Filed on behalf of: INO Therapeutics, LLC
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`Entered: November 5, 2015
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`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
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`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`PRAXAIR DISTRIBUTION, INC.
`Petitioner
`
`v.
`
`INO THERAPEUTICS LLC,
`Patent Owner
`_______________________
`
`Case IPR2015-00529
`U.S. Patent No. 8,846,112 B2
`_______________________
`
`Before LORA M. GREEN, TINA E. HULSE, and
`ROBERT A. POLLOCK, Administrative Patent Judges.
`
`
`
`PATENT OWNER INO THERAPEUTICS LLC’S RESPONSE TO
`PRAXAIR DISTRIBUTION INC’S PETITION FOR INTER PARTES
`REVIEW OF U.S. PATENT NO. 8,846,112
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`
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`

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`Case IPR2015-00529
`U.S. Patent No. 8,849,112
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`TABLE OF CONTENTS
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`
`I.
`
`II.
`
`Introduction ...................................................................................................... 1
`
`The ’112 Patent Claims Novel Methods For Providing iNO To
`Physicians For the Safe Administration To Neonates ..................................... 5
`
`A.
`
`The Development of the ’112 Patent .................................................... 5
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`1.
`
`2.
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`3.
`
`The Prior Use of iNO in Neonates Suffering From
`Hypoxic Respiratory Failure Only Excluded
`Neonates Dependent on Right-to-Left Shunting,
`Not Those With Preexisting LVD .............................................. 6
`
`The Original INOT22 Study Protocol Did Not
`Exclude Neonates with Non-RTL-Dependent LVD ................... 9
`
`Unanticipated SAEs Occurred During the INOT22
`Study, the Study Was Amended, and the Rate of
`SAEs Was Significantly Reduced ............................................. 11
`
`B.
`
`The ’112 Patent Prosecution History .................................................. 14
`
`1.
`
`2.
`
`The PTO Considered Many References Including
`3 of the 4 References Relied Upon by Petitioner
`and Used By the Board as A Basis for Institution .................... 14
`
`Petitioner Relies on the Same Statements Patent
`Owner Overcame During Prosecution ...................................... 15
`
`III.
`
`Person Of Ordinary Skill In The Art ............................................................. 17
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`IV. Claim Construction ........................................................................................ 18
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`A.
`
`The Board Erroneously Ignored the Claim Term
`“Pharmaceutically Acceptable Nitric Oxide Gas” .............................. 18
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`1.
`
`“Pharmaceutically Acceptable Nitric Oxide Gas”
`Is a Claim Limitation ................................................................ 19
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`U.S. Patent No. 8,849,112
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`2.
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`The Ordinary Meaning of “Pharmaceutically
`Acceptable” Nitric Oxide Is That Which is
`Suitably Safe for Pharmaceutical Use ...................................... 21
`
`B.
`
`The Board Erroneously Determined that “Providing …
`Information” is Not Functionally Related to the
`Remaining Claim Limitations Including
`“Pharmaceutically Acceptable Nitric Oxide” ..................................... 23
`
`1.
`
`2.
`
`King Is Inapposite To The Subject Claims ............................... 24
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`The “Providing ... Information” Limitations Must
`be Included in the Prior Art Analysis Because
`They Bear a Functional Relationship to the Other
`Recited Claim Steps .................................................................. 27
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`C.
`
`The Board Erroneously Disregarded Certain Claim
`Elements For Lack Of Statutory Subject Matter ................................. 33
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`V.
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`The Board’s Initial Determination Fails To Meet The Required
`Test For Anticipation ..................................................................................... 35
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`A.
`
`B.
`
`C.
`
`The Board’s Initial Determination Relies on an
`Anticipation Argument Not Made by Petitioner and to
`Which Patent Owner Was Unable to Respond ................................... 36
`
`The Board’s Anticipation Finding Improperly Conflates
`Whether the Problem Solved by the Invention was
`Present in the Prior Art with Whether the Invention Itself
`was Present in the Prior Art ................................................................. 37
`
`The Board’s Initial Determination Fails to Identify the
`Presence of Every Element of the Subject Claims in a
`Single Reference .................................................................................. 38
`
`VI. The Board’s Initial Determination Fails To Meet The Required
`Test For Obviousness .................................................................................... 39
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`A.
`
`There Are No Grounds for Obviousness Considering
`When All Substantive Claim Limitations Are Considered ................. 41
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`U.S. Patent No. 8,849,112
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`1.
`
`The Board’s Initial Determination Fails to Find
`Either (a) the Identification of Neonates with LVD
`Or (b) the Exclusion of Such Patients from
`Treatment with iNO in the Prior Art ......................................... 42
`
`B.
`
`The Board’s Initial Determination Ignores the
`Overwhelming Evidence of Non-Obviousness ................................... 48
`
`1.
`
`2.
`
`Those of Ordinary Skill in the Art Would Not be
`Motivated to Combine Prior Art Teachings
`Regarding Adult Cardiovascular Patients with
`Prior Art Teachings Regarding Neonatal
`Cardiovascular Patients ............................................................. 49
`
`Numerous Experts and Others in the Field of
`Neonatal Cardiology Failed To Appreciate the
`Patented Method, Even After Conducting Many
`Clinical Studies of iNO on Pediatric Patients ........................... 53
`
`C.
`
`Petitioner Fails to Address Any of Patent Owner’s
`“Compelling” and “Persuasive” Arguments Made During
`Prosecution .......................................................................................... 56
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`VII. Objective Criteria Compel A Finding That The Subject Claims
`Of The ’112 Patent Are Not Obvious ............................................................ 58
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`VIII. Conclusion ..................................................................................................... 60
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`U.S. Patent No. 8,849,112
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`I.
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`INTRODUCTION
`The Board’s initial determination to institute inter partes review of claims 1-
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`111 of the ’112 Patent (hereinafter the “subject claims”) failed to properly construe
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`and consider the claimed inventions based on the intrinsic evidence, the unanimous
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`opinions of both parties’ experts and those of skill in the art, and the controlling
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`case law. The ’112 Patent claims methods of providing pharmaceutically
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`acceptable nitric oxide gas to physicians for the safe treatment of hypoxic
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`respiratory failure in neonates. The subject claims disclose a solution to the
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`previously unknown problem that neonates suffering from hypoxic respiratory
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`failure who also suffer from left ventricle dysfunction (“LVD”) have a high risk of
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`serious adverse events (“SAEs”) such as pulmonary edema if they are administered
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`inhaled nitric oxide (“iNO”). The claimed solution to that previously unknown
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`problem allows for the provision of iNO to physicians for its safe administration to
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`critically ill infants.
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`The Board recognized the patentability of claims to similar subject matter in
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`its denial of Petitioner’s requests to institute IPR of four related patents.2 The
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`Board’s initial determination here is erroneous for several independent reasons.
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`1 This Response does not address claims 12-19 of the ’112 Patent.
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`2 See Decision Denying Institution of Inter Partes Review of Case Nos. IPR2015-
`
`00522, -00524, -00525 and -00526 (Paper 12) (“Decision Denying Inst.”).
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`U.S. Patent No. 8,849,112
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`First, the Board’s interpretation of the subject claims was flawed. Before
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`ever interpreting the claims, the Board determined that the “providing …
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`information” steps are directed to “non-statutory subject matter,” i.e., “printed
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`matter,” that allegedly lacked a “functional relationship” to the remainder of the
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`claims. This finding ignored the phrase “pharmaceutically acceptable nitric oxide
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`gas” and what it means with regard to the “providing … information” step.
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`In addition to relying on grounds not presented in the Petition, the Board’s
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`approach ignores long-standing Federal Circuit precedent that requires analysis of
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`the claims as a whole to determine validity. Individual claim elements can be
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`construed, but not ignored or read out. Because (as the Board recognized with
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`respect to the four related patents), the subject claims as written are neither
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`anticipated nor obvious, that should have been the end of the inquiry.
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`Second,
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`the Board’s
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`initial determination
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`that
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`the “providing …
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`information” steps are not functionally related to the remainder of the subject
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`claims was flawed. Respectfully, the Board failed to consider (or, because the
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`evidence was not then available to the Board, was unable to consider) the evidence
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`that conclusively shows that the claim step reciting the provision of information (or
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`labeling as required by certain dependent claims) is fundamentally related to the
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`claimed provision of pharmaceutically acceptable nitric oxide. Specifically, the
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`Board ignored the fact that the subject claims themselves require the provision of
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`U.S. Patent No. 8,849,112
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`“pharmaceutically acceptable” nitric oxide gas, (see preambles of claims 1 and 7),
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`which both parties’ experts agree must mean suitably safe for pharmaceutical use.
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`Because the “providing ... information” steps are directed towards that end, they
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`are functionally related to the other portions of the claim and must be considered in
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`the validity analysis.
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`Third, the Board’s initial determination fails to meet the standards for
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`proving anticipation and obviousness. Anticipation requires that each and every
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`claim limitation be present in a single reference, and an appropriate obviousness
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`determination requires that each and every claim limitation be present somewhere
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`in the prior art. The Petition did not even allege anticipation, and the Board made
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`no such findings. The invention of the ’112 Patent – the discovery of a safer
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`method for supplying iNO to physicians – is not in the prior art, and the Board
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`should have denied the petition.
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`Fourth, the Board incorrectly evaluated the prior art by reaching
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`conclusions concerning the treatment of neonates from data concerning the
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`treatment of adults. The evidence shows that persons of skill in the art do not
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`consider children (and particularly infants) “small adults.” This is particularly true
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`in the cardiac area, in which no one recognized that the risks of administering iNO
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`to address pulmonary hypertension in adults with LVD caused by lifelong dietary
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`habits and poor cardiovascular health (which cause adult-specific issues) could be
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`U.S. Patent No. 8,849,112
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`extrapolated to pediatric patients with LVD arising from differing cardiac
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`physiology and etiology.
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`Fifth, the Board’s initial determination ignores overwhelming objective
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`evidence of non-obviousness. The discovery underlying the claimed inventions
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`originated from a clinical study that involved administering iNO to pediatric
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`patients, including those suffering from LVD. That study was designed by experts
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`in pediatric cardiovascular diseases and was reviewed by more than ten
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`Independent Review Boards and the FDA, all of whom were charged with ensuring
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`the safety of the participating children. None suggested excluding pediatric
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`patients suffering from LVD. To the contrary, the physicians were surprised when
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`they observed SAEs, including death, and immediately altered the inclusion
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`criteria to exclude patients suffering from LVD. Given that those of extraordinary
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`skill in the art failed to appreciate the significance of excluding LVD patients, the
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`evidence fails to show that the claimed methods would have been obvious to a
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`person of ordinary skill in the art.
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`Sixth,
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`the Board’s
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`initial determination excluding
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`limitations from
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`dependent claims 3 and 5 because they were allegedly related to mental steps was,
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`in essence, a finding of lack of patent eligible subject matter under 35 U.S.C.
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`§ 101, which is outside the scope of the Board’s authority under 35 U.S.C.
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`§ 311(b). Moreover, by denying Patent Owner its right to a preliminarily respond
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`to material issues raised for the first time in the Board’s initial determination, the
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`Board exceeded its statutory authority and denied Patent Owner due process.
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`When the subject claims of the ’112 Patent are properly construed and
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`considered as a whole, it is clear that they—like the claims of the four related
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`patents for which the Board denied institution—are neither anticipated by nor
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`obvious over the prior art.
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`II. THE ’112 PATENT CLAIMS NOVEL METHODS FOR PROVIDING
`iNO TO PHYSICIANS FOR THE SAFE ADMINISTRATION TO
`NEONATES
`A. The Development of the ’112 Patent
`U.S. Patent No. 8,846,112, entitled “Methods of Distributing a
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`Pharmaceutical Product Comprising Nitric Oxide Gas for Inhalation,” (the “’112
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`Patent”) is directed to methods of providing nitric oxide gas to a medical provider
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`responsible for treating neonates with hypoxic respiratory failure. (See, e.g., Ex.
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`1001 at 1:20-25; 1:50-2:24.) In particular, the inventions of the ’112 Patent
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`comprise methods of providing nitric oxide gas, along with information sufficient
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`to cause a medical provider considering iNO treatment to avoid treating neonates
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`with pre-existing LVD. (Id.)
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`The inventions disclosed in the ’112 Patent arose from a discovery during
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`the INOT22 clinical study (Example 1 in the ’112 Patent) which involved
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`administering INOmax® (Patent Owner’s iNO product) to pediatric patients. (Id. at
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`U.S. Patent No. 8,849,112
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`9:35-14:25.) Designed by the leading experts in the field, the INOT22 study did
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`not exclude patients with pre-existing LVD. (Id. at 9:35-10:14.) Only after
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`observing numerous SAEs did the risks of administering iNO to patients with LVD
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`become apparent, leading to the claimed methods for safely providing that drug to
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`neonates. (Id. at 9:35-14:25.)
`
`1.
`
`The Prior Use of iNO in Neonates Suffering From Hypoxic
`Respiratory Failure Only Excluded Neonates Dependent on
`Right-to-Left Shunting, Not Those With Preexisting LVD
`Patent Owner’s INOmax® product is FDA-approved for administration by
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`inhalation to term and near-term infants (known as “neonates”) suffering from
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`hypoxic respiratory failure (abnormally low levels of oxygen in the bloodstream)
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`associated with clinical or echocardiographic evidence of pulmonary hypertension
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`(high pressure in the blood vessels going to the lungs). (Ex. 2023, Current
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`INOmax® Label.) In neonates, this hypertension is known as persistent pulmonary
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`hypertension of the newborn (“PPHN”). (Ex. 2020, Rosenthal Decl. at ¶ 41.)
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`During in utero development, circulation through the lungs is largely shut
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`down because the pulmonary vessels are tightly constricted. The fetal lungs are
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`filled with fluid and the fetus obtains oxygen across the placenta. (Id. at ¶ 39.)
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`Instead of blood being pumped from the right side of the heart through the lungs
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`and returning to the left side of the heart to be pumped to the rest of the body (as is
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`the case following birth), blood from the right side of the fetal heart bypasses the
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`lungs through a blood vessel connecting the outflow of the right heart directly to
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`the systemic circulation called the patent ductus arteriosus. (Id.) When children
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`are born, the ductus arteriosus normally closes and the pulmonary vessels relax.
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`As a result, the outflow of the right side of the heart is redirected to the now
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`oxygenated, ventilated, and functional lungs, and oxygenated blood is then
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`returned to the left side of the heart to be pumped to the rest of the body from the
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`left ventricle. (Id. at ¶ 40.)
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`In some neonates suffering from PPHN the pulmonary vessels fail to
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`adequately relax, and there is insufficient gas exchange, leading to hypoxic
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`respiratory failure. (Id. at ¶ 41.) iNO relaxes the small vessels that are in close
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`proximity to the aerated parts of the lung, allowing the blood in those vessels to
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`pick up oxygen and release carbon dioxide. (Id.) This increases the effective
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`blood flow to the lungs, and reduces the need for other high-risk therapies, such as
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`aggressive ventilation, administration of oxygen concentrations associated with
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`toxicity, and removal of blood from the infant to a heart-lung bypass machine that
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`re-oxygenates the blood. (Id.)
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`In some neonates with severe congenital heart disease involving the left
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`ventricle, the left side of the heart lacks the ability to pump blood to the rest of the
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`body. (Id. at ¶ 42.) For these neonates, a ductus arteriosus that remains open is
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`actually beneficial and can be life-saving. The high pulmonary vascular resistance,
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`resulting in pulmonary hypertension creates a right-to-left shunt through the patent
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`ductus arteriosus and allows the right ventricle to take on the role of the
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`nonfunctioning left ventricle by pumping adequately oxygenated blood directly to
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`the systemic circulation. (Id. at ¶ 42.) These neonates are described as being
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`dependent upon right-to-left shunting of blood (“RTL-Dependent”).
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`In RTL-Dependent neonates, pulmonary vasoconstriction
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`(normally
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`problematic as discussed above) is actually beneficial, as it diverts blood from the
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`right ventricle through the patent ductus arteriosus for systemic circulation. (Id. at
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`¶ 43.) If the pulmonary vascular resistance drops or is lowered in an infant that is
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`RTL-Dependent, the infant will have less blood flow to the body and coronary
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`arteries, and is at very high risk of low blood pressure, low cardiac output, severe
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`acidosis, cardiogenic shock, and sudden death. (Id.) Administering iNO to these
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`neonates can therefore be catastrophic. (Id.) Thus, when the FDA first approved
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`INOmax® as safe and effective, it was contraindicated for “the treatment of
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`neonates known to be dependent on right-to-left shunting of blood.” (Ex. 1014 at
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`4; Rosenthal Decl. at ¶ 44.)
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`INOmax® was not contraindicated for any other class of neonates including
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`those with LVD, but who were not RTL-Dependent (“non-RTL-Dependent”).
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`This was consistent with the prior clinical studies submitted in support of the
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`original FDA approval of INOmax® that administered iNO to pediatric patients,
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`including neonates, which did exclude non-RTL-Dependent neonates suffering
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`from LVD. (Rosenthal Decl. at ¶ 45; Ex. 1011; Ex. 2031.)
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`2.
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`The Original INOT22 Study Protocol Did Not Exclude
`Neonates with Non-RTL-Dependent LVD
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`Beginning in 2004, Patent Owner sponsored a clinical trial known as the
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`INOT22 Study, which compared the use and side effects of oxygen, iNO, and a
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`combination of oxygen and iNO for determining pulmonary reactivity. (Ex. 1001
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`at 10:14-16.) It was a randomized, multi-center study with 18 clinical study sites.
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`(Ex. 1001 at 9:57-59; Ex. 1056 at 508.)
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`The INOT22 study was designed by a committee of “internationally
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`recognized experts” in pediatric heart and lung disease (“the INOT22 Steering
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`Committee”) and Patent Owner, the study sponsor. (Ex. 1056 at 663, ¶ 8.) The
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`INOT22 Steering Committee included: (1) David L. Wessel, M.D., Professor of
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`Anesthesiology and Critical Care Medicine and of Pediatrics at the George
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`Washington University; (2) Robyn J. Barst, M.D., Professor Emeritus of Pediatrics
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`and Medicine, Columbia University College of Physicians and Surgeons, New
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`York; and (3) Duncan J. Macrae, M.D., Director, Children’s Services, Consultant
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`in Pediatric Critical Care at the Royal Brompton Hospital, London, U.K. (Ex.
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`1056 at 663, ¶ 8; id. at 448.) Both parties’ experts agree that these three—
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`particularly Drs. Wessel and Barst—were at the forefront of pediatric cardiology,
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`and had expertise relevant to the clinical use of iNO. (Rosenthal Decl. at ¶ 29; Ex.
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`2022, Beghetti Tr. at 70:6-12; 71:23-73:5; 238:21-241:16.)
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`The INOT22 protocol was carefully reviewed by Institutional Review
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`Boards (“IRB”) and/or Independent Ethics Committees (“IEC”) at each
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`participating study institution reviewed the Original INOT22 Protocol. (Ex. 1056
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`at 446, 471, 664, ¶ 11.) Those committees include practicing physicians and others
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`whose role is “the protection of the rights and welfare of human research subjects.”
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`(Id. at 665, ¶ 12; Rosenthal Decl. at ¶ 52.)
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`The U.S. Food & Drug Administration (“FDA”) and four FDA-equivalent
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`European National Health Authorities (United Kingdom, France, Netherlands and
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`Spain) also had the opportunity to review the Original INOT22 Protocol before the
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`study began (Ex. 1056 at 664-66, ¶¶ 11-14; Rosenthal Decl. at ¶ 53), and Patent
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`Owner requested guidance on clinical trials from its own Scientific Advisory
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`Board. (Id. at 664-65, ¶ 11.) In all, more than a hundred individuals “experienced
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`in and responsible for the review of clinical trial protocols for patient safety”
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`evaluated the INOT22 Protocol before the study began. (Id. at 665-66, ¶ 14;
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`Rosenthal Decl. at ¶ 54.)
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`Consistent with the then-current INOmax® label, only RTL-Dependent
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`patients were excluded from the INOT22 Protocol. (Ex. 1014 at 4; Rosenthal
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`Decl. at ¶ 44.) Notwithstanding design and review by the “best and brightest” in
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`their field, the INOT22 Protocol did not exclude pediatric patients with other types
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`of pre-existing LVD. (Ex. 1001 at 9:59-66; Ex. 1056 at 397-98; Rosenthal Decl. at
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`¶ 58.)
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`In other words, of the estimated 115+ medical professionals (including
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`IRBs, IECs, individual investigators, the FDA and European health authorities, and
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`the Patent Owners Scientific Advisory Board) who considered the safety of the
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`INOT22 Study patients, not one suggested there was a chance that iNO might
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`increase the likelihood of adverse events in pediatric patients with non-RTL-
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`Dependent LVD. (Ex. 2024 at 794-95; Rosenthal Decl. at ¶ 58.)
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`3.
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`Unanticipated SAEs Occurred During the INOT22 Study,
`the Study Was Amended, and the Rate of SAEs Was
`Significantly Reduced
`
`Despite the review by these renowned experts in the field, five SAEs were
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`observed in the first 24 subjects enrolled in the INOT22 study, a rate much higher
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`than the INOT22 Steering Committee and Patent Owner expected. (Ex. 1001 at
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`12:49-13:25; Ex. 1056 at 666, ¶ 15; Rosenthal Decl. at ¶ 59.) The SAEs were all
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`cardiovascular events, and included pulmonary edema (accumulation of fluid in the
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`lungs), cardiac arrest and hypotension (low blood pressure), and one child who
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`developed pulmonary edema died. (Id.)
`
`Some of the “patients suffering [SAEs] had severe [LVD], largely due to
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`viral
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`cardiomyopathy,
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`and
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`exhibited during
`
`their
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`right-sided
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`cardiac
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`catheterizations an increased pulmonary capillary wedge pressure (‘PCWP’) of
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`greater than 20 mm Hg, indicative of elevated pressures in the upper chamber of
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`the left side of the heart (the left atrium).” (Ex. 2024 at 1082, ¶ 21.) From these
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`results, the inventors “recognized that a second population of neonates existed . . .
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`that had an increased risk of adverse events when inhaled NO was administered,
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`namely: pediatric patients with left ventricular dysfunction . . . .” (Id. at 1145,
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`¶ 11; Rosenthal Decl. at ¶ 60.)
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`After these unexpected SAEs, the INOT22 study protocol was amended to
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`exclude patients with pre-existing non-RTL-Dependent LVD, i.e., those having a
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`PCWP greater than 20 mm Hg. (Ex. 1056 at 666, ¶¶ 15, 16; Ex. 1001 at 12:47-61;
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`Rosenthal Decl. at ¶ 61.) Following that change, “the rate of SAEs (including
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`SAEs associated with heart failure) was significantly reduced.” (Ex. 1056 at 667,
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`¶ 17; Rosenthal Decl. at ¶ 62.) While five SAEs were reported in the first 24
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`patients of the study, only two SAEs were reported in the last 100 patients after the
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`protocol was amended. (Ex. 1056 at 667, ¶ 17; Rosenthal Decl. at ¶ 62.)3
`
`
`3 This change in protocol therefore reduced the risk of patients experiencing a SAE
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`from 21% to 2%—a tenfold reduction in risk. Observing a difference this great or
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`greater, under a null hypothesis of no difference in SAE after the protocol
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`modification, is extremely unlikely (3 chances in 1,000, Fisher’s Exact p-value of
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`12
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`Given the difference in the pre- and post-protocol amendment SAE rates, on
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`February 25, 2009, Patent Owner submitted a change to the INOmax® label which
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`included a warning that the use of iNO in patients with pre-existing LVD could
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`cause SAEs, such as pulmonary edema. FDA approved the labeling change on
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`August 28, 2009. (Ex. 1056 at 667-68, ¶18; Ex. 1014, 2000 INOmax® Label;
`
`Rosenthal Decl. at ¶ 65.)
`
`Dr. David Wessel, chair of the INOT22 Steering Committee, stated that “[a]t
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`the time of the design of the INOT22 Study protocol, neither [he], the other
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`Steering Committee members, nor the study Sponsor appreciated or anticipated
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`that a child with left ventricular dysfunction who is not dependent on right-to-left
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`shunting of blood would be at additional risk when treated with [iNO]. This is the
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`reason such children were not originally excluded from the INOT22 Study entry
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`criteria.” (Ex. 2024 at 1099, ¶ 6.) Had the adverse events been obvious, Dr.
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`Wessel would have had to have “act[ed] either negligently or intentionally to harm
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`babies, and [he] most certainly [did] not.” (Id. at 1100, ¶ 8.)
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`The same applies to the “at least 115 individuals experienced in and
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`responsible for the review of clinical trial protocols for patient safety,” as well as
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`the FDA and four European Health Authorities that reviewed the original INOT22
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`0.003). (Rosenthal Decl. at ¶ 63.)
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`U.S. Patent No. 8,849,112
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`protocol. (Ex. 1056 at 665-66, ¶ 14.) None raised even a concern about increased
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`risk of using iNO in children with LVD who were non-RTL-Dependent. (Id. at
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`667, ¶ 17; Rosenthal Decl. at ¶ 56.) As inventor Dr. Baldassarre stated, prior to
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`initiation of the INOT22 Study, it defied “common sense to any expert in this
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`field” to not utilize iNO with this patient population. (Ex. 2024 at 532, ¶ 11.)
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`The ’112 Patent Prosecution History
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`B.
`Based on the surprising discovery that safe administration of iNO requires
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`excluding neonates with non-RTL-Dependent LVD, on June 30, 2009, Patent
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`Owner filed U.S. Patent Application No. 12/494,598, which issued as the ’112
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`Patent from a division of Application No. 13/683,236. (Ex. 1001 at 1:9-17.)
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`1.
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`The PTO Considered Many References Including 3 of the 4
`References Relied Upon by Petitioner and Used By the
`Board as A Basis for Institution
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`The Examiner extensively reviewed the ’112 Patent, considering 200
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`references and specifically addressing ten, before allowing the claims. (Ex. 1056
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`at 228-81, 329-43, 695-728, 773-74.) During the prosecution of the ’112 Patent
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`and its priority application, the Examiner specifically addressed Bernasconi (Ex.
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`1004), Loh (Ex. 1006), and the 2000 INOmax® label (Ex. 1014), three of the four
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`references on which the Petitioner and Board relied as a basis for institution. (Ex.
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`1056 at 332-333, 698, 709; Rosenthal Decl. at ¶ 70.) The fourth reference
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`presented in the Petition, Goyal (Ex. 1007), relates to a different drug
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`(nitroglycerin) and Petitioner’s expert relied on Goyal only for its teaching that
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`wedge pressure could be measured in children from 8 to 54 months. (Ex. 2022 at
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`227:12-21.)
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`2.
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`Petitioner Relies on the Same Statements Patent Owner
`Overcame During Prosecution
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`In finding the ’112 Patent claims patentable, the Examiner considered the
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`same evidence regarding use of iNO upon which Petitioner now relies. For
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`example, the Examiner stated: (1) Bernasconi “warn[s] of the negative effects of
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`[iNO] in patients with [LVD] leading to pulmonary edema,” and (2) Loh teaches
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`that “[iNO] in patients with LVD can increase [PCWP]” and “more severe [LVD]
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`was present in the patients who had the largest increases in [PCWP] with [iNO].”
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`(Ex. 1056 at 696-99.) From these references, the Examiner initially concluded (as
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`Petitioner now argues) that it is “obvious to teach/warn/instruct the artisan
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`administering iNO therapy that [iNO] may/could increase PCWP leading to a
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`potential risk of pulmonary edema,” and it is “simply common sense” that “the
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`treatment with [iNO] should be discontinued,” “if pulmonary edema occurs in a
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`patient who has pre-existing [LVD] and is treated with [iNO].” (Id. at 705, 707.)
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`During prosecution of the ’112 Patent and related applications, Patent Owner
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`submitted declarations from renowned expert in pediatric cardiology and co-
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`designer of the INOT22 study Dr. David L. Wessel; inventor and Vice President of
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`Case IPR2015-00529
`U.S. Patent No. 8,849,112
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`Clinical Research at Ikaria, Inc., Dr. James S. Baldassarre; and Executive Vice
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`President and Chief Scientific Officer at Ikaria, Inc. Dr. Douglas A. Greene. (Ex.
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`2024 at 1098-1100; Ex. 1056 at 647-52, 661-68.) They demonstrated that the
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`claimed inventions came not from a person of ordinary skill in the art applying
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`“common sense” to solve a problem, but instead represented a radical departure
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`from
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`the conventional application of “common sense”
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`that
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`iNO could
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`appropriately be provided to neonates with non-RTL-Dependent LVD.
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`The Examiner’s rejections were based on warnings about the risks of iNO
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`regarding either: (1) the administration of iNO to adults, or (2) the administration
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`of iNO to RTL-Dependent pediatric patients. (Ex. 1056 at 696-99.) As Dr. Greene
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`explained, these warnings related to patient populations distinct from the claimed
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`excluded group. (Id. at 650-51, ¶¶ 12-13; see also Rosenthal Decl. at ¶ 78.)
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`Dr. Greene explained that LVD in neonates is “drastically different” than
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`LVD in adults, starting with different causes due to the differing structure of the
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`adult and neonate hearts. (Ex. 1056 at 650-51, ¶¶ 12-13; see also Rosenthal Decl.
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`at ¶ 78.) For adults, LVD “is generally ischemic or hypertensive in origin, and is
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`associated with a stiff, non-compliant left ventricle that cannot fill properly
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`(‘diastolic dysfunction’).” In contrast, “[i]n children, [LVD] is generally not
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`ischemic or hypertensive.” Thus, “adult [LVD], but not childhood [LVD], would
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`lead to pulmonary vascular engorgement, requiring caution in the use of [iNO].”
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`(Ex. 1056 at 650-51, ¶¶ 12-13; see also Rosenthal Decl. at ¶ 79.) Dr. Greene also
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`explained that “[t]he underlying etiologies and hemodynamic characteristics of
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`both the primary heart disease and the increased pulmonary vascular resistance are
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`drastically different in adults, as compared to non-adults, such that one cannot
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`readily assume clinical results observed in adults will translate to neonates or
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`children.” (Ex. 1056 at 651, ¶ 13; see also Rosenthal Decl. at ¶ 80.) In the related
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`’966 Patent prosecution, the same Examiner agreed that LVD in neonates differs
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`from adults, and that, “data from adults cannot generally be extrapolated for
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`children.” (Ex. 2014 at 4, citing Ex. 2006 at 2.)
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`Incredibly, Petitioner’s expert Dr. Beghetti admitted that he did not review
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`any part of the ’112 Patent’s file history (or those of the four related patents)
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`before submitting his Declaration. (Ex. 2022 at 30:19-24.) When preparing for his
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`deposition, Dr. Beghetti reviewed only those sections of the ’11