Praxair Distribution, Inc.v.INO Therapeutics LLC

Patent Trial and Appeal Board

Jul 29, 2015

13683417 (P.T.A.B. Jul. 29, 2015)

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
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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
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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);
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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
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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).
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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
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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.
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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
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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