US008795741B2
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`(12) United States Patent
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`Baldassarre
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`(10) Patent No.:
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`(45) Date of Patent:
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`US 8,795,741 B2
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`*Aug. 5, 2014
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`(54) METHODS FOR TREATING PATIENTS WHO
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`ARE CANDIDATES FOR INHALED NITRIC
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`OXIDE TREATMENT
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`(56)
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`References Cited
`
`
`U.S. PATENT DOCUMENTS
`
`
`
`
`
`5,558,083 A
`
`5,651,358 A
`
`5,873,359 A
`
`6,063,407 A
`
`6,142,147 A
`
`6,601,580 B1
`
`
`7,557,087 B2
`
`
`2002/0185126 A1
`
`
`2003/0131848 A1
`
`
`2004/0106954 A1
`
`
`2009/0018136 A1
`
`
`2009/0029371 A1
`
`
`2009/0149541 A1
`
`
`2009/0176772 A1
`
`
`
`
`
`9/1996 Bathe et al.
`
`
`
`7/1997 Briend et al.
`
`
`2/1999 Zapol et al.
`
`
`
`5/2000 Zapol et al.
`
`
`
`11/2000 Head et al.
`
`
`
`8/2003 Bloch et al.
`
`
`
`7/2009 Rothbard et al.
`
`
`12/2002 Krebs
`
`
`7/2003 Stenzler
`
`
`6/2004 Whitehurst et al.
`
`
`
`1/2009 Oppenheimer et al.
`
`
`1/2009 Elliott
`
`
`6/2009 Stark et al.
`
`
`
`7/2009 Blackburn et al.
`
`
`
`
`
`
`
`
`
`EP
`
`WO
`
`WO
`
`WO
`
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`
`1682672
`7/2006
`
`
`WO2005004884
`1/2005
`
`
`WO2006127907
`11/2006
`
`
`2/2010
`WO2010019540
`
`
`OTHER PUBLICATIONS
`
`
`
`
`Rosales et al. (Pediatric Cardiology, 1999, 20:224-226).*
`
`
`
`
`
`
`Kieler-Jensen et al., “Inhaled nitric oxide in the evaluation of heart
`
`
`
`
`
`
`
`
`transplant candidates with elevated pulmonary vascular resistance”,
`
`
`
`
`
`
`
`J. Heart Lung Transplant, vol. 13, pp. 366-375 (1994).
`
`
`
`
`
`
`
`
`
`Kinsella et al., “Inhaled nitric oxide in premature neonates with
`
`
`
`
`
`
`
`severe hypoxaemic respiratory faliure: a randomised controlled
`
`
`
`
`
`trial,” The Lancet, vol. 354, pp. 1061-1065 (1999).
`
`
`
`
`
`
`
`
`Konduri et al., “A Randomized Trial ofEarlyVersus Standard Inhaled
`
`
`
`
`
`
`
`Nitric Oxide Therapy in Term and Near-Term Newborn Infants with
`
`
`
`
`
`
`
`
`
`Hypoxic Respiratory Failure,” Pediatrics, vol. 113 No. 3, pp. 559-564
`
`
`
`
`
`
`
`
`
`(2004).
`
`Krasuski et al., “Inhaled Nitric Oxide Selectively Dilates Pulmonary
`
`
`
`
`
`
`
`Vasculature in Adult Patients With Pulmonary Hypertension, Irre-
`
`
`
`
`
`
`
`spective of Etiology,” Journal ofthe American College of Cardiology
`
`
`
`
`
`(JACC), vol. 36, No. 7, pp. 2204-2211 (2000).
`
`
`
`
`
`
`
`Krohn, “Effect of inhaled nitric oxide on left ventricular and pulmo-
`
`
`
`
`
`
`
`
`
`nary vascular function,” The Journal of Thoracic and Cardiovascular
`
`
`
`
`
`
`
`
`Surgery, vol. 117(1), pp. 195-196 (1999).
`
`
`
`
`
`
`Kulik, “Inhaled nitric oxide in the management of congenital heart
`
`
`
`
`
`
`
`
`disease,” Current Opinion in Cardiology, vol. 11, pp. 75-80 (1996).
`
`
`
`
`
`
`
`
`
`Lavigne et al., “Cardiovascular Outcomes of Pediatric Seroreverters
`
`
`
`
`
`
`Perinatally Exposed to HAART,” Cardiovascular Toxicology, vol. 4,
`
`
`
`
`
`
`pp. 187-197 (2004).
`
`
`
`Letter ofAcceptance for AU 2010202422, dated Oct. 7, 2010.
`
`
`
`
`
`
`
`Letter of acceptance of AU application 2009202685, dated Aug. 10,
`
`
`
`
`
`
`2010, 3 pages.
`
`
`Lipschultz, “The effect of dexrazoxane on myocardial injury in
`
`
`
`
`
`
`
`
`doxorubicin-treated children with acute lymphoblastic leukemia,”
`
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`
`
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`New England Journal of Medicine, vol. 351, pp. 145-153 (2004).
`
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`(Continued)
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`Primary Examiner — Ernst Arnold
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`(74) Attorney, Agent, or Firm — Fish & Richardson P.C.
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`(57)
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`ABSTRACT
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`Disclosed are methods of reducing the risk that a medical
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`treatment comprising inhalation of nitric oxide gas will
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`induce an increase in pulmonary capillary wedge pressure in
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`the patient, leading to pulmonary edema.
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`(58) Field of Classification Search
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`None
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`See application file for complete search history.
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`44 Claims, No Drawings
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`001
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`PRAXAIR ET AL. 1001
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`(71) Applicant: INO Therapeutics LLC, Hampton, NJ
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`(US)
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`(72)
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`Inventor:
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`James S. Baldassarre, Doylestown, PA
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`(US)
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`(73) Assignee:
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`( * ) Notice:
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`INO Therapeutics LLC, Hampton, NJ
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`(US)
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`Subject to any disclaimer, the term of this
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`patent is extended or adjusted under 35
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`U.S.C. 154(b) by 0 days.
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`This patent is subject to a terminal dis-
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`claimer.
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`(21) Appl.No.: 13/683,417
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`Filed:
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`Nov. 21, 2012
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`Prior Publication Data
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`US 2013/0078321A1
`Mar. 28, 2013
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`(22)
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`(65)
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`Related U.S. Application Data
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`(63) Continuation of application No. 12/820,866, filed on
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`Jun. 22, 2010, now abandoned, which is a continuation
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`of application No. 12/494,598, filed on Jun. 30, 2009,
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`now abandoned, application No. 13/683,417, which is
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`a continuation of application No. 13/651,660, filed on
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`Oct. 15, 2012, which is a continuation of application
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`No. 12/821,041, filed on Jun. 22, 2010, now Pat. No.
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`8,293,284, which is a continuation of application No.
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`12/494,598, filed on Jun. 30, 2009, now abandoned.
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`(51)
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`(2006.01)
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`(2006.01)
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`(2006.01)
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`(2006.01)
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`(2006.01)
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`(2006.01)
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`(2006.01)
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`(2006.01)
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`(2006.01)
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`Int. Cl.
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`A61B 5/02
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`A01N 59/00
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`A61K 33/00
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`C01B 21/24
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`A61M 16/12
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`A61B 8/08
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`A61K 45/06
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`G06Q 99/00
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`A61K 31/21
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`A6IM 16/00
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`(52) U.S. Cl.
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`CPC .............. .. A61K 33/00 (2013.01), A61M 16/12
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`(2013.01), A61B 8/48 (2013.01), A61K 45/06
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`(2013.01), G06Q 99/00 (2013.01), A61K31/21
`
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`(2013.01)
`USPC .... .. 424/718; 128/200.24; 423/405; 600/483;
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`600/484; 600/485
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`001
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`

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`US 8,795,741 B2
`Page 2
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`(56)
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`References Cited
`
`
`OTHER PUBLICATIONS
`
`
`
`Lipschultz, “The incidence of pediatric cardiomyopathy in two
`
`
`
`
`
`
`
`regions ofthe United States,” New England Journal of Medicine, Apr.
`
`
`
`
`
`
`
`
`2003.
`<<http://www.nejm.org/doi/full/10.1056/
`24,
`
`
`
`NEJMoa021715>>.
`
`
`Lipshultz, “Ventricular dysfunction clinical research in infants, chil-
`
`
`
`
`
`
`
`dren and adolescents,” Progress in Pediatric Cardiology, vol. 12, pp.
`
`
`
`
`
`
`
`
`
`1-28 (2000).
`
`
`Lipshultz, “Chronic Progressive Cardiac Dysfunction Years After
`
`
`
`
`
`
`
`Doxorubicin Therapy for Childhood Acute Lymphoblastic Leuke-
`
`
`
`
`
`
`
`mia,” Journal of Clinical Oncology, vol. 23, No. 12, 8 pages (2005).
`
`
`
`
`
`
`
`
`
`
`Lipshultz, “Clinical research directions in pediatric cardiology,” Cur-
`
`
`
`
`
`
`
`rent Opinion in Pediatrics, vol. 21, pp. 585-593 (2009).
`
`
`
`
`
`
`
`
`Lipshultz, “Establishing norms for echocardiographic measurement
`
`
`
`
`
`of cardiovascular structures and function in children,” J. Appl.
`
`
`
`
`
`
`
`
`Physiol., vol. 99, pp. 386-388 (2005).
`
`
`
`
`
`
`Lipshultz et al., “Cardiovascular status of infants and children of
`
`
`
`
`
`
`
`
`
`women infected with HIV-1 (P2C2 HIV): a cohort study,” The Lan-
`
`
`
`
`
`
`
`
`
`
`cet, vol. 360, pp. 368-373 (2002).
`
`
`
`
`
`
`Lipshultz et al., “Cardiovascular Trials in Long-Term Survivors of
`
`
`
`
`
`
`
`Childhood Cancer,” Journal of Clinical Oncology, vol. 22, No. 5, pp.
`
`
`
`
`
`
`
`
`
`769-773 (2004).
`
`
`Lipshultz et al., “Long-Term Enalapril Therapy for Left Ventricular
`
`
`
`
`
`
`
`Dysfunction in Doxorubicin-Treated Survivors of Childhood Can-
`
`
`
`
`
`cer,” Journal of Clinical Oncology, vol. 20, No. 23, pp. 4517-4522
`
`
`
`
`
`
`
`
`
`
`(2002).
`
`Lipshultz, “Frequency of clinically unsuspected myocardial injury at
`
`
`
`
`
`
`a children’s hospital,” American Heart Journal, vol. 151, No. 4, pp.
`
`
`
`
`
`
`
`
`
`
`916-922 (2006).
`
`
`Loh et al ., “Cardiovascular Effects ofInhaled Nitric Oxide in Patients
`
`
`
`
`
`
`
`with Left Ventricular Dsyfunction,” Circulation, vol. 90, pp. 2780-
`
`
`
`
`
`
`
`
`
`2785 (1994).
`
`
`Macrae et al., “Inhaled nitric oxide therapy in neonates and children:
`
`
`
`
`
`
`
`
`
`reaching a European consensus,” Intensive Care Med., vol. 30, pp.
`
`
`
`
`
`
`
`
`
`372-380 (2004).
`
`
`Madriago et al., “Heart Failure in Infants and Children,” Pediatrics in
`
`
`
`
`
`
`
`
`Review, vol. 31, pp. 4-12 (2010).
`
`
`
`
`
`
`Magee et al., “Comparison of Supplemental Oxygen and Nitric
`
`
`
`
`
`
`
`Oxide for Inhalation plus oxygen in the evaluation ofthe reactivity of
`
`
`
`
`
`
`
`the pulmonary vasculature during Acute PulmonaryVasodilator Test-
`
`
`
`
`
`
`
`ing,” Oct. 1, 2004-Oct. 31, 2006, Research project description,
`1
`
`
`
`
`
`
`
`
`page, http://www.rbht.nhs.uldresearch.
`
`
`\/Ialloy, “Nitric Oxide Weaning, RT: For Decision Makers in Respi-
`
`
`
`
`
`
`
`
`
`ratory Care,” http://rtmagazine.com/issues/articles/2000-12_05.
`
`
`
`asp, 3 pages, Dec. 2000.
`
`
`
`
`Vlartinez et al., “Dermatological Cryosurgery in Primary Care with
`
`
`
`
`
`
`
`Dimethyl Ether Propane Spray in Comparison with Liquid Nitro-
`
`
`
`
`
`
`
`
`gen,” Atnecion Primaria, vol. 18, No. 5, pp. 211 and 216 (1996).
`
`
`
`
`
`
`
`
`
`
`
`Vlatsumoto et al., “Effect of Inhaled Nitric Oxide on Gas Exchange in
`
`
`
`
`
`
`
`
`Patients with Congestive Heart Failure,” Annals ofInternal Medicine,
`
`
`
`
`
`
`
`
`vol. 130, No. 1, pp. 40-44 (1999).
`
`
`
`
`
`
`VIeyler’s Side Effects of Drugs: The International Encyclopedia of
`
`
`
`
`
`
`
`Adverse Drug Reactions and Interactions, Nitric Oxide, Fifteenth
`
`
`
`
`
`
`
`
`Edition, Elsevier B.V. (2006).
`
`
`
`
`Vlichelakis et al., “Oral Sildenafil is an Effective and Specific Pul-
`
`
`
`
`
`
`
`
`
`monary Vasodilator in Patients with Pulmonary Arterial Hyperten-
`
`
`
`
`
`
`
`sion: Comparison with Inhaled Nitric Oxide,” Circulation vol. 105,
`
`
`
`
`
`
`
`
`
`pp. 2398-2403 (2002).
`
`
`
`Vliller et al., “Nutrition in Pediatric Cardiomyopathy,” Prog. Pediatr.
`
`
`
`
`
`
`
`Cardiol. vol. 24(1), pp. 59-71 (2007).
`
`
`
`
`
`
`\/Ione, “Effects of Environmental Exposures on the Cardiovascular
`
`
`
`
`
`
`System: Prenatal Period Through Adolescence,” Pediatrics. vol. 1 13,
`
`
`
`
`
`
`
`
`\Io. 4, pp. 1058-1069 (2004).
`
`
`
`
`\/Iorales-Blanhir et al., “Clinical value of vasodilator test with
`
`
`
`
`
`
`
`
`inhaled nitric oxide for predicting long-term response to oral
`
`
`
`
`
`
`
`
`
`vasodilators in pulmonary hypertension,” Respiratory Medicine, vol.
`
`
`
`
`
`
`98, pp. 225-234 (2004).
`
`
`
`
`
`002
`
`Moss et al., “Moss and Adams’ Heart Disease in Infants, Children,
`
`
`
`
`
`
`
`
`
`and Adolescents,” Coarctation of the Aorta, vol. 1, p. 991 in part
`
`
`
`
`
`
`
`
`
`
`
`(2007).
`
`Murray, “Angiotensin Converting Enzyme Inhibitory Peptides
`
`
`
`
`
`
`Derived from Food Proteins: Biochemistry, Bioactivity and Produc-
`
`
`
`
`
`
`
`
`tion,” Current Pharmaceutical Design, pp. 773-791 (2007).
`
`
`
`
`
`
`
`Murray et al., “Nitric Oxide and Septic Vascular Dysfunction,”
`
`
`
`
`
`
`
`Anesth. Analg. vol. 90, pp. 89-101 (2000).
`
`
`
`
`
`
`
`Natori et al., “Inhaled Nitric Oxide Modifies Left Ventricular Dias-
`
`
`
`
`
`
`
`
`
`tolic Stress in the Presence of Vasoactive Agents in Heart Failure,”
`
`
`
`
`
`
`
`
`Am. J. Respir Cult. Care Med, vol. 167, pp. 895-901 (2003).
`
`
`
`
`
`
`
`
`
`
`NIH CC: Critical Care Services, http://www.cc.nih.gov/ccmd/clini-
`
`
`
`
`
`
`cal_services.html; retrieved Mar. 10, 2011, 3 pages.
`
`
`
`
`
`
`“NIH Clinical Center 2 Critical Care Medicine Department Sample
`
`
`
`
`
`
`
`
`Rotations, Updated Jan. 2007 <<http://www.cc.nih.gov/ccmd/prof_
`
`
`
`
`
`opps/rotation.html>>”.
`
`NIH Clinical Center Services, retrieved at <http://www.cc.nih.gov/
`
`
`
`
`
`ccmd/clinical_services.htrn1>> on Aug. 18, 2010.
`
`
`
`
`NIH Clinical Center, Department Policy and Procedure Manual for
`
`
`
`
`
`
`
`
`the Critical Care Therapy and Respiratory Care Section; Nitric Oxide
`
`
`
`
`
`
`
`
`
`
`Therapy, sections 3.1-3.1.2 & 5.2.3 (2000).
`
`
`
`
`
`NIH Clinical Center 2 Critical Care Medicine Department Sample
`
`
`
`
`
`
`
`Rotations, Updated Jan. 2007.
`
`
`
`
`Notification of Reason for Rejection, mailed Jul. 30, 2010, from
`
`
`
`
`
`
`
`
`
`
`Japanese Patent Application No. 2009-157623 (cites foreign refer-
`
`
`
`
`
`
`
`
`ences).
`
`Office Action for AU 2010202422 dated Jul. 9, 2010, 3 pages.
`
`
`
`
`
`
`
`
`Office Action from AU 2009202685 dated Mar. 15, 2010.
`
`
`
`
`
`
`
`
`Office Action from AU 2010206032 dated Aug. 16, 2010 (3 pages).
`
`
`
`
`
`
`
`
`
`Office Action Response for AU 2009202685 to Mar. 15, 2010 0A,
`
`
`
`
`
`
`
`
`
`filed Jun. 8, 2010 (16 pages).
`
`
`
`
`
`Office Action Response for JP2007157623 filed on Nov. 12, 2009 (no
`
`
`
`
`
`
`
`
`English translation).
`
`
`Office Action Response to AU 2010202422 OA dated Jul. 9, 2010,
`
`
`
`
`
`
`
`response filed Sep. 1, 2010.
`
`
`
`
`www.fda.gov/downloads/Drugs/
`
`GuidanceComplianceRegulatoryInformation/Guidance/
`ucm073087.pdf, Mar. 1995.
`
`
`
`Notice ofAbandonment in U.S. Appl. No. 12/820,866, mailed Dec.
`
`
`
`
`
`
`
`20, 2012 (2 pages).
`
`
`
`Ameduri et al., Heart Failure in Children, MED-Continuing Medical
`
`
`
`
`
`
`
`Education, University of Minnesota. Jul. 29, 2009 (cited Nov. 12,
`
`
`
`
`
`
`
`
`
`2010); available from URL: ttp://www.cme.unm.edu/prod/groups/
`
`
`
`
`
`med/@pub/@med/@cme/documents/content/med_content_
`
`
`
`
`
`
`
`124593.pdf.
`
`Konduri, “Early inhaled nitric oxide therapy for term and near-term
`
`
`
`
`
`
`
`
`
`
`infants
`with
`hypoxic
`respiratory
`newborn
`failure:
`
`
`
`
`
`
`neurodevelopmental follow-up,” J. Pediatr. vol. 150(3), pp. 235-240,
`
`
`
`
`
`
`
`240.e.1 (2007).
`
`
`Barrington et al., “Inhaled nitric oxide for respiratory failure in
`
`
`
`
`
`
`
`
`
`preterm infants (review),” The Cochrane Collaboration, Wiley Pub-
`
`
`
`
`
`
`
`
`lishers, 3 pages (2009).
`
`
`
`Barst, Pediatr., “Vasodilator Testing with Nitric Oxide and/or Oxy-
`
`
`
`
`
`
`
`
`
`gen in Pediatric Pulmonary Hypertension,” Cardiol., vol. 31, pp.
`
`
`
`
`
`
`
`
`598-606 (2010).
`
`
`Macrae, “Drug therapy in persistent pulmonary hypertension of the
`
`
`
`
`
`
`newborn,” Semin. Neonatal, vol. 2, pp. 49-58 (1997).
`
`
`
`
`
`
`
`Miller et al., “Guidelines for the safe administration of inhaled nitric
`
`
`
`
`
`
`
`
`oxide,” Archives of Disease in Childhood, vol. 10, pp. F47-F49
`
`
`
`
`
`
`
`
`(1994).
`
`Office Action in U.S. Appl. No. 12/494,598, mailed Aug. 13, 2010
`
`
`
`
`
`
`
`
`
`(26 pages).
`
`
`Notice ofAbandonment in U.S. Appl. No. 12/494,598, mailed Sep.
`
`
`
`
`
`
`
`10, 2010 (2 pages).
`
`
`
`Office Action in U.S.App1.No. 12/820,866, mailed Sep. 23, 2010 (26
`
`
`
`
`
`
`
`
`
`
`pages).
`
`Lee & Hayes, Reply Amendment (Accelerated Exam-Transmittal
`
`
`
`
`
`Amendment/Reply) in U.S. Appl. No. 12/820,866 mailed Sep. 23,
`
`
`
`
`
`
`
`2010, filed Oct. 1, 2010 (22 pages).
`
`
`
`
`
`
`Office Action in U.S.App1.No. 12/820,866, mailed Nov. 2, 2010 (25
`
`
`
`
`
`
`
`
`
`pages).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`002
`
`

`
`
`
`US 8,795,741 B2
`Page 3
`
`
`Office Action in U.S. Appl. No. 12/821,020, mailed Jun. 15, 2012 (56
`
`
`
`
`
`
`
`
`
`
`pages).
`
`Fish & Richardson, PC., Amendment in Reply, in U.S. Appl. No.
`
`
`
`
`
`
`
`12/821,020, mailed Jun. 15, 2012, filed Aug. 15, 2012 (15 pages).
`
`
`
`
`
`
`
`
`
`
`
`Office Action in U.S. Appl. No. 12/821,041, mailed Aug. 17, 2010
`
`
`
`
`
`
`
`
`
`(32 pages).
`
`
`Lee & Hayes, Reply Amendment in U.S. Appl. No. 12/821,041,
`
`
`
`
`
`
`
`mailed Aug. 17, 2010, filed Feb. 14, 2011 (28 pages).
`
`
`
`
`
`
`
`
`
`
`Lee & Hayes, Supplemental Reply Amendment in U.S. Appl. No.
`
`
`
`
`
`
`
`12/821,041, mailed Aug. 17, 2010, filed Apr. 13,2011 (9 pages).
`
`
`
`
`
`
`
`
`
`Office Action in U.S. Appl. No. 12/821,041, mailed Jun. 27, 2011 (35
`
`
`
`
`
`
`
`
`
`
`pages).
`
`Fish & Richardson, P.C., Amendment in Reply to Office Action in
`
`
`
`
`
`
`
`U.S. Appl. No. 12/821,041, mailed Jun. 27, 2011, filed Jan. 6,2012
`
`
`
`
`
`
`
`
`
`
`
`(155 pages).
`
`
`Office Action in U.S. Appl. No. 12/821,041, mailed Feb. 10, 2012 (36
`
`
`
`
`
`
`
`
`
`
`pages).
`
`Fish & Richardson, P.C., in U.S. Appl. No. 12/821,041, Supplemen-
`
`
`
`
`
`
`
`
`tal Amendment and Remarks, filed May 11, 2012 (32 pages).
`
`
`
`
`
`
`
`
`
`Office Action in U.S. Appl. No. 12/821,041, mailed Jun. 19, 2012 (61
`
`
`
`
`
`
`
`
`
`
`pages).
`
`Fish & Richardson, P.C., Amendment in Reply to Office Action, in
`
`
`
`
`
`
`
`U.S.Appl.No. 12/821,041,mailedJun. 19,2012,filedAug. 15,2012
`
`
`
`
`(17 pages).
`
`
`Lee & Hayes Amendment in Reply to Office Action in U.S. Appl. No.
`
`
`
`
`
`
`
`
`12/820,866, mailed Jun. 8, 2011, filed Jul. 8,2011 (23 pages).
`
`
`
`
`
`
`
`
`
`Fish & Richardson, Brief on Appeal in U.S. Appl. No. 12/820,866,
`
`
`
`
`
`
`
`
`filed Oct. 4, 2011 (211 pages).
`
`
`
`
`
`Interview Summary in U.S. Appl. No. 12/821,020, mailed Jan. 25,
`
`
`
`
`
`
`
`
`2012 (4 pages).
`
`
`Adatia et al., “Inhaled Nitric Oxide and Hemodynamic Evaluation of
`
`
`
`
`
`
`
`
`Patients With Pulmonary Hyptertension Before Transplantation,”
`
`
`
`
`
`
`Journal of the American College of Cardiology, Elsevier, New York,
`
`
`
`
`
`
`
`
`NY, vol. 25, No. 7, p. 1663, Jun. 1, 1995.
`
`
`
`
`
`
`
`Advances in Pulmonary Hypertension, vol. 7(4), pp. 1-418, Winter
`
`
`
`
`
`
`
`2008-2009 (entire issue).
`
`
`
`Al-Alaiyan et al., “Inhaled nitric oxide in persistent pulmonary
`
`
`
`
`
`
`
`hypertension of the newborn refractory to high-frequency ventila-
`
`
`
`
`
`
`tion,” Crit. Care, vol. 3, No. 1, pp. 7-10 (1999).
`
`
`
`
`
`
`
`
`Argenziano et al., “Inhaled Nitric Oxide is not a Myocardial Depres-
`
`
`
`
`
`
`
`
`sant in a Porcine Model of Heart Failure,” The Journal of Thoracic
`
`
`
`
`
`
`
`
`and Cardiovascular Surgery, vol. 115, pp. 700-704 (1998).
`
`
`
`
`
`
`
`
`Atz et al., “Combined Effects of Nitric Oxide and Oxygen During
`
`
`
`
`
`
`
`
`
`
`Acute Pulmonary Vasodilator Testing,” Journal ofthe American Col-
`
`
`
`
`
`
`
`lege of Cardiology (JACC), vol. 33, No. 3, pp. 813-819 (1999).
`
`
`
`
`
`
`
`
`
`Atz et al., “Inhaled nitric oxide in the neonate with cardiac disease,”
`
`
`
`
`
`
`
`
`
`Seminars in Perinatology, vol. 21(5), pp. 441-455 (1997).
`
`
`
`
`
`
`
`AU 2009202685 Office Action dated Jun. 17, 2010 (3 pages).
`
`
`
`
`
`
`
`
`
`AU 2009202685 Office Action Response dated Jul. 29, 2010, 19
`
`
`
`
`
`
`
`
`
`pages.
`Azeka et al., “Effects of Low Doses of Inhaled Nitric Oxide Com-
`
`
`
`
`
`
`
`
`
`bined with Oxygen for the Evaluation of Pulmonary Vascular Reac-
`
`
`
`
`
`
`
`
`tivity in Patients with Pulmonary Hypertension,” Pedatric Cardiol.,
`
`
`
`
`
`
`
`vol. 23, pp. 20-26 (2002).
`
`
`
`
`
`Barrington et al., “Inhaled Nitric Oxide for Preterm Infants: A Sys-
`
`
`
`
`
`
`
`tematic Review,” Pediatrics, vol. 120; pp. 1088-1099, DOI: 10.1542/
`
`
`
`
`
`
`
`
`
`peds (2007).
`
`
`Barst et al., “Nitric Oxide in Combination with Oxygen versus Either
`
`
`
`
`
`
`
`
`
`Oxygen Alone or Nitric Oxide Alone for Acute Vasodilator Testing in
`
`
`
`
`
`
`
`
`Children with Pulmonary Hypertension: A Multicenter, Randomized
`
`
`
`
`
`
`Study,” INO Therapeutic s/Ikaria, Baltimore Convention Center, May
`
`
`
`
`
`
`
`
`3, 2009, 2 pages, Abstract, downloaded Jul. 2, 2009 from http://127.
`
`
`
`
`
`
`
`
`
`0.0.1:9080/PAS09A1/view.y?nu:PAS09L1_1507.
`
`Barst et al., “Vasodilator Testing with Nitric Oxide and/or Oxygen in
`
`
`
`
`
`
`
`
`
`Pediatric Pulmonary Hypertension,” Pediatric Cardiology; Published
`
`
`
`
`
`
`online Apr. 20, 2010, 9 pages.
`
`
`
`
`
`Beggs et al., “Cardiac Failure in Children,” 17th Expert Committee
`
`
`
`
`
`
`
`
`on the Selection and Use of Essential Medicines, Geneva, Mar. 2009,
`
`
`
`
`
`
`
`
`
`31 pages.
`
`
`Beghetti et al., “Inhaled nitric oxide can cause severe systemic
`
`
`
`
`
`
`
`
`hypotension,” Journal of Pediatrics, p. 844 (1997).
`
`
`
`
`
`Beghetti et al., “Inhaled nitric oxide and congenital cardiac disease,”
`
`
`
`
`
`
`
`
`Cardiol.Young, vol. 11, pp. 142-152 (2001).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`(56)
`
`
`References Cited
`
`
`OTHER PUBLICATIONS
`
`
`
`Lee & Hayes, Reply Amendment (Accelerated Exam-Transmittal
`
`
`
`
`
`
`Amendment/Reply) in U.S. Appl. No. 12/820,866 mailed Nov. 2,
`
`
`
`
`
`
`
`2010, filed Jan. 14,2011 (12 pages).
`
`
`
`
`
`
`Advisory Action in U.S. Appl. No. 12/820,866, mailed Feb. 23, 2011
`
`
`
`
`
`
`
`
`
`(2 pages).
`
`
`Lee & Hayes, Reply After Final (Accelerated Exam-Transmittal
`
`
`
`
`
`
`
`Amendment/Reply) in U.S. Appl. No. 12/820,866 mailed Sep. 23,
`
`
`
`
`
`
`
`
`2010, filed Mar. 1, 2011 (9 pages).
`
`
`
`
`
`Lee & Hayes, Reply After Final (Accelerated Exam-Transmittal
`
`
`
`
`
`
`
`Amendment/Reply) in U.S. Appl. No. 12/820,866 mailed Sep. 23,
`
`
`
`
`
`
`
`
`
`2010, filed Mar. 1,2011 (5 pages).
`
`
`
`
`
`Advisory Action in U.S. Appl. No. 12/820,866, mailed Mar. 25, 2011
`
`
`
`
`
`
`
`
`
`(3 pages).
`
`
`Lee & Hayes, Reply After Final (Accelerated Exam-Transmittal
`
`
`
`
`
`
`
`Amendment/Reply) in U.S. Appl. No. 12/820,866 mailed Nov. 2,
`
`
`
`
`
`
`
`2010, filed May 2,2011 (9 pages).
`
`
`
`
`
`Office Action in U.S. Appl. No. 12/820,866, mailed Jun. 8, 2011 (32
`
`
`
`
`
`
`
`
`
`pages).
`
`Office Action in U.S. Appl. No. 12/820,866, Aug. 24, 2011 (23
`
`
`
`
`
`
`
`
`
`
`pages).
`
`Fish & Richardson, P.C., Reply Brief in U.S. Appl. No. 12/820,866,
`
`
`
`
`
`
`
`
`filed Dec. 16, 2011 (21 pages).
`
`
`
`
`
`
`Fish & Richardson, P.C., Supplement to Reply Brief in U.S. Appl.
`
`
`
`
`
`
`
`
`No. 12/820,866, filed Jan. 3, 2012 (3 pages).
`
`
`
`
`
`
`Office Action in U.S. Appl. No. 12/820,980, mailed Aug. 17, 2010
`
`
`
`
`
`
`
`
`
`
`(33 pages).
`
`
`Lee & Hayes, Reply Amendment in U.S. Appl. No. 12/820,980,
`
`
`
`
`
`
`
`mailed Aug. 17, 2010, filed Sep. 17, 2010 (25 pages).
`
`
`
`
`
`
`
`
`
`
`Office Action in U.S. Appl. No. 12/820,980, mailed Oct. 28, 2010 (23
`
`
`
`
`
`
`
`
`
`
`
`pages).
`
`Supplemental Office Action in U.S. Appl. No. 12/820,980, mailed
`
`
`
`
`
`
`
`
`Nov. 2, 2010 (4 pages).
`
`
`
`Lee & Hayes, Reply after Final (Accelerated Exam-Transmittal
`
`
`
`
`
`
`
`Reply) in U.S. Appl. No. 12/820,980, mailedNov. 2, 2010, filedNov.
`
`
`
`
`
`
`
`
`12, 2010 (53 pages).
`
`
`
`
`Advisory Action in U.S. Appl. No. 12/820,980, mailed Nov. 29, 2010
`
`
`
`
`
`
`
`
`
`(3 pages).
`
`
`Lee & Hayes, Reply after Final (Accelerated Exam-Transmittal
`
`
`
`
`
`
`
`Reply) in U.S. Appl. No. 12/820,980, mailed Nov. 2, 2010, filed May
`
`
`
`
`
`
`
`
`
`
`2,2011 (23 pages).
`
`
`
`Office Action in U.S.Appl. No. 12/820,980, mailed Jun. 10,2011 (29
`
`
`
`
`
`
`
`
`
`pages).
`
`Lee & Hayes, Amendment in Reply to Office Action in U.S. Appl.
`
`
`
`
`
`
`
`
`No. 12/820,980, mailed Jun. 10, 201 1, filed Jul. 11, 2011 (115 pages).
`
`
`
`
`
`
`
`
`
`
`
`
`Office Action in U.S. Appl. No. 12/820,980, mailed Sep. 9, 2011 (25
`
`
`
`
`
`
`
`
`
`
`pages).
`Notice of Abandonment in U.S. Appl. No. 12/820,980, mailed Apr.
`
`
`
`
`
`
`
`
`11, 2012 (2 pages).
`
`
`
`Office Action in U.S. Appl. No. 12/821,020, mailed Aug. 13, 2010
`
`
`
`
`
`
`
`
`
`
`(24 pages).
`
`
`Lee & Hayes, Response to Office Action in U.S. Appl. No.
`
`
`
`
`
`
`
`
`12/821,020, mailed Aug. 13, 2010, filed Feb. 14,2011 (18 pages).
`
`
`
`
`
`
`
`
`
`
`Lee & Hayes, Supplemental Reply Amendment in U.S. Appl. No.
`
`
`
`
`
`
`
`12/821,020, filed Apr. 12,2011 (9 pages).
`
`
`
`
`
`Office Action in U.S. Appl. No. 12/821,020, mailed Jun. 27, 2011 (28
`
`
`
`
`
`
`
`
`
`
`
`pages).
`
`Fish & Richardson, P.C., Amendment in Reply to Office Action, in
`
`
`
`
`
`
`
`U.S. Appl. No. 12/821,020, mailed Jun. 27, 2011, filed Dec. 27, 2011
`
`
`
`
`
`
`
`
`
`
`
`
`(31 pages).
`
`
`Office Action in U.S. Appl. No. 12/821,020, mailed Jan. 31, 2012 (23
`
`
`
`
`
`
`
`
`
`
`
`pages).
`
`Interview Summary in U.S. Appl. No. 12/821,020, mailed Apr. 17,
`
`
`
`
`
`
`
`
`
`2012 (4 pages).
`
`
`Fish & Richardson, P.C., Statement of Substance of Interview and
`
`
`
`
`
`
`
`Comments on Examiner’s Interview Summary, in U.S. Appl. No.
`
`
`
`
`
`
`
`12/821,020, filed Apr. 23, 2012 (8 pages).
`
`
`
`
`
`
`Fish & Richardson, PC., Supplemental Amendment, in U.S. Appl.
`
`
`
`
`
`
`No. 12/821,020, filed Apr. 30, 2012 (10 pages).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`003
`
`003
`
`

`
`
`
`US 8,795,741 B2
`Page 4
`
`
`(56)
`
`
`References Cited
`
`
`OTHER PUBLICATIONS
`
`
`
`Behera et al., “Nesiritide Improves Hemodynamics in Children with
`
`
`
`
`
`
`
`Dilated Cardiomyopathy: A Pilot Study,” Pediatr. Cardiol., vol. 30,
`
`
`
`
`
`
`
`
`pp. 26-34 (2009).
`
`
`
`Bhagavan et al., “Potential role of ubiquinone (coenzyme Q10) in
`
`
`
`
`
`
`
`
`pediatric cardiomyopathy,” Clinical Nutrition, vol. 24, pp. 331-338
`
`
`
`
`
`
`
`
`(2005).
`
`Bichel et al., “Successful weaning from cardiopulmonary bypass
`
`
`
`
`
`
`
`after cardiac
`surgery using inhaled nitric oxide”, Pediatric
`
`
`
`
`
`
`
`
`Anaesthesia, vol. 7, pp. 335-339 (1997).
`
`
`
`
`
`Bin-Nun et al., “Role of iNO in the modulation of pulmonary vascu-
`
`
`
`
`
`
`
`
`lar resistance,” Journal ofPerinatology, vol. 28, pp. S84-S92 (2008).
`
`
`
`
`
`
`
`
`
`Bland, “Pulmonary vascular dysfuction in preterm lambs with
`
`
`
`
`
`
`
`
`chronic lung disease,” Am J Physical Lung Cell Mol. Physiol., vol.
`
`
`
`
`
`
`
`
`
`285: L76-L85 ( 2003).
`
`
`
`Bloch et al., Cardiovasc. Res. 2007, “Inhaled NO as a therapeutic
`
`
`
`
`
`
`
`agent,” vol. 75(2), pp. 339-348 (Jul. 15, 2007).
`
`
`
`
`
`
`
`
`Bocchi et al.,“Inhaled Nitric Oxide Leading to Pulmonary Edema in
`
`
`
`
`
`
`
`Stable Severe Heart Failure,” The American Journal of Cardiology,
`
`
`
`
`
`
`
`
`vol. 74, pp. 70-72 (1994).
`
`
`
`
`
`Bolooki, Clinical Application of the Intra-Aortic Balloon Pump, 3rd
`
`
`
`
`
`
`
`Ed., pp. 252-253 (1998).
`
`
`
`
`Branson, “Inhaled Nitric Oxide in Adults,” The Science Journal ofthe
`
`
`
`
`
`
`
`
`American Association for Respiratory Care 1997 Open Forum
`
`
`
`
`
`
`
`
`Abstracts, Dec. 7, 1997, 2 pages,
`retrieved at <<http://www.
`
`
`
`
`
`
`
`
`rcjournal.com/abstracts/1997/?id:A00000929>> on Dec. 22, 2010.
`
`
`
`
`Braunwald, Heart Failure, chapter 233 of Harrison’s Principles of
`
`
`
`
`
`
`
`
`Internal Medicine, 14th Edition, pp. 1287-1291 and 1360 (1998).
`
`
`
`
`
`
`
`
`
`Bublik et al., “Pediatric cardiomyopathy as a chronic disease: A
`
`
`
`
`
`
`perspective on comprehensive care programs, Progress in Pediatric,”
`
`
`
`
`
`
`Pediatric Cardiology, vol. 25, pp. 103-111 (2008).
`
`
`
`
`
`
`
`Budts et al., “Residual pulmonary vasoreactivity to inhaled nitric
`
`
`
`
`
`
`
`oxide in patients with severe obstructive pulmonary hypertension and
`
`
`
`
`
`
`
`
`Eisenmenger syndrome,” Heart, vol. 86, pp. 553-558 (2001).
`
`
`
`
`
`
`
`
`Canadian Office Action mailed May 31, 2011 for Canadian Patent
`
`
`
`
`
`
`
`
`
`Application No. 2671029, a counterpart foreign application of U.S.
`
`
`
`
`
`
`
`Appl. No. 12/494,598.
`
`
`
`Clark et al., “Low-Dose Nitric Oxide Therapy for Persistent Pulmo-
`
`
`
`
`
`
`
`
`nary Hypertension: 1-Year Follow-up,” Journal of Perinatology, vol.
`
`
`
`
`
`
`
`23, pp. 300-303 (2003).
`
`
`
`
`Clark et al., “Low-Dose Nitric Oxide Therapy for Persistent Pulmo-
`
`
`
`
`
`
`
`
`nary Hypertension of the Newborn,” New England Journal of Medi-
`
`
`
`
`
`
`
`
`cine, vol. 342, No. 7, pp. 469-474 (2000).
`
`
`
`
`
`
`
`Cockrill et al., “Comparison ofthe Effects ofNitric Oxide, Nitroprus-
`
`
`
`
`
`
`
`side, and Nifedipine on Hemodynamics and Right Ventricular Con-
`
`
`
`
`
`
`
`
`tractibility in Patients With Chronic Pulmonary Hypertension,”
`
`
`
`
`
`
`
`Chest, vol. 119, No. 1, pp. 128-136 (2001).
`
`
`
`
`
`
`
`Comparison of Supplemental Oxygen and Nitric Oxide for Inhala-
`
`
`
`
`
`
`
`
`tion in the Evaluation of the Reactivity ofthe PulmonaryVasculature
`
`
`
`
`
`During Acute Pulmonary Vasodilator Testing, http://clinicaltrials.
`
`
`
`
`
`
`gov/archive/NCT00626028/2009_01_12 Jan. 12, 2009.
`
`
`
`
`Cornfield et al., “Randomized, Controlled Trial of Low-dose Inhaled
`
`
`
`
`
`
`
`Nitric Oxide in the Treatment of Term and Near-term Infants With
`
`
`
`
`
`
`
`
`
`Respiratory Failure and Pulmonary Hypertension,” Pediatrics, vol.
`
`
`
`
`
`
`
`104, No. 5, pp. 1089-1094 (1999).
`
`
`
`
`
`Cox et al., “Factors Associated with Establishing a Causal Diagnosis
`
`
`
`
`
`
`
`
`for Children with Cardiomyopathy,” Pediatrics, vol. 118, No. 4, pp.
`
`
`
`
`
`
`
`
`
`1519-1531 (2006).
`
`
`Cujec et al., “Inhaled Nitric Oxide Reduction in Systolic Pulmonary
`
`
`
`
`
`
`
`
`Artery Pressure is Less in Patients with Decreased Left Ventricular
`
`
`
`
`
`
`
`
`Ejection Fraction,” Canadian Journal of Cardiology, vol. 13(9), pp.
`
`
`
`
`
`
`
`
`816-824 (1997).
`
`
`Cuthbertson et al., “UK guidelines for the use of inhaled nitric oxide
`
`
`
`
`
`
`
`
`
`
`therapy in adults ICUs,” Intensive Care Med., vol. 23, Springer-
`
`
`
`
`
`
`
`
`
`Verlag, pp. 1212-1218 (1997).
`
`
`
`
`Davidson et al., “Inhaled nitric oxide for the early treatment of
`
`
`
`
`
`
`
`
`
`
`persistent pulmonary hypertension of the term newborn: a random-
`
`
`
`
`
`
`
`double-masked,
`placebo-controlled,
`dose-response,
`ized,
`
`
`
`
`multicenter study,” Pediatrics, vol. 101 (3 Pt 1), pp. 325-334 (1998).
`
`
`
`
`
`
`
`
`
`
`004
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`page
`
`
`
`last
`
`
`
`Davidson et al., “Safety of Withdrawing Inhaled Nitric Oxide
`
`
`
`
`
`
`
`Therapy in Persistent Pulmonary Hypertension of the Newborn,”
`
`
`
`
`
`Pediatrics, vol. 104, No. 2, pp. 231-236 (1999).
`
`
`
`
`
`
`
`Day et al., “Pulmonary Vasodilatory Effects of 12 and 60 Parts Per
`
`
`
`
`
`
`
`
`Million Inhaled Nitric Oxide in Children with Ventricular Septal
`
`
`
`
`
`
`
`
`Defect,” The American Journal of Cardiology, vol. 75, pp. 196-198
`
`
`
`
`
`
`
`
`
`(1995).
`
`Definition of Contraindication on Medicine.net.com; http://www.
`
`
`
`
`
`medterms.com/script/main/art.asp?articlekey:17824; retrieved Mar.
`
`
`14, 2011; 2 pages.
`
`
`
`Delivery of Inhaled Nitric Oxide Therapy through an Adult or Pedi-
`
`
`
`
`
`
`
`
`atric Nasal Carmula, Reference: UTMB Respiratory Care Services
`
`
`
`
`
`
`
`
`Reviewed: May 31, 2005.
`
`
`
`Dickstein et al., “A Theoretic Analysis of the Effect of Pulmonary
`
`
`
`
`
`
`
`
`Vasodilation on Pulmonary Venous Pressure:
`Implications for
`
`
`
`
`
`
`
`Inhaled Nitric Oxide Therapy,” The Journal of Heart and Lung Trans-
`
`
`
`
`
`
`
`
`
`
`plant, pp. 715 -721 (1996).
`
`
`
`
`Dorland, “The American Illustrated Medical Dictionary,” 7th edition,
`
`
`
`
`
`
`
`W.B. Saunders Company, p. 113 (1914).
`
`
`
`
`
`Dorling, “Neurodevelopmental outcome following Nitric Oxide
`
`
`
`
`
`Therapy for Persistent Pulmonary Hypertension in Term Newborn
`
`
`
`
`
`
`Infants,” Neonatal Intensive Care Unit, Leicester Royal Infirmary,
`
`
`
`
`
`
`
`Aug. 8, 2003, modified Nov. 12, 2003, 3 pages.
`
`
`
`
`
`
`
`Douwes et al., “The Maze of Vasodilator Response Criteria,” Pub-
`
`
`
`
`
`
`
`
`lished online: Nov. 26, 2010, Pediatr. Cardiol., vol. 32, pp. 245-246
`
`
`
`
`
`
`
`
`
`
`
`(201 1).
`
`Ehrenkranz, “Inhaled Nitric Oxide in Full-Term and Nearly Full-
`
`
`
`
`
`
`
`
`Term Infants with Hypoxic Respiratory Failure,” The Neonatal
`
`
`
`
`
`
`
`
`Inhaled Nitric Oxide Study Group, N. Engl. J. Med., vol. 336, No. 9,
`
`
`
`
`
`
`
`
`
`
`pp. 597-605 (1997).
`
`
`
`http://www.cc.nih.gov/ccmd/clinical_services.htrnl,
`updated May 19, 2011.
`
`
`
`http://www.medterms.com/script/main/art.asp?articleke}?17824,
`
`Definition of Contraindication, last Editorial Review Mar. 19, 2012.
`
`
`
`
`
`
`
`
`Ovodov et al., “Nitric Oxide: Clinical Applications,” Seminars in
`
`
`
`
`
`
`
`Anesthesia, Saunders, CO, New York NY, vol. 19, No. 2, pp. 88-97
`
`
`
`
`
`
`
`
`
`
`
`(2000).
`
`Pazopanib Plus Lapatinib Compared to Lapatinib Alone in Subjects
`
`
`
`
`
`
`With Inflammatory Breast Cancer, p. 4, ClinicalTrials.gov, <<http://
`
`
`
`
`
`clinicaltrials.gov/ct2/show/NCT00558103>> Apr. 22, 2010.
`
`
`
`
`PCT/US2010/038652 Search Report dated Jul. 29, 2010, 16 pages.
`
`
`
`
`
`
`
`
`
`Pepke-Zaba et al., “Inhaled nitric oxide as a cause of selective pul-
`
`
`
`
`
`
`
`
`monary vasodilation in pulmonary hypertension,” The Lancet, vol.
`
`
`
`
`
`
`
`338, pp. 1173-1174 (1991).
`
`
`
`
`Ratnasamy et al., “Associations between neurohormonal and inflam-
`
`
`
`
`
`
`
`matory activation and heart failure in children,” American Heart
`
`
`
`
`
`
`
`
`
`Journal, pp. 527-533 (2008).
`
`
`
`
`Response filed Aug. 18, 2010 to EP Search Report dated May 10,
`
`
`
`
`
`
`
`
`
`
`2010 for EP09251949.
`
`
`
`Ricciardi et al., “Inhaled Nitric Oxide in Primary Pulmonary Hyper-
`
`
`
`
`
`
`
`
`tension: A Safe and Effective Agent for Predicting Response to
`
`
`
`
`
`
`
`
`Nifedipine,” Journal of the American College of Cardiology (JACC,)
`
`
`
`
`
`
`vol