FISH sc RICHARDSON P.C.
`
`Frederick P. Fish
`I8 si—I93o
`
`WK. Richardson
`I8s9—I9sI
`
`November 21 , 2012
`
`Attorney Docket N0.: 26047-0003006/3000-US-0008DIV
`
`Commissioner for Patents
`
`P.O. Box 1450
`Alexandria, VA 22313-1450
`
`Street Address
`One Marina Park Drive
`Boston, Massachusetts
`o2..1ro—r878
`
`M331 Adams
`P.O. Box 1022
`IVIINNEAPOLIS, MINNESOTA
`554404022
`
`Telephone
`617 “H070
`
`Facsimile
`
`877769794’
`WEB gm
`\W\WW'.FR.COM
`
`G3
`ATLANTA
`
`AUSTIN
`
`BOSTON
`
`DALLAS
`
`DELAWARE
`
`HOUSTON
`
`MUNICH
`
`NEW YORK
`
`SILICON VALLEY
`
`SOUTHERN CALIFORNIA
`
`TWIN CITIES
`
`WASIIINGTON, DC
`
`This application is a divisional of U.S. Application Serial No. 12/820,866, filcd
`June 22, 2010, which is a continuation of U.S. Serial No. 12/494,598, filed June 30,
`2009, and now abandoned. This application is also a divisional of U.S. Serial
`No. 13/651,660, filed October 15, 2012, which is a continuation of U.S. Application
`Serial No. 12/821,041 (now U.S. Patent No. 8,293,284), filed on June 22, 2010,
`which is a continuation of U.S. Application Serial No. 12/494,598, filed June 30,
`2009, and now abandoned.
`
`Invent0r(s): JAMES S. BALDAS SARRE AND RALF ROSSKAMP
`
`Title:
`
`METHODS OF DISTRIBUTING A PHARMACEUTICAL PRODUCT
`COMPRISING NITRIC OXIDE GAS FOR INHALATION
`
`Assignee:
`
`INO Therapeutics LLC
`
`Enclosed are the following papers, including those required to receive a filing date
`under 37 C.F.R. § 1.53(b):
`
`Specification
`Claims
`Abstract
`
`Pages
`22
`7
`1
`
`Declarations (2) with cover sheet
`
`3
`
`Enclosures:
`
`Certification and Request for Prioritized Examination (Track I) (1 page)
`Application Data Sheet (6 pages)
`Powcr of Attorney to Prosccutc Applications Before the USPTO (1 pagc)
`together with Statement Under 37 CFR 3.73 (c) (2 pages) and copies of 3
`assignments (James S. Baldassarre and Ralf Rosskamp to Ikaria Holdings,
`
`Mallinckrodt Hosp. Prods. IP Ltd.
`Exhibit 2005
`Praxair Distrib., Inc. et al., v. Mallinckrodt Hosp. Prods. IP Ltd.
`Case lPR2o16-00779
`
`001
`
`Ex. 2005-0001
`
`

`
`FISH 3; RICHARDSON P.C.
`
`Commissioner for Patents
`
`November 21, 2012
`Page 2
`
`Inc.; Ikaria Holdings, Inc. to Ikaria, Inc.; and Ikaria, Inc. to INO Therapeutics
`LLC) (83 pages)
`
`Basie Filing fee
`Search fee
`
`Examination fee
`
`Publication fee
`
`Track I processing fee
`
`Track I prioritized examination fee
`
`Application size fee for each 50 pages over 100
`
`Excess independent claim fee
`Excess claim fee
`
`Total Filing fee
`
`Total
`
`$390
`$620
`
`$250
`
`$300
`
`$130
`
`$4800
`
`$0
`
`$250
`$620
`
`$7360
`
`The fees totaling $7360 are being paid concurrently herewith on the Electronic Filing
`System (EFS) by way of Deposit Account authorization. Apply all charges or credits
`to Deposit Account No. 06-1050, referencing Attorney Docket No. 26047—0003006.
`
`If this application is found to be incomplete, or if a telephone conference would
`otherwise be helpful, please call the undersigned at (617) 542-5070.
`
`Direct all correspondence to the following:
`
`94169
`PTO Customer Number
`
`Respectfully submitted,
`
`/Janis K. Fraser/
`
`Janis K. Fraser, Ph.D., J.D.
`
`Reg. No. 34,819
`Enclosures
`JKF/nab
`229l8954.doc
`
`002
`
`Ex. 2005-0002
`
`

`
`FISH ac RICHARDSON P.C.
`
`Frederick P. Fish
`I8 534930
`
`WK. Richardson
`I8s9—I9sI
`
`21,
`
`Attorney Docket No.: 26047-0003006/3000-US-0008DIV
`
`Commissioner for Patents
`
`P.O. Box 1450
`AICXandrIa,
`
`Street Address
`One Marina Park Drive
`Boston, Massachusetts
`o:.:.1o—1878
`
`Address
`PO. Box 1022
`IVIINNEAPOLIS, MINNESOTA
`5;4.4o—ro2.2
`
`Telephone
`1_
`2—
`7
`6754 so 0
`
`Facsimilc
`
`877 769794’
`\WEB SITE
`WWW.FR.COM
`
`G3
`ATLANTA
`
`AUSTIN
`
`BOSTON
`
`DALLAS
`
`DELAWARE
`
`HOUSTON
`
`IVIUNICH
`
`NEW YORK
`
`SILICON VALLEY
`
`SOUTHERN CALIFORNIA
`
`TWIN CITIES
`
`WASIIINGTON, DC
`
`This application is a divisional of U.S. Application Scrial No. 12/820,866, filcd
`June 22, 2010, which is a continuation of U.S. Serial No. 12/494,598, filed June 30,
`2009, and now abandoned. This application is also a divisional of U.S. Serial
`No. 13/651,660, filed October 15, 2012, which is a continuation of U.S. Application
`Serial No. 12/821,041 (now U.S. Patent No. 8,293,284), filed on June 22, 2010,
`which is a continuation of U.S. Application Serial No. 12/494,598, filed June 30,
`2009, and now abandoned.
`
`InVentor(s): JAMES S. BALDASSARRE AND RALF ROSSKAMP
`
`Title:
`
`METHODS OF DISTRIBUTING A PHARMACEUTICAL PRODUCT
`COMPRISING NITRIC OXIDE GAS FOR INHALATION
`
`Assignee:
`
`INO Therapeutics LLC
`
`Enclosed are the following papers, including those required to receive a filing date
`under 37 C.F.R. § l.53(b):
`
`Specification
`Claims
`Abstract
`
`Pages
`22
`7
`1
`
`Declarations (2) with cover sheet
`
`3
`
`Enclosures:
`
`Certification and Request for Prioritized Examination (Track I) (1 page)
`Application Data Sheet (6 pages)
`Power of Attorney to Prosccutc Applications Before the USPTO (1 page)
`together with Statement Under 37 CFR 3.73 (c) (2 pages) and copies of 3
`assignments (James S. Baldassarre and Ralf Rosskamp to Ikaria Holdings,
`
`003
`
`Ex. 2005-0003
`
`

`
`FISH 3; RICHARDSON P.C.
`
`Commissioner for Patents
`
`November 21, 2012
`Page 2
`
`Inc.; Ikaria Holdings, Inc. to Ikaria, Inc.; and Ikaria, Inc. to INO Therapeutics
`LLC) (83 pages)
`
`Basie Filing fee
`Search fee
`
`Examination fee
`
`Publication fee
`
`Track I processing fee
`
`Track I prioritized examination fee
`
`Application size fee for each 50 pages over 100
`
`Excess independent claim fee
`Excess claim fee
`
`Total Filing fee
`
`Total
`
`$390
`$620
`
`$250
`
`$300
`
`$130
`
`$4800
`
`$0
`
`$250
`$620
`
`$7360
`
`The fees totaling $7360 are being paid concurrently herewith on the Electronic Filing
`System (EFS) by way of Deposit Account authorization. Apply all charges or credits
`to Deposit Account No. 06-1050, referencing Attorney Docket No. 26047—0003006.
`
`If this application is found to be incomplete, or if a telephone conference would
`otherwise be helpful, please call the undersigned at (617) 542-5070.
`
`Direct all correspondence to the following:
`
`94169
`PTO Customer Number
`
`Respectfully submitted,
`
`/Janis K. Fraser/
`
`Janis K. Fraser, Ph.D., J.D.
`
`Reg. No. 34,819
`Enclosures
`JKF/nab
`229l8954.doc
`
`004
`
`Ex. 2005-0004
`
`

`
`Electronic Patent Application Fee Transmittal
`
`Application Number:
`
`Filing Date:
`
`Title of lnventiow
`°
`
`METHODS FOR TREATING PATIENTS WHO ARE CANDIDATES FOR INHALED
`NITRIC OXIDE TREATMENT
`
`First Named Inventor/Applicant Name:
`
`James S. Baldassarre
`
`Filer:
`
`Janis K. Fraser/Nancy Bechet
`
`Attorney Docket Number:
`
`26047—0003006
`
`Filed as Large Entity
`
`Trackl Prioritized Examination - Nonprovisional Application under 35 USC 111(a) Filing Fees
`
`Sub-Total in
`USD($)
`
`Basic Filing:
`
`Description
`
`Utility application filing
`
`Utility Search Fee
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`Utility Examination Fee
`
`Request for Prioritized Examination
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`Claims in excess of20
`
`Independent claims in excess of3
`
`005
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`Ex. 2005-0005
`
`

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`Sub-Total in
`USD($)
`
`Description
`
`Miscellaneous-Filing:
`
`Publ. Fee- early, voluntary, or normal
`
`Processing Fee,except for Provis. apps
`
`1504
`
`1808
`
`l
`
`Petition:
`
`Patent-Appeals-and-Interference:
`
`Post-AIlowance-and-Post-Issuance:
`
`Extension-of-Time:
`
`Miscellaneous:
`
`Total in USD ($)
`
`006
`
`Ex. 2005-0006
`
`

`
`Electronic Acknowledgement Receipt
`
`Application Number:
`
`13683236
`
`International Application Number:
`
`Confirmation Number:
`
`T'tl° °f I'“'°"t'°"’
`
`METHODS FOR TREATING PATIENTS WHO ARE CANDIDATES FOR INHALED
`NITRIC OXIDE TREATMENT
`
`First Named lnventorIApplicant Name:
`
`James S. Baldassarre
`
`Customer Number:
`
`94169
`
`Janis K. Fraser/Paul Stovenour
`
`Filer Authorized By:
`
`Janis K. Fraser
`
`Attorney Docket Number:
`
`26047—0003006
`
`Receipt Date:
`
`21 -NOV-201 2
`
`Filing Date:
`
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`
`Utility under 35 USC111(a)
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`RAM confirmation Number
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`
`Document Descri
`
`tion
`
`P
`
`File Size(Bytes)/
`Message Digest
`
`Part /.zip (ifapp|.)
`
`007
`
`Ex. 2005-0007
`
`

`
`TrackOne Request
`
`Request26047_00O3006.pdf
`
`139133
`
`d4Z I Sebfl I fZ893dfd9I66ee1 b08db548e89
`651011
`
`240216
`26047_OO03006app|ication.pdf 0b91ca37c1d934ccc656254la72‘)d84b8I’lc
`89f]
`
`Multipart Description/PDF files in .zip description
`
`Document Description
`
`Specification
`
`Application Data Sheet
`
`ADS26047_0003006.pdf
`
`1396085
`
`U53 le8Z5f6a(9 l0b9b7DbeU36Zdb3aZ8c64-I
`Z(6b5
`
`Oath or Declaration filed
`
`120793
`declaration26047_0003006.pdf 04d63cf9b65d8bb5e3b99508b42a4628I29
`Uc89f
`
`Power of Attorney
`
`power0O3006.pdf
`
`Transmittal of New Application
`
`pap|tr26047_0003006.pdf
`
`Fee Worksheet (SB06)
`
`fee-info.pdf
`
`4309982
`
`r-rIIr1fi3fi( (470119n§0§4(l4§II8Ir( 07337 F79
`I348] b
`
`93940
`
`'|b8U928fd/1/f>5IUe4969999bebeUdb553IU
`38230
`
`43406
`
`D7((409cf1I710f31b:rJafa4b60190Z176ad
`/UC
`
`Total Files Size (in bytes)
`
`6343555
`
`Warnings:
`Information:
`
`Warnings:
`Information:
`
`Warnings:
`Information:
`
`Warnings:
`Information:
`
`Warnings:
`Information:
`
`Warnings:
`Information:
`
`Warnings:
`Information:
`
`008
`
`Ex. 2005-0008
`
`

`
`This Acknowledgement Receipt evidences receipt on the noted date by the USPTO ofthe indicated documents,
`characterized by the applicant, and including page counts, where applicable. It serves as evidence of receipt similar to a
`Post Card, as described in MPEP 503.
`
`New Applications Under 35 U.S.C. 111
`lfa new application is being filed and the application includes the necessary components for a filing date (see 37 CFR
`1.53(b)-(d) and MPEP 506), a Filing Receipt (37 CFR 1.54) will be issued in due course and the date shown on this
`Acknowledgement Receipt will establish the filing date ofthe application.
`
`National Stage of an International Application under 35 U.S.C. 371
`lfa timely submission to enter the national stage ofan international application is compliant with the conditions of 35
`U.S.C. 371 and other applicable requirements a Form PCT/D0/E0/903 indicating acceptance of the application as a
`national stage submission under 35 U.S.C. 371 will be issued in addition to the Filing Receipt, in due course.
`
`New International Application Filed with the USPTO as a Receiving Office
`lfa new international application is being filed and the international application includes the necessary components for
`an international filing date (see PCT Article 11 and MPEP 1810), a Notification of the International Application Number
`and of the International Filing Date (Form PCT/R0/105) will be issued in due course, subject to prescriptions concerning
`national security, and the date shown on this Acknowledgement Receipt will establish the international filing date of
`the application.
`
`009
`
`Ex. 2005-0009
`
`

`
`PTO/SB/424 (12-11)
`
`CERTIFICATION AND REQUEST FOR PRIORITIZED EXAMINATION
`
`UNDER 37 CFR 1.102(e) (Page 1 of1)
`
`Janess-Ba'dassarre -
`Title of
`METHODS OF DISTRIBUTING A PHARMACEUTICAL PRODUCT COMPRISING NITRIC
`Invention:
`OXIDE GAS I=OR INHALATION
`
`APPLICANT HEREBY CERTIFIES THE FOLLOWING AND REQUESTS PRIORITIZED EXAMINATION FOR
`THE ABOVE-IDENTIFIED APPLICATION.
`
`1. The processing fee set forth in 37 CFR 1.17(i), the prioritized examination fee set forth in 37
`CFR 1.17(c), and if not already paid, the publication fee set forth in 37 CFR 1.18(d) have been
`filed with the request. The basic filing fee, search fee, examination fee, and any required
`excess claims and application size fees are filed with the request or have been already been
`paid.
`
`The application contains or is amended to contain no more than four independent claims and
`no more than thirty total claims, and no multiple dependent claims.
`
`The applicable box is checked below:
`
`Iication Track One - Prioritized Examination under
`
`i.
`
`(a) The application is an original nonprovisional utility application filed under 35 U.S.C. 111( ).
`This certification and request is being filed with the utility application via EFS-Web.
`___oR___
`
`(b) The application is an original nonprovisional plant application filed under 35 U.S.C. 111(a).
`This certification and request is being filed with the plant application in paper.
`
`ii. An executed oath or declaration under 37 CFR 1.63 is filed with the application.
`
`Re uest for Continued Examination - Prioritized Examination under
`
`A request for continued examination has been filed with, or prior to, this form,
`If the application is a utility application, this certification and request is being filed via EFS-Web.
`The application is an original nonprovisional utility application filed under 35 U.S.C. 111(a), or is
`a national stage entry under 35 U.S.C. 371.
`. This certification and request is being filed prior to the mailing of a first Office action responsive
`to the request for continued examination.
`No prior request for continued examination has been granted prioritized examination status
`under 37 CFR1.102(e)(2).
`
`'
`
`Signature
`
`/Janis K. Fraserl
`
`Name Janis K. Fraser, Ph_D_, J_D.
`(Print/Typed)
`
`Date November 21, 2012
`
`Practitioner
`Registration Number 34,819
`
`Note: Signatures of all the inventors or assignees of record of the entire interest or their representative(s) are required in accordance with
`37 CFR 1.33 and 11.18. Please see 37 CFR 1.4(d) for the form of the signature. If necessary, submit multiple forms for more than one
`signature, see below*_
`
`E *Total of 1 forms are submitted.
`
`22918943.doc
`
`Ainericx n LegxINel. Inc.
`www.FUr11I:‘}VUxk_FiUw.L‘1JI1l
`
`M
`
`‘
`
`010
`
`Ex. 2005-0010
`
`

`
`Attorney Docket No. 26047-0003006/3000-US-0008DIV
`
`METHODS OF DISTRIBUTING A PI-LARMACEUTICAL PRODUCT COMPRISING
`NITRIC OXIDE GAS FOR INHALATION
`
`CROSS REFERENCE TO RELATED APPLICATIONS
`
`[0001]
`
`This application is a divisional of U.S. Application Serial No. 12/820,866, filed
`
`June 22, 2010, which is a continuation of U.S. Serial No. 12/494,598, filed June 30, 2009, and
`
`now abandoned. This application is also a divisional of U.S. Serial No. 13/651,660, filed
`
`October 15, 2012, which is a continuation of U.S. Application Serial No. 12/821,041 (now U.S.
`
`Patent No. 8,293,284), filed June 22, 2010, which is a continuation of U.S. Application Serial
`
`No. 12/494,598, filed June 30, 2009, and now abandoned.
`
`BACKGROUND OF THE INVENTION
`
`[0002]
`
`INOmax®, (nitric oxide) for inhalation is an approved drug product for the
`
`treatment of term and near—term (>34 weeks gestation) neonates having hypoxic respiratory
`
`failure associated with clinical or echocardiographic evidence of pulmonary hypertension.
`
`[0003]
`
`The use of inhaled NO (iNO) has been studied and reported in the literature.
`
`(Kieler—Jensen M et al., 1994, Inhaled Nitric Oxide in the Evaluation of Heart Transplant
`
`Candidates with Elevated Pulmonary Vascular Resistance, J Heart Lung Transplantation
`
`132366-375; Pearl RG et al., 1983, Acute Hemodynamic Effects of Nitroglycerin in Pulmonary
`
`Hypertension, American College ofPliysicians 99:9-13; Ajami GH et al., 2007, Comparison of
`
`the Effectiveness of Oral Sildenafil Versus Oxygen Administration as a Test for Feasibility of
`
`Operation for Patients with Secondary Pulmonary Arterial Hypertension, Pediatr Cardiol;
`
`Schulze-Neick I et al., 2003, Intravenous Sildenafil Is a Potent Pulmonary Vasodilator in
`
`Children With Congenital Heart Disease, Circulation 108(Suppl II):II-167-II-173; Lepore JJ et
`
`al., 2002, Effect of Sildenafil on the Acute Pulmonary Vasodilator Response to Inhaled Nitric
`
`Oxide in Adults with Primary Pulmonary Hypertension, The American Journal of Cardiology
`
`90:677-680; and Ziegler JW et al., 1998, Effects of Dipyridamole and Inhaled Nitric Oxide in
`
`Pediatric Patients with Pulmonary Hypertension, American Journal ofRespiratory and Critical
`
`Care Medicine 158: 1388-95).
`
`011
`
`Ex. 2005-0011
`
`

`
`Attorney Docket No. 260410003006/3000—US—0008l')TV
`
`SUMMARY OF THE INVENTION
`
`[0004]
`
`One aspect of the invention relates to a pre-screening methodology or protocol
`
`having exclusionary criteria to be evaluated by a medical provider prior to treatment of a patient
`
`with iNO. One objective of the invention is to evaluate and possibly exclude from treatment
`
`patients eligible for treatment with iNO, who have pre-existing left ventricular dysfunction
`
`(LVD). Patients who have pre-existing LVD may experience, and are at risk of, an increased
`
`rate of adverse events or serious adverse events (e.g., pulmonary edema) when treated with iNO.
`
`Such patients may be characterized as having a pulmonary capillary wedge pressure (PCWP)
`
`greater than 20 mm Hg, and should be evaluated on a case-by-case basis with respect to the
`
`benefit versus risk of using iNO as a treatment option.
`
`[0005]
`
`Accordingly, one aspect of the invention includes a method of reducing the risk
`
`or preventing the occurrence, in a human patient, of an adverse event (AE) or a serious adverse
`
`event (SAE) associated with a medical treatment comprising inhalation of nitric oxide, said
`
`method comprising the steps or acts of (a) providing pharmaceutically acceptable nitric oxide
`
`gas to a medical provider; and, (b) informing the medical provider that excluding human
`
`patients who have pre-existing left ventricular dysfunction from said treatment reduces the risk
`
`or prevents the occurrence of the adverse event or the serious adverse event associated with said
`
`medical treatment.
`
`[0006]
`
`Further provided herein is a method of reducing the risk or preventing the
`
`occurrence, in a human patient, of an adverse event or a serious adverse event associated with a
`
`medical treatment comprising inhalation of nitric oxide, said method comprising the steps or
`
`acts of (a) providing pharmaceutically acceptable nitric oxide gas to a medical provider; and,
`
`(b) informing the medical provider that human patients having pre-existing left ventricular
`
`dysfunction experience an increased risk of serious adverse events associated with said medical
`
`treatment.
`
`[0007]
`
`Another aspect of the invention is a method of reducing one or more of an AE or
`
`a SAE in an intended patient population in need of being treated with iNO comprising the steps
`
`or acts of (a) identifying a patient eligible for iNO treatment; (b) evaluating and screening the
`
`012
`
`Ex. 2005-0012
`
`

`
`Attorney Docket No. 260410003006/3000—US—0008T)IV
`
`patient to identify if the patient has pre-existing LVD, and (c) excluding from iNO treatment a
`
`patient identified as having pre-existing LVD.
`
`[0008]
`
`Another aspect of the invention is a method of reducing the risk or preventing the
`
`occurrence, in a patient, of one or more of an AE or a SAE associated with a medical treatment
`
`comprising iNO, the method comprising the steps or acts of (a) identifying a patient in need of
`
`receiving iNO treatment; (b) evaluating and screening the patient to identify if the patient has
`
`pre-existing LVD; and (c)administering iNO if the patient does not have pre-existing LVD,
`
`thereby reducing the risk or preventing the occurrence of the AE or the SAE associated with the
`
`iNO treatment. Alternatively, step
`
`may comprise further evaluating the risk versus benefit of
`
`utilizing iNO in a patient where the patients has clinically significant LVD before administering
`
`iNO to the patient.
`
`[0009]
`
`In an exemplary embodiment of the method, the method further comprises
`
`informing the medical provider that there is a risk associated with using inhaled nitric oxide in
`
`human patients who have preexisting or clinically significant left ventricular dysfunction and
`
`that such risk should be evaluated on a case by case basis.
`
`[0010]
`
`In another exemplary embodiment of the method, the method further comprises
`
`informing the medical provider that there is a risk associated with using inhaled nitric oxide in
`
`human patients who have left ventricular dysfunction.
`
`[001 1]
`
`In an exemplary embodiment of the methods described herein, a patient having
`
`pre-existing LVD is characterized as having PCWP greater than 20 mm Hg.
`
`[0012]
`
`In an exemplary embodiment of the method, the patients having pre-existing
`
`LVD demonstrate a PCWP Z 20 mm Hg.
`
`[0013]
`
`In another exemplary embodiment of the method, the iNO treatment further
`
`comprises inhalation of oxygen (02) or concurrent ventilation.
`
`[0014]
`
`In another exemplary embodiment of the method, the patients having pre-
`
`existing LVD have one or more of diastolic dysfunction, hypertensive eardiomyopathy, systolic
`
`dysfunction, isehemic eardiomyopathy, viral eardiomyopathy, idiopathic eardiomyopathy,
`
`autoimmune disease related eardiomyopathy, drug—related eardiomyopathy, toxin—related
`
`eardiomyopathy, structural heart disease, valvular heart disease, congenital heart disease, or
`
`associations thereof.
`
`013
`
`Ex. 2005-0013
`
`

`
`Attorney Docket No. 260410003006/3000—US—0008DIV
`
`[0015]
`
`In another exemplary embodiment of the method, the patient population
`
`comprises children.
`
`[0016]
`
`In another exemplary embodiment of the method, the patient population
`
`comprises adults.
`
`[0017]
`
`In another exemplary embodiment of the method, the patients who have pre-
`
`existing LVD are at risk of experiencing an increased rate of one or more AEs or SAES selected
`
`from pulmonary edema, hypotension, cardiac arrest, electrocardiogram changes, hypoxemia,
`
`hypoxia, bradycardia, or associations thereof.
`
`[0018]
`
`In another exemplary embodiment of the method, the intended patient population
`
`in need of being treated with inhalation of nitric oxide has one or more of idiopathic pulmonary
`
`arterial hypertension characterized by a mean pulmonary artery pressure (PAPm) > 25 mm Hg
`
`at rest, PCWP S 15 mm Hg, and a pulmonary vascular resistance index (PVRI) > 3 u-m2;
`
`congenital heart disease With pulmonary hypertension repaired and unrepaired characterized by
`
`PAPm > 25 mm Hg at rest and PVRI > 3 u~m2; cardiomyopathy characterized by PAPm >
`
`25 mm Hg at rest and PVRI > 3 u~m2; or the patient is scheduled to undergo right heart
`
`catheterization to assess pulmonary vasoreactivity by acute pulmonary Vasodilatation testing.
`
`[0019]
`
`In another exemplary embodiment of any of the above methods, the method
`
`further comprises reducing left ventricular afterload to minimize or reduce the risk of the
`
`occurrence of an adverse event or serious adverse event being pulmonary edema in the patient.
`
`The left ventricular afterload may be minimized or reduced by administering a pharmaceutical
`
`dosage form comprising nitroglycerin or calcium channel blocker to the patient. The left
`
`ventricular afterload may also be minimized or reduced using an intra-aortic balloon pump.
`
`DETAILED DESCRIPTION OF THE EXEMPLARY EMBODIMENTS
`
`[0020]
`
`IN Omax® (nitric oxide) for inhalation was approved for sale in the United States
`
`by the U.S. Food and Drug Administration (“FDA”) in 1999. Nitric oxide, the active substance
`
`in INOmax®, is a selective pulmonary vasodilator that increases the partial pressure of arterial
`
`oxygen (PaO2) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing
`
`pulmonary blood flow away from the lung regions with low ventilation/perfusion (V/Q) ratios
`
`toward regions with normal ratios.
`
`INOmax® significantly improves oxygenation, reduces the
`
`014
`
`Ex. 2005-0014
`
`

`
`Attorney Docket No. 26047—0003006/3000—US—0008DIV
`
`need for extracorporeal oxygenation, and is indicated to be used in conjunction with ventilatory
`
`support and other appropriate agents. The FDA-approved prescribing information for 1NOmax®
`
`in effect in 2009 is incorporated herein by reference in its entirety. The DOSAGE section of the
`
`prescribing information for 1NOmax® states that the recommended dose of INOmaX® is
`
`20 ppm, and that treatment should be maintained up to 14 days or until the underlying oxygen
`
`desaturation has resolved and the neonate is ready to be weaned from INOmax® therapy. The
`
`CONTRAINDICATIONS section of the prescribing information for INOmax® states that
`
`WOmaX® should not be used in the treatment of neonates known to be dependent on right-to-
`
`left shunting of blood.
`
`[0021]
`
`INOmax® is a gaseous blend of NO and nitrogen (0.08% and 99.92%
`
`respectively for 800 ppm; and 0.01% and 99.99% respectively for 100 ppm) and is supplied in
`
`aluminium cylinders as a compressed gas under high pressure. In general, INOmax® is
`
`administered to a patient in conjunction with ventilatory support and O2. Delivery devices
`
`suitable for the safe and effective delivery of gaseous NO for inhalation include the IN Ovent®,
`
`INOmax DS®, 1NOpulse®, INOblender®, or other suitable drug delivery and regulation
`
`devices or components incorporated therein, or other related processes, which are described in
`
`various patent documents including USPNs 5,558,083; 5,732,693; 5,752,504; 5,732,694;
`
`6,089,229; 6,109,260; 6,125,846; 6,164,276; 6,581,592; 5,918,596; 5,839,433; 7,114,510;
`
`5,417;950; 5,670,125; 5,670,127; 5,692,495; 5,514,204; 7,523,752; 5,699,790; 5,885,621; US
`
`Patent Application Serial Nos. 11/355,670 (US 2007/0190184); 10/520,270 (US
`
`2006/0093681); 11/401,722 (US 2007/0202083); 10/053,535 (US 2002/0155166); 10/367,277
`
`(US 2003/0219496); 10/439,632 (US 2004/0052866); 10/371,666 (US 2003/0219497);
`
`10/413,817 (US 2004/0005367); 12/050,826 (US 2008/0167609); and PCT/US2009/045266, all
`
`of which are incorporated herein by reference in their entirety.
`
`[0022]
`
`Such devices deliver INOmax® into the inspiratory limb of the patient breathing
`
`circuit in a way that provides a constant concentration of N O to the patient throughout the
`
`inspired breath. Importantly, suitable delivery devices provide continuous integrated
`
`monitoring of inspired O2, N02 and NO, a comprehensive alarm system, a suitable power
`
`source for uninterrupted NO delivery, and a backup NO delivery capability.
`
`015
`
`Ex. 2005-0015
`
`

`
`Attorney Docket No. 260410003006/3000—US—0008T)lV
`
`[0023]
`
`As used herein, the term "children" (and variations thereof) includes those being
`
`around 4 weeks to 18 years of age.
`
`[0024]
`
`As used herein, the term "adult“ (and variations thereof) includes those being
`
`over 18 years of age.
`
`[0025]
`
`As used herein, the terms “adverse event" and "AE" (and variations thereof)
`
`mean any untoward occurrence in a subject or clinical investigation subject administered a
`
`pharmaceutical product (such as nitric oxide) and which does not necessarily have a causal
`
`relationship with such treatment. An adverse event can therefore be any unfavorable and
`
`unintended sign (including an abnormal laboratory finding), symptom, or disease temporarily
`
`associated with the use of a medicinal/investigational product, whether or not related to the
`
`investigational product. A relationship to the investigational product is not necessarily proven
`
`or implied. However, abnormal values are not reported as adverse events unless considered
`
`clinically significant by the investigator.
`
`[0026]
`
`As used herein, the terms "adverse drug reaction" and "ADR" (and variations
`
`thereof) mean any noxious and unintended response to a medicinal product related to any dose.
`
`[0027]
`
`As used herein, the terms “serious adverse event" and “SAE" (or “serious adverse
`
`drug reaction" and "serious ADR") (and variations thereof) mean a significant hazard or side
`
`effect, regardless of the investigator's opinion on the relationship to the investigational product.
`
`A serious adverse event or reaction is any untoward medical occurrence that at any dose: results
`
`in death; is life-threatening (which refers to an event/reaction where the patient was at risk of
`
`death at the time of the event/reaction, however this does not refer to an event/reaction that
`
`hypothetically may have caused death if it were more severe); requires inpatient hospitalization
`
`or results in prolongation of existing hospitalization; results in persistent or significant
`
`disability/incapacity; is a congenital anomaly/birth defect; or is a medically important event or
`
`reaction. Medical and scientific judgment is exercised in deciding whether reporting is
`
`appropriate in other situations, such as important medical events that may not be immediately
`
`life threatening or result in death or hospitalization but may jeopardize the subject or may
`
`require medical or surgical intervention to prevent one of the other outcomes listed above——these
`
`are also considered serious. Examples of such medical events include cancer, allergic
`
`bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias
`
`016
`
`Ex. 2005-0016
`
`

`
`Attorney Docket No. 26047—0003006/3000—US—0008T)lV
`
`or convulsions that do not result in hospitalizations, or the development of drug dependency or
`
`drug abuse. Serious clinical laboratory abnormalities directly associated with relevant clinical
`
`signs or symptoms are also reported.
`
`[0028]
`
`Left Ventricular Dysfunction. Patients having pre-existing LVD may be
`
`described in general as those with elevated pulmonary capillary wedge pressure, including those
`
`with diastolic dysfunction (including hypertensive cardiomyopathy), those with systolic
`
`dysfunction, including those with cardiomyopathies (including ischemic or viral
`
`cardiomyopathy, or idiopathic cardiomyopathy, or autoimmune disease related cardiomyopathy,
`
`and side effects due to drug related or toxic-related cardiomyopathy), or structural heart disease,
`
`valvular heart disease, congenital heart disease, idiopathic pulmonary arterial hypertension,
`
`pulmonary hypertension and cardiomyopathy, or associations thereof.
`
`Identifying patients with
`
`pre—eXisting LVD is known to those skilled in the medicinal arts, and such techniques for
`
`example may include assessment of clinical signs and symptoms of heart failure, or
`
`echocardiography diagnostic screening.
`
`[0029]
`
`Pulmonary Capillary Wedge Pressure. Pulmonary capillary wedge pressure, or
`
`"PCWP", provides an estimate of left atrial pressure.
`
`ldcntifying patients with pre-existing
`
`PCWP is known to those skilled in the medicinal arts, and such techniques for example may
`
`include measuring by inserting a balloon-tipped, multi-lumen catheter (also known as a Swan-
`
`Ganz catheter). Measurement of PCWP may be used as a means to diagnose the severity of
`
`LVD (sometimes also referred to as left ventricular failure). PCWP is also a desired measure
`
`when evaluating pulmonary hypertension. Pulmonary hypertension is often caused by an
`
`increase in pulmonary vascular resistance (PVR), but may also arise from increases in
`
`pulmonary venous pressure and pulmonary blood volume secondary to left ventricular failure or
`
`mitral or aortic valve disease.
`
`[0030]
`
`In cardiac physiology, the term “afterload” is used to mean the tension produced
`
`by a chamber of the heart in order to contract. If the chamber is not mentioned, it is usually
`
`assumed to be the left ventricle. However, the strict definition of the term relates to the
`
`properties of a single cardiac myocyte. It is therefore of direct relevance only in the laboratory;
`
`in the clinic, the tenn “end—systolic pressure” is usually more appropriate, although not
`
`equivalent.
`
`017
`
`Ex. 2005-0017
`
`

`
`Attorney Docket No. 260410003006/3000—US—0008T)lV
`
`[0031]
`
`The term "left ventricular afterload" (and Variations thereof) refers to the pressure
`
`that the chamber of the heart has to generate in order to eject blood out of the chamber. Thus, it
`
`is a consequence of the aortic pressure, since the pressure in the ventricle must be greater than
`
`the systemic pressure in order to open the aortic valve. Everything else held equal, as afterload
`
`increases, cardiac output decreases. Disease processes that increase the left ventricular afterload
`
`include increased blood pressure and aortic valve disease. Hypertension (increased blood
`
`pressure) increases the left ventricular afterload because the left ventricle has to work harder to
`
`eject blood into the aorta. This is because the aortic valve won't open until the pressure
`
`generated in the left ventricle is higher than the elevated blood pressure. Aortic stenosis
`
`increases the afterload because the left ventricle has to overcome the pressure gradient caused
`
`by the stenotic aortic valve in addition to the blood pressure in order to eject blood into the
`
`aorta. For instance, if the blood pressure is 120/ 80, and the aortic valve stenosis creates a trans-
`
`valvular gradient of 30 mmHg, the left ventricle has to generate a pressure of 110 mmHg in
`
`order to open the aortic valve and eject blood into the aorta. Aortic insufficiency increases
`
`afterload because a percentage of the blood that is ejected forward regurgitates back through the
`
`diseased aortic valve. This leads to elevated systolic blood pressure. The diastolic blood
`
`pressure would fall, due to regurgitation. This would result in an increased pulse pressure.
`
`Mitral regurgitation decreases the afterload. During ventricular systole, the blood can
`
`regurgitate through the diseased mitral valve as well as be ejected through the aortic valve. This
`
`means that the left ventricle has to work less to eject blood, causing a decreased afterload.
`
`Afterload is largely dependent upon aortic pressure.
`
`[0032]
`
`An intra-aortic balloon pump (IABP) is a mechanical device that is used to
`
`decrease myocardial oxygen demand while at the same time increasing cardia