throbber
INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`INOMAX label teaches providing pharmaceutically acceptable
`nitric oxide gas for treatment:
`
`Claims 1-19 of the ΚΌ112 patent are unpatentable as obvious in view of
`Bernasconi, the INOMAX label, Loh, and Goyal
`
`U.S. Pat. No.
`8,846,112
`CLAIM 1
`A method of
`providing
`pharmaceutically
`acceptable nitric
`oxide gas, the method
`comprising:
`obtaining a cylinder
`containing
`compressed nitric
`oxide gas in the form
`of a gaseous blend of
`nitric oxide and
`nitrogen;
`
`Ex. 1014 (INOMAX label) at 4.
`
`INOMAX label teaches obtaining a cylinder containing
`compressed nitric oxide gas in the form of a gaseous blend of
`nitric oxide and nitrogen.
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`supplying the
`cylinder containing
`compressed nitric
`oxide gas to a
`medical provider
`responsible for
`treating neonates who
`have hypoxic
`respiratory failure,
`
`Ex. 1014 (INOMAX label) at 6-7.
`
`INOMAX label teaches supplying compressed nitric oxide gas
`to treat neonates with hypoxic respiratory failure including
`some who do not have left ventricular dysfunction.
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`1
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`including some who
`do not have left
`ventricular
`dysfunction;
`
`providing to the
`medical provider (i)
`information that a
`recommended dose of
`inhaled nitric oxide
`gas for treatment of
`neonates with
`hypoxic respiratory
`failure is 20 ppm
`nitric oxide and (ii)
`information that, in
`patients with pre-
`existing left
`ventricular
`dysfunction, inhaled
`nitric oxide may
`increase pulmonary
`capillary wedge
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1014 (INOMAX label) at 6-7.
`
`
`Ex. 1014 (INOMAX label) at 2.
`
`
`Ex. 1014 (INOMAX label) at 4.
`The content of the INOMAX label is information provided to a
`medical provider.
`
`Ex. 1014 (INOMAX label) at i.
`
`INOMAX label teaches the recommended dose of inhaled nitric
`oxide gas for the treatment of neonates with hypoxic
`respiratory failure is 20 ppm nitric oxide.
`
`
`2
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`pressure (PCWP),
`leading to pulmonary
`edema, the
`information of (ii)
`being sufficient to
`cause a medical
`provider considering
`inhaled nitric oxide
`treatment for a
`plurality of neonatal
`patients who (a) are
`suffering from a
`condition for which
`inhaled nitric oxide is
`indicated, and (b)
`have pre-existing left
`ventricular
`dysfunction, to elect
`to avoid treating one
`or more of the
`plurality of patients
`with inhaled nitric
`oxide in order to
`avoid putting the one
`or more patients at
`risk of pulmonary
`edema.
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1014 (INOMAX label) at 6.
`
`
`Ex. 1014 (INOMAX label) at 2.
`
`INOMAX label contains INDICATIONS and
`CONTRAINDICATIONS:
`
`Ex. 1014 (INOMAX label) at 4.
`
`Bernasconi also teaches the recommended dose of inhaled
`nitric oxide gas for treating neonates with hypoxic respiratory
`failure is 20 ppm nitric oxide.
`
`Ex. 1004 (Bernasconi) at 3.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`Bernasconi teaches the possibility of pulmonary edema upon
`administering inhaled nitric oxide to a patient with left
`ventricular dysfunction.
`
`3
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1004 (Bernasconi) at 8.
`
`Loh teaches measuring wedge pressure in patients in its study.
`
`Ex. 1006 (Loh) at Abstract.
`
`
`
`
`4
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2780-81.
`
`Loh teaches patients with left ventricular dysfunction show an
`increase in wedge pressure upon treatment with inhaled nitric
`oxide.
`
`
`
`Ex. 1006 (Loh) at 2780.
`
`
`Ex. 1006 (Loh) at 2781.
`
`
`
`
`
`Ex. 1006 (Loh) at 2781, Table 1.
`
`
`
`
`5
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2781, Fig. 2.
`
`Goyal teaches measuring wedge pressure in its population of
`patients.
`
`
`
`
`
`Ex. 1007 (Goyal) at 209
`
`
`6
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1007 (Goyal) at 209
`
`
`
`
`Ex. 1007 (Goyal) at 210, Table 2.
`
`Bernasconi teaches that a medical provider considering inhaled
`nitric oxide treatment for a plurality of neonatal patients who
`(a) are suffering from a condition for which inhaled nitric oxide
`is indicated, and (b) have pre-existing left ventricular
`dysfunction may elect to avoid treating one or more of the
`plurality of patients with inhaled nitric oxide in order to avoid
`putting the one or more patients at risk of pulmonary edema.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`7
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`CLAIM 2
`The method of claim
`1, wherein the
`information of (i) and
`the information of (ii)
`appear in prescribing
`information supplied
`to the medical
`provider with the
`cylinder containing
`compressed nitric
`oxide gas.
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`The INOMAX label is prescribing information provided with
`cylinders containing compressed nitric oxide gas.
`
`Ex. 1014 (INOMAX label) at i.
`
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`Ex. 1014 (INOMAX label) at 6.
`
`
`
`
`Ex. 1014 (INOMAX label) at 6-7.
`
`
`
`
`CLAIM 3
`The method of claim
`1, further comprising:
`
`8
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`performing at least
`one diagnostic
`process to identify a
`first neonatal patient
`who has hypoxic
`respiratory failure
`and is a candidate for
`20 ppm inhaled nitric
`oxide treatment;
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`INOMAX label teaches performing at least one diagnostic
`process to identify a neonatal patient who has hypoxic
`respiratory failure and is a candidate for 20 ppm inhaled nitric
`oxide treatment.
`
`Ex. 1014 (INOMAX label) at 4.
`
`
`Ex. 1014 (INOMAX label) at 6.
`
`Bernasconi teaches performing at least one diagnostic process
`to identify a neonatal patient who has hypoxic respiratory
`failure and is a candidate for 20 ppm inhaled nitric oxide
`treatment.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 3.
`
`Loh teaches performing at least one diagnostic process to
`identify a first neonatal patient who has hypoxic respiratory
`failure and is a candidate for inhaled nitric oxide treatment.
`
`
`9
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`
`Ex. 1006 (Loh) at 2780-81.
`
`Bernasconi teaches determining that the first neonatal patient
`has pre-existing left ventricular dysfunction.
`
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`determining that the
`first neonatal patient
`has pre-existing left
`ventricular
`dysfunction;
`
`Ex. 1004 (Bernasconi) at 8.
`
`Loh teaches determining that the first neonatal patient has pre-
`existing left ventricular dysfunction.
`
`
`10
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`
`
`
`
`
`
`
`Ex. 1006 (Loh) at 2780-81.
`
`
`Ex. 1006 (Loh) at 2783.
`
`
`11
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`
`evaluating the
`potential benefit of
`treating the first
`neonatal patient with
`20 ppm inhaled nitric
`oxide vs. the potential
`risk that inhaled nitric
`oxide could cause an
`increase in PCWP
`leading to pulmonary
`edema in patients
`who have pre-
`existing left
`ventricular
`dysfunction, in order
`to arrive at a decision
`of whether or not to
`treat the first neonatal
`patient with inhaled
`
`Ex. 1006 (Loh) at 2783.
`
`Bernasconi teaches evaluating benefit vs. risk that inhaled
`nitric oxide could lead to pulmonary edema in patients who
`have pre-existing left ventricular dysfunction.
`
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`Loh teaches the potential risk that inhaled nitric oxide could
`cause an increase in PCWP in patients who have pre-existing
`left ventricular dysfunction.
`
`
`Ex. 1006 (Loh) at 2780.
`
`
`
`12
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`nitric oxide;
`
`
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2781.
`
`
`
`Ex. 1006 (Loh) at 2781, Table 1.
`
`
`
`
`13
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2781, Fig. 2.
`
`Bernasconi teaches arriving at a decision of whether or not to
`treat the first neonatal patient with inhaled nitric oxide.
`
`Ex. 1004 (Bernasconi) at 8.
`
`INOMAX label discloses identifying a second neonatal patient
`as having hypoxic respiratory failure and not having left
`ventricular dysfunction.
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`14
`
`identifying a second
`neonatal patient as
`having hypoxic
`respiratory failure
`and not having left
`ventricular
`dysfunction; and
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`Ex. 1014 (INOMAX label) at 2.
`
`
`Ex. 1014 (INOMAX label) at 4.
`
`Bernasconi also teaches identifying a second neonatal patient
`as having hypoxic respiratory failure and not having left
`ventricular dysfunction.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`INOMAX label teaches treating the second neonatal patient
`with 20 ppm inhaled nitric oxide.
`
`
`treating the second
`neonatal patient with
`20 ppm inhaled nitric
`oxide.
`
`Ex. 1014 (INOMAX label) at 6.
`
`
`Ex. 1014 (INOMAX label) at 2.
`
`Bernasconi also discloses treating the second neonatal patient
`with 20 ppm inhaled nitric oxide.
`
`15
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`CLAIM 4
`The method of claim
`1, further comprising:
`performing at least
`one diagnostic
`process to identify a
`plurality of neonatal
`patients who have
`hypoxic respiratory
`failure and are
`candidates for inhaled
`nitric oxide
`treatment;
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`Ex. 1004 (Bernasconi) at 3.
`
`
`
`
`INOMAX label teaches performing at least one diagnostic
`process to identify a plurality of neonatal patients who have
`hypoxic respiratory failure and are candidates for inhaled nitric
`oxide treatment.
`
`Ex. 1014 (INOMAX label) at 4.
`
`
`Ex. 1014 (INOMAX label) at 6.
`
`Bernasconi teaches performing at least one diagnostic process
`to identify a plurality of neonatal patients who have hypoxic
`respiratory failure and are candidates for inhaled nitric oxide
`treatment.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 3.
`
`Loh teaches performing at least one diagnostic process to
`identify a plurality of neonatal patients who have hypoxic
`respiratory failure and are candidates for inhaled nitric oxide
`treatment.
`
`
`16
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`
`
`
`determining prior to
`treatment with
`inhaled nitric oxide
`whether or not each
`patient of the
`plurality has pre-
`existing left
`ventricular
`dysfunction;
`
`Ex. 1006 (Loh) at 2780-81.
`
`Bernasconi teaches determining prior to treatment with inhaled
`nitric oxide whether or not each patient of the plurality has pre-
`existing left ventricular dysfunction.
`
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`17
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`Loh teaches determining whether or not each patient of the
`plurality has pre-existing left ventricular dysfunction.
`
`
`
`
`
`
`
`
`Ex. 1006 (Loh) at 2780-81.
`
`
`18
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2783.
`
`
`
`
`
`
`determining that a
`first patient of the
`plurality does not
`have pre-existing left
`ventricular
`
`Ex. 1006 (Loh) at 2783.
`
`INOMAX label discloses determining that a first patient of the
`plurality does not have pre-existing left ventricular dysfunction.
`
`
`
`Ex. 1014 (INOMAX label) at 1.
`
`19
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`dysfunction;
`
`
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1014 (INOMAX label) at 2.
`
`
`Ex. 1014 (INOMAX label) at 4.
`
`Bernasconi also teaches determining that a first patient of the
`plurality does not have pre-existing left ventricular dysfunction.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`treating the first
`patient with 20 ppm
`inhaled nitric oxide;
`
`Ex. 1004 (Bernasconi) at 8.
`
`INOMAX label teaches treating the first patient with 20 ppm
`inhaled nitric oxide.
`
`
`Ex. 1014 (INOMAX label) at 6.
`
`
`Ex. 1014 (INOMAX label) at 2.
`
`Bernasconi also discloses treating the first patient with 20 ppm
`inhaled nitric oxide.
`
`20
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`determining that
`other patients of the
`plurality do have pre-
`existing left
`ventricular
`dysfunction;
`
`Ex. 1004 (Bernasconi) at 3.
`Bernasconi teaches determining that some patients of the
`plurality do have pre-existing left ventricular dysfunction.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`Loh teaches determining that some patients of the plurality do
`have pre-existing left ventricular dysfunction.
`
`
`21
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`
`
`
`
`
`
`
`Ex. 1006 (Loh) at 2780-81.
`
`
`Ex. 1006 (Loh) at 2783.
`
`
`22
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`for each patient of the
`plurality determined
`to have pre-existing
`left ventricular
`dysfunction,
`evaluating on a case-
`by-case basis the
`potential benefit of
`treating the patient
`with 20 ppm inhaled
`nitric oxide vs. the
`potential risk that
`inhaled nitric oxide
`could cause an
`increase in PCWP,
`leading to pulmonary
`edema;
`
`
`
`Ex. 1006 (Loh) at 2783.
`
`Bernasconi teaches for each patient of the plurality determined
`to have pre-existing left ventricular dysfunction, evaluating on
`a case-by-case basis the potential benefit of treating the patient
`with 20 ppm inhaled nitric oxide vs. the potential risk that
`inhaled nitric oxide could lead to pulmonary edema.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`Loh teaches for each patient of the plurality determined to have
`pre-existing left ventricular dysfunction, evaluating on a case-
`by-case basis whether inhaled nitric oxide caused an increase in
`PCWP.
`
`23
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2780.
`
`
`Ex. 1006 (Loh) at 2781.
`
`
`
`
`
`Ex. 1006 (Loh) at 2781, Table 1.
`
`
`
`
`24
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`for at least one
`patient of the
`plurality determined
`to have pre-existing
`left ventricular
`dysfunction,
`determining that the
`potential benefit of
`the treatment
`outweighs the
`potential risk
`described in the
`second warning; and
`treating the at least
`one patient with 20
`
`Ex. 1006 (Loh) at 2781, Fig. 2.
`
`Bernasconi teaches for at least one patient of the plurality
`determined to have pre-existing left ventricular dysfunction,
`determining that the potential benefit of the treatment
`outweighs the potential risk described in the second warning.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Bernasconi teaches treating the at least one patient with 20 ppm
`inhaled nitric oxide.
`
`25
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`ppm inhaled nitric
`oxide.
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 3.
`
`
`
`INOMAX label also teaches treating the at least one patient
`with 20 ppm inhaled nitric oxide.
`
`Ex. 1014 (INOMAX label) at 6.
`
`
`The INOMAX label is prescribing information supplied to the
`medical provider with the cylinder containing compressed
`nitric oxide gas.
`
`CLAIM 5
`The method of claim
`3, wherein the
`information of (i) and
`the information of (ii)
`appear in prescribing
`information supplied
`to the medical
`provider with the
`cylinder containing
`compressed nitric
`oxide gas.
`
`Ex. 1014 (INOMAX label) at i.
`
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`26
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1014 (INOMAX label) at 6.
`
`
`Ex. 1014 (INOMAX label) at 6-7.
`
`
`The INOMAX label is prescribing information supplied to the
`medical provider with the cylinder containing compressed
`nitric oxide gas.
`
`CLAIM 6
`The method of claim
`4, wherein the
`information of (i) and
`the information of (ii)
`appear in prescribing
`information supplied
`to the medical
`provider with the
`cylinder containing
`compressed nitric
`oxide gas.
`
`Ex. 1014 (INOMAX label) at i.
`
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`27
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
` Ex. 1014 (INOMAX label) at 6.
`
`
`CLAIM 7
`A method of
`providing
`pharmaceutically
`acceptable nitric
`oxide gas, the method
`comprising:
`obtaining a cylinder
`containing
`compressed nitric
`oxide gas in the form
`of a gaseous blend of
`nitric oxide and
`nitrogen;
`
`Ex. 1014 (INOMAX label) at 6-7.
`
`
`INOMAX label teaches providing pharmaceutically acceptable
`nitric oxide gas for treatment:
`
`Ex. 1014 (INOMAX label) at 4.
`
`INOMAX label teaches obtaining a cylinder containing
`compressed nitric oxide gas in the form of a gaseous blend of
`nitric oxide and nitrogen.
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`28
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`supplying the
`cylinder containing
`compressed nitric
`oxide gas to a
`medical provider
`responsible for
`treating neonates who
`have hypoxic
`respiratory failure,
`including some who
`do not have pre-
`existing left
`ventricular
`dysfunction; and
`
`providing to the
`medical provider (i)
`information that a
`recommended dose of
`inhaled nitric oxide
`gas for treatment of
`neonates with
`hypoxic respiratory
`failure is 20 ppm
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`Ex. 1014 (INOMAX label) at 6-7.
`
`INOMAX label teaches supplying compressed nitric oxide gas
`to treat neonates with hypoxic respiratory failure including
`some who do not have pre-existing left ventricular dysfunction.
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`Ex. 1014 (INOMAX label) at 6-7.
`
`
`Ex. 1014 (INOMAX label) at 2.
`
`
`Ex. 1014 (INOMAX label) at 4.
`The content of the INOMAX label is information provided to a
`medical provider.
`
`29
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`nitric oxide, (ii)
`information that
`patients who have
`pre-existing left
`ventricular
`dysfunction and are
`treated with inhaled
`nitric oxide may
`experience
`pulmonary edema,
`and (iii) a
`recommendation that,
`if pulmonary edema
`occurs in a patient
`who has pre-existing
`left ventricular
`dysfunction and is
`treated with inhaled
`nitric oxide, the
`treatment with
`inhaled nitric oxide
`should be
`discontinued.
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1014 (INOMAX label) at i.
`
`INOMAX label teaches the recommended dose of inhaled nitric
`oxide gas for the treatment of neonates with hypoxic
`respiratory failure is 20 ppm nitric oxide.
`
`
`Ex. 1014 (INOMAX label) at 6.
`
`
`Ex. 1014 (INOMAX label) at 2.
`
`INOMAX label contains INDICATIONS and
`CONTRAINDICATIONS:
`
`Ex. 1014 (INOMAX label) at 4.
`
`Bernasconi also teaches the recommended dose of inhaled
`nitric oxide gas for treating neonates with hypoxic respiratory
`failure is 20 ppm nitric oxide.
`
`30
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1004 (Bernasconi) at 3.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`Bernasconi teaches the possibility that patients who have pre-
`existing left ventricular dysfunction and are treated with
`inhaled nitric oxide may experience pulmonary edema.
`
`Ex. 1004 (Bernasconi) at 8.
`
`Bernasconi teaches that for patients who have pre-existing left
`ventricular dysfunction and are treated with inhaled nitric oxide
`may experience pulmonary edema, if pulmonary edema occurs
`in a patient who has pre-existing left ventricular dysfunction
`and is treated with inhaled nitric oxide, the treatment with
`inhaled nitric oxide should be discontinued.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`31
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`The INOMAX label is prescribing information supplied to the
`medical provider with the cylinder containing compressed
`nitric oxide gas.
`
`CLAIM 8
`The method of claim
`7, wherein the
`information of (i) and
`(ii) and the
`recommendation of
`(iii) appear in
`prescribing
`information supplied
`to the medical
`provider with the
`cylinder containing
`compressed nitric
`oxide gas.
`
`Ex. 1014 (INOMAX label) at i.
`
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`Ex. 1014 (INOMAX label) at 6.
`
`
`
`
`32
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`Ex. 1014 (INOMAX label) at 6-7.
`
`CLAIM 9
`The method of claim
`7, further comprising:
`performing at least
`one diagnostic
`process to identify a
`neonatal patient who
`has hypoxic
`respiratory failure
`and is a candidate for
`inhaled nitric oxide
`treatment;
`
`
`
`
`INOMAX label teaches performing at least one diagnostic
`process to identify a neonatal patient who has hypoxic
`respiratory failure and is a candidate for inhaled nitric oxide
`treatment.
`
`Ex. 1014 (INOMAX label) at 4.
`
`
`Ex. 1014 (INOMAX label) at 6.
`
`Bernasconi teaches performing at least one diagnostic process
`to identify a neonatal patient who has hypoxic respiratory
`failure and is a candidate for inhaled nitric oxide treatment.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 3.
`
`Loh teaches performing at least one diagnostic process to
`identify a neonatal patient who has hypoxic respiratory failure
`and is a candidate for inhaled nitric oxide treatment.
`
`
`33
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`
`
`
`determining prior to
`treatment with
`inhaled nitric oxide
`that the neonatal
`patient has pre-
`existing left
`ventricular
`dysfunction;
`
`Ex. 1006 (Loh) at 2780-81.
`
`Bernasconi teaches determining prior to treatment with inhaled
`nitric oxide that the neonatal patient has pre-existing left
`ventricular dysfunction.
`
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`34
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`Loh teaches determining prior to treatment with inhaled nitric
`oxide that the neonatal patient has pre-existing left ventricular
`dysfunction.
`
`
`
`
`
`
`
`
`Ex. 1006 (Loh) at 2780-81.
`
`
`35
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2783.
`
`
`
`
`
`
`Ex. 1006 (Loh) at 2783.
`
`Bernasconi teaches treating the neonatal patient with 20 ppm
`inhaled nitric oxide, whereupon the neonatal patient
`experiences pulmonary edema.
`
`
`
`treating the neonatal
`patient with 20 ppm
`inhaled nitric oxide,
`whereupon the
`neonatal patient
`
`36
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`experiences
`pulmonary edema;
`and
`
`in accordance with
`the recommendation
`of (iii), discontinuing
`the treatment with
`inhaled nitric oxide
`due to the neonatal
`patient's pulmonary
`edema.
`CLAIM 10
`The method of claim
`4, wherein the at least
`one patient is
`monitored for
`evidence of increased
`PCWP and/or for
`evidence of
`pulmonary edema
`during treatment with
`20 ppm inhaled nitric
`oxide.
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1004 (Bernasconi) at 8.
`
`Bernasconi teaches discontinuing the treatment with inhaled
`nitric oxide due to the neonatal patient's pulmonary edema.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`
`Bernasconi teaches the at least one patient is monitored for
`evidence of pulmonary edema during treatment with 20 ppm
`inhaled nitric oxide.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`Loh teaches at least one patient is monitored for evidence of
`increased PCWP during treatment with 20 ppm inhaled nitric
`oxide.
`
`
`37
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2780.
`
`
`Ex. 1006 (Loh) at 2781.
`
`
`
`
`
`Ex. 1006 (Loh) at 2781, Table 1.
`
`
`
`
`38
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`CLAIM 11
`The method of claim
`9,
`wherein
`the
`neonatal patient
`is
`monitored
`for
`evidence of increased
`PCWP
`and/or
`for
`evidence
`of
`pulmonary
`edema
`during treatment with
`20 ppm inhaled nitric
`oxide.
`
`Ex. 1006 (Loh) at 2781, Fig. 2.
`
`
`
`Bernasconi teaches the neonatal patient is monitored for
`evidence of pulmonary edema during treatment with 20 ppm
`inhaled nitric oxide.
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`39
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`Loh teaches the patient is monitored for evidence of increased
`PCWP during treatment with 20 ppm inhaled nitric oxide.
`
`
`Ex. 1006 (Loh) at 2780.
`
`
`Ex. 1006 (Loh) at 2781.
`
`
`
`
`
`Ex. 1006 (Loh) at 2781, Table 1.
`
`
`
`
`40
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2781, Fig. 2.
`
`Goyal teaches that increases in PCWP may be measured in any
`patient population.
`
`
`Ex. 1007 (Goyal) at 209
`
`
`
`41
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1007 (Goyal) at 209
`
`
`
`
`CLAIM 12
`A method
`comprising:
`
`Ex. 1007 (Goyal) at 210, Table 2.
`
`
`INOMAX label teaches a method involving supplying nitric
`oxide gas and information about administration of the gas.
`
`Ex. 1014 (INOMAX label) at 4.
`INOMAX label teaches obtaining a source of nitric oxide gas
`comprising a cylinder of compressed gas for inhalation by a
`patient.
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`obtaining a source of
`nitric oxide gas
`comprising a cylinder
`of compressed gas
`and/or a device that
`delivers nitric oxide
`gas into an
`inspiratory limb of a
`breathing circuit, for
`inhalation by a
`patient;
`
`42
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1014 (INOMAX label) at 6-7.
`
`INOMAX label also discloses obtaining a device that delivers
`nitric oxide gas into an inspiratory limb of a breathing circuit.
`
`
`Ex. 1014 (INOMAX label) at 6.
`
`INOMAX label teaches supplying the source of nitric oxide gas
`to a medical provider responsible for treating neonates who
`have hypoxic respiratory failure, including some who do not
`have left ventricular dysfunction.
`
`
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`supplying the source
`of nitric oxide gas to
`a medical provider
`responsible for
`treating neonates who
`have hypoxic
`respiratory failure,
`including some who
`do not have left
`ventricular
`dysfunction; and
`
`43
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1014 (INOMAX label) at 6-7.
`
`
`Ex. 1014 (INOMAX label) at 2.
`
`
`Ex. 1014 (INOMAX label) at 4.
`
`The content of the INOMAX label is information provided to a
`medical provider.
`
`Ex. 1014 (INOMAX label) at i.
`
`INOMAX label teaches the recommended dose of inhaled nitric
`oxide gas for the treatment of neonates with hypoxic
`respiratory failure is 20 ppm nitric oxide.
`
`44
`
`providing to the
`medical provider (i)
`information that a
`recommended dose of
`inhaled nitric oxide
`gas for treatment of
`neonates with
`hypoxic respiratory
`failure is 20 ppm
`nitric oxide and (ii)
`information that, in
`patients with pre-
`existing left
`ventricular
`dysfunction, inhaled
`nitric oxide may
`increase PCWP,
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`leading to pulmonary
`edema, the
`information of (ii)
`being sufficient to
`cause a medical
`provider considering
`inhaled nitric oxide
`treatment for a
`plurality of neonatal
`patients who (a) are
`suffering from a
`condition for which
`inhaled nitric oxide is
`indicated, and (b)
`have pre-existing left
`ventricular
`dysfunction, to elect
`to avoid treating one
`or more of the
`plurality of patients
`with inhaled nitric
`oxide in order to
`avoid putting the one
`or more patients at
`risk of pulmonary
`edema.
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`
`Ex. 1014 (INOMAX label) at 6.
`
`
`Ex. 1014 (INOMAX label) at 2.
`
`INOMAX label contains INDICATIONS and
`CONTRAINDICATIONS:
`
`Ex. 1014 (INOMAX label) at 4.
`
`Bernasconi also teaches the recommended dose of inhaled
`nitric oxide gas for treating neonates with hypoxic respiratory
`failure is 20 ppm nitric oxide.
`
`Ex. 1004 (Bernasconi) at 3.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`Bernasconi teaches the possibility of pulmonary edema upon
`administering inhaled nitric oxide to a patient with left
`ventricular dysfunction.
`
`45
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1004 (Bernasconi) at 8.
`
`Loh teaches measuring wedge pressure in patients in its study.
`
`Ex. 1006 (Loh) at Abstract.
`
`
`
`
`46
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2780-81.
`
`Loh teaches patients with left ventricular dysfunction show an
`increase in wedge pressure upon treatment with inhaled nitric
`oxide.
`
`
`
`Ex. 1006 (Loh) at 2780.
`
`
`Ex. 1006 (Loh) at 2781.
`
`
`
`
`
`Ex. 1006 (Loh) at 2781, Table 1.
`
`
`
`
`47
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1006 (Loh) at 2781, Fig. 2.
`
`Goyal teaches measuring wedge pressure in its population of
`patients.
`
`
`
`
`
`Ex. 1007 (Goyal) at 209
`
`
`48
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`Ex. 1007 (Goyal) at 209
`
`
`
`
`Ex. 1007 (Goyal) at 210, Table 2.
`
`Bernasconi teaches that a medical provider considering inhaled
`nitric oxide treatment for a plurality of neonatal patients who
`(a) are suffering from a condition for which inhaled nitric oxide
`is indicated, and (b) have pre-existing left ventricular
`dysfunction, may elect to avoid treating one or more of the
`plurality of patients with inhaled nitric oxide in order to avoid
`putting the one or more patients at risk of pulmonary edema
`
`Ex. 1004 (Bernasconi) at 8.
`
`
`Ex. 1004 (Bernasconi) at 8.
`
`49
`
`

`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`
`The INOMAX label is prescribing information supplied to the
`medical provider with the source of nitric oxide gas.
`
`
`
`U.S. Pat. No.
`8,846,112
`CLAIM 13
`The method of claim
`12, wherein the
`information of (i) and
`the information of (ii)
`appear in prescribing
`information supplied
`to the medical
`provider with the
`source of nitric oxide
`gas.
`
`Ex. 1014 (INOMAX label) at i.
`
`
`Ex. 1014 (INOMAX label) at 1.
`
`
`Ex. 1014 (INOMAX label) at 6.
`
`
`
`
`CLAIM 14
`A method
`comprising:
`
`Ex. 1014 (INOMAX label) at 6-7.
`
`
`INOMAX label teaches a method involving providing nitric
`oxide gas and information about administration of the gas.
`
`50
`
`

`
`
`
`U.S. Pat. No.
`8,846,112
`
`INOMAX label (Ex. 1014), Bernasconi (Ex. 1004), Loh (Ex.
`1006), and Goyal (Ex. 1007)
`
`obtaining a device
`that delivers nitric
`oxide gas into an
`inspiratory limb of a
`breathing circuit, for
`inhalation by a
`patient;
`
`Ex. 1014 (INOMAX label) at 4.
`INOMAX label teaches obtaining a cylinder that delivers nitric
`oxide gas into an inspiratory limb of a breathing circuit,

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