IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`PATENT TRIAL AND APPEAL BOARD
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`PRAXAIR DISTRIBUTION, INC. AND NOxBOX LIMITED
`Petitioner
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`v.
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`MALLINCKRODT HOSPITAL PRODUCTS IP LTD., AND INO
`THERAPEUTICS, INC. d/b/a IKARIA, INC.
`Patent Owner
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`_____________
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`DECLARATION OF DR. EDWARD LAWSON
`IN SUPPORT OF PETITION FOR
`INTER PARTES REVIEW OF U.S. PATENT NO. 8,282,966
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`1
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`PATENT TRIAL AND APPEAL BOARD
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`PRAXAIR DISTRIBUTION, INC. AND NOxBOX LIMITED
`Petitioner
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`v.
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`MALLINCKRODT HOSPITAL PRODUCTS IP LTD., AND INO
`THERAPEUTICS, INC. d/b/a IKARIA, INC.
`Patent Owner
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`_____________
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`DECLARATION OF DR. EDWARD LAWSON
`IN SUPPORT OF PETITION FOR
`INTER PARTES REVIEW OF U.S. PATENT NO. 8,282,966
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`1
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`I, Dr. Edward Lawson, declare that:
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`QUALIFICATIONS
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`1.
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` I am a Professor Emeritus in Pediatrics at Johns Hopkins University.
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`I have a Bachelor’s Degree from Harvard University and a Medical Degree from
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`Northwestern University Medical School. I interned in Pediatrics and did a
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`neonatology fellowship at Children’s Hospital Medical Center, Boston Hospital for
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`Women and Beth Israel Hospital in Boston, MA. I was a Research Fellow in
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`pediatrics at Harvard Medical School.
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`2.
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`I have practiced neonatology since 1978. During my practice, I held
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`various leadership and research positions. I have been active in managing
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`premature, full-term and older infants with hypoxic respiratory failure of many
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`different etiologies. I have extensive clinical experience with the utilization of
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`nitric oxide therapy for relief of persistent pulmonary hypertension, BPD and other
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`disorders.
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`3.
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`I was the Chair of the American Lung Association/American Thoracic
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`Society Research Committee. I am also an active member of many NIH study
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`sections where grants related to neonatal pulmonary research have been decided.
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`4.
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`I am currently the Editor-in-Chief for the Journal of Perinatology (the
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`Official Journal of the Section on Neonatal Perinatal Medicine of the American
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`Academy of Pediatrics). I also have experience as an editor for the Fetal and
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`Neonatal section of the Journal of Pediatrics.
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`5.
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`I joined the Johns Hopkins faculty in 1999. At Johns Hopkins I have
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`served as the Director of the Sutland/Pakula Family Newborn Critical Care Center,
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`in the Division of Neonatal and Perinatal Medicine. I also served as the Vice Chair
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`of the Department of Pediatrics at Hopkins Children’s Center.
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`6.
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`7.
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`A copy of my curriculum vitae is attached as Exhibit 1003.
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`I am not an employee of Praxair Distribution, Inc.; Praxair, Inc.,
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`NOxBOX Limited or any affiliated company. Rather, I have been engaged in the
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`present matter to provide my independent analysis of the issues raised in the
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`above-mentioned inter partes review of U.S. Patent No. 8,282,966 (“the ‘966
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`Patent”), Ex. 1001. I have received no compensation for this declaration beyond
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`my normal hourly compensation of $425 for time actually spent studying the
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`matter, and I will not receive any added compensation based on the outcome of any
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`proceeding relating to the ‘966 Patent.
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`8.
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`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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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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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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`9.
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`I have reviewed and am familiar with the ‘966 Patent. Ex. 1001.
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`Additionally, I have reviewed the following documents: (1) Ex. 1006, A.
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`Greenough & A. D. Miller, Neonatal Respiratory Disorders 149, 183–87, 392 (2nd
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`ed. 2003) (“Greenough”); (2) Ex. 1007, Jaypee, Pediatric & Neonatal Mechanical
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`Ventilation 148–58 (Praveen Khilnani ed., 1st ed. 2006) (“Jaypee”); and (3) Ex.
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`1008, A. Widlitz et al, Pulmonary arterial hypertension in children, European
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`Respiratory Journal, (January 2003) (“Widlitz”). I was already familiar with the
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`concepts and physiology of iNO and its uses. I have also reviewed the documents
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`cited elsewhere herein, as well as any documents cited in the declarations I have
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`submitted or will submit in other inter partes review petitions arising out of my
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`engagement in this matter. I have also reviewed the prosecution file history for the
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`‘966 Patent, as well as the other patents on which I have opined in this
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`engagement, particularly the declarations submitted during prosecution. Based on
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`the references and my experience and background, I do not agree that INOT22
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`study provides evidence that the claims are patentable; nor do I agree that the claim
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`elements were not known. Specifically, as discussed below, the allegedly
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`unknown aspects of the INOT22 study were clearly disclosed by, for example,
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`Greenough and Jaypee prior to June 30, 2009.
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`10. 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 OF ONE OF SKILL IN THE ART
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`BEFORE THE ‘966 PATENT
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`11. The ‘966 Patent is entitled “Methods of Reducing the Risk of
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`Occurrence of Pulmonary Edema in Children in Need of Treatment with Inhaled
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`Nitric Oxide.” Ex. 1001 at cover. The ‘966 Patent provides contraindications for
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`treatment of children with inhaled NO. Specifically the ‘966 Patent provides a pre-
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`screening protocol to determine whether a patient is at risk of an adverse event
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`upon treatment with NO, such as pulmonary edema.1 See Ex. 1001 at Abstract,
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`1:46-60. It essentially provides that if the patient demonstrates characteristics
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`suggesting that he or she is at risk of harm, then the patient should not be treated
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`with NO. Id. The evaluation includes a determination that patients who have left
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`ventricular dysfunction should be excluded from treatment. Id.
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`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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`1
`Pulmonary edema is a buildup of fluid in the lungs.
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`(a) performing echocardiography to identify a child in need of 20 ppm
`inhaled nitric oxide treatment for pulmonary hypertension, wherein
`the child is not dependent on right-to-left shunting of blood;
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`(b) determining that the child 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
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`(c) excluding the child from inhaled nitric oxide treatment based on the
`determination that the child has left ventricular dysfunction and so is at
`particular risk of pulmonary edema upon treatment with inhaled
`nitric oxide.
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`12.
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`In order to determine if a patient has a left ventricular dysfunction, a
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`practitioner may measure the pulmonary capillary wedge pressure (“wedge
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`pressure”) or perform an echocardiograph.2 Id. I am familiar with these protocols
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`and treatments, and was an expert in this area prior to the priority date of the ‘966
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`Patent on June 30, 2009. This expertise comes from the field of pediatric
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`cardiology and pulmonary hypertension where the differentiation between pre-
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`capillary pulmonary hypertension that includes normal wedge pressure and post-
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`capillary pulmonary hypertension is a key distinction in this field. In fact, unless
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`the patient has a left heart obstruction or dysfunction which is causing pulmonary
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`venous hypertension, the wedge pressure is normal. Given that these two types of
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`2 Echocardiography is the use of ultrasound waves to investigate the actions of
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`the heart.
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`pulmonary hypertension classifications react differently to therapeutic modalities,
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`it becomes exceedingly important to decipher between the two classifications.
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`This is well established in the pulmonary hypertension field, and lead to the
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`separation and distinct diagnostic classification of these two types of pulmonary
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`hypertension many years ago. See e.g., Ex. 1008, Widlitz, et al., Pulmonary
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`arterial hypertension in children, 21 Eur.Respir. J. 155-176 at 156-57 (2003)
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`(“Widlitz”); Ex. 1007, Jaypee at 156. Although the clinical classifications apply to
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`pulmonary hypertension generally, the teachings are equally applicable to the
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`context of pulmonary hypertension treated with inhaled NO and the effect of left
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`ventricular heart disease.
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`13. Pulmonary arterial hypertension is characterized by an increased
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`pulmonary artery pressure and increased pulmonary vascular resistance. See, e.g.
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`Ex. 1001 at 3:4-16. Nitric oxide is a selective pulmonary vasodilator that increases
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`the partial pressure of arterial oxygen by dilating pulmonary vessels in ventilated
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`areas of the lung, and directing blood flow away from areas with low
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`ventilation/perfusion ratios toward regions with normal ratios. Ex. 1001 at 3:32-
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`39. Before June 30, 2009, it was known to those of skill in the art that nitric oxide
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`may be used as a vasodilator.3 See, e.g. Ex. 1007, Jaypee at 148. Nitric oxide is
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`3 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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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`particularly useful in the treatment of pulmonary hypertension, as inhaled nitric
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`oxide can lead to selective pulmonary vasodilation, therefore reducing pulmonary
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`vascular resistance, decreasing pulmonary arterial pressure, and easing right
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`ventricular afterload. Ex. 1008, Widlitz at 156-57, 161. Once inhaled, the nitric
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`oxide diffuses across alveolar membranes to closely adjacent vessels. This
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`activates guanylate cyclase in pulmonary smooth muscle cells, which in turn
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`increases intracellular cyclic guanosine monophosphate (cGMP) production in the
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`cells. The increased cGMP causes pulmonary smooth muscles to relax resulting in
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`pulmonary arteriole dilation. Ex. 1008, Widlitz at 169-170.
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`14. While not all patients and not all conditions are responsive to
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`treatment with inhaled NO, pulmonary hypertension, specifically persistent
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`pulmonary hypertension of the newborn (PPHN), is a condition that may be treated
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`with inhaled NO. See, e.g. Ex. 1007, Jaypee at 149-150. Twenty parts per million
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`of inhaled NO is approved by the FDA to treat neonatal hypoxic respiratory
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`failure4 and has been approved since 2000. Id.; see also Ex. 1010, Center for Drug
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`4 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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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`Evaluation and Research, Application Number: NDA 20845, INOmax, Final
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`Printed
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`Labeling,
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`available
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`at
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`http://www.accessdata.fda.gov/drugsatfda_docs/nda/99/20845_inomax_prntlbl.pdf
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`(August 9, 2000) at 6 (“INOmax label”). It is indeed the only pathology for which
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`inhaled nitric oxide has been approved in the United States. 5 Id. While inhaled
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`NO certainly has its therapeutic benefits, experienced practitioners are also aware
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`of a few undesirable side effects and potential complications in certain patients.
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`One such well-known negative reaction is NO in patients with left ventricular
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`dysfunction. In these particular patients, inhaled NO can reduce 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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`of hypoxic respiratory failure, as the hypoxia is the condition that causes harm
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`to the patient.
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`5 INOmax, in conjunction with ventilatory support and other appropriate agents,
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`is indicated for the treatment of term and near-term (>34 weeks) neonates with
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`hypoxic respiratory failure associated with clinical or echocardiographic
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`evidence of pulmonary hypertension, where it improves oxygenation and
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`reduces the need for extracorporeal oxygenation. Ex. 1010 at 4; see also Ex.
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`1001 at 3:34-52.
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`vascular resistance, decreasing the afterload to the right heart, and ultimately
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`improving right heart output resulting in increased pulmonary venous return to the
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`left ventricle. In a poorly functioning left ventricle, this increased blood return
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`may not be entirely pumped forward resulting in increased pulmonary venous
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`pressure and pulmonary edema. Thus, practitioners thoroughly evaluate their
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`patients prior to treatment, and exclude patients from NO therapy upon
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`determination of left ventricular dysfunction. See, e.g., Ex. 1011, Pilbeam,
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`Mechanical Ventilation, Special Techniques in Mechanical Ventilation, § 4: Nitric
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`Oxide, (4th ed. 2006) (“Pilbeam”) at 4-6. Such examinations were commonly
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`done prior to June 30, 2009. Id.
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`15. Before June 30, 2009, it was known that, in addition to systolic and
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`diastolic left ventricular dysfunction, any obstruction to the pulmonary venous
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`flow, or lesions that may increase pulmonary venous pressure (such as obstructed
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`pulmonary venous return, mitral stenosis6 or insufficiency, etc.) increase the risk of
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`a patient suffering a serious adverse event upon treatment with inhaled NO. See,
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`e.g. Ex. 1007, Jaypee at 151-54. Furthermore, it was also known that NO may not
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`6 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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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`be beneficial in patients with a high degree of structural pulmonary abnormalities,
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`such as hypoplasia, as they interfere with the action of the gas.
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`16. 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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`patient, or to a plurality of patients. See generally Ex. 1006, Greenough, Ex. 1007,
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`Jaypee (disclosing studies
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`treating multiple patients with
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`inhaled NO).
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`Additionally, the INOmax label discloses that clinical trials identified a plurality of
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`patients to be treated with 20 ppm iNO. Ex. 1010 at 2-3.
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`17. 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. Serious adverse events may include conditions such as
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`those described in Jaypee, including pulmonary edema, significant bleeding,
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`worsening of oxygenation and methemoglobinemia. Ex. 1007 at 156.
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`18.
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`It was a well-known clinical practice on or before June 30, 2009, to
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`suggest an echocardiogram before administering inhaled NO.
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` Ex. 1006,
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`Greenough at 379-380. 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 shunt7
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`direction through the ductus arteriosus and the foramen ovale.
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`19. Additionally, wedge pressure over 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.8 As was known in the
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`7 A cardiovascular shunt is a diversion of the blood flow through an anomalous
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`opening from the left side of the heart to the right side (from the systemic to the
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`pulmonary circulation), or from the right side to the left side (from the
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`pulmonary to the systemic circulation).
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`8 Wedge pressure is referred to in the literature as pulmonary capillary wedge
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`pressure (“PCWP”), pulmonary arterial wedge pressure (“PAWP”), pulmonary
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`artery occlusion pressure, or merely “wedge.” See, e.g., Ex. 1012, M. Hoeper, et
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`al., Definitions and Diagnosis of Pulmonary Hypertension 62:25 J. of the
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`American College of Cardiology D44 (2013) (“Hoeper”) (noting that
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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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. 1013, 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. 1014, Goyal et al., Efficacy of nitroglycerin inhalation in reducing pulmonary
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`arterial hypertension in children with congenital heart disease, British Journal of
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`Anaesthesia, 97(2): 208-14 (2006). (“Goyal”) at 209, col. 1, lines 16-20 (showing
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`measurement of wedge pressure in infants and other children). A rise in wedge
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`pressure upon treatment with inhaled NO suggests left ventricular dysfunction.
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`One skilled in the art would have known prior to June 30, 2009, that older children
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`and adults could have wedge pressure measured with a catheter. While not
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`typically performed in neonates, one skilled in the art would have known to
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`measure wedge pressure with a catheter in emergency situations.
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`20. 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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`pulmonary capillary wedge pressure, pulmonary arterial wedge pressure, wedge
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`pressure, and wedge are all used to refer to the same concept and also noting
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`that “wedge” and “wedge pressure” are commonly used in daily clinical
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`practice, even in non-English speaking countries).
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`echocardiography. See, e.g., Ex. 1015, 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., 3:75-79 (2002) (“Pozzoli”). Wedge pressure may be extrapolated
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`by 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 pediatric 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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`21. 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 potential benefits of
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`treatment. If the diagnostic results were unclear, or if a potential benefit was
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`expected, as part of the diagnostic process, one skilled in the art would have known
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`to administer inhaled NO as a test to see how a patient would react to the drug and
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`to determine whether a patient had left ventricular dysfunction. Such a patient
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`would have been carefully evaluated
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`through
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`regular and
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`repeated
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`echocardiography and clinical evaluation while the test inhaled NO was
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`administered. If the patient responded in such a way as to suggest that he or she
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`had left ventricular dysfunction, full treatment with inhaled NO would not have
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`been prescribed, and the test treatment would have been stopped. All physicians
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`have a basic understanding of negative side effects, and one skilled in the art would
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`have known not to administer inhaled NO if it would cause harm to the patient that
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`outweighed the benefits of treatment.
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`Claim Interpretation
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`22.
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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). I understand that the Board
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`previously construed the claim phrase “term or near-term neonate” to mean “an
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`infant aged 1 month or younger born between around 37 and 40 weeks gestation or
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`greater than around 34 weeks gestation.” For the other claim terms in the ‘966
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`Patent, I applied the plain and ordinary meaning of all the other terms used in the
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`claims of the ‘966 Patent as those terms would have been known to one of ordinary
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`skill in the art. For my analysis, I was instructed to use June 30, 2009, as the point
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`in time for claim interpretation purposes.
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`Level of Skill in the Art
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`23.
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`In my opinion, a person of ordinary skill in the art would be a
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`neonatologist or pediatric cardiologist with experience treating neonatal heart and
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`lung disease and have 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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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`experienced neonatologist, pediatric cardiologist, pediatric pulmonologist or
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`pediatric intensivist.
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`24. 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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`GREENOUGH IN VIEW OF JAYPEE
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`25. Greenough is a textbook on neonatal respiratory disorders, including
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`indications and contraindications for iNO treatment and an entire chapter
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`dedication to the treatment of persistent pulmonary hypertension of the newborn.
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`Ex. 1006, at 183-187, 373-386. Greenough discloses that echocardiography is
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`essential for diagnosing and treating patients with conditions that may be benefited
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`by iNO. Ex. 1006 at 186, 379-380, 389. Greenough further discloses that
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`indications for iNO treatment include infants with hypoxic respiratory failure and
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`that a dosage of 20 ppm iNO is appropriate to treat infants with pulmonary
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`hypertension. Ex. 1006 at 184, 187, 381, Appendix 3. Greenough also discloses
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`that an elevated wedge pressure increases the risk for a pulmonary edema. Ex.
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`1006 at 392. Additionally, Greenough discloses that LVD can increase the risk of
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`pulmonary edema in patients treated with iNO and therefore, LVD is an “absolute
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`contraindication” for treatment with iNO. Ex. 1006 at 187, 392. Additionally, the
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`INOmax label discloses that echocardiography may be used to confirm that the
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`patient is a good candidate for iNO therapy, as well as to exclude patients with
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`conditions that may contraindicate the use of iNO as appropriate. Ex. 1010 at 4, 6.
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`26.
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`Jaypee is a textbook on pediatric neonatal mechanical ventilation that
`
`reviews pediatric conditions, including pulmonary hypertension and PPHN. Ex.
`
`1007. Jaypee discloses using echocardiography to determine signs of pulmonary
`
`hypertension. Ex. 1007 at 43. Jaypee further includes an entire chapter on iNO,
`
`which discloses a recommended dose of 20 ppm iNO to treat pulmonary
`
`hypertension. Ex. 1007 at 148, 150. Additionally, Jaypee teaches that patients
`
`with LVD or elevated capillary wedge pressure are at risk of having an adverse
`
`effect to iNO treatment that may lead to pulmonary edema. Ex. 1007 at 156.
`
`Additionally, the INOmax label discloses the FDA recommended dose for iNO
`
`treatment is 20 ppm, which can be used to treat both hypoxic respiratory failure
`
`and pulmonary hypertension in neonates. Ex. 1010 at 3, 4, 6.
`
`27. Based on the teachings of Greenough and Jaypee, in order to
`
`determine whether a patient in need of iNO treatment should have been excluded
`
`from iNO treatment as of June 30, 2009, it would have been necessary to first
`
`determine whether the patient had a condition that would benefit from iNO
`
`treatment, and if so, further determine whether the patient had any other
`
`physiological indicators that would contraindicate treatment with iNO. Before
`
`June 30, 2009, as part of the diagnostic process routinely conducted by a
`
`
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`18
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
`
`neonatologist or pediatric cardiologist, the doctor would have gathered information
`
`to determine whether the patient was in a physiological state that could be
`
`improved with iNO treatment and further, that the patient did not have any
`
`physiological indicators that would require the patient to be excluded from iNO
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`treatment.
`
`28. Greenough discloses
`
`that echocardiography
`
`is “essential” and
`
`“critical” for identifying and treating children with conditions, such as pulmonary
`
`hypertension, that may benefit from treatment with iNO. See Ex. 1006 at 379-380
`
`(“The echocardiogram plays an essential diagnostic role” and “In addition to
`
`demonstrating the presence of PPHN physiology, the echocardiogram is critical for
`
`the evaluation of left ventricular dysfunction and diagnosis of anatomical heart
`
`disease.”). Greenough also discloses that pulmonary hypertension in neonates may
`
`be treated with 20 ppm iNO. See, e.g., Ex. 1006 at 381 (“Inhaled nitric oxide
`
`(iNO) therapy at low doses (5-20 ppm) improves oxygenation…in patients with
`
`diverse causes of PPHN.”); id. at 184 (“NO at 10 and 20 ppm also caused a rapid
`
`improvement in oxygenation in nine newborn infants with PPHN . . . .”).
`
`29. As discussed below, Greenough
`
`teaches
`
`that
`
`left ventricular
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`dysfunction is an “absolute contraindication” to treatment with iNO. Ex. 1006 at
`
`187. This contraindication is not specific to RTL-dependent LVD (right to left
`
`dependent left ventricular dysfunction), but to all forms of LVD. In fact,
`
`
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`19
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`
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
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`Greenough separately lists “right ventricle dependent circulation” and “duct-
`
`dependent circulation” as separate contraindications for treatment with iNO,
`
`suggesting that the LVD contraindication must apply to non-RTL-dependent LVD.
`
`Ex. 1006 at 187. These conditions indicate dependency on right-to-left shunting of
`
`blood, i.e. RTL-dependent LVD. If the LVD contraindication only applied to
`
`RTL-dependent LVD, then listing LVD as its own contraindication would be
`
`redundant and unnecessary. Thus, Greenough teaches that the child in the claims
`
`who may be excluded from treatment with iNO is not dependent on right-to-left
`
`shunting of blood.
`
`30. Greenough teaches “[i]nfants at or near term should be considered for
`
`iNO if they have hypoxic respiratory failure, usually an OI greater than 25.” Ex.
`
`1006 at 187. Further, Greenough discloses treating patients with iNO therapy at 20
`
`ppm improves oxygenation, including in patients with hypoxic respiratory failure.
`
`Ex. 1006 at 187, 381 (“Inhaled nitric oxide (iNO) therapy at low doses (5-20ppm)
`
`improves oxygenation and decreases the need for ECMO therapy in patients with
`
`diverse causes of PPHN.”).
`
`31. Greenough discloses measuring of blood gases as another diagnostic
`
`tool to assess infants with respiratory problems, especially blood oxygen levels.
`
`See Ex. 1006 at 224 (“The monitoring of oxygenation is fundamental to the
`
`assessment of infants with respiratory problems. The gold standard is the partial
`
`
`
`20
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`
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,282,966
`
`pressure of oxygen in arterial blood (PaO2).”). As stated in Greenough, OI, or
`
`oxygenation index is a measure of (MAP x (FiO2 x 100)/PaO2). Id. at 495. As
`
`PaO2 is the partial pressure of oxygen in arterial blood, a person of skill in the art
`
`would have understood to measure blood oxygen levels in children to calculate the
`
`OI and determine if the child is hypoxic or already has hypoxic respiratory failure,
`
`when to use iNO treatment, and when to start or consider ECMO9. Id.
`
`32. Greenough also discloses using blood oxygen levels to identify
`
`hypoxemia. Ex. 1006 at 373 (“PPHN is characterized by hypoxemia…‘differential
`
`cyanosis’ is often present, which is defined by a difference in PaO2 between right
`
`radial artery versus descending aorta values greater or equal to 10 mmHg (1.33
`
`kPa), or an O2 saturation gradient greater than 5 percent.”). Jaypee discloses that
`
`patients with pulmonary hypertension may also be hypoxemic. Ex. 1007 at 149. It
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`is my opinion that a person of ordinary skill in the art, in view of Greenough and
`
`Jaypee would know to measure a patient’s blood oxygen level if the patient is
`
`suspected to have a respiratory problem. Further, a person of ordinary skill in the
`
`art would know from the PaO2 measurement whether or not the patient is hypoxic
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`(or lacking oxygen).
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