`
`
`
`Claims 1-29 of the ʼ966 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.
`8,282,966
`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 child in
`need of 20 ppm
`inhaled nitric oxide
`treatment for
`pulmonary
`hypertension,
`wherein the child is
`not dependent on
`right-to-left shunting
`of blood;
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`See Sections (a)-(c) of Claim 1 below.
`
`Ichinose teaches 20 ppm iNO is a known treatment.
`
`Ex. 1009 at 3106.
`
`
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Neonatal Group teaches a diagnostic process for identifying
`term infants in need of 20 ppm iNO for treatment of hypoxic
`respiratory failure caused by persistent pulmonary hypertension
`of the newborn (“PPHN”). The diagnostic process comprises
`performing an echocardiography.
`
`
`
`1
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1011 at Abstract.
`
`
`
`
`
`Ex. 1011 at 598.
`
`Macrae teaches the use of 20 ppm iNO to treat children with
`pulmonary hypertension.
`
`
`
`
`2
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1008 at 377-378.
`
`Macrae further 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 child identified in
`(a) has a pulmonary
`capillary wedge
`pressure greater than
`or equal to 20 mm Hg
`and thus has left
`ventricular
`dysfunction, so is at
`particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide;
`
`
`
`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. (Wedge pressure may also be called
`pulmonary capillary wedge pressure (“PCWP”), pulmonary
`arterial wedge pressure (“PAWP”), or merely “wedge.” All the
`
`3
`
`
`
`
`
`and
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`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.
`
`Ex. 1006 at Table 1.
`
`
`
`
`
`4
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`Additionally, Goyal teaches measuring wedge pressure in
`children.
`
`
`
`
`
`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.
`
`5
`
`
`
`(c) excluding the
`child from inhaled
`nitric oxide treatment
`based on the
`determination that the
`child has left
`ventricular
`dysfunction and so is
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`at particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide.
`
`CLAIM 2
`The method of claim
`1, wherein the child is
`a neonate.
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD.
`
`
`
`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.
`
`Macrae teaches that iNO can be used to treat a variety of
`conditions in neonates including PPHN.
`
`CLAIM 3
`The method of claim
`1, wherein step (b)
`comprises measuring
`the child's pulmonary
`capillary wedge
`pressure.
`
`
`
`Ex. 1008 at 373.
`
`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.
`
`
`
`6
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`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
`children.
`
`7
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`
`
`Ex. 1007 at 209.
`
`CLAIM 4
`The method of claim
`1, wherein the child's
`left
`ventricular
`dysfunction
`is
`attributable
`to
`congenital
`heart
`disease.
`
`
`
`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.
`
`
`
`
`8
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`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.
`
`Ex.1010 at 1033.
`
`
`
`
`
`See Sections (a)-(c) of Claim 6 below.
`
`9
`
`CLAIM 5
`The method of claim
`1, wherein the child 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
`child
`is
`excluded
`from
`inhaled nitric oxide
`treatment based on
`the determination that
`the child 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
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`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 child as
`being in need of 20
`ppm inhaled nitric
`oxide treatment for
`hypoxic respiratory
`failure, wherein the
`child is not dependent
`on right-to-left
`shunting of blood;
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ichinose teaches 20 ppm iNO is a known treatment.
`
`Ex. 1009 at 3106.
`
`
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Neonatal Group teaches a diagnostic process for identifying
`term infants in need of 20 ppm iNO for treatment of hypoxic
`respiratory failure caused by PPHN. The diagnostic process
`comprises measuring baseline arterial-blood gas values and
`developing an oxygenation index prior to iNO treatment.
`Patients required an oxygenation index of at least 25 to receive
`20 ppm iNO treatment.
`
`Ex. 1011 at Abstract.
`
`
`
`
`
`10
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1011 at 598.
`
`Macrae teaches the use of 20 ppm iNO to treat children with
`pulmonary hypertension.
`
`
`
`
`
`
`
`Ex. 1008 at 377-378.
`
`Macrae further teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with severe LVD with
`
`11
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`right-to-left ductal shunting. It teaches the use of
`echocardiography to exclude those patients prior to
`administering iNO.
`
`
`
`
`
`(b) determine
`determining that the
`child 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. 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.
`
`
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`12
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`children.
`
`
`
`
`
`Ex. 1007 at 209.
`
`13
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`(c) excluding the
`child from treatment
`with inhaled nitric
`oxide based on the
`determination that the
`child has left
`ventricular
`dysfunction and so is
`at particular risk of
`pulmonary edema
`upon treatment with
`inhaled nitric oxide.
`
`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.
`
`
`
`
`
`
`
`14
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`CLAIM 7
`The method of claim
`6, wherein the
`diagnostic process of
`step (a) further
`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 6.
`
`Neonatal Group further teaches that the diagnostic process for
`identifying infants in need of 20 ppm iNO comprises
`performing an echocardiography.
`
`CLAIM 8
`The method of claim
`6, wherein the child is
`a neonate.
`
`
`
`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 used to treat a variety of
`conditions in neonates including PPHN.
`
`
`
`
`15
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`CLAIM 9
`The method of claim
`6, wherein step (b)
`comprises measuring
`the child's pulmonary
`capillary wedge
`pressure.
`
`
`
`Ex. 1008 at 373.
`
`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.
`
`
`
`
`
`
`
`
`16
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`children.
`
`
`
`
`
`Ex. 1007 at 209.
`
`
`
`17
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`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.
`
`
`
`CLAIM 11
`The method of claim
`6, wherein the child 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 6.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD, as it can lead to increased left ventricular
`preload.
`
`
`
`18
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`treatment with
`inhaled nitric oxide,
`and the child is
`excluded from
`inhaled nitric oxide
`treatment based on
`the determination that
`the child 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.
`
`
`
`
`
`
`
`CLAIM 13
`A method of
`treatment comprising:
`(a) performing
`echocardiography to
`identify a plurality of
`
`
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`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.
`
`
`
`Ex. 1008 at 374.
`
`See Sections (a)-(e) of Claim 13 below.
`
`Ichinose teaches 20 ppm iNO is a known treatment.
`
`
`19
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`children who are in
`need of 20 ppm
`inhaled nitric oxide
`treatment for
`pulmonary
`hypertension,
`wherein the children
`are not dependent on
`right-to-left shunting
`of blood;
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1009 at 3106.
`
`
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Neonatal Group teaches a diagnostic process for identifying
`term infants in need of 20 ppm iNO for treatment of hypoxic
`respiratory failure caused by PPHN. The diagnostic process
`comprises performing an echocardiography.
`
`Ex. 1011 at Abstract.
`
`
`
`
`
`Ex. 1011 at 598.
`
`Macrae teaches the use of 20 ppm iNO to treat children with
`pulmonary hypertension.
`20
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`
`
`Ex. 1008 at 377-378.
`
`Macrae further 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.
`
`
`
`
`
`Ex. 1008 at 373-374.
`21
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`(b) determining that a
`first child 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;
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`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.
`
`
`
`
`
`
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`22
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`children.
`
`
`
`
`
`Ex. 1007 at 209.
`
`23
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`(c) determining that a
`second child 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.
`
`Ex. 1010 at 1033.
`
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with severe LVD. It
`
`
`
`
`
`24
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`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 child; 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.
`
`Ex. 1011 at Abstract.
`
`25
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1011 at 598.
`
`Additionally, Macrae teaches the use of 20 ppm iNO to treat
`children with pulmonary hypertension.
`
`
`
`
`
`
`
`(e) excluding the first
`child from treatment
`with inhaled nitric
`oxide, based on the
`
`
`
`Ex. 1008 at 377-378.
`Ichinose teaches that there may be negative effects, such as
`pulmonary edema, upon administering iNO to a patient that has
`LVD.
`
`26
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`determination that the
`first child 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. 1009 at 3109.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD.
`
`CLAIM 14
`The method of claim
`13, wherein step (a)
`further
`comprises
`measuring
`blood
`oxygen levels in the
`first
`and
`second
`children and thereby
`determining that the
`first
`and
`second
`children 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.
`
`27
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1011 at 598.
`
`
`
`
`
`CLAIM 15
`The method of claim
`13, wherein the
`second child 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 13.
`
`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 13.
`
`Loh teaches measuring a baseline wedge pressure prior to
`28
`
`CLAIM 16
`The method of claim
`13, wherein step (b)
`comprises measuring
`the first child's
`pulmonary capillary
`wedge pressure.
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`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
`children.
`
`29
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`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 13.
`
`Macrae teaches that echocardiography can be used to identify
`patients with congenital heart disease, including LVD.
`
`30
`
`
`
`CLAIM 17
`The method of claim
`13, wherein
`determining that the
`second child of the
`plurality does not
`have pre-existing left
`ventricular
`dysfunction
`comprises performing
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`echocardiography.
`
`CLAIM 18
`The method of claim
`13, wherein the left
`ventricular
`dysfunction is
`attributable to
`congenital heart
`disease.
`
`
`
`
`
`
`
`CLAIM 19
`The method of claim
`13, wherein the left
`ventricular
`dysfunction of the
`first child is
`attributable to
`congenital heart
`disease.
`
`
`
`
`
`
`
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`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.
`
`Ex. 1008 at 374.
`
`31
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`CLAIM 20
`The method of claim
`13, wherein the first
`child 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 child is
`excluded from
`inhaled nitric oxide
`treatment based on
`the determination that
`the first child 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 21
`The method of claim
`20, wherein the pre-
`existing left
`ventricular
`dysfunction of the
`first child 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 20.
`
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`32
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`CLAIM 22
`A method of
`treatment comprising:
`(a) identifying a
`plurality of children
`who are in need of 20
`ppm inhaled nitric
`oxide treatment,
`wherein the children
`are not dependent on
`right-to-left shunting
`of blood;
`
`
`
`Ex. 1008 at 374.
`
`See Sections (a)-(e) of Claim 22 below.
`
`Ichinose teaches 20 ppm iNO is a known treatment.
`
`Ex. 1009 at 3106.
`
`
`
`
`
`
`
`Ex. 1009 at 3109.
`
`Neonatal Group teaches a diagnostic process for identifying
`term infants in need of 20 ppm iNO for treatment of hypoxic
`respiratory failure caused by PPHN. The diagnostic process
`comprises performing an echocardiography.
`
`Ex. 1011 at Abstract.
`
`
`
`
`
`33
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1011 at 598.
`
`Macrae teaches the use of 20 ppm iNO to treat children with
`pulmonary hypertension.
`
`
`
`
`
`
`
`Ex. 1008 at 377-378.
`
`Macrae further teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with severe LVD with
`
`34
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`right-to-left ductal shunting. It teaches the use of
`echocardiography to exclude those patients prior to
`administering iNO.
`
`
`
`
`
`(b) in the first child of
`the plurality,
`measuring pulmonary
`capillary wedge
`pressure to determine
`that the first child 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. 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.
`
`Ex. 1006 at 2780.
`
`Ex. 1006 at 2781.
`
`
`
`
`
`
`
`35
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`Ex. 1006 at Table 1.
`
`Additionally, Goyal teaches measuring wedge pressure in
`children.
`
`
`
`
`
`Ex. 1007 at 209.
`
`36
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`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) in the second
`child of the plurality,
`performing
`echocardiography
`and/or measurement
`of pulmonary
`capillary wedge
`pressure to determine
`that the second child
`of the plurality does
`not have left
`ventricular
`dysfunction;
`
`Ex. 1010 at 1033.
`
`Macrae teaches that iNO can be harmful to babies with
`congenital heart disease, such as those with severe LVD. It
`
`
`
`
`
`37
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`teaches the use of echocardiography to identify those patients
`prior to administering iNO.
`
`
`
`
`
`(d) administering the
`20 ppm inhaled nitric
`oxide treatment to the
`second child; 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.
`
`Ex. 1011 at Abstract.
`
`38
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`Ex. 1011 at 598.
`
`Additionally, Macrae teaches the use of 20 ppm iNO to treat
`children with pulmonary hypertension.
`
`
`
`
`
`
`
`(e) excluding the first
`child from treatment
`with inhaled nitric
`oxide, based on the
`
`
`
`Ex. 1008 at 377-378.
`Ichinose teaches that there may be negative effects, such as
`pulmonary edema, upon administering iNO to a patient that has
`LVD.
`
`39
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`determination that the
`first child 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. 1009 at 3109.
`
`Germann teaches that treatment with iNO can be dangerous in
`patients with LVD.
`
`
`
`CLAIM 23
`The method of claim
`22, wherein step (a)
`comprises performing
`echocardiography to
`determine that the
`first and second
`children have
`pulmonary
`hypertension.
`
`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 22.
`
`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.
`
`Ex. 1011 at 598.
`
`
`40
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`CLAIM 24
`The method of claim
`22, wherein step (a)
`comprises measuring
`blood oxygen levels
`in the first and second
`children and thereby
`determining that the
`first and second
`children are hypoxic.
`
`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 22.
`
`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.
`
`Ex. 1011 at 598.
`
`
`41
`
`
`
`
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`CLAIM 25
`The method of claim
`22, wherein
`the
`second
`child
`has
`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 22.
`
`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 22.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`CLAIM 26
`The method of claim
`22, wherein the left
`ventricular
`dysfunction
`attributable
`congenital
`disease.
`
`is
`to
`heart
`
`
`
`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 22.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`42
`
`CLAIM 27
`The method of claim
`22, wherein the pre-
`existing
`left
`ventricular
`dysfunction of
`first
`child
`attributable
`congenital
`
`the
`is
`to
`heart
`
`
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`disease.
`
`CLAIM 28
`The method of claim
`22, wherein the first
`child 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 child is
`excluded from
`inhaled nitric oxide
`treatment based on
`the determination that
`the first child 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.
`
`Ichinose, Macrae, Germann, Neonatal Group, Loh, and
`Goyal
`
`
`
`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 22.
`
`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.
`
`
`
`
`
`
`
`
`
`
`
`
`
`43
`
`
`
`
`
`U.S. Pat. No.
`8,282,966
`CLAIM 29
`The method of claim
`28, wherein the pre-
`existing left
`ventricular
`dysfunction of the
`first child 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 28.
`
`Macrae teaches LVD can be attributable to congenital heart
`disease.
`
`Ex. 1008 at 374.
`
`
`
`
`
`
`
`
`
`
`
`44
`
`
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