Bernasconi, Loh, and Goyal
`
`
`Bernasconi teaches that there may be negative effects such as
`pulmonary edema upon administering inhaled nitric oxide
`(“iNO”) to a patient.
`
`
`Claims 1, 2, 4, 6-14, 17-23, 31, 32, 34, 35, 37-40, and 42-44 of the ʼ741 patent
`are unpatentable under 35 U.S.C. § 103(a) as obvious over Bernasconi in view
`of Loh and Goyal.
`
`U.S. Pat. No.
`8,795,741
`CLAIM 1
`A method of treating
`patients who are
`candidates for inhaled
`nitric oxide treatment,
`which method
`reduces the risk that
`inhalation of nitric
`oxide gas will induce
`an increase in
`pulmonary capillary
`wedge pressure
`(PCWP) leading to
`pulmonary edema in
`neonatal patients with
`hypoxic respiratory
`failure, the method
`comprising:
`
`Ex. 1004 at 8.
`Bernasconi teaches the FDA recommended dose for neonates
`with hypoxic respiratory failure is 20 ppm iNO.
`
`Ex. 1004 at 3.
`Additionally, Loh teaches measuring a baseline wedge pressure
`prior to administering iNO by having patients inhale room air
`and then performing measurements. (Wedge pressure may also
`be called pulmonary capillary wedge pressure (“PCWP”),
`pulmonary arterial wedge pressure (“PAWP”), or merely
`“wedge.” All the terms refer to the same concept). Loh further
`teaches that patients with LVD have a baseline wedge pressure
`that is greater than 20 mm Hg and that the wedge pressure
`increases upon treatment with iNO.
`
`
`
`
`
`1
`
`
`
`
`Bernasconi teaches that there may be negative effects such as
`pulmonary edema upon administering inhaled nitric oxide
`(“iNO”) to a patient.
`
`
`Claims 1, 2, 4, 6-14, 17-23, 31, 32, 34, 35, 37-40, and 42-44 of the ʼ741 patent
`are unpatentable under 35 U.S.C. § 103(a) as obvious over Bernasconi in view
`of Loh and Goyal.
`
`U.S. Pat. No.
`8,795,741
`CLAIM 1
`A method of treating
`patients who are
`candidates for inhaled
`nitric oxide treatment,
`which method
`reduces the risk that
`inhalation of nitric
`oxide gas will induce
`an increase in
`pulmonary capillary
`wedge pressure
`(PCWP) leading to
`pulmonary edema in
`neonatal patients with
`hypoxic respiratory
`failure, the method
`comprising:
`
`Ex. 1004 at 8.
`Bernasconi teaches the FDA recommended dose for neonates
`with hypoxic respiratory failure is 20 ppm iNO.
`
`Ex. 1004 at 3.
`Additionally, Loh teaches measuring a baseline wedge pressure
`prior to administering iNO by having patients inhale room air
`and then performing measurements. (Wedge pressure may also
`be called pulmonary capillary wedge pressure (“PCWP”),
`pulmonary arterial wedge pressure (“PAWP”), or merely
`“wedge.” All the terms refer to the same concept). Loh further
`teaches that patients with LVD have a baseline wedge pressure
`that is greater than 20 mm Hg and that the wedge pressure
`increases upon treatment with iNO.
`
`
`
`
`
`1
`
`
`
`U.S. Pat. No.
`8,795,741
`
`
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`
`2
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2782.
`
`Ex. 1006 at 2782, Table 2.
`3
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`Goyal teaches that wedge pressure may be measured in infants
`and children.
`
`Ex. 1007 at 209.
`
`
`
`a
`identifying
`(a)
`plurality of term or
`near-term
`neonatal
`patients who have
`hypoxic
`respiratory
`failure
`and
`are
`candidates
`for 20
`ppm
`inhaled nitric
`oxide treatment;
`
`
`
`Ex. 1007 at Table 1.
`See also parts (a)-(e)
`Bernasconi teaches that echocardiography may be used to
`confirm whether a patient has a condition which may be helped
`by iNO.
`
`Ex. 1004 at 8.
`Bernasconi teaches that a condition that may be helped by iNO
`treatment is neonatal hypoxic respiratory failure and that the
`FDA recommended dose for treating neonatal hypoxic
`respiratory failure is 20 ppm iNO.
`
`
`
`4
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`(b) determining that a
`first patient of the
`plurality does not
`have left ventricular
`dysfunction;
`
`Ex. 1004 at 3.
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO, as well as
`to exclude structural congenital heart disease that may
`contraindicate the use of iNO.
`
`Ex. 1004 at 8.
`Bernasconi teaches that there are reports of negative effects of
`iNO treatment in patients with left ventricular dysfunction
`(“LVD”), specifically pulmonary edema.
`
`(c) determining that a
`second patient of the
`plurality has left
`ventricular
`dysfunction, so is at
`particular risk of
`increased PCWP
`leading to pulmonary
`edema upon
`treatment with
`inhaled nitric oxide;
`
`Ex. 1004 at 8.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD including a risk of causing pulmonary
`edema.
`
`Ex. 1004 at 8.
`
`Additionally, Loh teaches measuring a baseline wedge pressure
`
`
`
`5
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`prior to administering iNO by having patients inhale room air
`and then performing measurements. Loh further teaches that
`patients with LVD have a baseline wedge pressure that is
`greater than 20 mm Hg and that the wedge pressure increases
`upon treatment with iNO.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`
`
`6
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`Ex. 1006 at 2782.
`
`
`
`
`
`7
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2782, Table 2.
`Goyal teaches that wedge pressure may be measured in infants
`and children before and after the treatment of pulmonary
`hypertension.
`
`
`
`Ex. 1007 at 209.
`
`
`
`
`
`8
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1007 at Table 1.
`Bernasconi teaches the FDA recommended dose for neonates
`with hypoxic respiratory failure is 20 ppm iNO.
`
`
`
`Ex. 1004 at 3.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD, including a risk of causing pulmonary
`edema.
`
`Ex. 1004 at 8.
`
`Additionally, Loh teaches measuring a baseline wedge pressure
`prior to administering iNO by having patients inhale room air
`and then performing measurements. Loh further teaches that
`
`9
`
`(d) administering 20
`ppm inhaled nitric
`oxide treatment to the
`first patient; and
`
`(e) excluding the
`second patient from
`treatment with
`inhaled nitric oxide,
`based on the
`determination that the
`second patient has
`left ventricular
`dysfunction, so is at
`particular risk of
`increased PCWP
`leading to pulmonary
`edema upon
`treatment with
`inhaled nitric oxide.
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`patients with LVD have a baseline wedge pressure that is
`greater than 20 mm Hg and that the wedge pressure increases
`upon treatment with iNO.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`
`
`10
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2782.
`
`Ex. 1006 at 2782, Table 2.
`11
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`CLAIM 2
`The method of claim
`1, wherein the first
`patient has congenital
`heart disease.
`
`Bernasconi, Loh, and Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 1.
`
`Bernasconi teaches that 20 ppm iNO treatment is effective in
`selectively lowering pulmonary vascular resistance in children
`with pulmonary hypertension and congenital heart disease.
`
`Ex. 1004 at 12.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 1.
`
`Bernasconi further teaches that negative effects of iNO
`treatment in patients with LVD can include not only pulmonary
`edema, but also rapid left heart failure.
`
`12
`
`Ex. 1004 at 8.
`
`
`
`CLAIM 4
`The method of claim
`1, wherein the second
`patient is determined
`to be at particular risk
`not only of increased
`PCWP
`leading
`to
`pulmonary
`edema,
`but also of other
`serious
`adverse
`events,
`upon
`treatment
`with
`inhaled nitric oxide,
`and
`the
`second
`patient
`is excluded
`from
`inhaled nitric
`oxide treatment based
`on the determination
`that
`the
`second
`patient
`has
`left
`ventricular
`dysfunction and so is
`at particular risk not
`only of
`increased
`PCWP
`leading
`to
`pulmonary
`edema,
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`but also other serious
`adverse events, upon
`treatment
`with
`inhaled nitric oxide.
`CLAIM 6
`The method of claim
`1,
`wherein
`determining that the
`first patient does not
`have pre-existing left
`ventricular
`dysfunction and the
`second patient does
`have pre-existing left
`ventricular
`dysfunction
`comprises performing
`at least one diagnostic
`process on each of
`the first and second
`patients.
`
`Bernasconi, Loh, and Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are above in Claim 1.
`
`Bernasconi teaches that it is important to know if a patient has
`LVD before administering treatment as Bernasconi further
`teaches that negative effects of iNO treatment in patients with
`LVD can include not only pulmonary edema, but also rapid left
`heart failure.
`
`Ex. 1004 at 8.
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO, as well as
`to exclude structural congenital heart disease that may
`contraindicate the use of iNO.
`
`CLAIM 7
`The method of claim
`1,
`wherein
`determining that the
`first patient does not
`have pre-existing left
`ventricular
`dysfunction and the
`second patient does
`
`Ex. 1004 at 8.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 1.
`
`Bernasconi teaches that it is important to know if a patient has
`LVD before administering treatment as Bernasconi further
`teaches that negative effects of iNO treatment in patients with
`LVD can include not only pulmonary edema, but also rapid left
`heart failure.
`
`
`
`13
`
`
`
`U.S. Pat. No.
`8,795,741
`have pre-existing left
`ventricular
`dysfunction
`comprises performing
`echocardiography on
`the first and second
`patients.
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1004 at 8.
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO, as well as
`to exclude structural congenital heart disease that may
`contraindicate the use of iNO.
`
`CLAIM 8
`The method of claim
`1, wherein the second
`patient has a PCWP
`that is greater than or
`equal to 20 mm Hg.
`
`Ex. 1004 at 8.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 1.
`
`Loh teaches measuring the wedge pressure prior to
`administering iNO to determine baseline conditions. Loh
`further teaches that patients with LVD have a baseline wedge
`pressure greater than 20 mm Hg.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`14
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`
`
`Ex. 1006 at 2781, Table 1.
`Goyal teaches that wedge pressure may be measured in infants
`and children before and after the treatment of pulmonary
`hypertension.
`
`Ex. 1007 at 209.
`
`
`
`
`
`15
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1007 at Table 1.
`
`Bernasconi teaches that there may be negative effects such as
`pulmonary edema upon administering iNO to a patient.
`
`
`
`Ex. 1004 at 8.
`Bernasconi teaches the FDA recommended dose for neonates
`with hypoxic respiratory failure is 20 ppm iNO.
`
`Ex. 1004 at 3.
`Additionally, Loh teaches measuring a baseline wedge pressure
`prior to administering iNO by having patients inhale room air
`and then performing measurements. Loh further teaches that
`patients with LVD have a baseline wedge pressure that is
`greater than 20 mm Hg and that the wedge pressure increases
`16
`
`CLAIM 9
`A method of treating
`patients who
`are
`candidates for inhaled
`nitric oxide treatment,
`which
`method
`reduces the risk that
`inhalation
`of
`the
`nitric oxide gas will
`induce an increase in
`PCWP
`leading
`to
`pulmonary edema in
`neonatal patients with
`hypoxic
`respiratory
`failure, said method
`comprising:
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`upon treatment with iNO.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`
`17
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2782.
`
`Ex. 1006 at 2782, Table 2.
`18
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`
`Goyal teaches that wedge pressure may be measured in infants
`and children.
`
`Ex. 1007 at 209.
`
`
`
`a
`identifying
`(a)
`plurality of term or
`near-term
`neonatal
`patients who have
`hypoxic
`respiratory
`failure
`and
`are
`candidates
`for 20
`ppm
`inhaled nitric
`oxide treatment;
`
`
`
`Ex. 1007 at Table 1.
`
`See also parts (a)-(e)
`Bernasconi teaches that echocardiography may be used to
`confirm whether a patient has a condition, which may be
`helped by iNO.
`
`Ex. 1004 at 8.
`Bernasconi teaches that a condition that may be helped by iNO
`treatment is neonatal hypoxic respiratory failure and that the
`FDA recommended dose for treating neonatal hypoxic
`respiratory failure is 20 ppm iNO.
`
`
`
`19
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`(b) determining that a
`first patient of
`the
`plurality does not
`have left ventricular
`dysfunction;
`
`Ex. 1004 at 3.
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO, as well as
`to exclude structural congenital heart disease that may
`contraindicate the use of iNO.
`
`Ex. 1004 at 8.
`Bernasconi teaches that there are reports of negative effects of
`iNO treatment in patients with LVD, specifically pulmonary
`edema.
`
`(c) determining that a
`second patient of the
`plurality
`has
`left
`ventricular
`dysfunction, so is at
`particular
`risk
`of
`increased
`PCWP
`leading to pulmonary
`edema
`upon
`treatment
`with
`inhaled nitric oxide;
`
`Ex. 1004 at 8.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD including a risk of causing pulmonary
`edema.
`
`Ex. 1004 at 8.
`
`Additionally, Loh teaches measuring a baseline wedge pressure
`
`
`
`20
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`prior to administering iNO by having patients inhale room air
`and then performing measurements. Loh further teaches that
`patients with LVD have a baseline wedge pressure that is
`greater than 20 mm Hg and that the wedge pressure increases
`upon treatment with iNO.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`
`
`21
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2782.
`
`Ex. 1006 at 2782, Table 2.
`22
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`Goyal teaches that wedge pressure may be measured in infants
`and children before and after the treatment of pulmonary
`hypertension.
`
`Ex. 1007 at 209.
`
`
`
`Ex. 1007 at Table 1.
`Bernasconi teaches the FDA recommended dose for neonates
`with hypoxic respiratory failure is 20 ppm iNO.
`
`
`
`Ex. 1004 at 3.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD, including a risk of causing pulmonary
`edema.
`
`23
`
`(d) administering 20
`ppm
`inhaled nitric
`oxide treatment to the
`first patient; and
`
`the
`excluding
`(e)
`second patient from
`treatment
`with
`inhaled nitric oxide
`based
`on
`the
`determination in (c),
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`or, despite the second
`patient's
`ongoing
`need for inhaled nitric
`oxide
`treatment for
`hypoxic
`respiratory
`failure, discontinuing
`the second patient's
`treatment
`with
`inhaled nitric oxide
`after it was begun, the
`discontinuation being
`in
`view
`of
`the
`determination in (c).
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1004 at 8.
`
`Additionally, Loh teaches measuring a baseline wedge pressure
`prior to administering iNO by having patients inhale room air
`and then performing measurements. Loh further teaches that
`patients with LVD have a baseline wedge pressure that is
`greater than 20 mm Hg and that the wedge pressure increases
`upon treatment with iNO.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`24
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`Ex. 1006 at 2782.
`
`
`
`
`
`25
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`
`
`Ex. 1006 at 2782, Table 2.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 9.
`
`Bernasconi further teaches that negative effects of iNO
`treatment in patients with LVD can include not only pulmonary
`edema, but also rapid left heart failure.
`
`CLAIM 10
`The method of claim
`9,
`wherein
`the
`discontinuation is in
`view of both
`the
`determination in (c)
`and
`the
`second
`patient's experiencing
`an
`adverse
`event
`upon treatment with
`inhaled nitric oxide.
`
`26
`
`Ex. 1004 at 8.
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`CLAIM 11
`The method of claim
`10, wherein
`the
`adverse
`event
`comprises pulmonary
`edema.
`
`Bernasconi, Loh, and Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 10.
`
`Bernasconi further teaches that negative effects of iNO
`treatment in patients with LVD can include pulmonary edema.
`
`CLAIM 12
`The method of claim
`10, wherein the
`adverse event
`comprises at least one
`of increased PCWP,
`systemic
`hypotension,
`bradycardia, or
`cardiac arrest.
`
`Ex. 1004 at 8.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 10.
`
`Loh teaches measuring the wedge pressure prior to
`administering iNO to determine baseline conditions. Loh
`further teaches that patients with LVD have a baseline wedge
`pressure greater than 20 mm Hg and that the wedge pressure
`increases upon iNO treatment.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`27
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`Ex. 1006 at 2782.
`
`
`
`
`
`28
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`
`
`Ex. 1006 at 2782, Table 2.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 9.
`
`Loh teaches measuring the wedge pressure prior to
`administering iNO to determine baseline conditions. Loh
`further teaches that patients with LVD have a baseline wedge
`pressure greater than 20 mm Hg.
`
`Ex. 1006 at 2780.
`
`
`
`CLAIM 13
`The method of claim
`9, wherein (c)
`comprises
`determining that the
`second patient has a
`pulmonary capillary
`wedge pressure that is
`greater than or equal
`to 20 mm Hg.
`
`
`
`
`
`29
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2781.
`
`
`
`
`
`Ex. 1006 at 2781, Table 1.
`Goyal teaches that wedge pressure may be measured in infants
`and children before and after the treatment of pulmonary
`hypertension.
`
`Ex. 1007 at 209.
`
`
`
`
`
`30
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`CLAIM 14
`The method of claim
`9, wherein the first
`patient has congenital
`heart disease.
`
`
`
`Ex. 1007 at Table 1.
`
`All the elements of the independent claim from which this
`claim depends are above in Claim 9.
`
`Bernasconi teaches that 20 ppm iNO treatment is effective in
`selectively lowering pulmonary vascular resistance in children
`with pulmonary hypertension and congenital heart disease.
`
`CLAIM 17
`The method of claim
`9, wherein
`the second patient is
`determined to be at
`particular
`risk not
`only of
`increased
`PCWP
`leading
`to
`pulmonary
`edema,
`but also of other
`serious
`adverse
`events,
`upon
`
`
`
`Ex. 1004 at 12.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 9.
`
`Bernasconi further teaches that negative effects of iNO
`treatment in patients with LVD can include not only pulmonary
`edema, but also rapid left heart failure.
`
`31
`
`
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1004 at 8.
`
`
`
`32
`
`U.S. Pat. No.
`8,795,741
`with
`treatment
`inhaled nitric oxide;
`and
`
`
`either (i) the second
`patient is excluded
`from inhaled nitric
`oxide treatment based
`on both the
`determination in (c)
`and the determination
`that the second
`patient is also at risk
`of other serious
`adverse events upon
`treatment with
`inhaled nitric oxide;
`or (ii) despite the
`second patient's
`ongoing need for
`inhaled nitric oxide
`treatment for hypoxic
`respiratory failure,
`the second patient's
`treatment with
`inhaled nitric oxide is
`discontinued after it
`was begun, the
`discontinuation being
`in view of both the
`determination in (c)
`and the determination
`that the second
`patient is also at risk
`of other serious
`adverse events upon
`treatment with
`inhaled nitric oxide.
`
`
`
`
`
`Bernasconi, Loh, and Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 17.
`
`Loh teaches measuring the wedge pressure prior to
`administering iNO to determine baseline conditions. Loh
`further teaches that patients with LVD have a baseline wedge
`pressure greater than 20 mm Hg and that the wedge pressure
`increases upon iNO treatment.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`CLAIM 18
`The method of claim
`17, wherein the other
`serious adverse
`events comprise one
`or more of increased
`PCWP, systemic
`hypotension,
`bradycardia, or
`cardiac arrest.
`
`
`
`
`
`33
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`Ex. 1006 at 2781, Table 1.
`
`Ex. 1006 at 2782.
`
`
`
`
`
`34
`
`
`
`U.S. Pat. No.
`8,795,741
`
`CLAIM 19
`The method of claim
`17, wherein the
`discontinuation is in
`view of: the
`determination in (c),
`the determination that
`the second patient is
`also at risk of other
`serious adverse
`events, and the
`second patient's
`experiencing an
`adverse event upon
`treatment with
`inhaled nitric oxide.
`CLAIM 20
`The method of claim
`19, wherein
`the
`adverse
`event
`experienced by
`the
`second
`patient
`comprises pulmonary
`edema.
`
`Bernasconi, Loh, and Goyal
`Ex. 1006 at 2782, Table 2.
`
`All the elements of the independent claim from which this
`claim depends are above in Claim 17.
`
`Bernasconi further teaches that negative effects of iNO
`treatment in patients with LVD can include not only pulmonary
`edema, but also rapid left heart failure.
`
`Ex. 1004 at 8.
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 19.
`
`Bernasconi further teaches that negative effects of iNO
`treatment in patients with LVD can include pulmonary edema.
`
`CLAIM 21
`The method of claim
`19, wherein the
`adverse event
`experienced by the
`second patient
`
`
`
`Ex. 1004 at 8.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 19.
`
`Loh teaches measuring the wedge pressure prior to
`administering iNO to determine baseline conditions. Loh
`35
`
`
`
`U.S. Pat. No.
`8,795,741
`comprises at least one
`of increased PCWP,
`systemic
`hypotension,
`bradycardia, or
`cardiac arrest.
`
`Bernasconi, Loh, and Goyal
`further teaches that patients with LVD have a baseline wedge
`pressure greater than 20 mm Hg and that the wedge pressure
`increases upon iNO treatment.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`
`
`36
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2782.
`
`Ex. 1006 at 2782, Table 2.
`37
`
`
`
`
`
`
`
`
`
`Bernasconi, Loh, and Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed i above in Claim 9.
`
`Bernasconi teaches that it is important to know if a patient has
`LVD before administering treatment as Bernasconi further
`teaches that negative effects of iNO treatment in patients with
`LVD can include not only pulmonary edema, but also rapid left
`heart failure.
`
`Ex. 1004 at 8.
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO, as well as
`to exclude structural congenital heart disease that may
`contraindicate the use of iNO.
`
`Ex. 1004 at 8.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 9.
`
`
`
`Bernasconi teaches that it is important to know if a patient has
`LVD before administering treatment as Bernasconi further
`teaches that negative effects of iNO treatment in patients with
`LVD can include not only pulmonary edema, but also rapid left
`heart failure.
`
`38
`
`U.S. Pat. No.
`8,795,741
`CLAIM 22
`The method of claim
`9,
`wherein
`determining that the
`first patient does not
`have pre-existing left
`ventricular
`dysfunction and the
`second patient does
`have pre-existing left
`ventricular
`dysfunction
`comprises performing
`at least one diagnostic
`process on each of
`the first and second
`patients.
`
`CLAIM 23
`The method of claim
`9,
`wherein
`determining that the
`first patient does not
`have pre-existing left
`ventricular
`dysfunction and the
`second patient does
`have pre-existing left
`ventricular
`dysfunction
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`comprises performing
`echocardiography on
`each of the first and
`second patients.
`
`CLAIM 31
`The method of claim
`1, wherein identifying
`the plurality of term
`or near-term neonatal
`patients who have
`hypoxic
`respiratory
`failure
`and
`are
`candidates
`for 20
`ppm
`inhaled nitric
`oxide
`treatment
`comprises performing
`at least one diagnostic
`process.
`CLAIM 32
`The method of claim
`9, wherein identifying
`the plurality of term
`or near-term neonatal
`patients who have
`hypoxic
`respiratory
`failure
`and
`are
`
`
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1004 at 8.
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO, as well as
`to exclude structural congenital heart disease that may
`contraindicate the use of iNO.
`
`Ex. 1004 at 8.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 1.
`
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO.
`
`Ex. 1004 at 8.
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 9.
`
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO.
`
`39
`
`
`
`U.S. Pat. No.
`8,795,741
`candidates
`for 20
`ppm
`inhaled nitric
`oxide
`treatment
`comprises performing
`at least one diagnostic
`process.
`CLAIM 34
`A method of treating
`patients who
`are
`candidates for inhaled
`nitric oxide treatment,
`which
`method
`reduces the risk that
`inhalation of nitric
`oxide gas will induce
`an
`increase
`in
`pulmonary capillary
`wedge
`pressure
`(PCWP)
`leading
`to
`pulmonary
`edema,
`the
`method
`comprising:
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1004 at 8.
`
`
`Bernasconi teaches that there may be negative effects such as
`pulmonary edema upon administering iNO to patients.
`
`Ex. 1004 at 8.
`Bernasconi teaches the FDA recommended dose for neonates
`with hypoxic respiratory failure is 20 ppm iNO.
`
`Ex. 1004 at 3.
`
`Additionally, Loh teaches measuring a baseline wedge pressure
`prior to administering iNO by having patients inhale room air
`and then performing measurements. Loh further teaches that
`patients with LVD have a baseline wedge pressure that is
`greater than 20 mm Hg and that the wedge pressure increases
`upon treatment with iNO.
`
`Ex. 1006 at 2780.
`
`40
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2781.
`
`
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`
`
`41
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2782.
`
`Ex. 1006 at 2782, Table 2.
`42
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`Goyal teaches that wedge pressure may be measured in infants
`and children.
`
`Ex. 1007 at 209.
`
`
`
`a
`identifying
`(a)
`plurality of patients
`who are children with
`a
`condition
`that
`makes
`them
`candidates
`for 20
`ppm
`inhaled nitric
`oxide treatment;
`
`Ex. 1007 at Table 1.
`See also parts (a)-(e)
`Bernasconi teaches that echocardiography may be used to
`confirm whether patients have a condition which may be
`helped by iNO.
`
`
`
`Ex. 1004 at 8.
`Bernasconi teaches the FDA recommended dose for treating
`neonatal hypoxic respiratory failure is 20 ppm iNO.
`
`
`
`43
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1004 at 3.
`Bernasconi teaches using 20 ppm iNO to treat pulmonary
`hypertension in children.
`
`(b) determining that a
`first patient of
`the
`plurality does not
`have left ventricular
`dysfunction;
`
`Ex. 1004 at 12.
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO, as well as
`to exclude structural congenital heart disease that may
`contraindicate the use of iNO.
`
`Ex. 1004 at 8.
`Bernasconi teaches that there are reports of negative effects of
`iNO treatment in patients with LVD.
`
`(c) determining that a
`second patient of the
`plurality
`has
`left
`ventricular
`dysfunction, so is at
`particular
`risk
`of
`increased
`PCWP
`leading to pulmonary
`edema
`upon
`treatment
`with
`inhaled nitric oxide;
`
`
`
`Ex. 1004 at 8.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD including a risk of causing pulmonary
`edema.
`
`Ex. 1004 at 8.
`
`
`44
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`Additionally, Loh teaches measuring a baseline wedge pressure
`prior to administering iNO by having patients inhale room air
`and then performing measurements. Loh further teaches that
`patients with LVD have a baseline wedge pressure that is
`greater than 20 mm Hg and that the wedge pressure increases
`upon treatment with iNO.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`
`
`45
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2782.
`
`Ex. 1006 at 2782, Table 2.
`46
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`Goyal teaches that wedge pressure may be measured in infants
`and children before and after the treatment of pulmonary
`hypertension.
`
`Ex. 1007 at 209.
`
`
`
`Ex. 1007 at Table 1.
`Bernasconi teaches the FDA recommended dose for treating
`neonatal hypoxic respiratory failure is 20 ppm iNO.
`
`
`
`(d) administering 20
`ppm
`inhaled nitric
`oxide treatment to the
`first patient; and
`
`Ex. 1004 at 3.
`Bernasconi teaches using 20 ppm iNO to treat pulmonary
`hypertension in children.
`
`Ex. 1004 at 12.
`
`47
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`the
`excluding
`(e)
`second patient from
`treatment
`with
`inhaled nitric oxide,
`based
`on
`the
`determination that the
`second patient has
`left
`ventricular
`dysfunction, so is at
`particular
`risk
`of
`increased
`PCWP
`leading to pulmonary
`edema
`upon
`treatment
`with
`inhaled nitric oxide.
`
`Bernasconi, Loh, and Goyal
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD, including a risk of causing pulmonary
`edema.
`
`Ex. 1004 at 8.
`
`Additionally, Loh teaches measuring a baseline wedge pressure
`prior to administering iNO by having patients inhale room air
`and then performing measurements. Loh further teaches that
`patients with LVD have a baseline wedge pressure that is
`greater than 20 mm Hg and that the wedge pressure increases
`upon treatment with iNO.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`48
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`Ex. 1006 at 2782.
`
`
`
`
`
`49
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2782, Table 2.
`Goyal teaches that wedge pressure may be measured in infants
`and children.
`
`
`
`Ex. 1007 at 209.
`
`
`
`
`
`50
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`
`
`Ex. 1007 at Table 1.
`
`All the elements of the independent claim from which this
`claim depends are disclosed above in Claim 34.
`
`Bernasconi further teaches that negative effects of iNO
`treatment in patients with LVD can include not only pulmonary
`edema, but also rapid left heart failure.
`
`51
`
`Ex. 1004 at 8.
`
`
`
`CLAIM 35
`The method of claim
`34, wherein
`the
`second
`patient
`is
`determined to be at
`particular
`risk not
`only of
`increased
`PCWP
`leading
`to
`pulmonary
`edema,
`but also of other
`serious
`adverse
`events,
`upon
`treatment
`with
`inhaled nitric oxide,
`and
`the
`second
`patient
`is excluded
`from
`inhaled nitric
`oxide treatment based
`on the determination
`that
`the
`second
`patient
`has
`left
`ventricular
`dysfunction and so is
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`at particular risk not
`only of
`increased
`PCWP
`leading
`to
`pulmonary
`edema,
`but also other serious
`adverse events, upon
`treatment
`with
`inhaled nitric oxide.
`CLAIM 37
`A method of treating
`patients who
`are
`candidates for inhaled
`nitric oxide treatment,
`which
`method
`reduces the risk that
`inhalation
`of
`the
`nitric oxide gas will
`induce an increase in
`PCWP
`leading
`to
`pulmonary edema in
`neonatal patients with
`hypoxic
`respiratory
`failure, said method
`comprising:
`
`Bernasconi, Loh, and Goyal
`
`
`Bernasconi teaches that there may be negative effects such as
`pulmonary edema upon administering iNO to a patient.
`
`Ex. 1004 at 8.
`Bernasconi teaches the FDA recommended dose for neonates
`with hypoxic respiratory failure is 20 ppm iNO.
`
`Ex. 1004 at 3.
`
`Additionally, Loh teaches measuring a baseline wedge pressure
`prior to administering iNO by having patients inhale room air
`and then performing measurements. Loh further teaches that
`patients with LVD have a baseline wedge pressure that is
`greater than 20 mm Hg and that the wedge pressure increases
`upon treatment with iNO.
`
`
`
`52
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`Ex. 1006 at 2781, Table 1.
`
`
`
`
`
`53
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`
`Ex. 1006 at 2782.
`
`Ex. 1006 at 2782, Table 2.
`54
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,795,741
`
`Bernasconi, Loh, and Goyal
`Goyal teaches that wedge pressure may be measured in infants
`and children.
`
`Ex. 1007 at 209.
`
`
`
`a
`identifying
`(a)
`p
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