Filed on behalf of: Mallinckrodt Hosp. Prods. IP Ltd.
`
`Entered: June 6, 2016
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`_______________________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`_______________________
`
`PRAXAIR DISTRIBUTION, INC. AND NOxBOX LIMITED,
`Petitioner
`
`v.
`
`MALLINCKRODT HOSPITAL PRODUCTS IP LTD.,
`Patent Owner
`_______________________
`
`Case IPR2016-00781
`U.S. Patent No. 8,846,112
`_______________________
`
`Before STEVEN AMITRANI, Trial Paralegal.
`
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`
`

`
`Case IPR2016-00781
`U.S. Patent No. 8,846,112
`
`TABLE OF CONTENTS
`
`I.
`
`
`II.
`
`
`Introduction ...................................................................................................... 1
`
`The ’112 Patent Claims Novel Methods for Providing
`Pharmaceutically Acceptable Nitric Oxide to Physicians for the Safe
`Administration to Neonates ............................................................................. 3
`
`A.
`
`The Development of the ’112 Patent .................................................... 3
`
`1.
`
`2.
`
`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 ......................................................................... 4
`
`The Original INOT22 Study Protocol Did Not Exclude
`Neonates with Non-RTL-Dependent LVD ................................. 8
`
`Unanticipated SAEs Occurred During the INOT22 Study,
`the Study Was Amended, and the Rate of SAEs Was
`Significantly Reduced ............................................................... 10
`
`B.
`
`The ’112 Patent Prosecution History .................................................. 13
`
`III.
`
`
`Person of Ordinary Skill in the Art ................................................................ 14
`
`IV.
`
` Claim Construction ........................................................................................ 14
`
`V.
`
`
`
`Petitioner Is Estopped From Requesting Inter Partes Review Under
`35 U.S.C. § 315(e)(1) .................................................................................... 15
`
`A.
`
`B.
`
`Petitioner Reasonably Could Have Raised The Proposed
`Grounds Including Greenough and Jaypee in its First IPR
`Petition ................................................................................................. 16
`
`The Petitioner and Real Parties-in-Interest From The -00529
`IPR Also Filed This Petition, and They Will Soon Be Barred
`From Requesting or Maintaining This Proceeding. ............................ 20
`
`VI.
`
` The Board Should Exercise its Discretion and Deny This Petition
`Under 35 U.S.C. § 325(d) .............................................................................. 21
`
`i
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`

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`Case IPR2016-00781
`U.S. Patent No. 8,846,112
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`A.
`
`B.
`
`C.
`
`The Board Should Deny Institution Because Petitioner Was
`Aware, or Should Have Been Aware, of the Allegedly New
`References Cited in the Instant Petition .............................................. 24
`
`The Board Should Deny Institution Because Petitioner
`Advances the Same or Substantially the Same Prior Art and
`Arguments As the First Petition .......................................................... 26
`
`The Board Should Deny Institution Because Petitioner Delayed
`in Filing the Present Petition and Unfairly Benefited from the
`Proceedings in the First IPR ................................................................ 31
`
` The Petition Fails to Show a Reasonable Likelihood that the Petitioner VII.
`
`
`Will Prevail with respect to the Challenged Claims ...................................... 37
`
`A. A POSA Would Not Have Relied Upon the Disclosure of
`Greenough ........................................................................................... 38
`
`1.
`
`2.
`
`3.
`
`4.
`
`A POSA Would Have Rejected the Statements in
`Greenough In Favor of the Instructions in the Label ................ 39
`
`A POSA Would Have Rejected the Statements in
`Greenough As Conclusory and Unsupported ........................... 40
`
`A POSA Would Have Rejected the Statements in
`Greenough As Inherently Contradictory ................................... 41
`
`A POSA Would Have Disregarded the Statements in
`Greenough As Inconsistent with the Body of Dr.
`Greenough’s Work .................................................................... 45
`
`B.
`
`C.
`
`D.
`
`E.
`
`A POSA Would Not Have Relied Upon the Disclosure in
`Jaypee .................................................................................................. 46
`
`Petitioner Misreads and Misrepresents the Disclosure of the
`Prior Art to a POSA............................................................................. 49
`
`Petitioner Continues to Ignore the Overwhelming Evidence of
`Non-Obviousness ................................................................................ 52
`
`Petitioner’s Expert Declaration Should be Afforded Minimal
`Weight ................................................................................................. 54
`
`ii
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`Case IPR2016-00781
`U.S. Patent No. 8,846,112
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`1.
`
`2.
`
`Dr. Lawson Does Not Meet the Level of Ordinary Skill
`in the Art Proposed by Petitioner .............................................. 55
`
`Dr. Lawson’s Testimony Should Be Given Minimal
`Weight Because it Does Not Represent Dr. Lawson’s
`Own Analysis ............................................................................ 58
`
`
`
` Conclusion ..................................................................................................... 61 VIII.
`
`iii
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`

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`Case IPR2016-00781
`U.S. Patent No. 8,846,112
`
`
`
`TABLE OF AUTHORITIES
`
`CASES
`Arista Networks, Inc. v. Cisco Sys., Inc.,
`No. IPR2015-01710 (P.T.A.B. Feb. 16, 2016), Paper 7 ...................................... 25
`
`Page(s)
`
`Avanir Pharm., Inc. v. Actavis S. Atl. LLC,
`36 F. Supp. 3d 475 (D. Del. 2014) ....................................................................... 38
`
`Butamax Advanced Biofuels LLC v. Gevo, Inc.,
`No. IPR2014-00581 (P.T.A.B. Oct. 14, 2014), Paper 8 ............................... 23, 32
`
`Conopco, Inc. dba Unilever v. Procter & Gamble Co.,
`No. IPR2014-00507 (P.T.A.B. July 7, 2014), Paper 17 ...................................... 22
`
`Conopco, Inc. dba Unilever v. Procter & Gamble Co.,
`No. IPR2014-00628 (P.T.A.B. Oct. 20, 2014), Paper 21 ............................. 25, 27
`
`CustomPlay, LLC v. ClearPlay, Inc.,
`No. IPR2014-00783 (P.T.A.B. Nov. 7, 2014), Paper 9 ....................................... 32
`
`Daiichi Sankyo Co. v. Apotex, Inc.,
`501 F.3d 1254 (Fed. Cir. 2007) ........................................................................... 57
`
`In re Jackson Nat’l Life Ins. Co. Premium Litig.,
`No. 96-MD-1122, 2000 WL 33654070 (W.D. Mich. Feb. 8, 2000) ................... 58
`
`In re NTP, Inc.,
`654 F.3d 1279 (Fed. Cir. 2011) ........................................................................... 16
`
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`No. IPR2013-00324 (P.T.A.B. Nov. 21, 2013), Paper 19 ........................... passim
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ........................................................................... 54
`
`Medtronic, Inc. v. Nuvasive, Inc.,
`No. IPR2014-00487 (P.T.A.B. Sept. 11, 2014), Paper 8 .............................. 22, 26
`
`Medtronic, Inc. v. Robert Bosch Healthcare Sys., Inc.,
`No. IPR2014-00436 (P.T.A.B. June 19, 2014), Paper 17 ............................ 26, 37
`
`iv
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`Case IPR2016-00781
`U.S. Patent No. 8,846,112
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`NetApp Inc. v. Crossroads Sys., Inc.,
`No. IPR2015-00772 (P.T.A.B. Sept. 3, 2015), Paper 12 ..................................... 32
`
`Numatics, Inc. v. Balluff, Inc.,
`66 F. Supp. 3d 934 (E.D. Mich. 2014) ......................................................... 58, 61
`
`NVIDIA Corp. v. Samsung Elecs. Co.,
`No. IPR2016-00134 (P.T.A.B. May 4, 2016), Paper 9 .................... 22, 24, 32, 33
`
`Samsung Elecs. Co. v. Rembrandt Wireless Techs., LP,
`No. IPR2015-00118 (P.T.A.B. Jan. 28, 2015), Paper 14 ............................. 22, 33
`
`Schott Gemtron Corp. v. SSW Holding Co.,
`No. IPR2013-00358 (P.T.A.B. Aug. 20, 2014), Paper 106 .......................... 56, 58
`
`Sundance, Inc. v. Demonte Fabricating Ltd.,
`550 F.3d 1356 (Fed. Cir. 2008) ........................................................................... 55
`
`Toyota Motor Corp. v. Cellport Sys., Inc.,
`No. IPR2015-01423 (P.T.A.B. Oct. 28, 2015), Paper 7 ...................................... 23
`
`Velander v. Garner,
`348 F.3d 1359 (Fed. Cir. 2003) ........................................................................... 55
`
`ViiV Healthcare UK Ltd. v. Lupin Ltd.,
`6 F. Supp. 3d 461 (D. Del. 2013),
`aff'd, 594 F. App’x 686 (Fed. Cir. 2015) ............................................................. 39
`
`Westlake Servs., LLC v. Credit Acceptance Corp.,
`No. CBM2014-00176 (P.T.A.B. May 14, 2015), Paper 28 ................................. 15
`
`Yorkey v. Diab,
`601 F.3d 1279 (Fed. Cir. 2010) ........................................................................... 55
`
`ZTE Corp. v. ContentGuard Holdings Inc.,
`No. IPR2013-00454 (P.T.A.B. Sept. 25, 2013), Paper 12 ............................ 31, 32
`
`STATUTES
`
`35 U.S.C. § 103(a) ................................................................................................... 37
`
`35 U.S.C. § 314(a) ................................................................................................... 37
`
`v
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`Case IPR2016-00781
`U.S. Patent No. 8,846,112
`
`35 U.S.C. § 315(e)(1) ....................................................................................... passim
`
`35 U.S.C. § 325(d) ........................................................................................... passim
`
`OTHER AUTHORITIES
`
`157 Cong. Rec. S1375 (daily ed. Mar. 8, 2011) (statement of Sen. Grassley) ........ 16
`
`157 Cong. Rec. S1375 (daily ed. Mar. 8, 2011) (statement of Sen. Kyl) ................ 16
`
`
`
`
`
`
`
`vi
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`Case IPR2016-00781
`U.S. Patent No. 8,846,112
`
`
`I.
`
`INTRODUCTION
`
`The Board should deny this follow-on petition filed by Praxair Distribution,
`
`Inc. and NOxBOX Limited (collectively, “Petitioner”) for three independent
`
`reasons.
`
`First, a final written decision will soon estop Petitioner from requesting or
`
`maintaining this proceeding altogether. 35 U.S.C. § 315(e)(1). Just a few weeks
`
`after Patent Owner files this Preliminary Response, the Board is scheduled to issue
`
`a final written decision addressing the patentability of the very same claims of the
`
`very same patent challenged here. See generally IPR2015-00529. Because
`
`Petitioner reasonably could have raised the currently-proposed grounds in the prior
`
`-00529 proceeding, the Board’s forthcoming final written decision will estop
`
`Petitioner from requesting or maintaining this IPR.
`
`Specifically, Petitioner now asserts that two references, A. Greenough &
`
`A.D. Miller, Neonatal Respiratory Disorders 149, 183-87, 382 (2nd ed. 2003)
`
`(“Greenough”) and Jaypee, Pediatric & Neonatal Mechanical Ventilation 148-58
`
`(Praveen Khilnani ed., 1st ed. 2006) (“Jaypee”) were somehow “not available”
`
`when it filed its -00529 petition sixteen months ago. But these are readily
`
`available textbooks that Petitioner’s own expert argues “one of skill in the art
`
`would have read . . . when treating children and/or neonates using iNO therapy.”
`
`Ex. 1002, Lawson Decl. ¶ 50. Or as Petitioner puts it, Greenough and Jaypee are
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`“all part of a collected literature” in this field. Pet. at 26; Ex. 1002, Lawson Decl.
`
`¶ 51. Indeed, even a cursory search using simple keywords found in the ’112
`
`Patent confirms that these two textbooks are readily available and easily identified.
`
`In fact, Jaypee and Greenough are the second and ninth hits respectively in a
`
`Google Book search using just the keywords “neonatal” and “nitric oxide.” Ex.
`
`2003, Google Book Search 1.
`
`Second, the Board should exercise its discretion and deny this Petition under
`
`35 U.S.C. § 325(d). Although it relies on different references, Petitioner advances
`
`substantially the same arguments it presented in the prior -00529 proceeding, in
`
`fact, cutting and pasting the exact same language from the -00529 petition into
`
`much of Petitioner’s “new” petition. Compare, e.g., Pet. at 30-33 with Ex. 2016, -
`
`00529 Pet. at 19-21. Petitioner knew of or should have known of Greenough and
`
`Jaypee, but is now using them to take the proverbial second bite at the apple,
`
`impermissibly using the previous proceeding as a roadmap.
`
`Third, should the Board reach the merits of this soon-to-be estopped petition,
`
`it should deny institution because Petitioner makes its obviousness arguments
`
`based on conclusory and unsupported statements in secondary evidentiary sources
`
`that a POSA would quickly reject as incorrect and unreliable. Further, Petitioner
`
`misstates what the asserted references teach and ignores the overwhelming
`
`evidence of non-obviousness. Moreover, Petitioner relies extensively on an expert
`
`2
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`declaration that should be afforded little or no weight because the expert lacks the
`
`requisite level of skill in the art according to the definition Petitioner previously
`
`proposed, and because this expert copied significant parts of his conclusory
`
`declaration from another expert, cutting and pasting excerpts from the expert
`
`declaration associated with the -00529 petition.
`
` THE ’112 PATENT CLAIMS NOVEL METHODS FOR PROVIDING
`II.
`PHARMACEUTICALLY ACCEPTABLE NITRIC OXIDE TO
`PHYSICIANS FOR THE SAFE ADMINISTRATION TO NEONATES
`A. The Development of the ’112 Patent
`The ’112 Patent, entitled “Methods of Distributing a Pharmaceutical Product
`
`Comprising Nitric Oxide Gas for Inhalation,” is directed to methods of providing
`
`pharmaceutically acceptable nitric oxide gas to a medical provider responsible for
`
`treating term and near-term infants (known as “neonates”) with hypoxic respiratory
`
`failure. See, e.g., Ex. 1001 at 1:20-25; 1:50-2:24. In particular, the ’112 Patent
`
`claims methods of providing pharmaceutically acceptable nitric oxide gas for the
`
`safe treatment of hypoxic respiratory failure in neonates. The subject claims
`
`disclose a solution to the previously unknown problem that neonates suffering
`
`from hypoxic respiratory failure who also suffer from pre-existing left ventricular
`
`dysfunction (“LVD”) have a high risk of experiencing serious adverse events
`
`(“SAEs”) such as pulmonary edema if they are administered inhaled nitric oxide
`
`(“iNO”). Thus, the claims of the ’112 Patent recite methods of providing nitric
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`oxide gas, along with information sufficient to cause a medical provider
`
`considering iNO treatment to avoid treating one or more neonates with pre-existing
`
`LVD. Id. at 14:27-52.
`
`The inventions disclosed in the ’112 Patent arose from a discovery during
`
`the INOT22 clinical study (Example 1 in the ’112 Patent) which involved
`
`administering INOmax® (Patent Owner’s iNO product) to pediatric patients. Id. at
`
`9:35-14:25. Designed by the leading experts in the field, the INOT22 study
`
`initially did not exclude patients with pre-existing LVD. Id. at 9:35-10:14. Only
`
`after observing numerous SAEs did the risks of administering iNO to patients with
`
`LVD become apparent, leading to a revision to the INOT22 protocol and the
`
`claimed methods for safely providing that drug to 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 approved by the U.S. Food & Drug
`
`Administration (“FDA”) for administration by inhalation to neonates suffering
`
`from hypoxic respiratory failure (abnormally low levels of oxygen in the
`
`bloodstream) associated with clinical or echocardiographic evidence of pulmonary
`
`hypertension (high pressure in the blood vessels going to the lungs). Ex. 2004,
`
`Current INOmax® Label. In neonates, pulmonary hypertension with hypoxic
`
`respiratory failure resulting from failure of transition to the usual post-natal
`
`4
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`circulation is known as persistent pulmonary hypertension of the newborn
`
`(“PPHN”). Ex. 2001, Rosenthal Decl. ¶ 34.
`
`During in utero development, circulation through the lungs is largely shut
`
`down because the pulmonary vessels are tightly constricted. The fetal lungs are
`
`filled with fluid and the fetus obtains oxygen across the placenta. Id. ¶ 32. Instead
`
`of blood being pumped from the right side of the heart through the lungs and
`
`returning to the left side of the heart to be pumped to the rest of the body (as is the
`
`case following birth), blood from the right side of the fetal heart bypasses the lungs
`
`through a blood vessel connecting the outflow of the right heart directly to the
`
`systemic circulation called the patent ductus arteriosus. Id. When children are
`
`born, the ductus arteriosus normally closes and the pulmonary vessels relax. As a
`
`result, the outflow of the right side of the heart is redirected to the now oxygenated,
`
`ventilated, and functional lungs, and oxygenated blood is then returned to the left
`
`side of the heart to be pumped to the rest of the body from the left ventricle. Id.
`
`¶ 33.
`
`In neonates suffering from PPHN, the pulmonary vessels fail to adequately
`
`relax, and there is insufficient gas exchange, leading to hypoxic respiratory failure.
`
`Id. ¶ 34. The appropriate administration of iNO relaxes the small vessels that are
`
`in close proximity to the aerated parts of the lung, allowing the blood in those
`
`vessels to pick up oxygen and release carbon dioxide. Id. This increases the
`
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`effective blood flow to the lungs, and reduces the need for other high-risk
`
`therapies, such as aggressive ventilation, administration of oxygen concentrations
`
`associated with toxicity, and removal of blood from the infant to a heart-lung
`
`bypass machine that re-oxygenates the blood. Id.
`
`In some neonates with severe congenital heart disease involving the left
`
`ventricle, the left side of the heart lacks the ability to pump a sufficient amount of
`
`blood to the rest of the body. Id. ¶ 35. For these neonates, a ductus arteriosus that
`
`remains open is actually beneficial and can be life-saving. The high pulmonary
`
`vascular resistance, resulting in pulmonary hypertension, creates a right-to-left
`
`shunt through the patent ductus arteriosus and allows the right ventricle to take on
`
`the role of the nonfunctioning left ventricle by pumping adequately oxygenated
`
`blood directly to the systemic circulation. Id. These neonates are described as
`
`being dependent upon right-to-left shunting of blood (“RTL-Dependent”).
`
`In RTL-Dependent neonates, pulmonary vasoconstriction
`
`(normally
`
`problematic as discussed above) is actually beneficial, as it diverts blood from the
`
`right ventricle through the patent ductus arteriosus for systemic circulation. Id.
`
`¶ 36. If the pulmonary vascular resistance drops or is lowered in an infant that is
`
`RTL-Dependent, the infant will have less blood flow to the body and coronary
`
`arteries, and is at very high risk of low blood pressure, low cardiac output, severe
`
`acidosis, cardiogenic shock, and sudden death. Id. Administering iNO to neonates
`
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`who are RTL-Dependent can therefore be catastrophic. Id. Thus, when the FDA
`
`first approved INOmax® as safe and effective, it was contraindicated for “the
`
`treatment of neonates known to be dependent on right-to-left shunting of blood.”
`
`Ex. 1010 at 004.
`
`INOmax® was not contraindicated for any other class of neonates including
`
`those with LVD, but who were not RTL-Dependent (“non-RTL-Dependent”).
`
`This was consistent with the prior clinical studies submitted in support of the
`
`original FDA approval of INOmax® that administered iNO to pediatric patients,
`
`including neonates, which did not exclude non-RTL-Dependent neonates suffering
`
`from LVD. Ex. 2001, Rosenthal Decl. ¶ 38; Ex. 1010 at 004.
`
`The lack of any such restriction in the approved labeling was also consistent
`
`with the conventional use of iNO at the time of the invention. Indeed, no clinical
`
`study prior to the INOT22 study had ever excluded these neonates. Ex. 2001,
`
`Rosenthal Decl. ¶ 39.
`
`Further, shortly before the time of the invention, a consensus meeting jointly
`
`organized by the European Society of Paediatric and Neonatal Intensive Care, the
`
`European Society of Paediatric Research, and
`
`the European Society of
`
`Neonatology put forth a set of “Consensus Guidelines on the Use of iNO in
`
`Neonates and Children” that mirrored the approved US labeling. Ex. 2006, EU
`
`Consensus at 372. These guidelines were established by an Advisory Board
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`consisting of “experts with proven scientific or clinical expertise relevant to the
`
`clinical use of iNO” as well as “a panel of experts who were invited to act as
`
`section leaders whose role was to review the literature.” Id. at 373. The
`
`Guidelines “were designed to allow the safe use of iNO therapy” and while they
`
`explained that iNO “may. . . be harmful in some babies with . . . severe left
`
`ventricular dysfunction with right-to-left ductal shunting,” they did not cite LVD
`
`alone as a risk factor. Id. at 374. Notably, Dr. Greenough was among the
`
`members of the consensus group producing these Guidelines.1 Id. at 378.
`
`2.
`
`The Original INOT22 Study Protocol Did Not Exclude
`Neonates with Non-RTL-Dependent LVD
`
`Beginning in 2004, Patent Owner sponsored a clinical trial known as the
`
`INOT22 Study, which compared the use and side effects of oxygen, iNO, and a
`
`combination of oxygen and iNO for determining pulmonary reactivity. Ex. 1001 at
`
`10:14-16. It was a randomized, multi-center study with 18 clinical study sites. Id.
`
`at 9:57-59.
`
`The INOT22 study was designed by a committee of “internationally
`
`recognized experts” in pediatric heart and lung disease (“the INOT22 Steering
`
`
`1 Additionally Duncan MacRae, a member of the INOT22 Steering Committee,
`
`was also an author of the EU Consensus Guidelines. Id.
`
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`Committee”) and Patent Owner, the study sponsor. Ex. 1005 at 663, ¶ 8. The
`
`INOT22 Steering Committee included: (1) David L. Wessel, M.D., Professor of
`
`Anesthesiology and Critical Care Medicine and of Pediatrics at the George
`
`Washington University; (2) Robyn J. Barst, M.D., Professor Emeritus of Pediatrics
`
`and Medicine, Columbia University College of Physicians and Surgeons, New
`
`York; and (3) Duncan J. MacRae, M.D., Director, Children’s Services, Consultant
`
`in Pediatric Critical Care at the Royal Brompton Hospital, London, U.K. Ex. 1005
`
`at 663, ¶ 9; id. at 448. These three—particularly Drs. Wessel and Barst—were at
`
`the forefront of the fields of pediatric cardiology and pediatric pulmonary
`
`hypertension, and each had extensive expertise relevant to the clinical use of iNO.
`
`Ex. 2001, Rosenthal Decl. ¶ 23.
`
`The INOT22 protocol was carefully reviewed by Institutional Review
`
`Boards (“IRB”) and/or Independent Ethics Committees (“IEC”) and by each
`
`participating study institution. Ex. 1005 at 446, 471, 664, ¶ 11. Those committees
`
`include practicing physicians and others whose role is “the protection of the rights
`
`and welfare of human research subjects.” Id. at 665, ¶ 12.
`
`The FDA and four FDA-equivalent European National Health Authorities
`
`(United Kingdom, France, Netherlands and Spain) also had the opportunity to
`
`review the Original INOT22 Protocol before the study began, id. at 664-66, ¶¶ 11-
`
`14, and Patent Owner requested guidance on clinical trials from its own Scientific
`
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`Advisory Board, id. at 664-65, ¶ 11. In all, more than 115 individuals
`
`“experienced in and responsible for the review of clinical trial protocols for patient
`
`safety” evaluated the INOT22 Protocol before the study began. Id. at 665-66, ¶ 14.
`
`Consistent with the then-current INOmax® Label, and with the prevailing
`
`practice in the field, only RTL-Dependent patients were excluded from the
`
`INOT22 Protocol. Ex. 1010 at 4. Notwithstanding design and review by the “best
`
`and brightest” in their field, the INOT22 Protocol (like the European Consensus
`
`Conference) did not exclude pediatric patients with other types of pre-existing
`
`LVD. Ex. 1001 at 9:59-66; Ex. 1005 at 397-98; Ex. 2001, Rosenthal Decl. ¶ 52.
`
`In other words, of the more than 115 medical and human research safety
`
`professionals (including IRBs, IECs, individual investigators, the FDA and
`
`European health authorities, and the Patent Owner’s Scientific Advisory Board)
`
`who considered the safety of the INOT22 Study patients, not one suggested there
`
`was a chance that iNO might increase the likelihood of SAEs in pediatric patients
`
`with non-RTL-Dependent LVD. Ex. 2007 at 794-95.
`
`3.
`
`Unanticipated SAEs Occurred During the INOT22 Study,
`the Study Was Amended, and the Rate of SAEs Was
`Significantly Reduced
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`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. 1005 at
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`10
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`666, ¶ 15. The SAEs were all cardiovascular events, and included pulmonary
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`edema (accumulation of fluid in the lungs), cardiac arrest, and hypotension (low
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`blood pressure). Id. One child who developed pulmonary edema unfortunately
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`died. Ex. 1001 at 12:63-13:36.
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`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
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`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. 2007 at 1082, ¶ 21. From these
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`results,
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`the
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`inventors “recognized
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`that a second population of neonates
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`existed . . . that had an increased risk of adverse events when inhaled NO was
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`administered, namely: pediatric patients with left ventricular dysfunction . . . .” Id.
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`at 1145, ¶ 11.
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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. 1005 at 666, ¶¶ 15, 16; Ex. 1001 at 12:47-61;
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`Ex. 2001, Rosenthal Decl. ¶ 55. Following that change, “the rate of SAEs
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`(including SAEs associated with heart failure) was significantly reduced.” Ex.
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`1005 at 667, ¶ 17; Ex. 2001, Rosenthal Decl. ¶ 56. While five SAEs were reported
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`in the first 24 patients of the study, only two SAEs were reported in the last 100
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`patients after the protocol was amended. Ex. 1005 at 667, ¶ 17.2
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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. 1005 at 667-68, ¶ 18.
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`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. 2007 at 1099, ¶ 6. Had the adverse events been obvious, Dr. Wessel
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`2 This change in protocol reduced the risk of patients experiencing a SAE from
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`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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`0.003). Ex. 2001, Rosenthal Decl. ¶ 57.
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`would have had to have “act[ed] either negligently or intentionally to harm babies,
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`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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`protocol. Ex. 1005 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. As
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`inventor Dr. Baldassarre stated, prior to initiation of the INOT22 Study, it defied
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`“common sense to any expert in this field” to not utilize iNO with this patient
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`population. Ex. 2007 at 532, ¶ 11. In fact, Greenough was published prior to the
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`INOT22 study but was insufficient to motivate any of the 115+ reviewers of the
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`study protocol to exclude neonates with non-RTL Dependent LVD, despite
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`Petitioner’s contention that “one of ordinary skill in the art would have
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`read . . . Greenough . . . .” Ex. 1002, Lawson Decl. ¶ 50.
`
`The ’112 Patent Prosecution History
`
`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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`The Examiner extensively reviewed the ’112 Patent, considering 200
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`references and specifically addressing ten, before allowing the claims. Ex. 1005 at
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`228-81 (IDS), 329-43 (4/24/2013 Office Action addressing several prior art
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`references), 695-728 (2/5/2014 Office Action addressing several prior art
`
`references), 773-74 (IDS), 785 (Notice of Allowance). During the prosecution of
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`the ’112 Patent and its priority application, the Examiner specifically addressed the
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`2000 INOmax® Label, Ex. 1010, on which Petitioner relies to argue for institution
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`of inter partes review. Id. at 155 (IDS).
`
` PERSON OF ORDINARY SKILL IN THE ART
`III.
`A person of ordinary skill in the art at the time of the inventions of the ’112
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`Patent (“POSA”) is a physician with experience treating pediatric heart and lung
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`disease and/or experience studying pediatric heart and lung disease. In addition,
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`such an
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`individual would have experience prescribing and administering
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`vasodilators and additional supportive therapies and/or experience designing
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`clinical trials related to pediatric heart and lung disease. In short, POSAs made up
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`a significant subset of the 115+ individuals who designed, reviewed, and approved
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`the Original INOT22 Protocol as well as the members of the European Conference
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`Consensus.
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`IV.
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` CLAIM CONSTRUCTION
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`For the purposes of this preliminary response, Patent Owner adopts the
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`Board’s previous construction of “term or near-term neonate” to mean “an infant
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`aged 1 month or younger born between around 37 and 40 weeks gestation or
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`greater than around 34 weeks gestation.” -00529 IPR, Paper No. 12 at 8. All other
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`terms should be interpreted in accordance with the appropriate claim construction
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`standard.
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`V.
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`
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`PETITIONER IS ESTOPPED FROM REQUESTING INTER PARTES
`REVIEW UNDER 35 U.S.C. § 315(E)(1)
`
`The Board’s forthcoming final written decision in the -00529 IPR will
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`foreclose the instant IPR in just a few weeks. Once a petitioner obtains a final
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`written decision on a patent claim in an IPR, that petitioner, or the real parties-in-
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`interest and privies, cannot request or maintain a second IPR with respect to