Praxair Distribution, Inc.v.INO Therapeutics LLCDownload PDFPatent Trial and Appeal BoardJul 29, 201513683417 (P.T.A.B. Jul. 29, 2015) Copy Citation Trials@uspto.gov Paper 12 (IPR2015-00522) 571.272.7822 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) 2 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.” IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 3 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. IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 4 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 IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 5 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).” IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 6 (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. D. The Asserted Grounds of Unpatentability 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 Loh,9 and Goyal10 § 103 1–3, 5–9, 11, 13–17, 20, 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). IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 7 References Basis Claims Challenged Bernasconi, INOmax label, Loh, Goyal, and Macrae11 § 103 4, 10, 12, 18, 19, 21, 26, 27, and 29 Ichinose,12 Neonatal Group,13 Macrae, Loh, Goyal, and Germann14 § 103 1–29 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, Loh, and Goyal § 103 1–3, 5–9, 11, 13, 14, 16– 18, 21, 23–27, and 29 Bernasconi, INOmax label, Loh, Goyal, and Macrae § 103 4, 10, 12, 15, 19, 20, 22, 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). IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 8 References Basis Claims Challenged Ichinose, Neonatal Group, Macrae, Loh, Goyal, and Germann § 103 1–30 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, Loh, and Goyal § 103 1, 2, 4, 6, 7, 9, 11–13, 15, 18, 20, 21, 23, and 25 Bernasconi, INOmax label, Loh, Goyal, and Macrae § 103 3, 5, 8, 10, 14, 16, 17, 19, 22, and 24 Ichinose, Macrae, Germann, Neonatal Group, Loh, and Goyal § 103 1–25 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 Bernasconi, Loh, INOmax label, Juliana,15 and Goyal § 103 24–27, 29, 30, and 33 Bernasconi, Loh, Macrae, and Goyal § 103 3, 5, 15, 16, 36, and 41 Bernasconi, Loh, INOmax label, Juliana, Macrae, and Goyal § 103 28 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). IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 9 References Basis Claims Challenged Ichinose, Neonatal Group, Macrae, Loh, Germann, and Goyal § 103 1–23, 31, 32, and 34–44 Ichinose, Neonatal Group, Macrae, Loh, INOmax label, Germann, and Goyal § 103 24–30 and 33 ANALYSIS II. A. Claim Construction 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,” IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 10 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” IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 11 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. 1. Bernasconi (Ex. 1004) Bernasconi reviews the “delivery and monitoring aspects of inhaled nitric oxide, its potential toxic and side effects and its applications in several IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 12 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. 2. INOmax Label (Ex. 1014) 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 IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 13 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. 5. Analysis 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 IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 14 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 IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 15 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 IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 16 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 IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 17 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. 1. Ichinose (Ex. 1009) Ichinose is a review article disclosing the uses and therapeutic potential of inhaled nitric oxide. Ex. 1009, 3106. Ichinose discusses the IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 18 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 3109. 2. Neonatal Group (Ex. 1011) Neonatal Group describes the results of a randomized, multicenter study to determine whether inhaled nitric oxide would reduce mortality or the initiation of extracorporeal membrane oxygenation in infants with hypoxic respiratory failure. Ex. 1011, Abstract. The study found that nitric oxide therapy reduced the use of extracorporeal membrane oxygenation, but had no apparent effect on mortality in critically ill infants with hypoxic respiratory failure. Id. 3. Macrae (Ex. 1008) Macrae discusses the use of inhaled nitric oxide in neonates and children with cardiorespiratory failure. Ex. 1008, Abstract. Macrae notes that studies of inhaled nitric oxide in term or near-term babies have used echocardiography to exclude patients with congenital heart disease as a cause of hypoxemia. Id. at 373–74. For example, Macrae states that inhaled nitric oxide may be harmful to babies with severe LVD with right-to-left ductal shunting. Id. at 374. IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 19 4. Germann (Ex. 1010) Germann discloses the use of inhaled nitric oxide to treat acute respiratory failure and pulmonary hypertension in adults. Ex. 1010, Abstract. Germann also provides expert recommendations for the use of inhaled nitric oxide in adults. Id. For example, for patients with chronic left ventricular failure, Germann states that some studies report sudden development of pulmonary edema in patients with severe congestive heart failure who were treated with inhaled nitric oxide. Id. at 1033. Germann further states that inhaled nitric oxide may be dangerous in patients with LVD. Id. 5. Analysis Petitioner asserts that the combination of Ichinose, Neonatal Group, Macrae, Loh, Goyal, and Germann teaches or suggests each limitation of each of the independent claims of the ’966 patent, the ’284 patent, and the ’163 patent. In particular, for the exclusion limitation of the independent claims of the ’966 patent, Petitioner asserts that a person of ordinary skill in the art would have known that “all patients with LVD, whether or not they depended on right-to-left shunting, were at risk of pulmonary edema if treated with iNO.” -522 Pet. 48 (citing Ex. 1009, 3109; Ex. 1002 ¶¶ 61, 67). Petitioner further argues that Ichinose discloses that patients with LVD treated with iNO are at risk of pulmonary edema. Id. (citing Ex. 1009, 3109). Moreover, Petitioner asserts that Germann discloses that “treating patients with LVD with iNO may be dangerous,” because Germann states that “[i]n the presence of left heart dysfunction it is increasingly recognised that iNO testing should be performed only after optimising heart failure therapy immediately prior to testing.” Id. at 48–49 (citing Ex. 1010, 1033; Ex. 1002 ¶ 67). Petitioner concludes that a person of ordinary skill in the art IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 20 reading Ichinose and Germann would have understood that patients with LVD were at risk of pulmonary edema upon treatment with iNO and “would have evaluated the risks associated with iNO treatment and excluded the patients from iNO treatment.” Id. at 49 (citing Ex. 1002 ¶¶ 63, 65, 67, 72; Ex. 1009, 3109; Ex. 1010, 1033). Petitioner makes the same arguments with respect to the ’284 and ’163 patents. -524 Pet. 46–47, 50–51; -525 Pet. 40– 41, 44–45. Patent Owner asserts that both Ichinose and Germann relate to patient populations that are distinct from the claimed excluded group, and Petitioner does not explain why the teachings of those references would be applied by a person of ordinary skill in the art to the claimed excluded group. -522 Prelim. Resp. 54. For example, Patent Owner notes that Germann relates to inhaled nitric oxide therapy in adults, not children. Id. at 55; see Ex. 1010, Title, Abstract. Patent Owner also notes that the reference cited by Ichinose as support for the risk of pulmonary edema, Beghetti (1997),16 was a letter to the editor in response to a case study reported in Henrichsen.17 Ex. 2004, 844. Henrichsen describes a baby with PPHN and LVD who developed systemic hypotension after exposure to inhaled nitric oxide. Ex. 1030, 183. That baby, however, was dependent on right-to-left shunting of blood, a condition which is expressly excluded from each of the claims. See id.; see, e.g., Ex. 1001, claim 1 (performing echocardiography to identify a child in need of iNO “wherein the child is not dependent on right-to-left shunting of 16 M. Beghetti et al., Letter to the Editor, Inhaled Nitric Oxide Can Cause Severe Systemic Hypotension, 130 J. PEDIATR. 844 (1997) (Ex. 2004). 17 T. Henrichsen et al., Letter to the Editor, Inhaled Nitric Oxide Can Cause Severe Systemic Hypotension, 129 J. PEDIATR. 183 (1996) (Ex. 1030). IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 21 blood”). Moreover, when specifically discussing the treatment of newborns, Ichinose states “[l]arge clinical trials have demonstrated that NO inhalation is safe in the hypoxemic term newborn.” Ex. 1009, 3108. After considering both parties’ arguments and evidence, we are not persuaded that Petitioner has shown sufficiently that the combination of Ichinose and Germann teaches or suggests the exclusion limitation of the claims, as Petitioner asserts. As explained above, we are not persuaded that Petitioner has shown sufficiently that a person of ordinary skill in the art would reasonably expect that children with LVD would be at risk of SAEs like pulmonary edema from iNO treatment. For example, we are not persuaded that a person of ordinary skill in the art would apply studies regarding iNO treatment in adults to treatment in children. We are, therefore, not persuaded that a person of ordinary skill in the art would apply Germann’s teachings for adult iNO treatment to the treatment of children. Similarly, we are not persuaded that a person of ordinary skill in the art would look to Ichinose and its observations with respect to a neonate dependent on right-to-left shunting of blood when such patients are excluded from the claimed methods. Finally, as explained above, we are persuaded by the fact that the experts in the field designing the INOT22 study did not exclude children with LVD from the original protocol. Accordingly, after considering both parties’ arguments and evidence, we are not persuaded that Petitioner has shown a reasonable likelihood that it would prevail in showing that any of the claims of the ’966 patent, the ’284 patent, and the ’163 patent are unpatentable as obvious over Ichinose, Neonatal Group, Macrae, Loh, Goyal, and Germann. IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 22 D. Obviousness of Claims 1–23, 31, 32, and 34–44 of the ’741 Patent over Ichinose, Neonatal Group, Macrae, Loh, Goyal, and Germann Petitioner asserts that claims 1–23, 31, 32, and 34–44 of the ’741 patent are unpatentable over Ichinose, Neonatal Group, Macrae, Loh, Goyal, and Germann. -526 Pet. 39–54. Regarding the exclusion limitations of independent claims 1, 9, 34, and 37, Petitioner argues that Ichinose discloses that patients with LVD treated with iNO are at risk of pulmonary edema, and that Loh discloses that patients with LVD show an increased wedge pressure upon iNO treatment. Id. at 46 (citing Ex. 1009, 3109; Ex. 1006, 2780–81, Table 1). Petitioner further argues that because patients with LVD were at risk of increased wedge pressure and pulmonary edema from iNO treatment, a person of ordinary skill in the art reading Ichinose and Loh “would have considered the benefits and risks of treating such patients with iNO and would have excluded such patients from or discontinued iNO treatment if the risks outweighed the benefits.” Id. Patent Owner asserts substantially the same arguments regarding Ichinose that it set forth with respect to the claims of the other involved patents. That is, it argues that Ichinose relates to a neonate dependent on right-to-left shunting of blood, which is “excluded from the ’741 claims.” -526 Prelim. Resp. 56. Patent Owner also argues that Loh, which was considered by the Examiner during prosecution, is directed to adult patients and has nothing to do with children who have LVD. Id. at 43 (citing Ex. 1006, 2780). After considering both parties’ arguments and evidence, we are not persuaded that Petitioner has shown sufficiently that the cited prior art teaches or suggests the exclusion limitations of the claims. As an initial matter, we note that the ’741 claims do not expressly exclude children IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 23 dependent on right-to-left shunting of blood, as Patent Owner asserts. Regardless, we find persuasive Patent Owner’s argument that Petitioner has failed to establish why a person of ordinary skill in the art would apply Loh’s teachings relating to adults to the treatment of children. We also find persuasive Patent Owner’s argument that the INOT22 study is evidence of nonobviousness, as explained above. Because Petitioner failed to address persuasively either of these arguments—despite the fact that both were raised during prosecution—we determine that Petitioner has not established a reasonable likelihood that it would prevail in showing that claims 1–23, 31, 32, and 34–44 of the ’741 patent are unpatentable over Ichinose, Neonatal Group, Macrae, Loh, Goyal, and Germann. E. Obviousness of Claims 24–30 and 33 of the ’741 Patent over Bernasconi, INOmax Label, Loh, Juliana, and Goyal Petitioner asserts that claims 24–27, 29, 30, and 33 of the ’741 patent are unpatentable over Bernasconi, INOmax label, Loh, Juliana, and Goyal. - 526 Pet. 54–60. Petitioner further asserts that claim 28, which depends from independent claim 24, is unpatentable over Bernasconi, INOmax label, Loh, Juliana, Macrae, and Goyal. Id. at 60. We determine that Petitioner has not established a reasonable likelihood that it would prevail on its assertions. 1. Juliana (Ex. 1010) Juliana describes a case of a full-term neonate with severe PPHN. Ex. 1010, Abstract. Cardiac ultrasound confirmed a right-to-left shunt through an open arterial duct. Id. at 627. The patient was not treated with inhaled nitric oxide because of the high cost of the treatment, but was treated successfully with one dose of sildenafil. Id. IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 24 2. Analysis As explained above, we interpret steps (d) and (e) of claim 24 as equivalent to the exclusion limitations of the other challenged claims. For the step of “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” of claim 24(d), Petitioner relies on its arguments with respect claim 1(c). -526 Pet. 34. That is, Petitioner argues that Bernasconi discloses that patients with LVD are at risk of pulmonary edema upon treatment with iNO. Id. at 20. Petitioner also argues that Loh discloses that patients with LVD have an increased wedge pressure upon iNO treatment, and that Goyal confirms that it was well known that wedge pressure could be measured in infants. Id. at 20–21. For step (e), “administering a second treatment regimen . . . 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,” Petitioner relies on Juliana’s disclosure that neonates with PPN can be treated with sildenafil instead of inhaled nitric oxide. Id. at 34 (citing Ex. 1032, Abstract, 627; Ex. 1002 ¶ 53). Petitioner then concludes that a person of ordinary skill in the art reading Juliana “would have understood to administer a treatment other than iNO, i.e., sildenafil.” Id. at 34–35. For the same reasons stated above, we are not persuaded that Petitioner has shown sufficiently that a person of ordinary skill in the art reading Bernasconi and Loh would reasonably expect neonates with LVD to be “at particular risk of increased PCWP leading to pulmonary edema upon treatment with inhaled nitric oxide,” as required by claim 24(d). Accordingly, we determine that Petitioner has not established a reasonable IPR2015-00522 (8,282,966 B2); IPR2015-00524 (8,293,284 B2); IPR2015-00525 (8,431,163 B2); IPR2015-00526 (8,795,741 B2) 25 likelihood that it would prevail in showing that claims 24–30 and 33 of the ’741 patent are unpatentable over the cited references. CONCLUSION III. We conclude that Petitioner has not demonstrated a reasonable likelihood of prevailing on its assertions that claims 1–29 the ’966 patent; claims 1–30 of the ’284 patent; claims 1–25 of the ’163 patent; and claims 1–44 of the ’741 patent are unpatentable as obvious. ORDER IV. In consideration of the foregoing, it is hereby ordered that the Petitions in IPR2015-00522, IPR2015-00524, IPR2015-00525, and IPR2015-00526 are denied. PETITIONER: Sanjay K. Murthy sanjay.murthy@klgates.com Sara Kerrane Sara.kerrane@klgates.com Margaux Nair margaux.nair@klgates.com Maria Doukas maria.doukas@klgates.com PATENT OWNER: Dominick A. Conde dconde@fchs.com Raymond R. Mandra rmandra@fchs.com Copy with citationCopy as parenthetical citation