Trials@uspto.gov
`571.272.7822
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`Paper 12 (IPR2015-00522)
`Paper 12 (IPR2015-00524)
`Paper 12 (IPR2015-00525)
`Paper 12 (IPR2015-00526)
`Entered: July 29, 2015
`
`
`
`
`
`
`
`UNITED STATES PATENT AND TRADEMARK OFFICE
`____________
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`____________
`
`PRAXAIR DISTRIBUTION, INC.,
`Petitioner,
`
`v.
`
`INO THERAPEUTICS, INC.,
`Patent Owner.
`____________
`
`Case IPR2015-00522 (8,282,966 B2)
`Case IPR2015-00524 (8,293,284 B2)
`Case IPR2015-00525 (8,431,163 B2)
`Case IPR2015-00526 (8,795,741 B2)1
`____________
`
`
`Before LORA M. GREEN, TINA E. HULSE, and ROBERT A. POLLOCK,
`Administrative Patent Judges.
`
`HULSE, Administrative Patent Judge.
`
`
`DECISION
`Denying Institution of Inter Partes Review
`37 C.F.R. § 42.108
`
`
`1 This Decision addresses issues that are common to each of the above-
`referenced cases. We, therefore, issue a single Decision that has been
`entered in each case. The parties may use this style caption when filing a
`single paper in multiple proceedings, provided that such caption includes a
`footnote attesting that “the word-for-word identical paper is filed in each
`proceeding identified in the caption.”
`
`
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`
`
`INTRODUCTION
`I.
`Petitioner, Praxair Distribution, Inc., filed Petitions requesting an inter
`partes review of: (1) claims 1–29 of U.S. Patent No. 8,282,966 ( “the ’966
`patent”) (Ex. 1001, IPR2015-00522); (2) claims 1–30 of U.S. Patent No.
`8,293,284 B2 (“the ’284 patent”) (Ex. 1001, IPR2015-00524); (3) claims
`1–25 of U.S. Patent No. 8,431,163 B2 (“the ’163 patent”) (Ex. 1001,
`IPR2015-00525); and (4) claims 1–44 of U.S. Patent No. 8,795,741 B2
`(“the ’741 patent”) (Ex. 1001, IPR2015-00526). Paper 1 (IPR2015-00522)
`(“-522 Pet.”).2 Patent Owner, INO Therapeutics LLC, filed a Preliminary
`Response to each Petition. Paper 8 (IPR2015-00522) (“-522 Prelim.
`Resp.”).3
`We have jurisdiction under 35 U.S.C. § 314, which provides that an
`inter partes review may not be instituted “unless . . . there is a reasonable
`likelihood that the petitioner would prevail with respect to at least 1 of the
`claims challenged in the petition.” 35 U.S.C. § 314(a). Upon considering
`the Petitions and Preliminary Responses, we determine that Petitioner has
`not established a reasonable likelihood that it would prevail in showing the
`unpatentability of any of the challenged claims in any of the proceedings.
`Accordingly, the Petition in each proceeding is denied.
`
`
`2 Petitioner filed Petitions as Paper 1 in each of the other proceedings. We
`refer to those Petitions as “-524 Pet.,” “-525 Pet.,” and “-526 Pet.”
`3 Patent Owner filed Preliminary Responses as Paper 8 in each of the other
`proceedings. We refer to those Preliminary Responses as “-524 Prelim.
`Resp.,” “-525 Prelim. Resp.,” and “-526 Prelim. Resp.”
`
`2
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`A.
`Related Proceedings
`Petitioner states that it is not aware of any current litigation involving
`any of the involved patents. -522 Pet. 7.4
`B.
`The Involved Patents
`The involved patents are all related and share substantially the same
`Specification. The Specification discloses methods of reducing the risk of
`an adverse event, such as pulmonary edema, associated with treating a
`patient with inhaled nitric oxide gas (“iNO”). Ex. 1001, Abstract. Nitric
`oxide is a lung-specific vasodilator that significantly improves blood
`oxygenation and reduces the need for extracorporeal oxygenation. Id. at
`3:33–42. INOmax®—nitric oxide for inhalation—is an FDA-approved drug
`for treatment of term and near term (>34 weeks gestation) neonates who
`have hypoxic respiratory failure associated with evidence of pulmonary
`hypertension, known as persistent pulmonary hypertension in the newborn
`(“PPHN”). Id. at 1:18–22, 6:23–29.
`The Specification also describes the INOT22 Study, which was
`conducted, in part, to assess the safety and effectiveness of INOmax® in
`patients four weeks to eighteen years of age undergoing assessment of
`pulmonary hypertension. Id. at 9:18–30, 43–44. Initially, the study protocol
`did not include a baseline pulmonary capillary wedge pressure (“PCWP”)
`value as an exclusion criteria.5 Id. at 12:25–26. During the study, at least
`
`4 Petitioner makes similar arguments in its papers and cites similar evidence
`in each of the cases. Accordingly, citations to papers and exhibits in this
`Decision refer to those filed in IPR2015-00522, unless stated otherwise.
`5 PCWP provides an estimate of left atrial pressure, which may be used to
`diagnose the severity of left ventricular dysfunction and to measure
`pulmonary hypertension. Ex. 1001, 5:9–18.
`
`3
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`two patients developed signs of pulmonary edema. Id. at 13:2–3. The
`Specification states that “[t]his is of interest because pulmonary edema has
`previously been reported with the use of iNO in patients with LVD [left
`ventricular dysfunction], and may be related to decreasing PVR [pulmonary
`vascular resistance] and overfilling of the left atrium.” Id. at 13:3–6. The
`Specification further states that “after the surprising and unexpected
`identification of SAEs [serious adverse events] in the early tested patients, it
`was determined that patients with pre-existing LVD had an increased risk of
`experiencing an AE or SAE [such as pulmonary edema] upon
`administration.” Id. at 12:26–30, 13:62–64. The study protocol was
`amended to exclude patients with a baseline PCWP greater than 20 mmHg,
`which was selected to avoid enrolling children with LVD who “would be
`most likely at-risk for these SAEs.” See id. at 12:32–38.
`C.
`Illustrative Claim
`Petitioner challenges: (1) claims 1–29 the ’966 patent (IPR2015-
`00522); (2) claims 1–30 of the ’284 patent (IPR2015-00524); (3) claims 1–
`25 of the ’163 patent (IPR2015-00525); and (4) claims 1–44 of the ’741
`patent (IPR2015-00526). The challenged claims are all similar. Claim 1 of
`the ’966 patent is illustrative and is reproduced below:
`1. A method of reducing the risk of occurrence of pulmonary
`edema associated with a medical treatment comprising
`inhalation of 20 ppm nitric oxide gas, said method comprising:
`(a) performing echocardiography to identify a child in need
`of 20 ppm inhaled nitric oxide treatment for pulmonary
`hypertension, wherein the child is not dependent on right-
`to-left shunting of blood;
`(b) determining that the child identified in (a) has a
`pulmonary capillary wedge pressure greater than or equal
`to 20 mm Hg and thus has left ventricular dysfunction, so
`
`4
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`is at particular risk of pulmonary edema upon treatment
`with inhaled nitric oxide; and
`(c) excluding the child from inhaled nitric oxide treatment,
`based on the determination that the patient has left
`ventricular dysfunction and so is at particular risk of
`pulmonary edema upon treatment with inhaled nitric
`oxide.
`Common among almost all the independent claims of all the involved
`patents is a limitation like step (c) of claim 1 above, which excludes a patient
`from treatment with inhaled nitric oxide based on a determination that the
`patient has left ventricular dysfunction and so is at particular risk of
`pulmonary edema upon treatment with inhaled nitric oxide. See claims
`1(c),6 6(c), 13(e), and 22(e) of the ’966 patent (Ex. 1001, IPR2015-00522);
`claims 1(c), 6(c), 13(e), and 23(e) of the ’284 patent (Ex. 1001, IPR2015-
`00524); claims 1(c) and 6(e) of the ’163 patent (Ex. 1001, IPR2015-00525);
`claims 1(e) and 34(e) of the ’741 patent (Ex. 1001, IPR2015-00526).
`However, not all of the independent claims recite the exact language
`as claim 1(c) above. Certain claims recite excluding a patient from
`treatment with inhaled nitric oxide or, despite the patient’s ongoing need for
`treatment for hypoxic respiratory failure, discontinuing treatment with
`inhaled nitric oxide after it has begun, where the exclusion or
`discontinuation is based on a determination that the patient has left
`ventricular dysfunction and so is at particular risk of pulmonary edema upon
`treatment with inhaled nitric oxide. See claims 12(c) and 20(e) of the ’163
`patent (Ex. 1001, IPR2015-00525); claims 9(e) and 37(e) of the ’741 patent
`
`
`6 For ease of reference, we refer to particular steps of particular claims, e.g.,
`step (c) of claim 1, as “claim 1(c).”
`
`5
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`(Ex. 1001, IPR2015-00526). Additionally, claim 24 of the ’741 patent
`recites “(d) determining that a second patient . . . has pre-existing left
`ventricular dysfunction, so is at particular risk of increased PCWP leading to
`pulmonary edema upon treatment with inhaled nitric oxide” and then
`“(e) administering a second treatment regimen to the second patient
`[determined to have LVD], wherein the second treatment regimen does not
`comprise either (i) administration of inhaled nitric oxide for 14 days or
`(ii) administration of inhaled nitric oxide until the second patient’s hypoxia
`has resolved.” Ex. 1001, claim 24 (IPR2015-00526).
`Despite the differences in claim language, we interpret the above
`“exclusion limitations” to all require excluding a patient from inhaled nitric
`oxide treatment—either by never treating the patient or discontinuing
`treatment—after determining that the patient has left ventricular dysfunction
`and so is at particular risk of pulmonary edema upon treatment with inhaled
`nitric oxide.
`
`The Asserted Grounds of Unpatentability
`D.
`In IPR2015-00522, Petitioner challenges the patentability of claims
`1–29 of the ’966 patent on the following grounds (-522 Pet. 14–58):
`References
`Basis
`Claims Challenged
`Bernasconi,7 INOmax label,8
`§ 103
`1–3, 5–9, 11, 13–17, 20,
`Loh,9 and Goyal10
`22–25, and 28
`
`
`7 A. Bernasconi and M. Beghetti, Inhaled Nitric Oxide Applications in
`Paediatric Practice, 4 IMAGES PAEDIATR. CARDIOL. 4–29 (2002) (Ex. 1004).
`8 Final Printed Labeling for INOmaxTM (nitric oxide) for inhalation
`(Ex. 1014).
`
`6
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`References
`Basis
`Claims Challenged
`Bernasconi, INOmax label,
`§ 103
`4, 10, 12, 18, 19, 21, 26,
`Loh, Goyal, and Macrae11
`27, and 29
`Ichinose,12 Neonatal Group,13
`1–29
`Macrae, Loh, Goyal, and
`Germann14
`
`§ 103
`
`§ 103
`
`In IPR2015-00524, Petitioner challenges the patentability of claims
`1–30 of the ’284 patent on the following grounds (-524 Pet. 12–56):
`References
`Basis
`Claims Challenged
`Bernasconi, INOmax label,
`§ 103
`1–3, 5–9, 11, 13, 14, 16–
`Loh, and Goyal
`18, 21, 23–27, and 29
`Bernasconi, INOmax label,
`4, 10, 12, 15, 19, 20, 22,
`Loh, Goyal, and Macrae
`28, and 30
`
`9 E. Loh et al., Cardiovascular Effects of Inhaled Nitric Oxide in Patients
`with Left Ventricular Dysfunction, 90 CIRCULATION 2780–85 (1994)
`(Ex. 1006).
`10 P. Goyal et al., Efficacy of Nitroglycerin Inhalation in Reducing
`Pulmonary Arterial Hypertension in Children with Congenital Heart
`Disease, 97 BRITISH J. ANESTHESIA 208–14 (2006) (Ex. 1007).
`11 D. J. Macrae et al., Inhaled Nitric Oxide Therapy in Neonates and
`Children: Reaching a European Consensus, 30 INTENSIVE CARE MED. 372–
`80 (2004) (Ex. 1008).
`12 F. Ichinose et al., Inhaled Nitric Oxide: A Selective Pulmonary
`Vasodilator: Current Uses and Therapeutic Potential, 109 CIRCULATION
`3106–11 (2004) (EX. 1009).
`13 The Neonatal Inhaled Nitric Oxide Study Group, Inhaled Nitric Oxide in
`Full-Term and Nearly Full-Term Infants with Hypoxic Respiratory Failure,
`336 NEW ENG. J. MED. 597–604 (1997) (Ex. 1011).
`14 P. Germann et al., Inhaled Nitric Oxide Therapy in Adults: European
`Expert Recommendations, 31 INTENSIVE CARE MED. 1029–41 (2005)
`(EX. 1010).
`
`7
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`References
`Basis
`Claims Challenged
`Ichinose, Neonatal Group,
`§ 103
`1–30
`Macrae, Loh, Goyal, and
`Germann
`
`In IPR2015-00525, Petitioner challenges the patentability of claims
`1–25 of the ’163 patent on the following grounds (-525 Pet. 12–54):
`References
`Basis
`Claims Challenged
`Bernasconi, INOmax label,
`§ 103
`1, 2, 4, 6, 7, 9, 11–13,
`Loh, and Goyal
`15, 18, 20, 21, 23, and
`25
`3, 5, 8, 10, 14, 16, 17,
`19, 22, and 24
`1–25
`
`§ 103
`
`§ 103
`
`Bernasconi, INOmax label,
`Loh, Goyal, and Macrae
`Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and
`Goyal
`
`In IPR2015-00526, Petitioner challenges the patentability of claims
`1–44 of the ’741 patent on the following grounds (-526 Pet. 13–60):
`References
`Basis
`Claims Challenged
`Bernasconi, Loh, and Goyal
`§ 103
`1, 2, 4, 6–14, 17–23, 31,
`32, 34–35, 37–40, and
`42–44
`24–27, 29, 30, and 33
`
`§ 103
`
`§ 103
`
`§ 103
`
`3, 5, 15, 16, 36, and 41
`
`28
`
`Bernasconi, Loh, INOmax
`label, Juliana,15 and Goyal
`Bernasconi, Loh, Macrae, and
`Goyal
`Bernasconi, Loh, INOmax
`label, Juliana, Macrae, and
`Goyal
`
`
`15 A. Juliana and F. Abbad, Severe Persistent Pulmonary Hypertension of
`the Newborn in a Setting Where Limited Resources Exclude the Use of
`Inhaled Nitric Oxide: Successful Treatment with Sildenafil, 164 EUR. J.
`PEDIATR. 626–29 (2005) (Ex. 1032, IPR2015-00526).
`
`8
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`References
`Basis
`Claims Challenged
`Ichinose, Neonatal Group,
`§ 103
`1–23, 31, 32, and 34–44
`Macrae, Loh, Germann, and
`Goyal
`Ichinose, Neonatal Group,
`Macrae, Loh, INOmax label,
`Germann, and Goyal
`
`
`24–30 and 33
`
`§ 103
`
`
`ANALYSIS
`II.
`Claim Construction
`A.
`In an inter partes review, the Board interprets claim terms in an
`unexpired patent according to the broadest reasonable construction in light
`of the specification of the patent in which they appear. See In re Cuozzo
`Speed Techs., LLC, No. 2014-1301, 2015 WL 4097949, at *5–*8 (Fed. Cir.
`July 8, 2015); 37 C.F.R. § 42.100(b). Under that standard, and absent any
`special definitions, we give claim terms their ordinary and customary
`meaning, as would be understood by one of ordinary skill in the art at the
`time of the invention. See In re Translogic Tech., Inc., 504 F.3d 1249, 1257
`(Fed. Cir. 2007). Any special definitions for claim terms must be set forth
`with reasonable clarity, deliberateness, and precision. See In re Paulsen,
`30 F.3d 1475, 1480 (Fed. Cir. 1994).
`1.
`“child” and “children”
`The term “child” or “children” appears in each of the independent
`claims of the ’966 patent and independent claims 34 and 37 of the ’741
`patent. Ex. 1001, claims 1, 6, 13, and 22 (IPR2015-00522); Ex. 1001,
`claims 34 and 37 (IPR2015-00526).
`Petitioner asserts that the Specification states that “the term ‘children’
`(and variations thereof) includes those being around 4 weeks to 18 years of
`age.” -522 Pet. 10 (quoting Ex. 1001, 4:13–14). Given the word “includes,”
`
`9
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`Petitioner argues that the term “children” is not limited to children in that
`age range. Additionally, Petitioner notes that dependent claims 2 and 8
`specify that “the child is a neonate,” therefore confirming that the age range
`for a “child” is broader than the range stated in the Specification. Id.
`Patent Owner argues that the term “child” does not include human
`beings prior to birth. -522 Prelim. Resp. 21. Patent Owner also notes that
`the Specification defines adults as “those over 18 years of age.” Id. (quoting
`Ex. 1001, 4:15–16). Because the Specification defines patients who are over
`18 years of age as adults, Patent Owner contends that the terms “child” and
`“children” should be construed to mean “humans from birth until 18 years of
`age.” Id. at 23.
`We find Patent Owner’s arguments persuasive and determine that
`Patent Owner’s proposed construction is the broadest reasonable
`interpretation in light of the Specification.
`2.
`“term or near-term neonate”
`The claim phrase “term or near-term neonate” appears in each of the
`independent claims of the ’284 patent and the ’163 patent. Ex. 1001, claims
`1, 6, 13, and 23 (IPR2015-00524); Ex. 1001, claims 1, 6, 12, and 20
`(IPR2015-00525). The phrase also appears in independent claims 1, 9, and
`24 of the ’741 patent. Ex. 1001, claims 1, 9, and 24 (IPR2015-00526).
`Petitioner does not offer a specific construction for this term. Patent
`Owner, however, relies on the Specification and medical dictionary
`definitions to assert the following constructions for the following terms:
`(1) “neonate” is “an infant aged 1 month or younger”; (2) “near-term” is
`“greater than around 34 weeks gestation”; and (3) “term” is “between around
`37 and around 40 weeks gestation.” -524 Prelim. Resp. 21–22. Specifically,
`Patent Owner notes that the Specification states that “near term neonates”
`
`10
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`are those having achieved “> 34 weeks gestation.” Id. at 21 (citing -524
`Ex. 1001, 6:27–28). Patent Owner also provides medical dictionary
`definitions for the term “infant” and “neonate” that are consistent with its
`proposed constructions. Id. (citing Ex. 2007, 967–68, 1288).
`We find Patent Owner’s arguments persuasive and determine that
`Patent Owner’s proposed constructions are the broadest reasonable
`interpretation in light of the Specification. That is, we construe the phrase
`“term or near-term neonate” to mean “an infant aged 1 month or younger
`born between around 37 and 40 weeks gestation or greater than around 34
`weeks gestation.”
`B. Obviousness of the ’966 Patent, the ’284 Patent, the ’163 Patent, and
`certain of the ’741 Patent Claims over Bernasconi, INOmax Label, Loh, and
`Goyal
`Petitioner asserts that each of the independent claims in the ’966
`patent, the ’284 patent, and the ’163 patent is unpatentable as obvious over
`Bernasconi, INOmax label, Loh, and Goyal. -522 Pet. 14–32. Petitioner
`also asserts that independent claims 1, 9, 34, and 37 of the ’741 patent are
`unpatentable as obvious over Bernasconi, Loh, and Goyal. -526 Pet. 13–25.
`As support, Petitioner submits the testimony of Dr. Maurice Beghetti in each
`proceeding. Ex. 1002. Patent Owner opposes Petitioner’s assertions. See,
`e.g., -522 Prelim. Resp. 35–50. We determine, on the current record, that
`Petitioner has not established a reasonable likelihood that it would prevail in
`showing any of those challenged claims is unpatentable as obvious over the
`cited prior art.
`
`Bernasconi (Ex. 1004)
`1.
`Bernasconi reviews the “delivery and monitoring aspects of inhaled
`nitric oxide, its potential toxic and side effects and its applications in several
`
`11
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`cardiopulmonary disorders in paediatrics.” Ex. 1004, Abstract; see also
`Title. Bernasconi states that “[d]ose response studies have been performed
`in persistent pulmonary hypertension of the newborn (PPHN)” and that
`“[t]he recommended dose by the FDA for the treatment of neonatal hypoxic
`respiratory failure is 20 ppm.” Id. at 3. Bernasconi also states that
`PPHN
`is a syndrome associated with diverse neonatal
`cardiopulmonary disorders, which are characterised by a high
`pulmonary vascular resistance with right to left shunt of
`deoxygenated blood across the ductus arteriosus and/or the
`foramen ovale. The role of echocardiography to confirm the
`diagnosis and conduct
`therapy
`is
`therefore essential.
`Echocardiography also excludes structural congenital heart
`disease, which would contraindicate the use of iNO.
`Id. at 8.
`Bernasconi also teaches that iNO may lead to pulmonary edema in
`patients with LVD and, thus, emphasizes a need for “careful observation and
`intensive monitoring during [nitric oxide] inhalation” in patients with LVD.
`Id.
`
`INOmax Label (Ex. 1014)
`2.
`INOmax label contains information provided to medical providers
`(Ex. 1014 at i) regarding approved iNO uses and contraindications (id. at 4,
`6). In particular, the reference states that “INOmax, in conjunction with
`ventilatory support and other appropriate agents, is indicated for the
`treatment of term and near-term (>34 weeks) neonates with hypoxic
`respiratory failure associated with clinical or echocardiographic evidence of
`pulmonary hypertension, where it improves oxygenation and reduces the
`need for extracorporeal membrane oxygenation.” Id. at 4. INOmax label
`warns that the drug “should not be used in the treatment of neonates known
`to be dependent on right-to-left shunting of blood.” Id. INOmax label states
`
`12
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`that for “Pediatric Use[, n]itric oxide for inhalation has been studied in a
`neonatal population” (id. at 5) and recommends a dose of 20 ppm iNO for
`neonatal patients with hypoxic respiratory failure (id. at 6).
`3.
`Loh (Ex. 1006)
`Loh describes a study of the hemodynamic effects of a ten-minute
`inhalation of nitric oxide (80 ppm) in nineteen adult patients with moderate
`to severe heart failure due to LVD. Ex. 1006, 2780. Loh further describes
`measuring the PCWP in the patients studied. Id. at 2781.
`4.
`Goyal (Ex. 1007)
`Goyal describes a study of the efficacy of inhaled nitroglycerin in
`reducing pulmonary arterial hypertension in children with congenital heart
`disease. Ex. 1007, Abstract. During the study, PCWP was measured for all
`of the patients before and after treatment with inhaled nitroglycerin. Id. at
`209.
`
`Analysis
`5.
`Petitioner argues that the combination of Bernasconi, INOmax label,
`Loh, and Goyal teaches or suggests each limitation of the independent
`claims in the ’966 patent, the ’284 patent, and the ’163 patent. Petitioner
`also argues that the combination of Bernasconi, Loh, and Goyal teaches or
`suggests each limitation of independent claims 1, 9, 34, and 37 of the ’741
`patent. In particular, regarding the exclusion limitations of the claims,
`Petitioner asserts that Bernasconi discloses that patients with LVD treated
`with inhaled nitric oxide are at risk of pulmonary edema. -522 Pet. 27
`(regarding independent claims 1 and 6 of the ’966 patent) (citing Ex. 1004,
`8; Ex. 1002 ¶ 38); see also id. at 32 (regarding independent claims 13 and 22
`of the ’966 patent). According to Petitioner, a person of ordinary skill in the
`art “would have known not to harm patients by administering iNO to
`
`13
`
`

`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`patients at particular risk of developing pulmonary edema.” Id. at 27 (citing
`Ex. 1004, 8; Ex. 1002 ¶¶ 24, 34, 38). Petitioner then concludes that a person
`of ordinary skill in the art “would have known to exclude certain neonates
`identified as having LVD from iNO treatment.” Id. (citing Ex. 1004, 8;
`Ex. 1002 ¶ 38). Petitioner makes the same arguments with respect to the
`independent claims of the ’284 patent and the ’163 patent, and independent
`claims 1, 9, 34, and 37 of the ’741 patent. See -524 Pet. 25, 30; -525 Pet 23,
`28; -526 Pet. 13–25.
`We are not persuaded by Petitioner’s argument. Bernasconi teaches
`that there are “several reports of the negative effects of inhaled NO in
`patients with left ventricular dysfunction.” Ex. 1004, 8. Those negative
`effects include the risk of pulmonary edema. Id. But the Specification
`acknowledges that the risk of pulmonary edema was already known, stating
`“pulmonary edema has previously been reported with the use of iNO in
`patients with LVD.” Ex. 1001, 13:4–5. And, as Patent Owner notes, despite
`this knowledge in the art, Bernasconi does not conclude that patients should
`be excluded from inhaled nitric oxide treatment as a result of a
`determination that a patient has LVD, as required by the claims. See -522
`Prelim. Resp. 41. Instead, Bernasconi merely cautions for the “need for
`careful observation and intensive monitoring during NO inhalation in
`patients with left ventricular failure, if left ventricular afterload is not
`lowered concomitantly.” See Ex. 1004, 8 (emphasis added). Thus, contrary
`to the claim language, Bernasconi teaches that iNO treatment may be given
`to patients with LVD, as long as those patients are monitored carefully
`during treatment.
`We are also not persuaded that Petitioner has shown sufficiently that
`the teachings of Bernasconi would suggest to a person of ordinary skill in
`
`14
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`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`the art that children with LVD are at an increased risk of pulmonary edema
`and should, therefore, be excluded from treatment with inhaled nitric oxide.
`Petitioner’s declarant, Dr. Beghetti—who is an author of Bernasconi—states
`that “the discussion of adverse effects of iNO on patients with LVD is
`applicable to all patients, including the ‘[n]eonates with hypoxaemic
`respiratory failure’ addressed in the ‘Inhaled nitric oxide applications’
`section of Bernasconi.” Ex. 1002 ¶ 36. Dr. Beghetti continues, stating that
`“the risk of pulmonary oedema resulting from iNO therapy in patients with
`LVD is a risk in neonates and non-neonates alike.” Id. Finally, Dr. Beghetti
`concludes that after reading Bernasconi, evaluating the patient, and weighing
`the therapeutic benefits of iNO, “one skilled in the art would have
`understood that certain patients who have left ventricular dysfunction would
`be at risk of pulmonary oedema, even if not dependent on right-to-left
`shunting of blood, and should not be treated with inhaled NO.” Id. ¶ 38.
`Dr. Beghetti, however, does not provide any objective support for his
`opinion that such patients “should not be treated with inhaled NO” (id.),
`particularly when Bernasconi itself taught that treatment with iNO was
`acceptable, as long as the patient is carefully monitored. We, therefore, do
`not give persuasive weight to Dr. Beghetti’s unsupported opinion. See
`37 C.F.R. § 42.65(a) (stating opinion testimony that does not disclose
`underlying facts or data “is entitled to little or no weight”); Ashland Oil, Inc.
`v. Delta Resins & Refractories, Inc., 776 F.2d 281, 294 (Fed. Cir. 1985)
`(finding a lack of objective support for expert opinion “may render the
`testimony of little probative value in a validity determination”).
`Moreover, Dr. Beghetti provides no persuasive support for his opinion
`that a person of ordinary skill in the art reading Bernasconi would
`understand that the risk of pulmonary edema from iNO therapy in patients
`
`15
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`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`with LVD “is a risk in neonates and non-neonates alike.” Ex. 1002 ¶ 36. In
`contrast, Patent Owner provides a number of prior art references that explain
`that LVD in adults is different than LVD in children, and that state “children
`are not simply little adults.” -522 Prelim. Resp. 30 (citing Ex. 2004, 2;
`Ex. 1017, 117; Ex. 2009, 1215; Ex. 2010, 5, 8; Ex. 2011, 544; Ex. 2006, 2).
`The INOT22 study also provides compelling evidence that the claims
`are not obvious. As noted above, the Specification acknowledges that it was
`known in the art that iNO treatment in patients with LVD may cause
`pulmonary edema. Ex. 1001, 13:6–7. Nevertheless, those patients were not
`excluded from the original protocol of the study, which, according to the
`Specification, “was the largest and most rigorous pharmacodynamics study
`of iNO conducted to date.” Id. at 13:44–46. We find persuasive Patent
`Owner’s argument and evidence that, if it were obvious to a person of
`ordinary skill in the art to exclude children with LVD from treatment with
`iNO, the experts in the field who designed the study—including the named
`author of the Macrae reference relied on by Petitioner—would have
`excluded those children from the original protocol. -522 Prelim. Resp. 45,
`34.
`
`Finally, during prosecution of the involved patents, the applicants
`made many of the same arguments that Patent Owner makes in its
`Preliminary Responses. That is, the applicants argued that studies on adults
`with LVD, like that described in Loh, could not be extrapolated to results in
`children, because “LVD in children or neonates is ‘drastically different’ than
`LVD in adults.” -522 Prelim. Resp. 15–17 (citation omitted). The
`applicants also argued that the fact that children with LVD were not
`excluded from the original protocol of the INOT22 study is evidence of
`nonobviousness. Id. at 48. Petitioner, however, does not address any of
`
`16
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`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`these arguments in its Petition, despite including the file history as an
`exhibit. See Ex. 1052. Given the Examiner found these arguments
`persuasive and allowed the claims, we agree with Patent Owner that
`Petitioner and its declarant should have addressed these arguments in the
`Petitions to show a reasonable likelihood of success on the merits.
`Accordingly, we find that Petitioner has failed to show sufficiently
`that the cited art teaches or suggests the exclusion limitation of the claims.
`Thus, after considering the parties’ arguments and evidence, we are not
`persuaded that Petitioner has established a reasonable likelihood of success
`that it would prevail in showing any of the claims of the ’966 patent, the
`’284 patent, and the ’163 patent are unpatentable as obvious over
`Bernasconi, INOmax label, Loh, and Goyal, or that claims 1–23, 31, 32, and
`34–44 of the ’741 patent are unpatentable as obvious over Bernasconi, Loh,
`and Goyal.
`C. Obviousness of the ’966 Patent, the ’284 Patent, and the ’163 Patent
`Claims over Ichinose, Neonatal Group, Macrae, Loh, Goyal, and Germann
`
`Relying on the testimony of Dr. Beghetti, Petitioner also asserts that
`each of the independent claims of the ’966 patent, the ’284 patent, and
`the ’163 patent is unpatentable as obvious over Ichinose, Neonatal Group,
`Macrae, Loh, Goyal, and Germann. -522 Pet. 41–53. Patent Owner opposes
`Petitioner’s assertion. -522 Prelim. Resp. 53–55. We determine, on the
`current record, that Petitioner has not established a reasonable likelihood that
`it would prevail in showing the cited references render any of those
`challenged claims obvious.
`Ichinose (Ex. 1009)
`1.
`Ichinose is a review article disclosing the uses and therapeutic
`potential of inhaled nitric oxide. Ex. 1009, 3106. Ichinose discusses the
`
`17
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`

`IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2);
`IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2)
`approval of iNO for the treatment of newborns with hypoxic respiratory
`failure associated with clinical or echocardiographic evidence of pulmonary
`hypertension. Id. at 3107–08. Ichinose also states that, although early
`studies of inhaled nitric oxide to treat pulmonary hypertension used
`concentrations of 5 to 80 ppm, it has since been recognized that
`concentrations greater than 20 ppm provide little additional therapeutic
`benefit in most patients. Id. at 3106. Ichinose further states that inhalation
`of low levels of nitric oxide appears to be safe, but that “it is important to be
`aware of the possibility that inhaled NO can produce pulmonary vasodilation
`and may overwhelm a failing [left ventrical], thereby producing pulmonary
`edema.” Id. at