Claims 1-3, 5-9, 11, 13-14, 16-18, 21, 23-27 and 29 of the ʼ284 patent are
`unpatentable as Obvious Over Bernasconi in View of INOMAX label, Loh, and
`Goyal.
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`See Sections (a)-(c) of Claim 1 below.
`
`Bernasconi teaches that echocardiography is essential to
`identify and treat pediatric patients with conditions, such as
`pulmonary hypertension, that may be treated with inhaled nitric
`oxide (“iNO”).
`
`Ex. 1004 at 8.
`Bernasconi further teaches treating neonates with persistent
`pulmonary hypertension of the newborn (“PPHN”) with iNO
`and that the FDA recommended dose for neonatal hypoxic
`respiratory failure is 20 ppm iNO.
`
`
`
`U.S. Pat. No.
`8,293,284
`CLAIM 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
`term or
`near-term
`neonate
`patient in need of 20
`ppm
`inhaled nitric
`oxide
`treatment for
`pulmonary
`hypertension,
`wherein the patient is
`not dependent on
`right-to-left shunting
`of blood;
`
`
`
`Ex. 1004 at 3.
`INOMAX label teaches that echocardiography can be used to
`identify patients with pulmonary hypertension that may be
`
`
`
`1
`
`
`unpatentable as Obvious Over Bernasconi in View of INOMAX label, Loh, and
`Goyal.
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`See Sections (a)-(c) of Claim 1 below.
`
`Bernasconi teaches that echocardiography is essential to
`identify and treat pediatric patients with conditions, such as
`pulmonary hypertension, that may be treated with inhaled nitric
`oxide (“iNO”).
`
`Ex. 1004 at 8.
`Bernasconi further teaches treating neonates with persistent
`pulmonary hypertension of the newborn (“PPHN”) with iNO
`and that the FDA recommended dose for neonatal hypoxic
`respiratory failure is 20 ppm iNO.
`
`
`
`U.S. Pat. No.
`8,293,284
`CLAIM 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
`term or
`near-term
`neonate
`patient in need of 20
`ppm
`inhaled nitric
`oxide
`treatment for
`pulmonary
`hypertension,
`wherein the patient is
`not dependent on
`right-to-left shunting
`of blood;
`
`
`
`Ex. 1004 at 3.
`INOMAX label teaches that echocardiography can be used to
`identify patients with pulmonary hypertension that may be
`
`
`
`1
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`treated with iNO.
`
`Ex. 1014 at 4.
`INOMAX label further teaches the FDA recommended dose for
`iNO treatment is 20 ppm.
`
`Ex. 1014 at 6.
`INOMAX label further teaches that iNO should not be used in
`patients dependent on right-to-left shunting of blood.
`
`Ex. 1014 at 4.
`Bernasconi teaches that there are negative effects of iNO in
`patients with left ventricular dysfunction (“LVD”) including a
`risk of causing pulmonary edema.
`
`Ex. 1004 at 8.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. (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.
`
`(b) determining that
`the patient identified
`in (a) has a
`pulmonary capillary
`wedge pressure
`greater than or equal
`to 20 mm Hg and
`thus has left
`ventricular
`dysfunction, so is at
`particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide;
`and
`
`
`
`2
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`Ex. 1006 at Table 1.
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`
`
`Ex. 1007 at 209.
`
`3
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`(c) excluding the
`patient 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.
`CLAIM 2
`The method of claim
`1, wherein step (b)
`comprises performing
`echocardiography.
`
`Ex. 1007 at Table 1.
`Bernasconi teaches that patients with LVD treated with iNO
`are at risk of pulmonary edema.
`
`
`
`Ex. 1004 at 8.
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 1.
`
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO, as well as
`to exclude a condition that may contraindicate the use of iNO.
`
`
`
`4
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`Ex. 1004 at 8.
`Bernasconi further teaches that patients with LVD treated with
`iNO are at risk of pulmonary edema.
`
`CLAIM 3
`The method of claim
`1, wherein step (b)
`comprises measuring
`the patient's
`pulmonary capillary
`wedge pressure.
`
`Ex. 1004 at 8.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 1.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. Loh further teaches that patients with LVD
`have a baseline wedge pressure that is greater than 20 mm Hg.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`5
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`6
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`
`Ex. 1007 at Table 1.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 1.
`
`Bernasconi 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.
`
`7
`
`CLAIM 5
`The method of claim
`1, wherein the patient
`is determined to be at
`particular
`risk not
`only of pulmonary
`edema, but also of
`other
`Serious
`Adverse Events, upon
`treatment
`with
`inhaled nitric oxide,
`and
`the patient
`is
`excluded
`from
`inhaled nitric oxide
`treatment based on
`the determination that
`the patient has left
`ventricular
`dysfunction and so is
`at particular risk not
`only of pulmonary
`edema, but also of
`other
`Serious
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`Adverse Events, upon
`treatment
`with
`inhaled nitric oxide.
`CLAIM 6
`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) carrying out a
`diagnostic process
`comprising
`measuring blood
`oxygen level, to
`identify a term or
`near-term neonate
`patient as being in
`need of 20 ppm
`inhaled nitric oxide
`treatment for hypoxic
`respiratory failure,
`wherein the patient is
`not dependent on
`right-to-left shunting
`of blood;
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`See Sections (a)-(c) of Claim 6 below.
`
`Bernasconi teaches the FDA recommended dose for treating
`hypoxic respiratory failure is 20 ppm.
`
`Ex. 1004 at 3.
`
`INOMAX label teaches the FDA recommended dose for iNO
`treatment is 20 ppm.
`
`Ex. 1014 at 6.
`INOMAX label further teaches clinical trials measured a
`patient’s arterial blood gas before allowing the patient to be
`randomized for iNO treatment for hypoxic respiratory failure.
`
`
`
`8
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`(b) determining that
`the patient has a
`pulmonary capillary
`wedge pressure
`greater than or equal
`to 20 mm Hg and
`thus has left
`ventricular
`dysfunction, so is at
`particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide;
`and
`
`Ex. 1014 at 2, 3.
`INOMAX label further teaches that iNO should not be used in
`patients dependent on right-to-left shunting of blood.
`
`Ex. 1014 at 4.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD including a risk of causing pulmonary
`edema.
`
`Ex. 1004 at 8.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. Loh further teaches that patients with LVD
`have a baseline wedge pressure that is greater than 20 mm Hg.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`9
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`10
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`(c) excluding the
`patient from
`treatment with
`inhaled nitric oxide
`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.
`CLAIM 7
`The method of claim
`6, wherein the
`diagnostic process of
`step (a) further
`comprises performing
`echocardiography.
`
`Ex. 1007 at Table 1.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD, including a risk of causing pulmonary
`edema.
`
`
`
`Ex. 1004 at 8.
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 6.
`
`Bernasconi teaches that echocardiography is essential to
`identify and treat pediatric patients with conditions, such as
`pulmonary hypertension, that may be treated with iNO.
`
`
`
`11
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1004 at 8.
`
`INOMAX label teaches that echocardiography can be used to
`identify patients with pulmonary hypertension that may be
`treated with iNO.
`
`Ex. 1014 at 4.
`
`
`
`CLAIM 8
`The method of claim
`6, wherein step (b)
`comprises performing
`echocardiography.
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`and Loh as outlined above in Claim 6.
`
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO, as well as
`to exclude a condition that may contraindicate the use of iNO.
`
`Ex. 1004 at 8.
`
`Bernasconi further teaches that patients with LVD treated with
`iNO are at risk of pulmonary edema.
`
`Ex. 1004 at 8.
`
`12
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`CLAIM 9
`The method of claim
`6, wherein step (b)
`comprises measuring
`the patient's
`pulmonary capillary
`wedge pressure.
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 6.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. Loh further teaches that patients with LVD
`have a baseline wedge pressure that is greater than 20 mm Hg.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`13
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`Ex. 1007 at Table 1.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 6.
`
`Bernasconi teaches that negative effects of iNO treatment in
`patients with LVD can include not only pulmonary edema, but
`also rapid left heart failure.
`
`14
`
`CLAIM 11
`The method of claim
`6, wherein the patient
`is determined to be at
`particular risk not
`only of pulmonary
`edema, but also of
`other Serious
`Adverse Events, upon
`treatment with
`inhaled nitric oxide,
`and the patient is
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`excluded from
`inhaled nitric oxide
`treatment based on
`the determination that
`the patient has left
`ventricular
`dysfunction and so is
`at particular risk not
`only of pulmonary
`edema, but also other
`Serious Adverse
`Events, upon
`treatment with
`inhaled nitric oxide.
`CLAIM 13
`A method of
`treatment comprising:
`(a) performing
`echocardiography to
`identify a plurality of
`term or near-term
`neonate patients who
`are in need of 20 ppm
`inhaled nitric oxide
`treatment for
`pulmonary
`hypertension,
`wherein the patients
`are not dependent on
`right-to-left shunting
`of blood;
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1004 at 8.
`
`
`See Sections (a)-(e) of Claim 13 below.
`
`Bernasconi teaches that echocardiography is essential to
`identify and treat pediatric patients with conditions, such as
`pulmonary hypertension, that may be treated with iNO.
`
`Ex. 1004 at 8.
`Bernasconi further teaches treating neonates with persistent
`PPHN with iNO and that the FDA recommended dose for
`neonatal hypoxic respiratory failure is 20 ppm iNO.
`
`Ex. 1004 at 3.
`
`INOMAX label teaches that echocardiography can be used to
`
`
`
`15
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`identify patients with pulmonary hypertension that may be
`treated with iNO.
`
`Ex. 1014 at 4.
`INOMAX label further teaches the FDA recommended dose for
`iNO treatment is 20 ppm.
`
`Ex. 1014 at 6.
`INOMAX label further teaches that iNO should not be used in
`patients dependent on right-to-left shunting of blood.
`
`Ex. 1014 at 4.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD including a risk of causing pulmonary
`edema.
`
`Ex. 1004 at 8.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. Loh further teaches that patients with LVD
`have a baseline wedge pressure that is greater than 20 mm Hg.
`
`(b) determining that a
`first patient of the
`plurality has a
`pulmonary capillary
`wedge pressure
`greater than or equal
`to 20 mm Hg and
`thus has left
`ventricular
`dysfunction, so is at
`particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide;
`
`Ex. 1006 at 2780.
`
`16
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1006 at 2781.
`
`
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`17
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1007 at Table 1.
`Bernasconi teaches that echocardiography is essential to
`identify and treat pediatric patients with conditions that may be
`treated with iNO and identifying conditions that may
`contraindicate iNO.
`
`
`
`(c) determining that a
`second patient of the
`plurality does not
`have left ventricular
`dysfunction;
`
`Ex. 1004 at 8.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. Loh further teaches that patients with LVD
`have a baseline wedge pressure that is greater than 20 mm Hg.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`18
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`19
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1007 at Table 1.
`Bernasconi teaches a treatment comprising administering 20
`ppm nitric oxide gas to treat neonates.
`
`
`
`(d) administering the
`20 ppm inhaled nitric
`oxide treatment to the
`second patient; and
`
`Ex. 1004 at 3.
`
`INOMAX label teaches the FDA recommended dose for iNO
`treatment is 20 ppm.
`
`Ex. 1014 at 6.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD, including a risk of causing pulmonary
`edema.
`
`20
`
`
`
`(e) excluding the first
`patient from
`treatment with
`inhaled nitric oxide,
`based on the
`determination that the
`first patient has left
`ventricular
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`dysfunction, so is at
`particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide.
`
`CLAIM 14
`The method of claim
`13, wherein step (a)
`further
`comprises
`measuring
`blood
`oxygen levels in the
`first
`and
`second
`patients and thereby
`determining that the
`first
`and
`second
`patients are hypoxic.
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1004 at 8.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 13.
`
`INOMAX label teaches clinical trials measured a patient’s
`arterial blood gas before allowing the patient to be randomized
`for iNO treatment for hypoxic respiratory failure.
`
`CLAIM 16
`The method of claim
`13, wherein the
`second patient has
`congenital heart
`disease.
`
`Ex. 1014 at 2, 3.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 13.
`
`Bernasconi teaches that 20 ppm iNO treatment is effective in
`selectively lowering pulmonary vascular resistance in children
`with pulmonary hypertension and congenital heart disease.
`
`
`
`
`21
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`CLAIM 17
`The method of claim
`13, wherein step (b)
`comprises measuring
`the first patient's
`pulmonary capillary
`wedge pressure.
`
`Ex. 1004 at 12.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 13.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. Loh further teaches that patients with LVD
`have a baseline wedge pressure that is greater than 20 mm Hg.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`22
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`23
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`
`Ex. 1007 at Table 1.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`and Loh as outlined above in Claim 13.
`
`Bernasconi teaches that echocardiography may be used to
`confirm a diagnosis and conduct therapy with iNO, as well as
`to exclude a condition that may contraindicate the use of iNO.
`
`Ex. 1004 at 8.
`
`Bernasconi further teaches that patients with LVD treated with
`iNO are at risk of pulmonary edema.
`
`Ex. 1004 at 8.
`
`24
`
`CLAIM 18
`The method of claim
`13, wherein
`determining that the
`first patient of the
`plurality has pre-
`existing left
`ventricular
`dysfunction and the
`second patient of the
`plurality does not
`have pre-existing left
`ventricular
`dysfunction
`comprises performing
`echocardiography on
`the first and second
`patients.
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`CLAIM 21
`The method of claim
`13, wherein the first
`patient is determined
`to be at particular risk
`not only of
`pulmonary edema,
`but also of other
`Serious Adverse
`Events, upon
`treatment with
`inhaled nitric oxide,
`and the first patient is
`excluded from
`inhaled nitric oxide
`treatment based on
`the determination that
`the first patient has
`left ventricular
`dysfunction and so is
`at particular risk not
`only of pulmonary
`edema, but also other
`Serious Adverse
`Events, upon
`treatment with
`inhaled nitric oxide.
`CLAIM 23
`A method of
`treatment comprising:
`(a) identifying a
`plurality of term or
`near-term neonate
`patients who are in
`need of 20 ppm
`inhaled nitric oxide
`
`
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 13.
`
`Bernasconi 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.
`
`
`See Sections (a)-(e) of Claim 23 below.
`
`Bernasconi teaches that echocardiography is essential to
`identify and treat pediatric patients with conditions, such as
`pulmonary hypertension, that may be treated with iNO.
`
`25
`
`
`
`U.S. Pat. No.
`8,293,284
`treatment, wherein
`the patients are not
`dependent on right-
`to-left shunting of
`blood;
`
`Bernasconi, INOMAX label, Loh, and Goyal
`Ex. 1004 at 8.
`Bernasconi further teaches treating neonates with PPHN with
`iNO and that the FDA recommended dose for neonatal hypoxic
`respiratory failure is 20 ppm iNO.
`
`Ex. 1004 at 3.
`
`INOMAX label teaches that echocardiography can be used to
`identify patients with pulmonary hypertension that may be
`treated with iNO.
`
`Ex. 1014 at 4.
`INOMAX label further teaches the FDA recommended dose for
`iNO treatment is 20 ppm.
`
`Ex. 1014 at 6.
`INOMAX label further teaches that iNO should not be used in
`patients dependent on right-to-left shunting of blood.
`
`Ex. 1014 at 4.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD including a risk of causing pulmonary
`edema.
`
`26
`
`(b) in a first patient of
`the plurality,
`measuring pulmonary
`capillary wedge
`pressure to determine
`that the first patient
`of the plurality has a
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`pulmonary capillary
`wedge pressure
`greater than or equal
`to 20 mm Hg and
`thus has left
`ventricular
`dysfunction, so is at
`particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide;
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1004 at 8.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. Loh further teaches that patients with LVD
`have a baseline wedge pressure that is greater than 20 mm Hg.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`27
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`28
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1007 at Table 1.
`Bernasconi teaches that echocardiography is essential to
`identify and treat pediatric patients with conditions that may be
`treated with iNO and identifying conditions that may
`contraindicate iNO.
`
`
`
`Ex. 1004 at 8.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. Loh further teaches that patients with LVD
`have a baseline wedge pressure that is greater than 20 mm Hg.
`
`(c) in a second patient
`of the plurality,
`performing
`echocardiography
`and/or measurement
`of pulmonary
`capillary wedge
`pressure to determine
`that the second
`patient of the
`plurality does not
`have left ventricular
`dysfunction;
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`29
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`30
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1007 at Table 1.
`Bernasconi teaches a treatment comprising administering 20
`ppm nitric oxide gas to treat neonates.
`
`
`
`(d) administering the
`20 ppm inhaled nitric
`oxide treatment to the
`second patient; and
`
`Ex. 1004 at 3.
`
`INOMAX label teaches the FDA recommended dose for iNO
`treatment is 20 ppm.
`
`Ex. 1014 at 6.
`Bernasconi teaches that there are negative effects of iNO in
`patients with LVD, including a risk of causing pulmonary
`edema.
`
`
`31
`
`(e) excluding the first
`patient from
`treatment with
`inhaled nitric oxide,
`based on the
`determination that the
`first patient has left
`ventricular
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`dysfunction, so is at
`particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide.
`
`CLAIM 24
`The method of claim
`23, wherein step (a)
`comprises performing
`echocardiography to
`determine that the
`first and second
`patients have
`pulmonary
`hypertension.
`
`CLAIM 25
`The method of claim
`23, wherein step (a)
`comprises measuring
`blood oxygen levels
`in the first and second
`patients and thereby
`determining that the
`first and second
`patients are hypoxic.
`
`
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1004 at 8.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 23.
`
`Bernasconi teaches that echocardiography is essential to
`identify and treat pediatric patients with conditions, such as
`pulmonary hypertension, that may be treated with iNO.
`
`Ex. 1004 at 8.
`
`INOMAX label teaches that echocardiography can be used to
`identify patients with pulmonary hypertension that may be
`treated with iNO.
`
`Ex. 1014 at 4.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 23.
`
`INOMAX label teaches clinical trials measured a patient’s
`arterial blood gas before allowing the patient to be randomized
`for iNO treatment for hypoxic respiratory failure.
`
`32
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`CLAIM 26
`The method of claim
`23, wherein
`the
`second patient has
`congenital
`heart
`disease.
`
`Ex. 1014 at 2, 3.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 23.
`
`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 27
`The method of claim
`23, wherein step (b)
`comprises measuring
`the first patient's
`pulmonary capillary
`wedge pressure.
`
`Ex. 1004 at 12.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 23.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. Loh further teaches that patients with LVD
`have a baseline wedge pressure that is greater than 20 mm Hg.
`
`Ex. 1006 at 2780.
`
`33
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`Ex. 1006 at 2781.
`
`
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`34
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`
`
`Ex. 1007 at Table 1.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Bernasconi, INOMAX label,
`Loh, and Goyal as outlined above in Claim 23.
`
`Bernasconi 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.
`
`35
`
`CLAIM 29
`The method of claim
`23, wherein the first
`patient is determined
`to be at particular risk
`not only of
`pulmonary edema,
`but also of other
`Serious Adverse
`Events, upon
`treatment with
`inhaled nitric oxide,
`and the first patient is
`excluded from
`inhaled nitric oxide
`treatment based on
`the determination that
`the first patient has
`pre-existing left
`ventricular
`dysfunction and so is
`at particular risk not
`only of pulmonary
`
`
`
`
`
`Bernasconi, INOMAX label, Loh, and Goyal
`
`U.S. Pat. No.
`8,293,284
`edema, but also other
`Serious Adverse
`Events, upon
`treatment with
`inhaled nitric oxide.
`
`
`36
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