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. 8,846,112
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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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`
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`DECLARATION OF DR. EDWARD LAWSON
`IN SUPPORT OF PETITION FOR
`INTER PARTES REVIEW OF U.S. PATENT NO. 8,846,112
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`1
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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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. 8,846,112
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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. 8,846,112 (“the ‘112
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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 ‘112 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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`3
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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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 ‘112 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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`1010, Center for Drug Evaluation and Research, Application Number: NDA20845,
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`INOmax,
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`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). (“INOmax Label”). I was already familiar with the concepts and
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`physiology of iNO and its uses. I have also reviewed the documents cited
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`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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`‘112 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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`4
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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`unknown aspects of the INOT22 study were clearly disclosed by, for example,
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`Greenough, the INOmax Label, and Jaypee prior to June 30, 2009.
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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 ONE OF SKILL IN THE ART BEFORE
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`THE ‘112 PATENT
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`11. The ʼ112 Patent is entitled “Methods of Distributing a Pharmaceutical
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`Product Comprising Nitric Oxide Gas for Inhalation.” Ex. 1001 at Cover. The
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`ʼ112 Patent discusses supplying inhaled NO1 (for example, a cylinder of NO gas)
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`to doctors
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`along with
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`information/instructions
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`regarding dosage
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`and
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`contraindications for treatment. Ex. 1001, Abstract. The ʼ112 Patent discusses a
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`canister of iNO along with information regarding a pre-screening protocol to
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`determine whether a patient has a condition, such as left ventricular dysfunction
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`(“LVD”), that could lead to an Adverse Event or Serious Adverse Event such as
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`pulmonary edema if the patient is treated with inhaled NO. See, e.g., Ex. 1001 at
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`1:50-56; 9:24-33; 12:49-61. It also explains that if a patient is determined to have
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`LVD, he or she is at risk of suffering a Serious Adverse Event such as pulmonary
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`1 “Inhaled nitric oxide” is abbreviated as “iNO.”
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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`edema2 upon treatment with iNO. Ex. 1001 at Abstract; 1:50-56. The ’112 Patent
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`suggests that these patients should be “possibly exclude[d] from treatment.” Ex.
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`1001 at 1:53-54.
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`12. Claim 1 of the ’112 Patent is representative:
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`A method of providing pharmaceutically acceptable nitric oxide gas,
`the method comprising:
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`obtaining a cylinder containing compressed nitric oxide gas in the
`form of a gaseous blend of nitric oxide and nitrogen;
`supplying the cylinder containing compressed nitric oxide gas to a
`medical provider responsible for treating neonates who have hypoxic
`respiratory failure, including some who do not have left ventricular
`dysfunction;
`providing to the medical provider (i) information that a recommended
`dose of inhaled nitric oxide gas for treatment of neonates with
`hypoxic respiratory failure is 20 ppm nitric oxide
`and (ii) information that, in patients with pre-existing left ventricular
`dysfunction, inhaled nitric oxide may increase pulmonary capillary
`wedge pressure (PCWP), leading to pulmonary edema, the
`information of (ii) being sufficient to cause a medical provider
`considering inhaled nitric oxide treatment for a plurality of neonatal
`patients who (a) are suffering from a condition for which inhaled
`nitric oxide is indicated, and (b) have pre-existing left ventricular
`dysfunction, to elect to avoid treating one or more of the plurality of
`patients with inhaled nitric oxide in order to avoid putting the one or
`more patients at risk of pulmonary edema.
`Ex. 1001 at 14:28-52.
`13.
`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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`2 Pulmonary edema is a buildup of fluid in the lungs.
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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`pressure”) or perform an echocardiograph.3 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 ‘112
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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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`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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`3 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. 8,846,112
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`14. 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 3:18-23. Nitric oxide is a selective pulmonary vasodilator that
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`increases the partial pressure of arterial oxygen by dilating pulmonary vessels in
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`ventilated 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.4 See, e.g. Ex. 1007, Jaypee at 148. Nitric oxide is a
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`gaseous chemical compound used to treat patients with severe breathing problems.
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`Nitric oxide is particularly useful in the treatment of pulmonary hypertension, as
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`inhaled nitric oxide can lead to selective pulmonary vasodilation, therefore
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`reducing pulmonary vascular resistance, decreasing pulmonary arterial pressure,
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`and easing right ventricular afterload. Ex. 1008, Widlitz at 156-57, 161. Once
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`inhaled, the nitric oxide diffuses across alveolar membranes to closely adjacent
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`vessels. This activates guanylate cyclase in pulmonary smooth muscle cells, which
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`in turn increases intracellular cyclic guanosine monophosphate (cGMP) production
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`in the cells. The increased cGMP causes pulmonary smooth muscles to relax
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`resulting in pulmonary arteriole dilation. Ex. 1008, Widlitz at 169-170.
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`4 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. 8,846,112
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`15. 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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`failure5 and has been approved since 2000. Id.; see also Ex. 1010, Center for Drug
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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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`5 Hypoxic respiratory failure and hypoxemic respiratory failure, conditions where
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`the cells of the body do not have enough oxygen, may be caused by pulmonary
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`hypertension. Therefore, treatment of pulmonary hypertension would also
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`result in treatment of hypoxic respiratory failure caused by pulmonary
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`hypertension. Hypoxic respiratory failure may lead to hypoxia (a condition
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`characterized by low oxygen in all organs; where the tissue does not have
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`enough oxygen). Treatment of hypoxia may be understood to include treatment
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`of hypoxic respiratory failure, as the hypoxia is the condition that causes harm
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`to the patient.
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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`inhaled nitric oxide has been approved in the United States. 6 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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`vascular resistance, decreasing the afterload to the right heart, and ultimately
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`improving right heart output and venous return to the left ventricle. In a poorly
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`functioning left ventricle, pulmonary edema can occur. Thus, practitioners
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`thoroughly evaluate their patients prior to treatment, and exclude patients from NO
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`therapy upon determination of left ventricular dysfunction See, e.g., Ex. 1011,
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`Pilbeam, Mechanical Ventilation, Special Techniques in Mechanical Ventilation, §
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`4: Nitric Oxide, (4th ed. 2006) (“Pilbeam”) at 4-6. Such examinations were
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`commonly done prior to June 30, 2009. Id.
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`6 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. 8,846,112
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`16. 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 stenosis7 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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`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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`17. As part of the general medical practice before June 30, 2009, doctors
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`implemented a clinical diagnostic procedure to assess patient conditions, treatment
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`options, and potential risks from any potential treatment. First, doctors would
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`assess the condition of the patient to see if the patient had a condition likely to be
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`helped by inhaled NO, such as pulmonary hypertension. Second, doctors would
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`assess whether inhaled NO would likely trigger adverse events in the patient. This
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`process was performed for all patients. As is clear from the studies which include
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`numerous patients, one skilled in the art would have understood that a process for
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`selecting a patient to be treated, or a method of treatment, could be applied to one
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`7 Mitral stenosis is a condition where the mitral valve, which separates the upper
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`and lower chambers on the left side of the heart, does not open fully, restricting
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`blood flow.
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`11
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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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, as Greenough and Jaypee both disclose diagnostic processes for
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`determining whether a patient should be treated with iNO, one skilled in the art
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`would understand that multiple patients may be tested and/or treated (e.g. a single
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`test may have multiple outcomes: either, a patient is a candidate for treatment, or a
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`patient is not). Additionally, the INOmax label discloses that clinical trials
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`identified a plurality of patients to be treated with 20 ppm iNO. Ex. 1010 at 2-3.
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`18. 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.
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`19.
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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. Indeed, before June
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`30, 2009, my team followed this practice before starting nitric oxide, and the
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`intensive care or neonatology specialists consistently confirmed that it was done
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`before treatment. We even often assessed the efficacy by echocardiography
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`through the evaluation of pulmonary pressure, right ventricular anatomy and
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`12
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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`function as well as shunt8 direction through the ductus arteriosus and the foramen
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`ovale.
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`20. 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.9 As was known in the
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`art prior to June 30, 2009, wedge pressure can be measured by inserting a
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`pulmonary catheter with an inflated balloon into a small pulmonary arterial branch
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`8 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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`9 Wedge pressure is referred to in the literature as pulmonary capillary wedge
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`pressure (“PCWP”), pulmonary arterial wedge pressure (“PAWP”), or merely
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`“wedge.” See, e.g., Ex. 1012, M. Hoeper, et al., Definitions and Diagnosis of
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`Pulmonary Hypertension 62:25 J. of the American College of Cardiology D44
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`(2013) (“Hoeper”) (noting that pulmonary capillary wedge pressure, pulmonary
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`arterial wedge pressure, wedge pressure, and wedge are all used to refer to the
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`same concept and also noting that “wedge” and “wedge pressure” are
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`commonly used in daily clinical practice, even in non-English speaking
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`countries).
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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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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`21. Before June 30, 2009, it was well-known that wedge pressure could
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`also be determined through extrapolation based on information gained through
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`echocardiography. See, e.g., Ex. 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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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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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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`22. 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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`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
`
`been prescribed, and the test treatment would have been stopped. All physicians
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`15
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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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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`23.
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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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`greater than around 34 weeks gestation” to a person of ordinary skill in the art. For
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`the other claim terms in the ‘112 Patent, I applied the plain and ordinary meaning
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`of all the other terms used in the claims of the ‘112 Patent as those terms would
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`have been known to one of ordinary skill in the art. For my analysis, I was
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`instructed to use June 30, 2009, as the point in time for claim interpretation
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`purposes.
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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`Level of Skill in the Art
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`24.
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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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`experienced neonatologist, pediatric cardiologist, pediatric pulmonologist or
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`pediatric intensivist.
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`25. 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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`INOmax LABEL AND GREENOUGH IN VIEW OF JAYPEE
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`17
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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`26. The ‘112 Patent contains a discussion of the FDA approval for sale of
`
`a product called INOmax®. See generally Ex. 1001 at 3:34-4:22. As part of this
`
`FDA approval, the ’112 Patent discusses certain approved “prescribing information
`
`for INOmax®” that was “in effect in 2009.” Ex. 1001 at 3:45-47. The reference I
`
`refer to as the INOmax label contains this prescribing information. See Ex. 1014.
`
`This reference was submitted to the FDA in 1999, and published in 2000. Thus,
`
`INOmax label was published and available several years before the June 30, 2009
`
`earliest priority date of the ’112 Patent.
`
`27.
`
`In general,
`
`the INOmax
`
`label reference contains prescribing
`
`information that was distributed to medical providers purchasing and using
`
`INOmax® branded iNO gas for therapy. It describes INOmax as “a drug
`
`administered by inhalation” whose active substance is nitric oxide. Ex. 1010 at 1.
`
`INOmax label describes that “INOmax is a gaseous blend of nitric oxide (0.8%)
`
`and nitrogen (99.2%).” Ex. 1010 at 1. It also states that INOmax is “supplied in
`
`aluminum cylinders” of varying sizes and concentrations. Ex. 1010 at 1, 6-7.
`
`Consistent with the discussion above, the INOmax label informed medical
`
`providers that “nitric oxide produces pulmonary vasodilation” and can be used to
`
`treat neonates with PPHN to improve oxygenation. Ex. 1010 at. 1.
`
`28. The INOmax label reference contains “prescribing information” that
`
`was given to medical providers responsible for treating those individuals to whom
`
`
`
`18
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
`
`INOmax label is directed - that is, neonates who have hypoxic respiratory failure.
`
`See Ex. 1010 at 4 (iNO indicated for treatment of “neonates with hypoxic
`
`respiratory failure”). The INOmax label does not indicate that a practitioner should
`
`determine if such neonates do or do not have LVD and therefore discloses treating
`
`neonates with hypoxic respiratory failure but without LVD. Ex. 1010 at 4. A
`
`person of skill in the art reading the INOmax label reference understands that it
`
`discloses a protocol (or method) for administering nitric oxide gas, and that the
`
`protocol information contained in the INOmax label is provided to medical
`
`providers along with cylinders of nitric oxide gas to educate the providers as to the
`
`use of the nitric oxide gas.
`
`29. The INOmax label reference therefore discloses providing cylinders of
`
`a gaseous blend of nitric oxide and nitrogen to medical providers who will be
`
`treating patients with the drug. Ex. 1010 at 1. Further, the INOmax label reference
`
`discloses that iNO is indicated for treatment of term and near-term neonates with
`
`hypoxic respiratory failure, meaning that the information contained therein is
`
`provided to medical providers who will be treating such patients.
`
`30. The INOmax label reference contains an “Administration” section that
`
`discusses FDA-approved delivery mechanisms. Ex. 1010 at 6. This section states
`
`that “[t]he nitric oxide delivery systems used in the clinical trials provided
`
`operator-determined concentrations of nitric oxide in the breathing gas, and the
`
`
`
`19
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
`
`concentration was constant throughout the respiratory cycle.” Ex. 1010 at 6. To a
`
`person of skill in the art, this passage (and the rest of the “Administration” section)
`
`discloses a device that delivers nitric oxide gas into an inspiratory limb of a
`
`breathing circuit.” Since the INOmax label reference mandates such delivery
`
`devices for those medical providers wishing to treat neonates with nitric oxide, it
`
`discloses both obtaining such a device and supplying such a device to the medical
`
`provider.
`
`31. The INOmax label reference also contains “INDICATIONS” and
`
`“CONTRAINDICATIONS” sections. Ex. 1010 at 4. The “INDICATIONS”
`
`section contains information communicated to medical providers to explain the
`
`characteristics of neonatal patients indicated for treatment. Ex. 1010 at 4.
`
`“CONTRAINDICATIONS” contains
`
`information communicated
`
`to medical
`
`providers to explain situations in which inhaled nitric oxide should not be used for
`
`treatment of neonates. Ex. 1010 at 4. Contraindications are indicative of the
`
`risk/benefit analysis that must be undertaken in order to decide to treat or not treat
`
`infants with iNO. There are two types of contraindications: absolute and relative.
`
`Absolute contraindications mean that a patient showing the contraindication must
`
`be excluded from treatment. Relative contraindications provide information that
`
`patients expressing the contraindicated condition should be treated cautiously and
`
`if one skilled in the art does decide to begin treatment, if negative effects occur,
`
`
`
`20
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
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`treatment should be stopped. The contraindications on the INOmax label appear to
`
`be relative contraindications.
`
`32. A person of skill
`
`in
`
`the art would understand
`
`that
`
`the
`
`“INDICATIONS” and “CONTRAINDICATIONS” sections contain the iNO
`
`indications and contraindications approved by the FDA. However, a person of
`
`skill in the art would also understand that the INOmax label reference more
`
`generally discloses providing information to medical providers regarding when to
`
`use iNO and when not to use iNO. Thus, as additional indications and
`
`contraindications become known, the INOmax label reference suggests to those of
`
`skill in the art that those additional indications and contraindications would have
`
`been provided to medical providers.
`
`33. The INOmax label states that “[t]he recommended dose of INOmax is
`
`20 ppm.” Ex. 1010 at 6. Since the INOmax label reference discloses that INOmax
`
`is “indicated for the treatment of term and near-term (>34 weeks) neonates with
`
`hypoxic respiratory failure…” (Ex. 1010 at 4, emphasis added), it discloses
`
`providing a medical provider with information that a recommended dose of inhaled
`
`nitric oxide gas for treatment of hypoxic respiratory failure is 20 ppm nitric oxide.
`
`34. The INOmax label further discloses that the determination of whether
`
`a neonate has hypoxic respiratory failure can be based on a diagnostic process in
`
`the form of “echocardiographic evidence of pulmonary hypertension.” Ex. 1010 at
`
`
`
`21
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`Declaration of Dr. Edward Lawson Regarding U.S. Patent No. 8,846,112
`
`4. Accordingly, the INOmax label discloses
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