Attorney Docket No.2 26047-0003006 1' Client Ref: 3000—US—0O08DIV
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`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
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`Applicant
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`Serial No.
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`: 1613
`Art Unit
`: James S. Baldassarre
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`: Ernst V. Arnold
`Examiner
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`Conf. No.
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`: 5655
`‘I. METHODS OF DISTRIBUTING A PHARMACEUTICAL PRODUCT
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`COMPRISING NITRIC OXIDE GAS FOR INHALATION
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`Commissioner for Patents
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`P.O. Box 1450
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`Alexandria, VA 22313-1450
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`DECLAMRATION OF JAMES S. BALDASSARRE, M.D., UNDER 37 C.F.R. § 1.132
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`1, James S. Baldassarre, do hereby declare the following:
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`l.
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`2.
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`I am the inventor of the subject matter claimed in the present application.
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`I have over 25 years of experience as a physician, and over 15 years of experience
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`directing clinical research in the pharmaceutical industry.
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`3.
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`I held the position of Vice President of Clinical Research at Ikaria, Inc. (lkaria),
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`the assignee of U.S. Patent Application No. 12/821,020, firom October 2003 until September
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`2013.
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`I currently serve as a paid consultant of Ikaria and its subsidiary INO Therapeutics LLC,
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`and retain an equity interest in the company. My curriculum vitae is attached as Exhibit 1.
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`Ikaria markets pharmaceutical grade nitric oxide (N0) gas under the brand
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`name INOMAX® (nitric oxide) for inhalation. INOMAX® was approved by the U.S. Food and
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`Drug Administration (FDA) in December 1999, after extensive clinical study and FDA review,
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`for the treatment of term and near-term (>34 Weeks) neonates with hypoxic respiratory failure
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`associated with clinical or echocardiographic evidence of pulmonary hypertension, where it
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`improves oxygenation and reduces the need for extracorporeal membrane oxygenation (ECMO).
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`5.
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`Upon approval of INOMAX®, and up to the time the present invention was
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`made, the iNOMAX® label contained language communicating, in pertinent part, the following
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`general warnings and contraindication:
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`001
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`PRAXAIR ET AL. 1017
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`Attorney Docket No: 26047—0003006 ." 3000-US~0008DlV
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`INOmax® should not be discontinued abruptly, as it may result in an increase in
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`pulmonary artery pressure (PAP) and/or worsening ofblood oxygenation (Pa0;).
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`Deterioration in oxygenation and elevation in PAP may also occur in children with no
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`apparent response to INOmax....
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`Following discontinuation
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`or reduction of nitric oxide the methemogiobin levels returned to baseline over a period
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`of hours...
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`INOmax should be administered with monitoringfor Pa0;, methemoglobin and N0g,m
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`INOmax® should not be used in the treatment ofneonates known to be dependent on
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`right-to-left shunting ofblood.
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`Thus, the original lNOMAX® label did not include any warning or precaution with respect to a
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`risk of pulmonary edema in patients with pre-existing left ventricular dysfunction (LVD).
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`6.
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`In May 2004, INO Therapeutics LLC] (INOT) initiated a clinical trial entitled
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`“Comparison of Supplemental Oxygen and Nitric Oxide for Inhalation Plus Oxygen in the
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`Evaluation of the Reactivity of the Pulmonary Vasculature During Acute Pulmonary Vasodilator
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`Testing," designated the “lNOT22" trial, to compare the utility and side effects of oxygen (02),
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`inhaled NO, and a combination of inhaled NO and 02 for determining pulmonary reactivity.
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`was the Medical Monitor responsible for the design and execution of the INOT22 study.
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`The INOT22 study was a randomized, rnulti-center study having an expected
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`enrollment of 150 patients in approximately 18 study sites over approximately 2 years. The
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`expected patient population for enrollment into the lNO'l'22 study was subjects between the ages
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`of four weeks and 18 years with idiopathic pulmonary arterial hypertension, congenital heart
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`disease (with or without intravascular shunt) with pulmonary hypertension, or a cardiomyopathy,
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`and who were undergoing diagnostic right heart catheterization scheduled to include acute
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`pulmonary vasodilation testing to assess pulmonary Vasoreactivity. The purpose of the study
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`was to assess the safety and effectiveness of inhaled NO as a diagnostic agent in pediatric
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`patients undergoing assessment of pulmonary hypertension (primary obj ectivc), and to confirm
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`the hypothesis that inhaled NO is selective for the pulmonary vasculature (secondary objective).
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`INO Therapeutics LLC is a wholly owned subsidiary of lkaria, Inc., and holder of the NDA for l'NOMAX®.
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`2 James S. Baldassarre
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`2 13/683,236
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`1 November 21, 2012
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`: 3 of 8
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`Attorney Docket No.: 2604743003006 1' 3000-US—0008DIV
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`8.
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`The INOT22_st_u_dy was established and designed by the study sponsor (INOT)
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`and 3. Steering Committee comprising internationally recognized experts in the field of pediatric
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`heart and lung disease, whose members assisted INOT in developing the lNOT22 protocol,
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`monitor the progress of the trial, and provide recommendations to INOT on changes in the
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`procedures and conduct of the trial.
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`9.
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`The Steering Committee consisted of:
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`a. David L. Wessel, MD, presently Senior Vice President, The Center for
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`Hospital Based Specialties, and Division Chief, Pediatric Critical Care
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`Medicine, at Children’s National Medical Center, Washington, DC;
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`b. Robyn J. Barst, MD, formerly Professor Emeritus of Pediatrics and
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`Medicine, Columbia University College of Physicians and Surgeons, New
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`York; and
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`c. Duncan J. Macrae, MD, presently Director, Pediatric Intensive Care,
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`Royal Brompton Hospital, London, UK.
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`The original INOT22 study protocol designed by INOT and the Steering
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`Committee did not exclude study patients with preexisting left ventricular dysfunction who were
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`not dependent on right-to-lefl shunting of blood. The original INOT22 protocol designed by
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`INOT and the Steering Committee contained the following inclusion and exclusion criteria:
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`Inclusion Criteria
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`The patient must meet the following criteria:
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`1.
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`Have any one ofthe three disease categories:
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`a.
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`Idiopathic Pulmonary Arterial Hypertension
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`1'. PAPm >25mmHg at rest, PCWP: I5mmHg, and PVRI>3 arm’? or diagnosed
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`clinically with no previous catlzeterization.
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`b.
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`CHD with pulmonary hypertension repaired and unrepaired,
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`': November 21, 2012
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`:' 4 of 8 -
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`Attorney Docl<etNo.: 26047-0003006/3000—US-OOOSDIV
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`i. PAPm > 25mrnHg at rest, and PVRI >3 u’ in) or diagnosed clinically
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`with no previous catheterization.
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`c.
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`Cardioinyopatlzy
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`i. PAPm>25mmHg at rest, and PVRI>3u-mg or diagnosed clinically with
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`no previous catheterization.
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`Scheduled to undergo right heart catheterization to assess pulmonary vasoreactivity by
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`acute pulmonary vasodilation testing.
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`Males orfemales, ages 4 weeks to 18 years, inclusive.
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`Signed IRB/IEC approved informed consent (and assent Ifapplicable).
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`2,
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`Exclusion Criteria
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`3.
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`The patent will be excludedfrom enrollment ifany ofthe following are true:
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`Focal pulmonary infiltrates on chest radiograph.
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`Diagnosed with severe obstructive or restrictive pulmonary disease that is significantly
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`contributing to the patient ’s pulmonary hypertension.
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`Received treatment with nitric oxidefor inhalation within 30 days prior to study
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`initiation, are on other investigarional medications, nitroglycerin, sodium nitroprusside,
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`sildenafil, other PDE—5 inhibitors, or prostacyclin.
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`4.
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`Pregnant (urine HCG +).
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`11.
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`Afler the INOT22 study protocol design, but prior to study initiation and
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`enrollment, the original INOT22 study protocol was reviewed by an Institutional Review Board
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`(IRE) and/or independent Ethics Committee (IEC) at each of the 18 participating study
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`institutions, including review by the principal investigator within each study institution. In
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`addition, prior to study initiation and enrollment, the original INOT22 study protocol was
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`reviewed by the US Food and Drug Administration (FDA) and separately reviewed by each
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`national Health Authority (European equivalent to FDA) within the four European countries
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`participating in the lNOT22 trial (United Kingdom, France, Netherlands and Spain). Further,
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`INOT regularly requested input and scientific guidance on the clinical trial fiom its own
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`Applicant
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`Serial No.
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`: James S. Baldassarre
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`: 13/683,236
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`2 November 21, 2012
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`:: 5 of8
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`Attorney Docket No.: 26047—0O(33006 / 3000—US—000 SDIV
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`Scientific Advisory Board. At no time did any member of the Steering Committee, INOT, an
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`IRB or IEC, an individual principal investigator, a Scientific Advisory Board member, FDA or
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`European Health Authority suggest that subjects with preexisting left ventricular dysfunction
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`who are not dependent on right—to-left shunt should be excluded from the INOT22 study or that
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`such subjects would be predicted to have an increased risk of adverse events or serious adverse
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`events arising from the administration to them of inhaled nitric oxide.
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`12.
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`Under FDA regulations, an IRB is an appropriately constituted group that has
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`been formally designated to review and monitor biomedical research involving human subjects.
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`In accordance with FDA regulations, an IRB has the authority to approve, require modifications
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`in (to secure approval), or disapprove research. This group review serves an important role in
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`the protection of the rights and welfare of human research subjects. The purpose of IRB review
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`is to assure, both in advance and by periodic review, that appropriate steps are taken to protect
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`the rights and welfare of humans participating as subjects in the research. To accomplish this
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`purpose, IRES use a group process to review research protocols to ensure protection of the
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`rights and welfare of human subjects of research. An IRB must have at least five members and
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`each member must have enough experience, expertise and diversity to make an informed
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`decision on whether the research is ethical, informed consent is sufficient and the appropriate
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`safeguards have been put in place (see 21 CFR Part 56).
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`13.
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`In Europe, an IEC is an independent body in an EC Member State consisting of
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`healthcare professionals and non-medical members whose responsibility is to protect the rights,
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`safety and well-being of human subjects involved in a clinical trial and to provide public
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`assurance of that protection by expressing an opinion on a proposed clinical trial protocol, the
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`suitability of the investigators, and the adequacy of facilities involved in a trial (see Directive
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`2001/20/EC).
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`14.
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`in total, at least 115 individuals experienced in and responsible for the review of
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`clinical trial protocols for patient safety, in addition to the FDA and four European Health
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`Authorities, reviewed the original. fNOT22 protocol prior to initiation of the INOTZZ study.
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`: James S.Ba1dassarre
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`': November 21, 2012
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`r 6 of 8
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`Attorney Docket No; 26047-00030061’ 3000—US-OOOSDIV
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`Again, not a single individual or authority raised a concern about an increased risk associated
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`with the use of inhaled nitric oxide in study subjects with preexisting lefl ventricular
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`dysfunction who were not dependent on right-to-left shunt.
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`15.
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`Afier initiation and enrollment of the first 24 subjects in INOT22, there were
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`5 serious adverse events (SAES) — a rate much higher than expected by INOT and the Steering
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`Committee based on prior clinical experience. These were all cardiovascular events, and
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`included pulmonary edema, cardiac arrest and hypotension (low blood pressure).
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`16.
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`Thereafter, INOT and the Steering Committee convened to review the unexpected
`SAES described above, and upon review and discussion, expressed concern that the unexpected
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`SAES may be due to the administration of inhaled NO in subjects having preexisting LVD.
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`Accordingly, based upon a review of the cases, the exclusion criteria of the INOT22 protocol
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`were amended to thereafter exclude subjects with preexisting LVD. For purposes of the study,
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`the exclusion criteria were amended to exclude subjects from enrollment if the subjects
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`demonstrated an elevated pulmonary capillary wedge pressure (PCWP), defined within the study
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`as subjects having a PCWP greater than 20 mmHg. A11 study sites were notified immediately.
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`The amended exclusion criteria, including the newly added criterion 5, were as follows:
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`The patient will be excludedfiom enrollment ifany ofthe following are true:
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`1. Focal pulmonary infiltrates on chest radiograph.
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`2. Diagnosed with severe obstructive or restrictive pulmonary disease that is significantly
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`contributing to the patient it pulmonary hypertension.
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`3. Received treatment with nitric oxidefor inhalation within 30 days prior to study
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`initiation, are on other investigational medications. nitroglycerin, sodium
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`nitroprusstde, sildenafil, other PDE—5 inhibitors, or prostucyclin.
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`4. Pregnant (urine HCG +).
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`5. Baseline PCWP > 20 mmHg.
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`: James S. Baldassarre
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`: November2l,20l2
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`: 7of3
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`Attorney Docket No.: 26047-0003006/3000-US-OOOSDIV
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`17.
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`Upon conclusion of the INOT22 study, INOT noted that, subsequent to excluding
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`patients with preexisting LVD (i.e., baseline PCWP > 20 mmHg), the rate of SAEs (including
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`SAES associated with heart failure) was significantly reduced. There were 5 SAEs among the
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`first 24 subjects prior to the additional exclusion criterion, but only 2 SAES among the
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`100 subjects2 in the study who were enrolled and treated after the additional exclusion criterion
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`was in place. Furthermore, there were 2 SAES among the 4 subjects with evidence of pre-
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`existing lett ventricular dysfunction, but only 5 SAES amongst the 120 subjects without evidence
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`of left ventricular dysfunction. This result was unexpected and came as a great surprise to those
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`Working on the study.
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`18.
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`Based upon this unexpected finding, INOT submitted a labeling supplement to
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`FDA on February 25, 2009, seeking to amend the prescribing information for INOMAX® to '
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`include a warning statement for physicians indicating that the use of inhaled NO in patients with
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`preexisting LVD could cause SAES, such as pulmonary edema. No such warning regarding pre-
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`existing LVD was previously required to appear in the prescribing information for inhaled NO in
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`the US. Following 1NOT’s submission of the labeling supplement to FDA, FDA agreed that a
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`warning regarding pre-existing L_VD was required. On August 28, 2009, FDA approved the
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`lNOMAX® label supplement that included the following new information:
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`WARNINGS AND PRECA UT1ONS
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`In patients with pre-existing lefi ventricular dywnction, inhaled nitric
`Heart‘ Failure:
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`oxide may increase pulmonary capillary wedge pressure leading to pulmonary edema
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`(5.4).
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`2 In a prior declaration signed by me in a related case (and previously submitted in the present case at least once,
`e.g., as part of Item 14 of an Information Disclosure Statement filed on December 7, 2012), l inadvertently misstated
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`this number as “80 subjects". See 1] 14 of the Declaration of James S. Baldassarre, M.D., under 3'? C.F.R. § 1.132
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`signed on September 29, 2010. The correct number is 100.
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`007
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`Applicant
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`2 James S. Baldassatre
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`8 of 8
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`Attorney Docket No.: 26047-0003006.’ 3000-US-0008Dl'V
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`5
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`WARNINGS AND PRECA U7']ONS
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`Heart Failure: Patient: who had pre-existing left ventricular dysfimction treated
`5.4
`with inhaled m'trz'c oxide, even for short durations, experienced serious adverse events
`(e.g., pulmonary edema).
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`Thereafter, similar warnings were added to the lNOmax® label in Japan, Europe, Canada and
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`Australia.
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`19.
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`In my expert opinion, prior completion of the lNO'l‘22 study and analysis of the
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`adverse events that occurred during that study, it was not common sense to any expert in this
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`field of medicine to exclude neonates, near-term neonates or children diagnosed with pre-
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`existing LVD from having inhaled NO administered for diagnostic or treatment purposes, unless,
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`of course, the subject was also known to be dependent on right-to-lefi shunting of blood (a
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`contraindication on the prescribing information for lNOMAX®).
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`20.
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`I hereby declare that all statements made herein of my own knowledge are true
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`and that all statements made on information and belief are believed to be true; and further that
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`these statements were made with the knowledge that willful false statements and the like so
`made are plmishable by fine or imprisonment, or both, under Section 1001 ofTitle 18 of the
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`United States Code, and that such willful false statements may jeopardize the validity of any
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`patent that may issue on the present application.
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`23074909.doc
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`008