Filed on behalf of: Mallinckrodt Hosp. Prods. IP Ltd.
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`
`
`
`
`
`Entered: June 30, 2016
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`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 IPR2016-00779
`U.S. Patent No. 8,293,284
`_______________________
`
`Before STEVEN AMITRANI, Trial Paralegal.
`
`
`PATENT OWNER’S PRELIMINARY RESPONSE
`
`
`
`

`
`Case IPR2016-00779
`U.S. Patent No. 8,293,284
`
`TABLE OF CONTENTS
`
`I.
`
`
`II.
`
`
`Introduction ...................................................................................................... 1
`
`The ’284 Patent Claims Novel Methods for Providing Inhaled Nitric
`Oxide to Neonates ............................................................................................ 2
`
`A.
`
`The Development of the ’284 Patent .................................................... 2
`
`1.
`
`2.
`
`3.
`
`The Prior Use of iNO in Neonates and Children Only
`Excluded Those Dependent on Right-to-Left Shunting,
`Not Those With Preexisting LVD .............................................. 3
`
`The Original INOT22 Study Protocol Did Not Exclude
`Neonates with Non-RTL-Dependent LVD ................................. 7
`
`Unanticipated SAEs Occurred During the INOT22 Study,
`the Study Was Amended, and the Rate of SAEs Was
`Significantly Reduced ................................................................. 9
`
`B.
`
`The ’284 Patent Prosecution History .................................................. 12
`
`III.
`
`
`Person of Ordinary Skill in the Art ................................................................ 13
`
`IV.
`
` The Board Should Exercise its Discretion to Deny Institution Under
`35 U.S.C. §§ 314 and 325 .............................................................................. 13
`
`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 .............................................. 15
`
`The Board Should Deny Institution Because Petitioner Delayed
`in Filing the Present Petition and Unfairly Benefited from its
`Delay .................................................................................................... 20
`
`Petitioner Advances the Same or Substantially the Same Prior
`Art and Arguments As in the First Petition ......................................... 24
`
`V.
`
`
`
`The Petition Fails to Show a Reasonable Likelihood that the Petitioner
`Will Prevail with respect to the Challenged Claims ...................................... 28
`
`A.
`
`Petitioner Has Not Established A Motivation to Combine
`Teachings ............................................................................................. 30
`
`i
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`

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`Case IPR2016-00779
`U.S. Patent No. 8,293,284
`
`1.
`
`2.
`
`3.
`
`4.
`
`There Was No Known Problem to Establish a Reason to
`Combine References ................................................................. 30
`
`Dr. Lawson’s Conclusory Expert Testimony is
`Insufficient to Create a Motivation to Combine
`References ................................................................................. 31
`
`Petitioner Continues to Ignore the Overwhelming
`Evidence of Non-Obviousness .................................................. 34
`
`Petitioner Provides No Motivation to Combine Specific
`Disclosures to Arrive at the Claimed Inventions ...................... 37
`
`B.
`
`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 ................ 38
`
`A POSA Would Have Rejected the Statements in
`Greenough As Conclusory and Unsupported ........................... 39
`
`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
`
`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
`
`The Board Should Afford Petitioner’s Expert Declaration
`Minimal Weight .................................................................................. 53
`
`VI.
`
` The Principles of Administrative Res Judicata Preclude Petitioner
`from Filing the Present Petition ..................................................................... 57
`
`
`
` Conclusion ..................................................................................................... 61 VII.
`
`ii
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`

`
`Case IPR2016-00779
`U.S. Patent No. 8,293,284
`
`
`
`TABLE OF AUTHORITIES
`
`CASES
`
`Page(s)
`
`Allergan, Inc. v. Sandoz Inc.,
`726 F.3d 1286 (Fed. Cir. 2013) ........................................................................... 34
`
`Alza Corp. v. Mylan Labs., Inc.,
`464 F.3d 1286 (Fed. Cir. 2006) ........................................................................... 34
`
`Arista Networks, Inc. v. Cisco Sys., Inc.,
`No. IPR2015-01710, Paper No. 7 (P.T.A.B. Feb. 16, 2016) ............................... 19
`
`B&B Hardware, Inc. v. Hargis Indus., Inc.,
`135 S. Ct. 1293 (2015) ............................................................................ 57, 60, 61
`
`Butamax Advanced Biofuels LLC v. Gevo, Inc.,
`No. IPR2014-00581, Paper No. 8 (P.T.A.B. Oct. 14, 2014) ............................... 21
`
`Conopco, Inc. v. Procter & Gamble Co.,
`No. IPR2014-00628, Paper No. 21 (P.T.A.B. Oct. 20, 2014) ............................. 19
`
`Daiichi Sankyo Co. v. Apotex, Inc.,
`501 F.3d 1254 (Fed. Cir. 2007) ........................................................................... 56
`
`Great W. Cas. Co. v. Intellectual Ventures II LLC,
`No. IPR2016-00453, Paper No. 12 (P.T.A.B. June 9, 2016) .............................. 14
`
`Harmonic Inc. v. Avid Tech., Inc.,
`815 F.3d 1356 (Fed. Cir. 2016) ........................................................................... 13
`
`Intelligent Bio-Sys., Inc. v. Illumina Cambridge Ltd.,
`No. IPR2013-00324, Paper No. 19 (P.T.A.B. Nov. 21, 2013) ............................ 20
`
`InTouch Techs., Inc. v. VGo Commc’ns, Inc.,
`751 F.3d 1327 (Fed. Cir. 2014) ........................................................................... 32
`
`Kinetic Concepts, Inc. v. Smith & Nephew, Inc.,
`688 F.3d 1342 (Fed. Cir. 2012) ........................................................................... 30
`
`Leo Pharm. Prods., Ltd. v. Rea,
`726 F.3d 1346 (Fed. Cir. 2013) ........................................................................... 31
`
`iii
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`

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`Case IPR2016-00779
`U.S. Patent No. 8,293,284
`
`Mars Inc. v. Nippon Conlux Kabushiki-Kaisha,
`58 F.3d 616 (Fed. Cir. 1995) ............................................................................... 59
`
`Medtronic, Inc. v. Robert Bosch Healthcare Sys., Inc.,
`No. IPR2014-00436, Paper No. 17 (P.T.A.B. June 19, 2014) ............................ 28
`
`NetApp Inc. v. Crossroads Sys., Inc.,
`No. IPR2015-00772, Paper No. 12 (P.T.A.B. Sept. 3, 2015) .............................. 21
`
`NVIDIA Corp. v. Samsung Elecs. Co.,
`No. IPR2016-00134, Paper No. 9 (P.T.A.B. May 4, 2016)......................... passim
`
`Panasonic Corp. v. Optical Devices, LLC,
`No. IPR2014-00302, Paper No. 9 (P.T.A.B. July 11, 2014) ............................... 34
`
`Samsung Elecs. Co. v. Rembrandt Wireless Techs., LP,
`No. IPR2015-00118, Paper No. 14 (P.T.A.B. Jan. 28, 2015) ............................. 22
`
`Schott Gemtron Corp. v. SSW Holding Co.,
`No. IPR2013-00358, Paper No. 106 (P.T.A.B. Aug. 20, 2014) ................... 54, 57
`
`Streck, Inc. v. Research & Diagnostic Sys., Inc.,
`665 F.3d 1269 (Fed. Cir. 2012) ........................................................................... 33
`
`Sundance, Inc. v. DeMonte Fabricating Ltd.,
`550 F.3d 1356 (Fed. Cir. 2008) .................................................................... 54, 57
`
`Ube Maxell Co. v. Celgard, LLC,
`No. IPR2015-01511, Paper No. 10 (P.T.A.B. Jan. 7, 2016)......................... 25, 27
`
`Unilever, Inc. v. Procter & Gamble Co.,
`No. IPR2014-00506, Paper No. 17 (P.T.A.B. July 7, 2014) ............................... 16
`
`United States v. Utah Constr. & Mining Co.,
`384 U.S. 394 (1966) ............................................................................................. 57
`
`Velander v. Garner,
`348 F.3d 1359 (Fed. Cir. 2003) ........................................................................... 54
`
`Yorkey v. Diab,
`601 F.3d 1279 (Fed. Cir. 2010) ........................................................................... 53
`
`iv
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`

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`Case IPR2016-00779
`U.S. Patent No. 8,293,284
`
`ZTE Corp. v. ContentGuard Holdings Inc.,
`No. IPR2013-00454, Paper No. 12 (P.T.A.B. Sept. 25, 2013) ............................ 21
`
`STATUTES
`
`35 U.S.C. § 103(a) ................................................................................................... 29
`
`35 U.S.C. § 314(a) ........................................................................................... passim
`
`35 U.S.C. § 314(d) ................................................................................................... 58
`
`35 U.S.C. § 315(e)(1) ............................................................................................... 60
`
`35 U.S.C. § 325(d) ........................................................................................... passim
`
`RULES
`
`37 C.F.R. § 42.108(c) ............................................................................................... 13
`
`37 C.F.R. § 42.71 ..................................................................................................... 58
`
`
`
`
`
`
`
`v
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`

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`Case IPR2016-00779
`U.S. Patent No. 8,293,284
`
`
`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, the Board should exercise its discretion and deny this petition under 35
`
`U.S.C. §§ 314(a) and 325(d). Petitioner advances substantially the same
`
`arguments it presented in the prior IPR-00524 petition. Further, Petitioner knew or
`
`should have known of both Neonatal Respiratory Disorders 149, 183-87, 392
`
`(Anne Greenough & Anthony D. Milner eds., 2d ed. 2003) (“Greenough”) and
`
`Praveen Khilnani, Pediatric and Neonatal Mechanical Ventilation 148-58 (1st ed.
`
`2006) (“Jaypee”), and does not contend that it was unaware of A. Widlitz et al.,
`
`Pulmonary Arterial Hypertension in Children, in volume 21 of European
`
`Respiratory Journal (Jan. 2003) (“Widlitz”) when it filed its first petition.
`
`Petitioner is now using these references to take a second bite at the apple,
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`impermissibly using the Board’s denial of institution in the previous proceeding as
`
`a roadmap.
`
`Second, should the Board reach the merits, it should deny institution because
`
`Petitioner fails to demonstrate that a person of ordinary skill in the art (“POSA”) at
`
`the time of the inventions of the ’284 Patent would have been motivated to
`
`implement the claimed exclusion limitations, or that it was reasonable to expect
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`U.S. Patent No. 8,293,284
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`that neonates and children would have had an increase of pulmonary edema when
`
`administered inhaled nitric oxide (“iNO”).
`
` Further, Petitioner makes its
`
`obviousness arguments based on unsupported statements in secondary evidentiary
`
`sources that a POSA would quickly reject as incorrect and unreliable. Moreover,
`
`Petitioner misstates what the asserted references ostensibly teach and ignores the
`
`overwhelming evidence of non-obviousness. Finally, Petitioner relies upon
`
`conclusory testimony from an expert who does not meet Petitioner’s proposed
`
`level of ordinary skill.
`
`Third, the Board should deny the instant petition because it is precluded by
`
`the doctrine of administrative res judicata.
`
` THE ’284 PATENT CLAIMS NOVEL METHODS FOR PROVIDING
`II.
`INHALED NITRIC OXIDE TO NEONATES
`A. The Development of the ’284 Patent
`The ’284 Patent, entitled “Methods of Reducing the Risk of Occurrence of
`
`Pulmonary Edema in Term or Near-term Neonates in Need of Treatment with
`
`Inhaled Nitric Oxide,” is directed to methods of providing iNO to neonates while
`
`reducing the risks of adverse events (“AEs”) or serious adverse events (“SAEs”)
`
`associated with iNO treatment. See, e.g., Ex. 1001 at 1:49-2:6. 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 SAEs such as pulmonary
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`edema if they are administered iNO. The claims of the ’284 Patent recite methods
`
`of reducing the risks of SAEs associated with administering iNO, wherein patients
`
`are evaluated for, and excluded from iNO treatment based on, pre-existing LVD.
`
`Id. at 14:7-16:56.
`
`The inventions disclosed in the ’284 Patent arose from a discovery during
`
`the INOT22 clinical study (Example 1 in the ’284 Patent) which involved
`
`administering INOmax® (Patent Owner’s iNO product) to pediatric patients. Id. at
`
`9:28-14:5. Designed by the leading experts in the field, the INOT22 study initially
`
`did not exclude patients with pre-existing LVD. Id. at 9:49-56. Only after
`
`observing numerous SAEs did the inventors understand the risks of administering
`
`iNO to patients with LVD, leading to a revision to the INOT22 protocol and the
`
`claimed methods for safely providing that drug to neonates. Id. at 9:28-16:56.
`
`1.
`
`The Prior Use of iNO in Neonates and Children Only
`Excluded Those 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 and children
`
`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. In
`
`neonates, pulmonary hypertension with hypoxic respiratory failure resulting from
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`failure of transition to the usual post-natal circulation is known as persistent
`
`pulmonary hypertension of the newborn (“PPHN”). Ex. 2001, ¶ 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
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`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
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`systemic circulation called the ductus arteriosus. Id. When children are born, the
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`ductus arteriosus normally closes and the pulmonary vessels relax. As a result, the
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`outflow of the right side of the heart is redirected to the now oxygenated,
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`ventilated, and functional lungs, and oxygenated blood is then returned to the left
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`side of the heart to be pumped to the rest of the body from the left ventricle. Id.
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`¶ 33.
`
`In neonates suffering from PPHN, the pulmonary vessels fail to adequately
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`relax, and there is insufficient gas exchange, leading to hypoxic respiratory failure.
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`Id. ¶ 34. The appropriate administration of iNO relaxes the small vessels that are
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`in close proximity to the aerated parts of the lung, allowing the blood in those
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`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
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`therapies, such as aggressive ventilation, administration of oxygen concentrations
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`associated with toxicity, and removal of blood from the infant to a heart-lung
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`bypass machine that re-oxygenates the blood. Id.
`
`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 a sufficient amount of
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`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
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`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
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`(normally
`
`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.
`
`¶ 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
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`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.”
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`Ex. 1010 at 4; Ex. 2001, ¶ 37.
`
`INOmax® was not contraindicated for any other class of neonates or children
`
`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
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`pediatric patients, including neonates, which did not exclude non-RTL-Dependent
`
`neonates suffering from LVD. Ex. 2001, ¶ 38; Ex. 1010.
`
`The lack of any such restriction in the approved labeling was also consistent
`
`with the conventional use of iNO at the time of the inventions. Indeed, no clinical
`
`trial prior to the INOT22 study had ever excluded such patients. Ex. 2001, ¶ 39.
`
`Further, shortly before the time of the inventions, 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 U.S. labeling. Ex. 2006 at 372.
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`These guidelines were established by an Advisory Board consisting of “experts
`
`with proven scientific or clinical expertise relevant to the clinical use of iNO” as
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`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.” Id. at 378. They explain that iNO “may . . . be
`
`harmful in some babies with . . . severe left ventricular dysfunction with right-to-
`
`left ductal shunting.” Id. at 374 (emphasis added). 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
`
`10:5-7. It was a randomized, multi-center, multi-national study with 18 clinical
`
`study sites. Ex. 1001 at 9:47-49; Ex. 2005 at 662, ¶ 7.
`
`The INOT22 study was designed by a committee of “internationally
`
`recognized experts” in pediatric heart and lung disease (“the INOT22 Steering
`
`Committee”) and Patent Owner, the study sponsor. Ex. 2005 at 663, ¶ 8. The
`
`
`1 Duncan MacRae, one of the designers of the INOT22 study was an author of the
`
`EU Consensus Guidelines. Id. at 372.
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`INOT22 Steering Committee included: (1) David L. Wessel, M.D., Senior Vice
`
`President, The Center for Hospital Based Specialties, and Division Chief, Pediatric
`
`Critical Care Medicine, at Children’s National Medical Center; (2) Robyn J. Barst,
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`M.D., Professor Emeritus of Pediatrics and Medicine, Columbia University
`
`College of Physicians and Surgeons, New York; and (3) Duncan J. MacRae, M.D.,
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`Director, Children’s Services, Consultant in Pediatric Critical Care at the Royal
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`Brompton Hospital, London, U.K. Id. at 663, ¶ 9. These three physicians—
`
`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, ¶ 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. 2005 at 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
`
`(from the 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 Advisory Board, id. at 664-65, ¶ 11. In all, more than one hundred
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`and fifteen 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 both the then-current INOmax® label, and 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
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`LVD. Ex. 1001 at 9:49-56.
`
`In other words, of the more than one hundred and fifteen 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
`
`Despite the review by these renowned experts in the field, five SAEs were
`
`observed in the first 24 subjects enrolled in the INOT22 study, a rate much higher
`
`than the INOT22 Steering Committee and Patent Owner expected. Ex. 2005 at
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`9
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`666, ¶ 15. The SAEs were all cardiovascular events, and included pulmonary
`
`edema (accumulation of fluid in the lungs), cardiac arrest, and hypotension (low
`
`blood pressure). One child who developed pulmonary edema unfortunately died.
`
`Ex. 2001, ¶ 53.
`
`Some of the “patients suffering [SAEs] had severe [LVD], largely due to
`
`viral
`
`cardiomyopathy,
`
`and
`
`exhibited during
`
`their
`
`right-sided
`
`cardiac
`
`catheterizations[,] an increased pulmonary capillary wedge pressure (‘PCWP’) of
`
`greater than 20 mm Hg, indicative of elevated pressures in the upper chamber of
`
`the left side of the heart (the left atrium).” Ex. 2007 at 1082, ¶ 21. From these
`
`results,
`
`the
`
`inventors “recognized
`
`that a second population of neonates
`
`existed . . . that had an increased risk of adverse events when inhaled NO was
`
`administered, namely: pediatric patients with left ventricular dysfunction . . . .”
`
`Id. at 1145, ¶ 11.
`
`After these unexpected SAEs, the INOT22 study protocol was amended to
`
`exclude patients with pre-existing non-RTL-Dependent LVD, e.g., those having a
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`PCWP greater than 20 mm Hg. Ex. 2005 at 666, ¶ 16. Following that change, “the
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`rate of SAEs (including SAEs associated with heart failure) was significantly
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`reduced.” Id. at 667, ¶ 17. While five SAEs were reported in the first 24 patients
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`of the study, only two SAEs were reported in the last 100 patients after the
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`protocol was amended. Id.2
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`On February 25, 2009, Patent Owner submitted a change to the INOmax®
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`Label that included a warning that the use of iNO in patients with pre-existing
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`LVD could cause SAEs, such as pulmonary edema. FDA approved the labeling
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`change on August 28, 2009. Ex. 2005 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 SAEs 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, ¶ 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. 2005 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 and Jaypee were
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`insufficient to motivate any of the 115+ reviewers of the INOT22 study protocol to
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`exclude patients with non-RTL-Dependent LVD, despite Petitioner’s allegations
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`they had actual knowledge of both references. See Ex. 1002, ¶ 40.
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`The ’284 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 22, 2010, Patent
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`Owner filed U.S. Patent Application No. 12/821,041, which issued as the ’284
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`Patent, a continuation of Application No. 12/494,598. Ex. 1001 at 1:10-16. The
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`Examiner extensively reviewed the ’284 Patent and its related patents, considering
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`200 references and specifically addressing ten, before allowing the claims. See,
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`e.g., Ex. 1005 at 44-51, 314-44,
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` PERSON OF ORDINARY SKILL IN THE ART
`III.
`A person of ordinary skill in the art at the time of the inventions of the ’284
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`Patent is a physician with experience treating pediatric heart and lung disease
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`and/or experience studying pediatric heart and lung disease. In addition, such an
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`individual would have experience prescribing and administering vasodilators and
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`additional supportive therapies and/or experience designing clinical trials related to
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`pediatric heart and lung disease. POSAs made up a significant subset of the 115+
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`individuals who designed, reviewed, and approved the Original INOT22 Protocol
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`as well as the members of the European Conference Consensus.
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`IV.
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` THE BOARD SHOULD EXERCISE ITS DISCRETION TO DENY
`INSTITUTION UNDER 35 U.S.C. §§ 314 AND 325
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`The Board has substantial latitude in determining whether to institute a
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`petition. Harmonic Inc. v. Avid Tech., Inc., 815 F.3d 1356, 1367 (Fed. Cir. 2016)
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`(“[T]he PTO is permitted, but never compelled, to institute an IPR proceeding.”).
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`The statute provides: “[t]he Director may not authorize an inter partes review to
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`be instituted unless the Director determines that” the petitioner is reasonably likely
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`to prevail. 35 U.S.C. § 314(a) (emphasis added); 37 C.F.R. § 42.108(c) (delegating
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`the discretion to the Board). Further, “[i]n determining whether to institute or
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`order a proceeding . . . , the Director may take into account whether, and reject the
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`petition or request because, the same or substantially the same prior art or
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`arguments previously were presented to the Office.” 35 U.S.C. § 325(d) (emphasis
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`added).
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`In deciding whether to institute review, the Board considers a non-
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`exhaustive list of seven factors: (1) the finite resources of the Board, (2) the
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`requirement to issue a final written decision within one year, (3) whether the same
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`petitioner already filed a previous petition directed to the same claims, (4) whether
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`the petitioner knew or should have known about the newly asserted art, (5) whether
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`the petitioner already received patent owner’s preliminary response or the Board’s
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`institution decision, (6) the length of time that has elapsed since petitioner learned
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`of the newly asserted art, and (7) the petitioner’s explanation for the time it waited
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`to file the second petition. NVIDIA Corp. v. Samsung Elecs. Co., No. IPR2016-
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`00134, Paper No. 9 at 7 (P.T.A.B. May 4, 2016); Great W. Cas. Co. v. Intellectual
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`Ventures II LLC, No. IPR2016-00453, Paper No. 12 at 7-8 (P.T.A.B. June 9, 2016)
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`(different panel, repeating the same list). Each of these factors counsels against
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`institution in this case.
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`The Board should exercise its discretion under §§ 314(a) and 325(d) to deny
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`the instant petition. First, Petitioner knew or should have known of the newly
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`asserted Greenough and Jaypee references when it filed its first petition. Second,
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`Petitioner is abusing the IPR process by using previous IPR proceedings, including
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`the Board’s decision, as roadmaps to remedy the deficiencies in its first petition.
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`Indeed, it filed its first petition well over a year ago and filed this one a mere two
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`days before the statutory bar to take full advantage of those proceedings. Third,
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`Petitioner advances the same or substantially the same prior art and arguments that
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`it previously presented in its first petition challenging the same claims of the same
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`patent.
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`A. The Board Should Deny Institution Because Petitioner Was
`Aware, or Should Have Been Aware, of the Allegedly New
`References Cited in the Instant Petition
`Petitioner was aware, or should have been aware, of both Greenough and
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`Jaypee when it filed its first petition challenging the ’284 Patent, despite its
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`a