Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`See Sections (a)-(c) of Claim 1 below.
`
`Ichinose teaches 20 ppm inhaled nitric oxide (“iNO”) is a
`known treatment.
`
`
`Claims 1-30 of the ʼ284 patent are unpatentable under 35 U.S.C. § 103(a) as
`Obvious Over Ichinose in View of Macrae, Germann, Neonatal Group, Loh,
`and Goyal.
`
`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. 1009 at 3106.
`
`
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Neonatal Group teaches using echocardiography to identify
`neonates suffering from hypoxic respiratory failure caused by
`persistent pulmonary hypertension of the newborn (“PPHN”)
`and in need of iNO treatment and also teaches treating these
`identified neonates with 20 ppm iNO.
`
`
`
`
`1
`
`
`Goyal
`
`
`See Sections (a)-(c) of Claim 1 below.
`
`Ichinose teaches 20 ppm inhaled nitric oxide (“iNO”) is a
`known treatment.
`
`
`Claims 1-30 of the ʼ284 patent are unpatentable under 35 U.S.C. § 103(a) as
`Obvious Over Ichinose in View of Macrae, Germann, Neonatal Group, Loh,
`and Goyal.
`
`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. 1009 at 3106.
`
`
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Neonatal Group teaches using echocardiography to identify
`neonates suffering from hypoxic respiratory failure caused by
`persistent pulmonary hypertension of the newborn (“PPHN”)
`and in need of iNO treatment and also teaches treating these
`identified neonates with 20 ppm iNO.
`
`
`
`
`1
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1011 at Abstract.
`
`
`
`
`
`Ex. 1011 at 598.
`
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with severe left
`ventricular dysfunction (“LVD”) with right-to-left ductal
`shunting. It teaches the use of echocardiography to exclude
`those patients prior to administering iNO.
`
`
`
`
`
`(b) determining that
`the patient identified
`in (a) has a
`
`
`
`Ex. 1008 at 373-374.
`Ichinose teaches that there may be negative effects such as
`pulmonary edema upon administering iNO to a patient.
`
`2
`
`
`
`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;
`and
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1009 at 3109.
`
`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.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`3
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`4
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1007 at Table 1.
`Ichinose teaches that there may be negative effects, such as
`pulmonary edema, upon administering iNO to a patient that has
`LVD.
`
`
`
`Ex. 1009 at 3109.
`German teaches that treatment with iNO can be dangerous in
`patients with LVD.
`
`
`
`(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. 1010 at 1033.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 1.
`
`
`
`
`
`5
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with LVD with right-to-
`left ductal shunting. It teaches the use of echocardiography to
`identify patients with LVD.
`
`
`
`
`
`CLAIM 3
`The method of claim
`1, wherein step (b)
`comprises measuring
`the patient's
`pulmonary capillary
`wedge pressure.
`
`Ex. 1008 at 373-374.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, 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.
`
`
`
`
`
`
`
`6
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`7
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1007 at Table 1.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 1.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`CLAIM 4
`The method of claim
`1,
`wherein
`the
`patient's
`left
`ventricular
`dysfunction
`attributable
`congenital
`disease.
`
`is
`to
`heart
`
`
`
`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
`
`Ex. 1008 at 374.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 1.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD, as it can lead to increased left ventricular
`preload.
`
`
`
`8
`
`
`
`U.S. Pat. No.
`8,293,284
`with
`treatment
`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
`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
`
`
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex.1010 at 1033.
`
`
`
`
`
`See Sections (a)-(c) of Claim 6 below.
`
`Ichinose teaches 20 ppm iNO is a known treatment.
`
`Ex. 1009 at 3106.
`
`9
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`respiratory failure,
`wherein the patient is
`not dependent on
`right-to-left shunting
`of blood;
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1009 at 3109.
`
`Neonatal Group teaches identifying neonates with hypoxic
`respiratory failure and then treating them with 20 ppm iNO.
`The neonates treated had their arterial-blood gas values
`measured prior to treatment and an oxygenation index
`developed based on this measurement. In order to receive iNO
`treatment, neonates required an oxygenation index of at least
`25 and were in a state of hypoxic respiratory failure.
`
`Ex. 1011 at Abstract.
`
`
`
`
`
`Ex. 1011 at 598.
`
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with severe LVD with
`right-to-left ductal shunting. It teaches the use of
`echocardiography to exclude those patients prior to
`administering iNO.
`
`
`
`
`
`10
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1008 at 373-374. l.
`Ichinose teaches that there may be negative effects such as
`pulmonary edema upon administering iNO to a patient.
`
`
`
`
`
`Ex. 1009 at 3109.
`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
`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. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`11
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`12
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1007 at Table 1.
`Ichinose teaches that there may be negative effects, such as
`pulmonary edema, upon administering iNO to a patient that has
`LVD.
`
`
`
`Ex. 1009 at 3109.
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD.
`
`
`
`(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
`
`Ex. 1010 at 1033.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 6.
`
`
`
`
`
`13
`
`
`
`U.S. Pat. No.
`8,293,284
`comprises performing
`echocardiography.
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`Neonatal Group further teaches that the diagnostic process for
`identifying neonates with hypoxic respiratory failure and in
`need of 20 ppm iNO comprises performing an
`echocardiography.
`
`CLAIM 8
`The method of claim
`6, wherein step (b)
`comprises performing
`echocardiography.
`
`
`
`Ex. 1011 at 598.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 6.
`
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with LVD with right-to-
`left ductal shunting. It teaches the use of echocardiography to
`identify patients with LVD.
`
`
`
`
`
`Ex. 1008 at 373-374.
`
`
`
`14
`
`
`
`
`
`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.
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, 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.
`
`Ex. 1006 at Table 1.
`15
`
`
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`Ex. 1007 at 209.
`
`
`
`
`
`CLAIM 10
`The method of claim
`6, wherein the left
`ventricular
`dysfunction
`attributable
`congenital
`disease
`
`is
`to
`heart
`
`Ex. 1007 at Table 1.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 6.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`Ex. 1008 at 374.
`
`
`16
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`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
`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 12
`The method of claim
`11, wherein the left
`ventricular
`dysfunction is
`attributable to
`congenital heart
`disease.
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 6.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD, as it can lead to increased left ventricular
`preload.
`
`Ex.1010 at 1033.
`
`
`
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 11.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`
`
`17
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`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;
`
`
`
`Ex. 1008 at 374.
`
`See Sections (a)-(e) for Claim 13 below.
`
`Ichinose teaches 20 ppm iNO is a known treatment.
`
`Ex. 1009 at 3106.
`
`
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Neonatal Group teaches using echocardiography to identify
`neonates suffering from hypoxic respiratory failure caused by
`PPHN and in need of iNO treatment and also teaches treating
`these identified neonates with 20 ppm iNO.
`
`
`Ex. 1011 at Abstract.
`
`18
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1011 at 598.
`
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with severe LVD with
`right-to-left ductal shunting. It teaches the use of
`echocardiography to exclude those patients prior to
`administering iNO.
`
`
`
`
`
`(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
`
`
`
`Ex. 1008 at 373-374.
`Ichinose teaches that there may be negative effects such as
`pulmonary edema upon administering iNO to a patient.
`
`
`
`Ex. 1009 at 3109.
`
`Loh teaches measuring a baseline wedge pressure prior to
`administering iNO. Loh further teaches that patients with LVD
`
`19
`
`
`
`U.S. Pat. No.
`8,293,284
`pulmonary edema
`upon treatment with
`inhaled nitric oxide;
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`have a baseline wedge pressure that is greater than 20 mm Hg.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`
`
`20
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1007 at 209.
`
`
`
`
`(c) determining that a
`second patient of the
`plurality does not
`have left ventricular
`dysfunction;
`
`Ex. 1007 at Table 1.
`Ichinose teaches that there may be negative effects, such as
`pulmonary edema, upon administering iNO to a patient that has
`LVD.
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD.
`
`
`
`21
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1010 at 1033.
`
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with severe LVD. It
`teaches the use of echocardiography to identify those patients
`with LVD prior to administering iNO.
`
`
`
`
`
`Ex. 1008 at 373-374.
`Ichinose teaches 20 ppm iNO is a known treatment.
`
`
`
`
`
`
`
`(d) administering the
`20 ppm inhaled nitric
`oxide treatment to the
`second patient; and
`
`Ex. 1009 at 3106.
`
`Ex. 1009 at 3109.
`
`
`22
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`Neonatal Group teaches 20 ppm iNO treatment for patients
`with hypoxic respiratory failure that may be caused by PPHN.
`
`Ex. 1011 at Abstract.
`
`
`
`
`
`(e) excluding the first
`patient from
`treatment with
`inhaled nitric oxide,
`based on the
`determination that the
`first patient has left
`ventricular
`dysfunction, so is at
`particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide.
`
`Ex. 1011 at 598.
`Ichinose teaches that there may be negative effects, such as
`pulmonary edema, upon administering iNO to a patient that has
`LVD.
`
`
`
`Ex. 1009 at 3109.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD.
`
`
`
`
`
`23
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`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.
`
`Ex. 1010 at 1033.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 13.
`
`Neonatal Group teaches a diagnostic process for identifying
`patients in need of 20 ppm iNO treatment for hypoxic
`respiratory failure. The diagnostic process comprises
`measuring baseline arterial-blood gas values and obtaining a
`baseline oxygenation index to determine eligibility for
`treatment with iNO.
`
`Ex. 1011 at Abstract.
`
`Ex. 1011 at 598.
`
`
`
`
`
`
`
`24
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`CLAIM 15
`The method of claim
`14, wherein the left
`ventricular
`dysfunction is
`attributable to
`congenital heart
`disease.
`
`Ex. 1011 at 598.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 14.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`CLAIM 16
`The method of claim
`13, wherein the
`second patient has
`congenital heart
`disease.
`
`
`
`Ex. 1008 at 374.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 13.
`
`Germann teaches that iNO treatment can be used on patients
`with congenital heart disease.
`
`
`Ex. 1010 at 1033.
`
`
`25
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`CLAIM 17
`The method of claim
`13, wherein step (b)
`comprises measuring
`the first patient's
`pulmonary capillary
`wedge pressure.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, 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.
`
`
`
`
`
`
`
`26
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, 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 Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 13.
`
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with LVD with right-to-
`left ductal shunting. It teaches the use of echocardiography to
`identify patients with LVD.
`
`27
`
`
`
`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
`
`
`
`
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`U.S. Pat. No.
`8,293,284
`ventricular
`dysfunction
`comprises performing
`echocardiography on
`the first and second
`patients.
`
`
`
`CLAIM 19
`The method of claim
`13, wherein the left
`ventricular
`dysfunction
`attributable
`congenital
`disease.
`
`is
`to
`heart
`
`Ex. 1008 at 373-374.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 13.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`
`
`Ex. 1008 at 374.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 13.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`CLAIM 20
`The method of claim
`13, wherein the left
`ventricular
`dysfunction of the
`first patient is
`attributable to
`congenital heart
`disease.
`
`Ex. 1008 at 374.
`
`28
`
`
`
`
`
`
`
`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 22
`The method of claim
`21, wherein the left
`ventricular
`dysfunction of the
`first patient is
`attributable to
`congenital heart
`disease.
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 13.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD, as it can lead to increased left ventricular
`preload.
`
`
`
`Ex.1010 at 1033.
`
`
`
`
`
`
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 21.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`
`
`29
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`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
`treatment, wherein
`the patients are not
`dependent on right-
`to-left shunting of
`blood;
`
`
`
`Ex. 1008 at 374.
`
`See Sections (a)-(e) of Claim 23 below.
`Ichinose teaches 20 ppm iNO is a known treatment.
`
`Ex. 1009 at 3106.
`
`
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Neonatal Group teaches using echocardiography to identify
`neonates suffering from hypoxic respiratory failure caused by
`PPHN and in need of iNO treatment and also teaches treating
`these identified neonates with 20 ppm iNO.
`
`Ex. 1011 at Abstract.
`
`
`
`
`
`30
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1011 at 598.
`
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with severe LVD with
`right-to-left ductal shunting. It teaches the use of
`echocardiography to exclude those patients prior to
`administering iNO.
`
`
`
`
`
`(b) in a first patient of
`the plurality,
`measuring pulmonary
`capillary wedge
`pressure to determine
`that the first patient
`of the plurality has a
`pulmonary capillary
`wedge pressure
`greater than or equal
`to 20 mm Hg and
`
`
`
`Ex. 1008 at 373-374.
`Ichinose teaches that there may be negative effects such as
`pulmonary edema upon administering iNO to a patient.
`
`Ex. 1009 at 3109.
`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.
`
`
`
`31
`
`
`
`U.S. Pat. No.
`8,293,284
`thus has left
`ventricular
`dysfunction, so is at
`particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide;
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`
`
`32
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1007 at 209.
`
`Ex. 1007 at Table 1.
`Ichinose teaches that there may be negative effects, such as
`pulmonary edema, upon administering iNO to a patient that has
`LVD.
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD.
`
`(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. 1010 at 1033.
`
`
`33
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with severe LVD. It
`teaches the use of echocardiography to identify those patients
`with LVD prior to administering iNO.
`
`
`
`
`
`(d) administering the
`20 ppm inhaled nitric
`oxide treatment to the
`second patient; and
`
`Ex. 1008 at 373-374.
`Ichinose teaches 20 ppm iNO is a known treatment.
`
`Ex. 1009 at 3106.
`
`
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Neonatal Group teaches 20 ppm iNO treatment for patients
`with hypoxic respiratory failure that may be caused by PPHN.
`
`
`
`34
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1011 at Abstract.
`
`Ex. 1011 at 598.
`Ichinose teaches that there may be negative effects, such as
`pulmonary edema, upon administering iNO to a patient that has
`LVD.
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD.
`
`(e) excluding the first
`patient from
`treatment with
`inhaled nitric oxide,
`based on the
`determination that the
`first patient has left
`ventricular
`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
`
`Ex. 1010 at 1033.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 23.
`
`
`
`
`
`
`35
`
`
`
`U.S. Pat. No.
`8,293,284
`first and second
`patients have
`pulmonary
`hypertension.
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`Neonatal Group teaches that the diagnostic process for
`identifying infants in need of iNO treatment for hypoxic
`respiratory failure that could be caused by PPHN included
`echocardiography.
`
`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.
`
`
`
`Ex. 1011 at 598.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 23.
`
`Neonatal Group teaches a diagnostic process for identifying
`patients in need of 20 ppm iNO treatment for hypoxic
`respiratory failure. The diagnostic process comprises
`measuring baseline arterial-blood gas values and obtaining a
`baseline oxygenation index to determine eligibility for
`treatment with iNO.
`
`
`Ex. 1011 at Abstract.
`
`36
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1011 at 598.
`
`
`
`
`
`CLAIM 26
`The method of claim
`23, wherein
`the
`second patient has
`congenital
`heart
`disease.
`
`Ex. 1011 at 598.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 23.
`
`Germann teaches that iNO treatment can be used on patients
`with congenital heart disease.
`
`
`
`
`Ex. 1010 at 1033.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 23.
`
` Loh teaches measuring a baseline wedge pressure prior to
`
`37
`
`CLAIM 27
`The method of claim
`23, wherein step (b)
`comprises measuring
`the
`first
`patient's
`pulmonary capillary
`wedge pressure.
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`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.
`
`
`
`
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`infants.
`
`
`
`
`38
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1007 at 209.
`
`
`
`
`
`Ex. 1007 at Table 1.
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 23.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`CLAIM 28
`The method of claim
`23, wherein the left
`ventricular
`dysfunction of
`first
`patient
`attributable
`congenital
`disease.
`
`the
`is
`to
`heart
`
`Ex. 1008 at 374.
`
`
`
`
`39
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,293,284
`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
`edema, but also other
`Serious Adverse
`Events, upon
`treatment with
`inhaled nitric oxide.
`CLAIM 30
`The method of claim
`29, wherein the left
`ventricular
`dysfunction of the
`first patient is
`attributable to
`congenital heart
`disease.
`
`
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 23.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD, as it can lead to increased left ventricular
`preload.
`
`Ex.1010 at 1033.
`
`
`
`
`
`All the elements of the independent claim from which this
`claim depends are disclosed in Ichinose, Macrae, Germann,
`Neonatal Group, Loh, and Goyal as outlined above in
`Claim 29.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`40
`
`
`
`U.S. Pat. No.
`8,293,284
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1008 at 374.
`
`
`
`
`
`
`
`
`
`
`41
`
`
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