Attorney Docket No. 26047-0003002
`
`IN THE UNITED STATES PATENT AND TRADEMARK OFFICE
`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`: June 22, 2010
`Filed (cid:9)
`
`Art Unit : 1613
`Examiner : Ernst V. Arnold
`Conf. No. : 2913
`
`Title (cid:9)
`
`: METHODS OF TREATING TERM AND NEAR-TERM NEONATES HAVING
`HYPDXIC RESPIRATORY FAILURE ASSOCIATED WITH CLINICAL OR
`ECHOCARDIOGRAPHIC EVIDENCE OF PULMONARY HYPERTENSION
`
`Mail Stop Appeal Brief - Patents
`Commissioner for Patents
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`BRIEF ON APPEAL
`
`This application is under Accelerated Examination.
`
`Appellant is appealing the final rejection of claims 28-42 in the Final Office
`
`Action dated August 24, 2011. A Notice of Appeal was filed and received by the U.S. Patent
`
`and Trademark Office on September 1, 2011.
`
`I.
`
`Real Party in Interest
`
`The Real Party in Interest is Ikaria Holdings, Inc., the assignee of record.
`
`Affiliates of Ikaria Holdings, Inc. include Ikaria, Inc. and INO Therapeutics LLC.
`
`II.
`
`Related Appeals and Interferences
`
`There are no prior or pending related appeals, judicial proceedings, or
`
`interferences.
`
`CERTIFICATE OF (A) MAILING BY FIRST CLASS MAIL OR (B) TRANSMISSION
`I hereby certify under 37 CFR § 1.8(a) that this correspondence is either (A) addressed as set out in
`37 CFR §1.1(a) and being deposited with the United States Postal Service as first class mail with
`sufficient postage, or (B) being transmitted by facsimile in accordance with 37 CFR § 1.6(d) or via
`the Office electronic filing system in accordance with 37 CFR § I.6(a)(4), on the date indicated
`below.
`
`October 4, 2011
`Date of Deposit or Transmission
`/Lisa G. Gray/
`Signature
`Lisa G. Gray
`Typed or Printed Name of Person Signing Certificate
`
`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`1
`
`(cid:9)
`(cid:9)
`

`

`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`Filed (cid:9)
`: June 22, 2010
`Page (cid:9)
`: 2 of 56
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`Attorney's Docket No.: 26047-0003002
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`III.
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`Status of Claims
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`Claims 1-27 are canceled.
`
`Claims 28-42 are rejected and under appeal.
`
`IV.
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`Status of Amendments
`
`No amendments have been filed subsequent to the August 24, 2011, mailing date
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`of the Final Office Action, and none are being submitted herewith.
`
`V.
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`Summary of Claimed Subject Matter
`
`Independent claims 28, 32 and 37 are summarized below. Support in the
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`specification is indicated by paragraph numbers derived from the specification as filed.
`
`Independent claim 28 is directed to a method of reducing the risk of occurrence,
`
`in a term or near-term neonate patient (i.e., >34 weeks gestation; see the specification at
`
`paragraph [0033]), of one or more adverse events or serious adverse events associated with a
`
`medical treatment comprising inhalation of nitric oxide gas. ("Adverse events" and "serious
`
`adverse events" are terms of art describing two related but distinct categories of events in the
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`pharmaceutical field; see, e.g., the definitions in the specification at paragraphs [0025] and
`
`[0027].) The method includes the steps of (a) identifying a term or near-term neonate patient in
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`need of inhaled nitric oxide treatment, wherein the patient is not known to be dependent on right-
`
`to-left shunting of blood; (b) determining that the patient identified in (a) has pre-existing left
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`ventricular dysfunction; and (c) excluding the patient from inhaled nitric oxide treatment based
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`on the determination that the patient has pre-existing left ventricular dysfunction. Support for
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`claim 28 can be found, e.g., at paragraphs [0004], [0007], [0008], [0020] (as amended in the
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`Response filed July 8, 2011, to include material previously incorporated by reference), [0025],
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`[0027], [0028], [0033], and [0051] of the specification.
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`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`2
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`

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`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`: June 22, 2010
`Filed (cid:9)
`Page (cid:9)
`: 3 of 56
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`Attorney's Docket No.: 26047-0003002
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`Independent claim 32 is directed to a method of reducing the risk of occurrence,
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`in a teim or near-term neonate patient, of one or more adverse events or serious adverse events
`
`associated with a medical treatment comprising inhalation of nitric oxide gas. The method
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`includes the steps of (a) identifying a term or near-term neonate patient in need of inhaled nitric
`
`oxide treatment, wherein the patient is not known to be dependent on right-to-left shunting of
`
`blood; (b) determining by diagnostic screening that the patient identified in (a) has pre-existing
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`left ventricular dysfunction; and (c) excluding the patient from treatment with inhaled nitric
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`oxide based on the determination that the patient has pre-existing left ventricular dysfunction.
`
`This claim is similar to claim 28, except that step (b) of claim 32 specifies use of "diagnostic
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`screening." See, e.g., the specification at paragraph [0028].
`Support for claim 32 can be found, e.g., at paragraphs [0004], [0007], [0008],
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`[0020] (as amended in the Response filed July 8, 2011, to include material previously
`
`incorporated by reference), [0025], [0027], [0028], [0033], and [0051] of the specification.
`
`Independent claim 37 is directed to a method of reducing the risk of occurrence,
`
`in a plurality of term or near-term neonate patients, of one or more adverse events or serious
`
`adverse events associated with medical treatment comprising inhalation of nitric oxide gas. The
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`method includes the steps of (a) identifying a plurality of term or near-term neonate patients who
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`are in need of inhaled nitric oxide treatment, wherein the patients are not known to be dependent
`
`on right-to-left shunting of blood; (b) determining that a first patient of the plurality has pre-
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`existing left ventricular dysfunction and a second patient of the plurality does not;
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`(c) administering the inhaled nitric oxide treatment to the second patient; and (d) excluding the
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`first patient from treatment with inhaled nitric oxide, based on the determination that the first
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`patient has pre-existing left ventricular dysfunction.
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`Support for claim 37 can be found, e.g., at paragraphs [0004], [0007], [0008],
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`[0020] (as amended in the Response filed July 8, 2011, to include material previously
`
`incorporated by reference), [0025], [0027], [0028], [0033], and [0051] of the specification. In
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`particular, the concept of a "plurality" of patients is supported by the discussion of "patients"
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`(plural) at paragraph [0004] and "a patient population" at paragraph [0007]. Paragraph [0007]
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`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
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`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`: June 22, 2010
`Filed (cid:9)
`Page (cid:9)
`: 4 of 56
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`Attorney's Docket No.: 26047-0003002
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`also supports the recitation of a first patient who is determined to have left ventricular
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`dysfunction and so is excluded from treatment with inhaled nitric oxide. The recitation of a
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`second patient who is determined not to have left ventricular dysfunction and so is administered
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`inhaled nitric oxide is supported, e.g., at paragraph [0008]. (The terms "first" and "second" in
`
`claim 37 are merely standard linguistic devices useful to distinguish between two patients, and
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`do not imply any particular temporal order.)
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`As required by the accelerated examination program of which this application is a
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`part, Appellant does not separately argue the patentability of any dependent claim in this appeal
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`brief. Appellant agrees that the dependent claims are grouped together with, and not argued
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`separately from, the independent claim from which they depend.
`
`VI. Ground of Rejection to be Reviewed on Appeal
`
`The sole ground of rejection to be reviewed on appeal is whether claims 28-42 are
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`unpatentable under 35 U.S.C. § 103(a) over a combination of four references: the 2007 drug
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`label insert for INOmax® (nitric oxide) for inhalation ("the 2007 INOmax0 insert"; included as
`
`Exhibit 1 for the Board's convenience); Atz & Wessel (Seminars in Perinatology 1997,
`
`21(5), 441-455; Exhibit 2); Kinsella et al. (The Lancet 1999, 354, 1061-1065; Exhibit 3); and
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`Loh et al. (Circulation 1994, 90, 2780-2785; Exhibit 4).1
`
`Claims 28-42 are also provisionally rejected as being unpatentable for
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`nonstatutory obviousness-type double patenting over claims 29-42 of co-pending U.S.
`
`Application No. 12/820,980; over claims 21-30 of copending Application No. 12/821,020; and
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`over claims 21-29 and 37 of copending Application No. 12/821,041.2 For purposes of the
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`present appeal, Appellant does not contest these provisional rejections insofar as they are applied
`
`to the claims as currently written, and intends to file appropriate Terminal Disclaimers to moot
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`these rejections if doing so is warranted at the time the present claims are otherwise deemed
`
`I Final Office Action, August 24, 2011 (the "Final Office Action"), at 3.
`2 Id, at 14-17.
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`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
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`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`Filed (cid:9)
`: June 22, 2010
`: 5 of 56
`Page (cid:9)
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`Attorney's Docket No.: 26047-0003002
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`allowable. Accordingly, the Board of Patent Appeals and Interferences need not address the
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`obviousness-type double patenting rejections at this time.3
`
`VII, Argument
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`A. (cid:9)
`
`Summary of the Argument
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`The issue presented on this appeal is simple and straightforward. The claimed
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`invention is directed to a method of reducing the risk of adverse events in neonate patients that
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`suffer from left ventricular dysfunction (LVD) and are not dependent on right-to-left shunting of
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`blood.` For simplicity, this set of neonates is referred to herein as the "Claimed Patient
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`Population." The present inventors discovered that the Claimed Patient Population suffers from
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`an elevated risk of adverse events when treated with inhaled nitric oxide.5 The Examiner does
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`not dispute that this discovery is novel and not anticipated by any of the cited prior art
`
`references.6
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`The prior art does teach, however, that administration of inhaled nitric oxide may
`
`result in adverse events in two other distinct patient populations: (i) neonate patients
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`dependent on right-to-left shunting of blood, and (ii) adults suffering from LVD (together, the
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`"Prior Art Patient Populations").7 The three very distinct patient populations at issue are
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`summarized in the diagram below:
`
`3 Ex Parte Malicia, 95 U.S.P.Q.2d 1884 (B.P.A.I. June 22, 2010).
`4 See Declaration of Douglas A. Greene, M.D. under 37 C.F.R. § 1.132, dated April 29, 2011 ("First Greene Dec."),
`110-14 (discussing neonate cardiology and right-to-left shunting of blood at a patent ductus arteriosus). The First
`Greene Dec. was originally submitted with the May 2, 2011 Reply filed by Appellant. A copy of the First Greene
`Dec. is enclosed in the Evidence Appendix (ix) as Exhibit 5.
`5 Declaration of David L. Wessel, M.D., under 37 CFR § 1.132 ("Wessel Dec."), ¶ 9. The Wessel Dec. was made
`of record on July 27, 2011, and is enclosed in the Evidence Appendix (ix) as Exhibit 6.
`6 Final Office Action at 9 ("The difference between the instant application and INOmax®, Atz et al., Loh et al., and
`Kinsella et al., is that INOmaxe, Atz et al., Loh et al., and Kinsella et al., do not expressly teach the method of
`reducing the risk of occurrence in a term or near term neonate patient of one or more adverse events or serious
`adverse events associated with iNO therapy comprising identifying a term or near term neonate patient in need of
`iNO treatment and is not known to be dependent on right to left shunting of blood, determining if the patient has
`pre-existing LVD and excluding the patient from iNO treatment if they have pre-existing LVD or administering iNO
`if they do not have pre-existing LVD of instant claims 28-42." (Emphasis added)).
`7 Wessel Dec. ¶ 7.
`
`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`5
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`

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`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`: June 22, 2010
`Filed (cid:9)
`Page (cid:9)
`: 6 of 56
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`Attorney's Docket No.: 26047-0003002
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`Patient has LVD and IS dependent
`on right-to-left shunting of blood
`Not Applicable
`
`Patient has LVD and IS NOT dependent
`on right-to-left shunting of blood
`Prior Art Patient Population
`
`Adults
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`Neonates
`
`Prior Art Patient Population
`
`Claimed "- dent Popukition
`
`The Examiner contends that disclosure of an increased likelihood of adverse
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`events in the Prior Art Patient Populations would have made it obvious to expect a similar
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`increase in adverse events in the Claimed Patient Population.8 The Board should reverse this
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`rejection because: (i) it is contrary to historical fact, and (ii) the Examiner provides no analysis
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`based upon the etiology and/or pathophysiology of the various conditions that would explain
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`why a risk of adverse events in the Prior Art Patient Populations would lead one skilled in the art
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`to expect an increased likelihood of adverse events in the Claimed Patient Population.9 In fact,
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`all of the evidence of record is to the contrary and demonstrates that the etiology and
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`pathophysiology of these patient populations are clinically distinct and would not justify any
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`such conclusion.I°
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`The evidence of record supporting reversal of the Examiner's rejection includes
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`the following:
`
`1. (cid:9)
`
`Direct evidence that those skilled in the art were well aware for many years
`
`of the increased risk of adverse events in the Prior Art Patient Populations and
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`nevertheless did not predict an increased risk of adverse events in the Claimed Patient
`
`Population.
`
`a. The record includes declaration testimony (including the declaration of
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`Dr. Wessel, senior author of the Atz & Wessel reference relied on extensively by the Examiner)
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`that, immediately prior to Appellants' invention, three leading experts in inhaled nitric oxide
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`8 Final Office Action at 9.
`9 See generally Final Office Action (entirely failing to address (a) Appellant's evidence of why experts in the field
`did not expect increased risk to the Claimed Patient Population and (b) physical attributes of the Prior Art Patient
`Populations that might provide a clue that the Claimed Patient Population would be adversely affected by inhaled
`nitric oxide).
`I° See, e.g., Declaration of Douglas A. Greene, M.D. under 37 C.F.R. § 1.132, dated July 7, 2011 ("Second Greene
`Dec."), imj 8-9, 22, 25, 27. The Second Greene Dec. was originally submitted with the July 8, 2011 Reply. A copy
`of the Second Greene Dec. is enclosed in the Evidence Appendix (ix) as Exhibit 7.
`
`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`6
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`

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`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No, : 12/820,866
`Filed (cid:9)
`June 22, 2010
`: 7 of 56
`Page (cid:9)
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`Attorney's Docket No.: 26047-0003002
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`therapy designed a study protocol that was reviewed and approved by 18 Institutional Review
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`Boards and Independent Ethics Committees composed of over 100 specialists at leading medical
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`institutions in the United States and Europe." Not one of these experts or other experienced
`
`specialists predicted the increased risk of adverse events in the Claimed Patient Population that
`
`the Examiner, with 20-20 hindsight, now concludes should have been obvious to those
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`practitioners.12 As pointed out by Dr. Wessel in his declaration, it is ironic that his own Atz &
`
`Wessel reference is so heavily relied on by the Examiner to suggest the obviousness of an
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`increased risk of adverse events in the Claimed Patient Population when he himself, the
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`publication's senior author, failed to anticipate or predict this increased risk.13 Notably, the
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`Examiner does not dispute the historical facts described above and does not cite any evidence
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`tending to contradict the conclusion that, in the real world prior to Appellant's invention, actual
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`practitioners who routinely administered inhaled nitric oxide to actual neonates in need thereof
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`did not consider the Claimed Patient Population to be at increased risk of adverse events.
`
`b. (cid:9)
`
`The record includes direct evidence that, prior to Appellant's invention,
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`experts at the U.S. Food and Drug Administration (FDA) and a number of other national Health
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`Authorities outside the United States had multiple separate opportunities to consider the question
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`of whether inhaled nitric oxide should be withheld from the Claimed Patient Population, and
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`each time did not reach that conclusion.14 Only after Appellant's invention did FDA require an
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`amendment to the label for inhaled nitric oxide warning about the potential for increased adverse
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`events in patients with LVD.15 Again, the Examiner does not dispute these historical facts, and
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`does not cite or rely on any evidence tending to contradict the conclusion that the regulatory
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`11 Wessel Dec. ¶ 8; See also the Declaration of James S. Baldassarre, M.D. under 37 C.F.R. § 1.132, dated July 7,
`2011 ("Second Baldassarre Dec."), ¶ 11. The Second Baldassarre Dec. was originally submitted with the July 8,
`2011 Reply and is enclosed in the Evidence Appendix (ix) as Exhibit 8.
`12 Second Baldassarre Dec. ¶ 8.
`13 Wessel Dec. ¶ 8.
`14 See, e.g., Second Baldassarre Dec. ¶ 8-11. See also
`littp://www.fda.gov/drugs/resourcesforyou/consumershicin I 43534.htm ("Most drugs that undergo preclinical
`(animal) testing never even make it to human testing and review by the FDA. The drugs that do must undergo the
`agency's rigorous evaluation process, which scrutinizes everything about the drug--from the design of clinical trials
`to the severity of side effects to the conditions under which the drug is manufactured.").
`15 Declaration of James S. Baldassarre, M.D. under 37 C.F.R. § 1.132, dated Sept. 29, 2010 ("First Baldassarre
`Dec.") 1116. The First Baldassarre Dec. was originally submitted with the October 1, 2010 Reply and is included in
`the Evidence Appendix (ix) as Exhibit 9.
`
`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
`
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`

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`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`Filed (cid:9)
`: June 22, 2010
`Page (cid:9)
`: 8 of 56
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`Attorney's Docket No.: 26047-0003002
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`agencies actually charged with ensuring the public's safety did not consider the Claimed Patient
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`Population to be at increased risk of adverse events before Appellant's invention.
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`2. (cid:9)
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`Direct evidence that the etiology and pathophysiology of the Claimed Patient
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`Population is clinically differentiated from the Prior Art Patient Populations so that it
`
`would not have been obvious to expect adverse events in the Claimed Patient Population in
`
`view of risks in the Prior Art Patient Populations.
`
`a.
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`The record includes declaration testimony that the physiological reason
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`that inhaled nitric oxide is dangerous for the first Prior Art Patient Population (i.e., neonates with
`
`LVD who are dependent on right-to-left shunting of blood) is that these neonates have a
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`combination of cardiac anomalies that leaves their systemic circulation utterly dependent on a
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`right-to-left flow of blood through a patent (open) ductus arteriosus; inhaled nitric oxide, by
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`diverting blood to the lungs at the expense of the ductus arteriosus, can precipitate collapse of the
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`systemic circulation and death in this particular population.I6 This issue of systemic circulatory
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`collapse is wholly inapplicable to the Claimed Patient Population since, by definition, the latter
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`patients are not dependent on right-to-left shunting of blood.I7 Accordingly, the known risk of
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`adverse events in neonates dependent on right-to-left shunting of blood through a patent ductus
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`arteriosus would not cause one to predict similar adverse events in the Claimed Patient
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`Population.18 The Examiner does not address these scientific facts and does not cite or rely on
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`any evidence tending to contradict the conclusion that adverse events from inhaled nitric oxide in
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`neonates dependent on right-to-left shunting of blood would be considered by those skilled in the
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`art to be irrelevant to the Claimed Patient Population.
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`b.
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`The record includes declaration testimony that LVD in the second Prior
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`Art Patient Population (i.e., adults with LVD) results primarily from diastolic dysfunction
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`caused by a stiff, non-compliant heart that cannot fill properly.19 This pathology is entirely
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`different than that of neonates with LVD, who suffer primarily from systolic dysfunction
`resulting from a soft, flabby heart that cannot push blood out.20
`
`The record further includes
`
`16 First Greene Dec. In 13-14.
`17 d . 111113-16.
`18 Id. ¶ 20.
`19 Id. ¶115-16.
`20 Id.
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`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
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`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`: June 22, 2010
`Filed (cid:9)
`Page (cid:9)
`: 9 of 56
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`Attorney's Docket No.: 26047-0003002
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`express declaration testimony that, in light of these pathological differences, "the hemodynamic
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`responses to pulmonary vasodilation by inhaled NO in children or neonates . . cannot be
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`reasonably predicted from the hemodynamic responses to pulmonary vasodilation by inhaled NO
`of adults . . .)521 Again, the Examiner does not address these scientific facts and does not cite
`or rely on any 'evidence tending to contradict the conclusion that adverse events from inhaled
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`nitric oxide in this Prior Art Patient Population would not suggest to those skilled in the art
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`anything relevant with respect to the Claimed Patient Population.
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`Unlike most cases considered by this Board, the record of this case includes an
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`overwhelming volume of highly pertinent factual evidence establishing that persons skilled in the
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`art did not consider the claimed subject matter to be obvious at the time of Appellant's
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`invention.22 In fact, the factual evidence contains evidence that leading experts considered this a
`startling discovery.23 Further, the record includes declaration evidence explaining in detail the
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`etiological and pathophysiological mechanisms underlying the conditions of the Prior Art Patient
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`Populations and why those conditions fail to suggest an increased risk of adverse events in the
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`Claimed Patient Population.24 In response, the Examiner cites no countervailing evidence and
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`provides no alternative explanation that even attempts to establish any sort of etiological or
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`pathophysiological link between the Claimed Patient Population and the Prior Art Patient
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`Populations. It is not appropriate for the Examiner to substitute his own personal opinion
`
`without any evidence to the contrary. Accordingly, the rejection of the present claims under
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`35 U.S.C. § 103 for obviousness should be reversed.
`
`21 Second Greene Dec. ¶ 22.
`22 See, e.g., Wessel Dec. ¶ 6; First Baldassarre Dec. ¶ 11; First Greene Dec. ¶ 17,
`23 Wessel Dec. ¶ 9 ("it was unanticipated and surprising that children with left ventricular dysfunction who are not
`dependent on right-to-left shunting would be at increased risk"); First Greene Dec. ¶ 21 ("Surprisingly and
`unexpectedly, severe adverse events...were noted during the early phase of the study, and the study was stopped.");
`Second Baldassarre Dec. 1112 ("unexpected serious adverse events (including at least one death) occurred during the
`course of the...study" and "the study protocol was amended").
`24 Second Greene Dec. ¶ 22.
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`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
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`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`Filed (cid:9)
`: June 22, 2010
`: 10 of 56
`Page (cid:9)
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`B. Background
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`1.
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`Inhaled Nitric Oxide
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`Attorney's Docket No.: 26047-0003002
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`Inhaled nitric oxide is a pulmonary-specific vasodilator that has been
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`administered for more than a decade to a total of over 300,000 critically ill patients at hospitals
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`around the world to alleviate what can be life-threatening pulmonary hypertension in neonates
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`and other patients.25 Nitric oxide for inhalation was approved by FDA in December 1999, and is
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`marketed under the trademark INOmax8.26 INOmax® is FDA-approved for term and near-term
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`neonates (defined as >34 weeks gestation) with hypoxic respiratory failure associated with
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`clinical or echocardiographic evidence of pulmonary hypertension, where it improves
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`oxygenation and reduces the need for extracorporeal membrane oxygenation (ECMO).27
`
`2.
`
`The INOT22 Study
`
`Beginning in 2004, INO Therapeutics LLC ("INOT") sponsored a clinical trial
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`formally entitled "Comparison of Supplemental Oxygen and Nitric Oxide for Inhalation Plus
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`Oxygen in the Evaluation of the Reactivity of the Pulmonary Vasculature During Acute
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`Pulmonary Vasodilatory Testing"28 and known as the INOT22 Study. The purpose of the study
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`was to assess the safety and effectiveness of inhaled nitric oxide as a diagnostic agent in pediatric
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`patients undergoing assessment of pulmonary hypertension (primary objective), and to confirm
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`the hypothesis that inhaled nitric oxide is selective for the pulmonary vasculature (secondary
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`objective).29
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`As described in the First Baldassarre Declaration, "the INOT22 Study was an
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`open, prospective, randomized, multi-center, controlled diagnostic trial, with an expected total
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`enrollment of a minimum of 150 patients, in approximately 18 study sites in the US and Europe
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`over approximately 2 years."3° "The expected patient population for enrollment into the INOT22
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`Study were subjects between the ages of 4 weeks and 18 years with idiopathic pulmonary arterial
`
`25 First Greene Dec. ¶ 8; CritiCally caring about CritiCal Care, httn://www.slideshare.net/changezkn/critically-
`caring-about-critical-care (last visited Sep. 20, 2011).
`26 INOmax, http://inomax.com/about-ikaria (last visited Sep. 20, 2011).
`27 See the "Indications" section at the top of page 2 of the 2007 INOmax® insert.
`28 First Baldassarre Dec. ¶ 4.
`29 First Greene Dec. ¶ 18.
`39 First Baldassarre Dec. ¶ 5.
`
`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`10
`
`

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`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`Filed (cid:9)
`: June 22, 2010
`Page (cid:9)
`: 11 of 56
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`Attorney's Docket No.: 26047-0003002
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`hypertension, congenital heart disease with pulmonary hypertension and cardiomyopathies, and
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`who were undergoing diagnostic right heart catheterization scheduled to include pulmonary
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`vasodilation testing to assess pulmonary vasoreactivity."31
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`The INOT22 Study was designed by the study sponsor, INOT, and a Steering
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`Committee made up of internationally recognized experts in the field of pediatric heart and lung
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`disease.32
`
`The Steering Committee consisted of:
`
`a. David L. Wessel, MD, presently Division Chief, Pediatric Critical Care
`Medicine at Children's National Medical Center, Washington, DC;
`b. Robyn J. Barst, MD, presently Professor Emeritus of Pediatrics and
`Medicine, Columbia University College of Physicians and Surgeons, New
`York; and
`c. Duncan J. Macrae, MD, presently Director, Pediatric Intensive Care, Royal
`Brompton Hospital, London, U.K.33
`
`The original exclusion criteria for the INOT22 Study did not exclude patients in
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`the Claimed Patient Population (i.e., patents with pre-existing left ventricular dysfunction who
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`are not dependent on right-to-left shunting of blood).34 In particular, the original INOT22 Study
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`protocol contained the following inclusion and exclusion criteria:
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`Inclusion Criteria
`The patient must meet the following criteria:
`I. Have any one of the three disease categories:
`a. Idiopathic Pulmonary Arterial Hypertension
`i. PAPm >25mmHg at rest, PCWP < 15mmHg,
`and PM > 3 u.,n2 or diagnosed clinically with no previous
`catheterization
`b. CHD [Congenital Heart Disease] with pulmonary
`hypertension repaired and unrepaired,
`i. PAPm >25mmHg at rest, and PVRI > 3 u.m2
`or diagnosed clinically with no previous catheterization
`c. Cardiomyopathy
`
`31 Id.T6.
`
`33 Id. If 8.
`341d ¶11.
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`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`11
`
`

`

`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`Filed (cid:9)
`: June 22, 2010
`: 12 of 56
`Page (cid:9)
`
`Attorney's Docket No.: 26047-0003002
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`i. PAPm >25mmHg at rest, and PVRI > 3 umr2
`or diagnosed clinically with no previous catheterization
`2. Scheduled to undergo right heart catheterization to assess
`pulmonary vasoreactivity by acute pulmonary vasodilation
`testing.
`3. Males or females, ages 4 weeks to 18 years, inclusive.
`4. Signed IRB/IEC approved informed consent (and assent if
`applicable).
`
`Exclusion Criteria
`The patient will be excluded from enrollment f any of the
`following are true:
`I. Focal pulmonary infiltrates on chest radiograph.
`2. Diagnosed with severe obstructive or restrictive pulmonary
`disease that is significantly contributing to the patient's
`pulmonary hypertension.
`3. Received treatment with nitric oxide for inhalation within 30
`days prior to study initiation, are on other investigational
`medications, nitroglycerin, sodium nitroprusside, sildenafil,
`other PDE-5 inhibitors, or prostacyclin.
`4. Pregnant (urine HCG
`
`The original INOT22 investigational plan and study protocol were reviewed and
`approved by the Institutional Review Board (IRB) and/or Independent Ethics Committee (IEC)
`at each of the 18 participating study institutions, including review by the principal investigator
`within each study institution.36 The original study protocol was also reviewed by experts at FDA
`and each National Health Authority (European equivalent to FDA) within the four European
`countries participating in the INOT22 Study: United Kingdom, France, Netherlands, and Spain.37
`In addition, INOT regularly requested input and scientific guidance on clinical trials, such as the
`INOT22 Study, from its own Scientific Advisory Board (SAB).38
`At no time did the study sponsor, any of the experts on the Steering Committee,
`any of the principal investigators, any of the IRBs, any of the IECs, any of the SAB members,
`
`35 Id, ¶ 9.
`" Id, ¶ 10.
`37 Second Greene Dec. ¶ 26.
`38 Second Baldassarre Dec. 118.
`
`IKARIA EXHIBIT 2013
`Praxair v. INO Therapeutics
`IPR2015-00525
`
`12
`
`

`

`Applicant : James S. Baldassarre et al. (cid:9)
`Serial No. : 12/820,866
`: June 22, 2010
`Filed (cid:9)
`Page (cid:9)
`: 13 of 56
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`Attorney's Docket No.: 26047-0003002
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`any of the FDA experts, or any of the European Health Authority experts (altogether estimated to
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`total at least 115 medical professionals) suggest that the exclusion criteria for the INOT22 Study
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`protocol be amended to exclude the Claimed Patient Population.39 In other words, of the
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`estimated 115+ medical professionals tasked with the duty to consider potential safety
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`issues for INOT22 Study patients, none—not a single one—suggested there was a chance
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`that inhaled nitric oxide might increase the likelihood of adverse events in the Claimed
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`Patient Population 4°
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`Upon administration of inhaled nitric oxide to the first 24 subjects enrolled in
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`INOT22, five serious adverse events were recorded — a rate much higher than expected based on
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`prior clinical experience with inhaled nitric oxide. Each of these five serious adverse events
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`(SAEs) was a cardiovascular event, such as pulmonary edema, cardiac arrest or hypotension (low
`
`blood pressure).4I
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`In February 2005, INOT and the Steering Committee convened to review the
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`unexpected SAEs described above, and upon review and discussion, submitted a protocol
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`amendment to FDA to thereafter exclude subjects from enrollment if they demonstrated an
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`elevated pulmonary capillary wedge pressure (PCWP), defined within the study as subjects
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`having a PCWP greater than 20 mmHg, a symptom of LVD. All study sites were notified
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`immediately.42
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`After conclusion of the study, analysis of the data revealed that modification of
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`the exclusion criteria significantly reduced the rate of serious adverse events (including serious
`
`adverse events associated with heart failure). This analysis demonstrated that there were 5 SAEs
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`among the first 24 subjects (i.e., those enrolled prior to amendment of the exclusion criteria), but
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`only 2 SAEs among the next 80 subjects in the study (i.e., enrolled after amendment of the
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`exclusion criteria). Further analysis of the data showed that a total of four subjects had pre-
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`existing LVD, and of these four, 50% experienced SAEs. Of the 120 subj