001) in view of certain prior art references cited by Petitioner.
`
`14.
`
`I have been informed by counsel for Patent Owner that the analysis of
`
`the validity of a patent claim is performed from the perspective of a person of
`
`ordinary skill in the art at the time of the patented invention. I understand that the
`
`earliest patent application leading to the ’163 Patent was filed on June 30, 2009.
`
`15.
`
`In forming my opinions, I have relied on the ’163 Patent’s claims,
`
`disclosure, and file history, on the prior art exhibits to the Petition, the documents
`
`cited by Dr. Edward Lawson in his declaration, any other materials cited in this
`
`declaration, and my own experience, expertise, and knowledge of the person of
`
`ordinary skill in the art in the relevant timeframe.
`
`6
`
`Ex. 2001-0008
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`16.
`
`I am being compensated for my time spent in connection with this
`
`matter at a rate of $400.00 per hour or $4,000 per day for testimony at deposition.
`
`My compensation does not depend on the outcome of this proceeding or the
`
`conclusions in this declaration.
`
`17. To the extent that I am presented with new information concerning the
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`subject matter of this declaration or affecting any of my assumptions, I reserve the
`
`right to supplement this declaration accordingly.
`
`III. APPLICABLE STANDARDS AND CONTROLLING PRINCIPLES
`A. Obviousness
`18.
`I have been informed by counsel for the Patent Owner that an issued
`
`patent claim is invalid as obvious if it can be shown that the differences between
`
`the patented subject matter and the prior art are such that the subject matter as a
`
`whole would have been obvious, at the time the invention was made, to a person
`
`having ordinary skill in the art. Relevant considerations include the level of
`
`ordinary skill in the art; the scope and content of the prior art; differences between
`
`the prior art and the claims at issue; and the so-called objective factors of non-
`
`obviousness. I have been informed by counsel for the Patent Owner that such
`
`objective factors of non-obviousness can include unexpected results.
`
`19.
`
`I have been informed by counsel for the Patent Owner that, in order to
`
`evaluate the obviousness of any claim of the ’163 Patent over a given prior art
`
`7
`
`Ex. 2001-0009
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`combination, I should analyze whether the prior art references, included
`
`collectively in the combination, disclose each and every element of the allegedly
`
`invalid claim as those references are read by the person of ordinary skill in the art
`
`by a preponderance of the evidence, at the time of the invention. I understand that
`
`such preponderance of the evidence is satisfied if the proposition is more likely
`
`than not to be true.
`
`B.
`20.
`
`Person of Ordinary Skill in the Art
`
`I have been informed by counsel for the Patent Owner that the “person
`
`of ordinary skill in the art at the time of the inventions” is a hypothetical person
`
`who is presumed to be familiar with the relevant scientific field and its literature at
`
`the time of the inventions. This hypothetical person is also a person of ordinary
`
`creativity, capable of understanding the scientific principles applicable to the
`
`pertinent field.
`
`21.
`
`It is my opinion that the person of ordinary skill in the art in the field
`
`of the ’163 Patent would be a physician with experience treating pediatric heart
`
`and lung disease and/or experience studying pediatric heart and lung disease. In
`
`addition, such an individual would have experience prescribing and administering
`
`8
`
`Ex. 2001-0010
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`vasodilators and additional supportive therapies and/or experience designing
`
`clinical trials related to pediatric heart and lung disease.1
`
`22. Based on my training and experience, I believe I am (and was as of
`
`June 30, 2009) a person of greater than ordinary skill in the relevant art. In my
`
`roles as director of the pediatric cardiac intensive care program at Seattle
`
`Children’s Hospital, as pediatric cardiology fellowship director at the Cleveland
`
`Clinic, and as the director of both inpatient medicine and cardiovascular research
`
`for the pediatric and congenital heart program at the Cleveland Clinic, I managed
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`and trained more than 50 less experienced physicians in the fields of pediatric
`
`cardiology, pediatric critical care, and neonatology. By June 30, 2009, I had
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`worked with and supervised individuals who were persons of ordinary skill in the
`
`art as defined above. This permits me to give an opinion about the qualifications
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`of one of ordinary skill at the time of the invention as well as how such a person
`
`would understand the ’163 Patent claims and prior art at the time of the inventions.
`
`23. Likewise, I am familiar with and have reviewed the credentials of the
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`members of the INOT222 Steering Committee Drs. David Wessel, Robyn Barst,
`
`
`1 My definition of the level of ordinary skill is consistent with the level I proposed
`
`in the declaration I submitted in the -00529 IPR of related U.S. Patent No.
`
`8,846,112, and in the co-pending district court litigation.
`
`9
`
`Ex. 2001-0011
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`and Duncan Macrae and conclude that each was a person of greater than ordinary
`
`skill in the relevant art as of the time of the design and implementation of the
`
`INOT22 study. In particular, I note that I have shared patients with Drs. Wessel
`
`and Barst, and I know them both to have had expertise relevant to the clinical use
`
`of iNO by June 30, 2009, and consider them both to have been at the forefront of
`
`pediatric cardiology at that time.
`
`24.
`
`I note that Dr. Lawson’s proposed definition of a person of ordinary
`
`skill in the art as set forth in his declaration (Ex. 1002 ¶ 23) is as follows:
`
`[A] person of ordinary skill in the art would be a neonatologist or
`pediatric cardiologist with experience treating neonatal heart and lung
`disease and have 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 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
`
`
`2 I understand that the members of the INOT22 Steering Committee designed the
`
`original INOT22 study protocol discussed below.
`
`10
`
`Ex. 2001-0012
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`respiratory failure. The person of ordinary skill in the art would also
`have 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
`neonatologist, pediatric cardiologist, pediatric pulmonologist or
`pediatric intensivist.
`
`25. My opinions, as stated in this declaration, would be the same if
`
`rendered from the perspective of a person of ordinary skill in the art as defined by
`
`Dr. Lawson. However, I note that Dr. Lawson likely does not have a practice
`
`background
`
`sufficiently
`
`enriched
`
`in
`
`cardiovascular medicine
`
`and
`
`echocardiographic methods and interpretation to meet the level of ordinary skill in
`
`the art he proposes.
`
`IV. GENERAL TECHNOLOGY BACKGROUND
`
`26.
`
`INOmax® (nitric oxide gas) is a drug administered by inhalation.
`
`INOmax® was approved by the FDA in 1999 for treatment of term and near-term
`
`(>34 weeks gestation) neonates with hypoxic respiratory failure associated with
`
`clinical or echocardiographic evidence of pulmonary hypertension, such as
`
`elevated pulmonary arterial pressure (“PAP”). Ex. 1010 at 1, 4.
`
`27.
`
` INOmax® is a gaseous blend of nitric oxide (0.8%) and nitrogen
`
`(99.2%) and is supplied to medical providers in aluminum cylinders as a
`
`11
`
`Ex. 2001-0013
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`compressed gas under high pressure. Ex. 1010 at 1. According to its FDA-
`
`approved label, INOmax® must be delivered to the patient by a medical provider
`
`through a special delivery device that assures delivery of a constant concentration
`
`of nitric oxide throughout the respiratory cycle, and that is calibrated so as not to
`
`cause generation of excessive inhaled nitrogen dioxide. Id. at 6.
`
`28.
`
`Inhaled nitric oxide (“iNO”) produces pulmonary vasodilation
`
`increasing blood flow, improving oxygenation and reducing the need for
`
`extracorporeal membrane oxygenation (the removal of blood from the infant to a
`
`heart-lung bypass machine that oxygenates the blood and pumps it back into the
`
`infant). Id. at 1, 4.
`
`29. Normal ventilation and lung perfusion allows for deoxygenated blood
`
`to be pumped from the heart along the pulmonary artery and reach the capillaries
`
`adjacent to the alveoli of the lungs. There, gas exchange takes place, and
`
`oxygenated blood is returned to the heart through the pulmonary vein and
`
`thereafter circulated throughout the body.
`
`30. When alveoli are dysfunctional and not ventilated, hypoxic pulmonary
`
`vasoconstriction of blood vessels near the dysfunctional alveoli reduces the amount
`
`of blood passing by the dysfunctional lung units. The blood that does pass
`
`dysfunctional lung units is not able to exchange gas normally, so the amount of
`
`oxygen in the blood that returns to the heart is reduced. In addition, such
`
`12
`
`Ex. 2001-0014
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`pulmonary vasoconstriction increases the pulmonary vascular resistance, causing
`
`or contributing to pulmonary hypertension, right to left shunting, and hypoxic
`
`respiratory failure.
`
`31. Finally, administration of pharmaceutically acceptable nitric oxide
`
`causes vasodilation of vessels near the functional alveoli and allows for improved
`
`gas exchange, improvement of right to left shunting, lower pulmonary vascular
`
`resistance, and improvement in hypoxic respiratory failure.
`
`32. The way iNO works in the body gives rise to special considerations in
`
`neonates. During in utero development, circulation through the lungs is largely
`
`shut down because the pulmonary vessels are tightly constricted (in other words,
`
`there is high resistance in the pulmonary vessels in the normal fetus). The fetal
`
`lungs are not filled with air and the fetus obtains oxygen from the mother across
`
`the placenta into the systemic circulation. Instead of blood being pumped from the
`
`right side of the heart through the fetal lungs and then returning to the left side of
`
`the heart to be pumped to the rest of the body, as it is normally after birth, most of
`
`the blood from the right side of the fetal heart bypasses the fetal lungs through a
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`blood vessel connecting the outflow of the right heart directly to the systemic
`
`circulation called the patent ductus arteriosus.
`
`33. When children are born, the ductus arteriosus normally closes and the
`
`pulmonary vessels relax. As a result, the outflow of the right side of the heart is
`
`13
`
`Ex. 2001-0015
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`redirected to the now oxygenated, ventilated, and functional lungs, and oxygenated
`
`blood is then returned to the left side of the heart to be pumped to the rest of the
`
`body from the left ventricle.
`
`34.
`
`In certain neonates suffering from persistent pulmonary hypertension
`
`of the newborn (“PPHN”), the pulmonary vessels fail to adequately relax, and
`
`there is insufficient gas exchange, leading to hypoxic respiratory failure. For these
`
`neonates, inhaled nitric oxide may be beneficial. When inhaled, nitric oxide
`
`relaxes the small vessels that are in close proximity to the aerated parts of the lung
`
`(a phenomenon known in the art as selective pulmonary vasodilation), thus
`
`allowing the blood in those vessels to pick up oxygen and release carbon dioxide.
`
`This increases the effective blood flow to the lungs, improving oxygenation and
`
`reducing the need for other therapies known to be associated with very high risk of
`
`complications and morbidity, such as aggressive ventilation strategies,
`
`administration of oxygen concentrations associated with ocular toxicity, and use of
`
`extracorporeal membrane oxygenation (the removal of blood from the infant to a
`
`heart-lung bypass machine that oxygenates the blood and pumps it back into the
`
`infant).
`
`35. However, in some with severe congenital heart disease involving the
`
`left ventricle, the left side of the heart lacks the ability to pump a sufficient amount
`
`of blood to the body to support life. This category of congenital heart disease is
`
`14
`
`Ex. 2001-0016
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`known as Hypoplastic Left Heart Syndrome. Without intervention it is virtually
`
`always lethal. For these neonates, prior to palliative neonatal heart surgery, the
`
`patency of the ductus arteriosus is required to allow a path for blood to pass from
`
`the right ventricle to the aorta. This physiologic arrangement is tenuous however,
`
`because the branches of the pulmonary artery that carry blood to the right and left
`
`lungs may “steal” flow from the ductus arteriosus and aorta in favor of having it
`
`pass to the lungs. High pulmonary vascular resistance, resulting in pulmonary
`
`hypertension creates a right-to-left shunt through the patent ductus arteriosus and
`
`allows the right ventricle to take on the role of the nonfunctioning left ventricle by
`
`pumping adequately oxygenated blood directly to the systemic circulation (across
`
`the ductus arteriosus and into the aorta). These neonates are described as being
`
`dependent upon right-to-left shunting of blood.
`
`36.
`
`In neonates who are dependent upon right to left shunting of blood,
`
`pulmonary vasoconstriction is essential to diverting sufficient blood from the right
`
`heart through the patent ductus arteriosus to the systemic circulation. If the
`
`pulmonary vascular resistance drops or is lowered in an infant that is dependent
`
`upon right to left shunt, the infant will have less blood flow to the body and
`
`coronary arteries, and is at very high risk of low blood pressure, low cardiac
`
`output, severe acidosis, cardiogenic shock, and sudden death. Administration of
`
`inhaled nitric oxide to these neonates would be catastrophic.
`
`15
`
`Ex. 2001-0017
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`37. Thus, when INOmax® was first approved by the FDA, it was only
`
`contraindicated for “the treatment of neonates known to be dependent on right-to-
`
`left shunting of blood.” Ex. 1010 at 4.
`
`38.
`
`INOmax® was not contraindicated in any other class of neonates or
`
`children. This was consistent with the clinical studies submitted in support of the
`
`original FDA approval of the drug and referenced on the 2000 INOmax® Label.
`
`These studies, referred to as the NINOS and CINRGI studies, administered iNO to
`
`pediatric patients, including neonates. See Ex. 2039, Neonatal Group at 597-98;
`
`Ex. 2040, Clark 2000 at 469-70. Notably, neither of these studies excluded
`
`pediatric patients with left ventricular dysfunction (“LVD”). See Ex. 2039,
`
`Neonatal Group at 598 (describing subject inclusion/exclusion criteria); Ex. 2040,
`
`Clark 2000 at 469-70 (describing subject inclusion/exclusion criteria).
`
`39.
`
`In fact, I have reviewed every recorded clinical trial of the use of iNO
`
`in pediatric patients before the time of the inventions, and while some excluded
`
`subjects with “known congenital heart disease,” “life-threatening anomalies,”
`
`dependence on right to left shunting, and “major congenital anomalies,” none
`
`excluded pediatric patients for having LVD. Indeed, Dr. Lawson does not cite a
`
`single such study in his declaration.
`
`40. As discussed below, the inventions of the ’163 Patent relate to a
`
`different population of pediatric patients—those with LVD who were not
`
`16
`
`Ex. 2001-0018
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`dependent upon right to left ductal shunting. See, e.g., Ex. 1001 at Abstract; 1:50-
`
`62.
`
`V. DEVELOPMENT OF THE INVENTIONS OF THE ’163 PATENT
`41.
`In May 2004, the Patent Owner initiated a multinational, randomized,
`
`controlled study of 150 patients entitled “Comparison of Supplemental Oxygen
`
`and Nitric Oxide for Inhalation Plus Oxygen in the Evaluation of the Reactivity of
`
`the Pulmonary Vasculature During Acute Pulmonary Vasodilator Testing” (the
`
`“INOT22 study”). Ex. 1001 at 9:26-14:15; Ex. 2005 at 662, ¶ 6.
`
`42. The INOT22 study was to be an open, prospective, randomized,
`
`multi-center, controlled diagnostic trial, with an expected total enrollment of a
`
`minimum of 150 patients, in approximately 18 study sites over approximately two
`
`years. Ex. 2005 at 662, ¶ 7.
`
`43. The INOT22 study compared the utility and side effects of short term
`
`inhalation of iNO alone, iNO plus oxygen, and oxygen alone in pediatric patients
`
`with pulmonary hypertension. Ex. 1001 at 10:29-38; 10:5-7; Ex. 2005 at 662, ¶ 6.
`
`44.
`
`In my experience, the design of a clinical study, such as the INOT22
`
`study, involves the review and approval of the study protocol (including inclusion
`
`and exclusion criteria) by numerous boards, committees and agencies.
`
`45. As is typical in the context of clinical studies, based on my review of
`
`documents filed with the Patent Office, the original INOT22 study protocol was
`
`17
`
`Ex. 2001-0019
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`reviewed by an Institutional Review Board, (“IRB”) and/or Independent Ethics
`
`Committee (“IEC”) at each of the participating study institutions, including review
`
`by the principal investigator within each study institution. Ex. 2005 at 664-665,
`
`¶ 11.
`
`46. Under FDA regulations, an IRB is an appropriately constituted group
`
`that has been formally designated to review and monitor biomedical research
`
`involving human subjects. In accordance with FDA regulations, an IRB has the
`
`authority to approve, require modification in, or disapprove research. An IRB
`
`must have at least five members and each member must have enough experience,
`
`expertise and diversity to make an informed decision on whether the research is
`
`ethical, informed consent is sufficient and the appropriate safeguards have been put
`
`in place. See 21 C.F.R. Part 56.
`
`47. As is typical in the context of clinical studies, the original INOT22
`
`study protocol was also reviewed by the FDA and separately reviewed by each
`
`European equivalent to the FDA within the four European countries participating
`
`in the INOT22 study. Ex. 2005 at 664-665, ¶ 11.
`
`48. All told, as is standard practice in clinical studies and as Dr.
`
`Baldassarre testified, the original INOT22 protocol was reviewed by members of
`
`(1) the INOT22 Steering Committee, (2) IRBs, IECs, and the primary investigator
`
`at each study institution, and (3) US and European regulatory agencies. Id.
`
`18
`
`Ex. 2001-0020
`
`
`
`Declaration of Geoffrey L. Rosenthal, M.D., Ph.D., in Support of Patent Owner’s
`Preliminary Response to Praxair’s Petition for IPR of U.S. Patent No. 8,431,163
`
`49. According to the criteria required for IRBs to approve human subjects
`
`research, as outlined in 45 C.F.R. §§ 46.404-409, there are additional protections
`
`for children involved as subjects in research.
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