US008282966B2
`
`
`
`
`
`
`
`(12) United States Patent
`Baldassarre et al.
`
`
`
`
`
`
`(10) Patent No.:
`
`
`(45) Date of Patent:
`
`
`
`
`US 8,282,966 B2
`
`
`*Oct. 9, 2012
`
`(54) METHODS OF REDUCING THE RISK OF
`
`
`
`
`
`OCCURRENCE OF PULMONARY EDEMA IN
`
`
`
`CHILDREN IN NEED OF TREATMENT WITH
`
`
`
`
`INHALED NITRIC OXIDE
`
`
`
`
`(75)
`
`
`Inventors: James S. Baldassarre, Doylestown, PA
`
`
`
`
`(US); Ralf Rosskamp, Chester, NJ (US)
`
`
`
`
`
`
`(73) Assignee:
`
`
`
`( * ) Notice:
`
`
`
`
`INO Therapeutics LLC, Hampton, NJ
`
`
`
`
`(US)
`
`Subject to any disclaimer, the term of this
`
`
`
`
`
`
`patent is extended or adjusted under 35
`
`
`
`
`U.S.C. 154(b) by 0 days.
`
`
`
`This patent is subject to a terminal dis-
`
`
`
`
`
`claimer.
`
`
`
`
`
`(21) Appl.No.: 12/821,020
`
`(22)
`
`
`
`Filed:
`
`
`Jun. 22, 2010
`
`
`
`
`(65)
`
`
`
`Prior Publication Data
`
`
`
`US 2010/0330207 A1
`Dec. 30, 2010
`
`
`
`
`
`
`
`Related U.S. Application Data
`
`
`
`
`(63) Continuation of application No. 12/494,598, filed on
`
`
`
`
`
`
`Jun. 30, 2009, now abandoned.
`
`
`
`
`
`
`(51)
`
`
`Int. Cl.
`
`
`(2006.01)
`A01N 59/00
`
`
`
`(2006.01)
`A61K 33/00
`
`
`
`(2006.01)
`C01B 21/24
`
`
`
`(2006.01)
`A6]M 16/00
`
`
`
`(52) U.S. Cl.
`.................. .. 424/718; 128/200.24; 423/405
`
`
`
`
`
`
`(58) Field of Classification Search ...................... .. None
`
`
`
`
`
`
`See application file for complete search history.
`
`
`
`
`
`
`
`
`(56)
`
`
`References Cited
`
`
`U.S. PATENT DOCUMENTS
`
`
`
`2/1999 Zapol et al.
`5,873,359 A
`
`
`
`
`5/2000 Zapol et al.
`6,063,407 A
`
`
`
`
`8/2003 Bloch et al.
`6,601,580 B1
`
`
`
`
`
`7/2009 Rothbard et al.
`7,557,087 B2
`
`
`
`
`
`6/2004 Whitehurst et al.
`2004/0106954 A1
`
`
`
`
`
`
`2009/0018136 A1
`1/2009 Oppenheimer et al.
`
`
`
`
`
`1/2009 Elliott
`2009/0029371 A1
`
`
`
`
`6/2009 Starket al.
`2009/0149541 A1
`
`
`
`
`7/2009 Blackburn et al.
`2009/0176772 A1
`
`
`
`
`
`FOREIGN PATENT DOCUMENTS
`
`
`
`1682672 A1
`7/2006
`
`
`
`WO2005004884 A2
`1/2005
`
`
`
`WO2006127907 A2
`11/2006
`
`
`
`WO2010019540 A1
`2/2010
`
`
`OTHER PUBLICATIONS
`
`
`Beghetti et al. (Journal of Pediatrics, 1997, p. 844).*
`
`
`
`
`
`
`Macrae et al. (Intensive Care Med 2004, 30, pp. 372-380).*
`
`
`
`
`
`
`
`
`
`Atz et al. (Seminars in Perinatology 1997, 21(5), pp. 441-455).*
`
`
`
`
`
`
`
`
`Kinsella et al. (The Lancet 1999, 354, pp. 1061-1065).*
`
`
`
`
`
`
`
`
`The NIH (Critical Care Therapy and Respiratory Care Section; Nitric
`
`
`
`
`
`
`
`
`
`
`Oxide Therapy, May 2000, 13 pages).*
`
`
`
`
`
`Bolooki (Clinical Application of the Intra-Aortic Balloon Pump
`
`
`
`
`
`
`
`
`1998, 3rd Ed. pp. 252-253).*
`
`
`
`
`
`
`EP
`
`WO
`
`WO
`
`WO
`
`
`
`
`
`
`
`
`
`
`Henrichsen (Journal of Pediatrics 1996, 129(1) p. 183). 2 pages.*
`
`
`
`
`
`
`
`(Krohn the Journal of Thoracic and Cardiovascular Surgery 1999,
`
`
`
`
`
`
`
`
`117(1) pp. 195-196). 2 pages.*
`
`
`
`
`Semigran (Abstract of J Am Coll Cardiol 1994; 24: 982-988). 5
`
`
`
`
`
`
`
`pages.*
`
`Hayward (Cardiovascular Research 1999; 43:628-638) 11 pages.*
`
`
`
`
`
`
`Beghetti et al. (the Journal of Pediatrics 1997 p. 844).*
`
`
`
`
`
`
`
`Bocchi the American Journal of Cardiology 1994, 74, pp. 70-72. 4
`
`
`
`
`
`
`
`
`
`pages).*
`
`Davidson et al. (Pediatrics 1998, 101 (3) pp. 325-334).*
`
`
`
`
`
`
`
`
`The Neonatal Inhaled Nitric Oxide Study Group (The New England
`
`
`
`
`
`
`
`
`
`Journal of Medicine 1997, 336(9), pp. 597-604).*
`
`
`
`
`
`
`Macrae (Semin Neonatal 1997, 2, 49-58).*
`
`
`
`
`
`Miller et al. (Achives of Disease in Childhood 1994, 70, F47-F49.*
`
`
`
`
`
`
`
`
`Wheeler et al. (Pediatric Critical Care Medicine 2007, Springer, p.
`
`
`
`
`
`
`
`
`278).*
`
`Kazerooni et al. (Cardiopulmonary Imaging 2004, Lippincott Will-
`
`
`
`
`
`
`
`iams & Wilkins, pp. 234-235).*
`
`
`
`
`Hurford et al. (Nitric Oxide: Biology and Pathobiology 2000 Aca-
`
`
`
`
`
`
`
`
`
`demic Press, Chapter 56, pp. 931-945).*
`
`
`
`
`
`
`Weinberger et al. (Toxicology Sciences 2001, 59, 5-16).*
`
`
`
`
`
`
`
`Moss et al. (Moss andAdams’ Heart Disease in Infants, Children, and
`
`
`
`
`
`
`
`
`Adolescents, 2007, vol. 1, p. 991 in part).*
`
`
`
`
`
`
`Bocchi et al. The American Journal of Cardiology 1994, 74, pp:
`
`
`
`
`
`
`
`
`
`70-72. 4 pages).*
`
`
`Kazerooni et al. Cardiopulmonary Imaging 2004, Lippincott Will-
`
`
`
`
`
`
`
`iams & Wilkins p. 235 (2 pages).*
`
`
`
`
`“Inhaled Nitric Oxide and Hypoxic Respiratory Failure in Infants
`
`
`
`
`
`
`
`
`With Congenital Diaphragmatic Hernia”, The Neonatal Inhaled
`
`
`
`
`
`
`
`Nitric Oxide Study Group (NINOS), Pediatrics, vol. 99, No. 6, Jun. 6,
`
`
`
`
`
`
`
`
`
`
`1997, pp. 838-845.
`
`
`
`“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, 1997, vol. 336, No. 9, pp.
`
`
`
`
`
`
`
`
`
`
`597-605.
`
`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, Jun. 1, 1995, p. 1663.
`
`
`
`
`
`
`
`Al-Alaiyan S et al., “Inhaled nitric oxide in persistent pulmonary
`
`
`
`
`
`
`
`hypertension of the newborn refractory to high-frequency ventila-
`
`
`
`
`
`
`tion”, Crit Care, vol. 3, No. 1, 1999, pp. 7-10. Argenziano, et al.,
`
`
`
`
`
`
`
`
`
`
`
`“Inhaled Nitric Oxide is not a Myocardial Depressant in a Porcine
`
`
`
`
`
`
`
`Model of Heart Failure”, The Journal ofThoracic and Cardiovascular
`
`
`
`
`
`
`
`
`Surgery, 1998, vol. 115, pp. 700-704.
`
`
`
`
`
`
`Atz AM et al., “Combined Effects of Nitric Oxide and Oxygen
`
`
`
`
`
`
`
`
`
`During Acute PulmonaryVasodilator Testing”, Journal ofthe Ameri-
`
`
`
`
`
`
`can College of Cardiology (JACC), vol. 33, No. 3, Mar. 1, 1999, pp.
`
`
`
`
`
`
`
`
`
`
`813-819.
`
`Barrington, et al., Inhaled Nitric Oxide for Preterm Infants: A Sys-
`
`
`
`
`
`
`
`
`tematic Review, Pediatrics 2007; 120; 1088-1099, DOI: 10.1542/
`
`
`
`
`
`
`
`
`peds.2007-0726.
`
`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 Hypertemsion: A Multicenter, Random-
`
`
`
`
`
`
`ized Study”, INO Therapeutic s/Ikaria, Baltimore Convention Center,
`
`
`
`
`
`
`
`
`May 3, 2009, 2 pages, Abstract, downloaded Jul. 2, 2009 from http://
`
`
`
`
`
`
`
`
`
`127.0.0.119080/PASO9A1/view.y?nu:PASO9L1_1507.
`
`Bland, “Pulmonary vascular dysfuction in preterm lambs with
`
`
`
`
`
`
`
`
`chronic lung disease”, Am J Physical Lung Cell Mol Physiol 285:
`
`
`
`
`
`
`
`
`
`L76-L85, 2003.
`
`
`
`(Continued)
`
`
`
`
`Primary Examiner — Ernst Arnold
`
`
`
`(74) Attorney, Agent, or Firm — Fish & Richardson P.C.
`
`
`
`
`
`(57)
`ABSTRACT
`
`
`The invention relates methods ofreducing the risk or prevent-
`
`
`
`
`
`
`
`
`ing the occurrence of an adverse event (AE) or a serious
`
`
`
`
`
`
`
`
`adverse event (SAE) associated with a medical treatment
`
`
`
`
`
`
`
`comprising inhalation of nitric oxide.
`
`
`
`
`29 Claims, No Drawings
`
`
`
`
`
`001
`
`PRAXAIR ET AL. 1001
`
`001
`
`

`
`
`
`US 8,282,966 B2
`Page 2
`
`
`OTHER PUBLICATIONS
`
`
`Bocchi EA et al.,“Inhaled Nitric Oxide Leading to Pulmonary Edema
`
`
`
`
`
`
`
`in Stable Severe Heart Failure”, The American Journal ofCardiology,
`
`
`
`
`
`
`
`
`
`vol. 74, Jul. 1, 1994, pp. 70-72.
`
`
`
`
`
`
`
`Budts W et al., “Residual pulmonary vasoreactivity to inhaled nitric
`
`
`
`
`
`
`
`oxide in patients with severe obstructive pulmonary hypertension and
`
`
`
`
`
`
`
`
`Eisenmenger syndrome”, Heart, vol. 86, 2001, pp. 553-558.
`
`
`
`
`
`
`
`
`Clark RH et al., “Low-Dose Nitric Oxide Therapy for Persistent
`
`
`
`
`
`
`
`
`
`Pulmonary Hypertension: 1-Year Follow-up”, Journal of Perinatol-
`
`
`
`
`
`
`ogy, (2003) 23:300-303.
`
`
`
`Clark, et al., Low-Dose Nitric Oxide Therapy for Persistent Pulmo-
`
`
`
`
`
`
`
`
`nary Hypertension: 1-Year Follow-up, Journal of Perinatology 2003;
`
`
`
`
`
`
`
`23: 300-303.
`
`
`Cockrill BA et al., “Comparison of the Effects of Nitric Oxide,
`
`
`
`
`
`
`
`
`
`Nitroprusside, and Nifedipine on Hemodynamics and Right
`
`
`
`
`
`
`
`Ventricular Contractibility in Patients With Chronic Pulmonary
`
`
`
`
`
`
`
`Hypertension”, Chest, vol. 119, No. 1, Jan. 2001, pp. 128-136.
`
`
`
`
`
`
`
`
`
`Cornfield DN 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 (Nov. 5, 1999).
`
`
`
`
`
`
`
`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, 1997, vol. 13
`
`
`
`
`
`
`
`
`(9), pp. 816-824.
`
`
`
`Davidson D 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, Mar. 1998; 101(3 Pt 1):325-34.
`
`
`
`
`
`
`
`Davidson D et al., “Safety of Withdrawing Inhaled Nitric Oxide
`
`
`
`
`
`
`
`Therapy in Persistent Pulmonary Hypertension of the Newborn”,
`
`
`
`
`
`
`
`Pediatrics, vol. 104, No. 2, Aug. 2, 1999, pp. 231-236.
`
`
`
`
`
`
`
`
`Day RW 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, Jan. 15, 1995,
`
`
`
`
`
`
`
`
`
`
`pp. 196-198.
`
`
`Dickstein, et al., “A Theoretic Analysis of the Effect of Pulmonary
`
`
`
`
`
`
`
`
`Vasodilation on Pulmonary Venous Pressure:
`Implications for
`
`
`
`
`
`
`
`Inhaled Nitric Oxide Therapy”, The Journal ofHeart and Lung Trans-
`
`
`
`
`
`
`
`
`
`
`plant Jul. 1996, pp. 715-721.
`
`
`
`
`
`Ivy, et al., “Dipyridamole attenuates rebound pulmonary hyperten-
`
`
`
`
`
`
`
`
`sion after inhaled nitric oxide withdrawal in postoperative congenital
`
`
`
`
`
`
`
`
`heart disease”, J Thorac Cardiovasc Surg 1998; 115:875-882.
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`
`Ferguson, et al., “Inhaled nitric oxide for hypoxemic respiratory
`
`
`
`
`
`
`
`
`failure: Passing bad gas?”, Canadian Medical Association Journal,
`
`
`
`
`
`
`
`
`Jan. 11, 2000; 162 (1), pp. 85-86.
`
`
`
`
`
`
`Field, Neonatal Ventilation With Inhaled Nitric Oxide Versus Venti-
`
`
`
`
`
`
`
`
`
`latory Support Without Inhaled Nitric Oxide for Preterm Infants With
`
`
`
`
`
`
`
`
`
`Severe Respiratory Failure: The INNOVO Multicentre Radomised
`
`
`
`
`
`
`
`Controlled Trial
`(ISRCTN 17821339),
`“Pediatrics”
`Journal
`
`
`
`
`
`
`2005: 1 15:926-936, DOI: 10.1542/peds.2004-1209.
`
`
`
`
`Findlay, “Paradoxical Haemodynamic Response to Inhaled Nitric
`
`
`
`
`
`
`Oxide”, International Journal of Intensive Care 1998 GB, vol. 5, No.
`
`
`
`
`
`
`
`
`
`4, 1998, pp. 134-139.
`
`
`
`
`Finer NN et al., “Randomized, Prospective Study of Low-Dose Ver-
`
`
`
`
`
`
`
`sus High-Dose Inhaled Nitric Oxide in the Neonate With Hypoxic
`
`
`
`
`
`
`
`
`
`Respiratory Failure”, Pediatrics, vol. 108, No. 4, Oct. 4, 2001.
`
`
`
`
`
`
`
`
`Greenough, “Inhaled nitric oxide in the neonatal period”, Expert
`
`
`
`
`
`
`
`
`Opinion on Investigational Drugs, 2000 Ashley Publications Ltd,
`
`
`
`
`
`
`
`1354-3784, 9 pages.
`
`
`Hayward CS et al., “Effect ofInhaled Nitric Oxide on Normal Human
`
`
`
`
`
`
`
`
`LeftVentricular Function,”JACC,vol. 30,No. 1, Jul. 1997, pp.49-56.
`
`
`
`
`
`
`Hayward CS et al., “Inhaled Nitric Oxide in Cardiac Failure: Vascular
`
`
`
`
`
`
`
`
`Versus Ventricular Effects”, Journal of Cardiovascular Pharmacol-
`
`
`
`
`
`
`
`ogy, vol. 27, 1996, pp. 80-85, Abstract Only.
`
`
`
`
`
`
`
`
`Hayward et al., “Left Ventricular Chamber Function During Inhaled
`
`
`
`
`
`
`
`
`Nitric Oxide in Patients with Dilated Cardiomyopathy”, J. Cardio-
`
`
`
`
`
`
`
`vascular Pharmacology, vol. 34, Iss. 5, Nov. 1999, pp. 749-754,
`
`
`
`
`
`
`
`
`
`
`Abstract.
`
`
`O02
`
`Henrichsen, et al., “Inhaled Oxide Can Cause Severe Systemic
`
`
`
`
`
`
`
`
`Hypotension”, Journal of Pediatrics, Mosby-Year Book, St. Louis,
`
`
`
`
`
`
`MO, vol. 129, No. 1, Jul. 1996, p. 183.
`
`
`
`
`
`
`Inglessis I et al., “Does inhaled nitric oxide support the hemodynamic
`
`
`
`
`
`
`
`
`
`of spontaneous breathing patients with cardiogenic shock related to
`
`
`
`
`
`
`
`
`right ventricular myocardial infarction? Reply”, JACC, vol. 45, No.
`
`
`
`
`
`
`
`
`
`6, Mar. 15, 2005, pp. 965-966.
`
`
`
`
`
`
`Inglessis I et al., “Hemodynamic effects of inhaled nitric oxide in
`
`
`
`
`
`
`
`
`
`right ventricular myocardial
`infarction and cardiogenic shock”,
`
`
`
`
`
`
`
`JACC, vol. 44, No. 4, Aug. 18, 2004, pp. 793-798.
`
`
`
`
`
`
`
`
`
`“Inhaled Nitric Oxide (INO) in Hypoxic Respiratory Failure”, Study
`
`
`
`
`
`
`
`
`description, study sponsored by INO Therapeutics, ClinicalTrials.
`
`
`
`
`
`
`gov Identifier NCT00922532, Jun. 16, 2009, 4 pages.
`
`
`
`
`
`
`
`Krasuski RA et al., “Inhaled Nitric Oxide Selectively Dilates Pulmo-
`
`
`
`
`
`
`
`
`nary Vasculature in Adult Patients With Pulmonary Hypertension,
`
`
`
`
`
`
`
`Irrespective of Etiology”, Journal of the American College of Cardi-
`
`
`
`
`
`
`ology (JACC), vol. 36, No. 7, Dec. 2000, pp. 2204-2211.
`
`
`
`
`
`
`
`
`
`Lipshultz, “Ventricular dysfunction clinical research in infants, chil-
`
`
`
`
`
`
`
`dren and adolescents”, Progress in Pediatric Cardiology 12 (2000)
`
`
`
`
`
`
`
`1-28.
`Loh, et al., “Cardiovascular Effects of Inhaled Nitric Oxide in
`
`
`
`
`
`
`
`
`Patients with Left Ventricular Dsyfunction,” Circulation, Aug. 7,
`
`
`
`
`
`
`
`1994, 90, pp. 2780-2785.
`
`
`
`
`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. 1-31, 2006, Reserach project description, 1 page, http://
`
`
`
`
`
`
`
`
`
`www.rbht.nhs.uldresearch.
`
`Matsumoto A et al., “Effect of Inhaled Nitric Oxide on Gas Exchange
`
`
`
`
`
`
`
`
`in Patients with Congestive Heart Failure”, Annals of Internal Medi-
`
`
`
`
`
`
`
`
`
`cine, vol. 130, No. 1, 1999:40-44.
`
`
`
`
`
`Morales-Blanhir J 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, 2004, pp. 225-234.
`
`
`
`
`Murray, et al., “Nitric Oxide and Septic Vascular Dysfunction”,
`
`
`
`
`
`
`
`Anesth Analg 2000; 90:89-101.
`
`
`
`
`Natori S et al., “Inhaled Nitric Oxide Modifies Left Ventricular Dias-
`
`
`
`
`
`
`
`
`
`tolic Stress in the Presence of Vasoactive Agents in Heart Failure”,
`
`
`
`
`
`
`
`
`Am J Respir Crit Care Med, vol. 167, pp. 895-901, 2003.
`
`
`
`
`
`
`
`
`
`
`Ovodov, et al., “Nitric Oxide: Clinical Applications”, Seminars in
`
`
`
`
`
`
`
`Aneshesia, Saunders, CO, NewYorkNY, vol. 19, No. 2, Jun. 1,2000,
`
`
`
`
`
`
`
`
`
`pp. 88-97.
`
`
`Pepke-Zaba J et al., “Inhaled nitric oxide as a cause of selective
`
`
`
`
`
`
`
`pulmonary vasodilation in pulmonary hypertension”, The Lancet,
`
`
`
`
`
`vol. 338, Nov. 9, 1991, pp. 1173-1174.
`
`
`
`
`
`
`Ricciardi MJ et al., Inhaled Nitric Oxide in Primary Pulmonary
`
`
`
`
`
`
`
`
`Hypertension: A Safe and Effective Agent for Predicting Response to
`
`
`
`
`
`
`Nifedipine, Journal of the American College of Cardiology (JACC,)
`
`
`
`
`
`
`vol. 32, No. 4, Oct. 1998, pp. 1068-1073.
`
`
`
`
`
`
`
`Roberts, Inhaled Nitric Oxide and Persistent Pulmonary Hyperten-
`
`
`
`
`
`
`
`
`sion ofthe Newborn, The New England Journal of Medicine, Feb. 27,
`
`
`
`
`
`
`
`
`
`1997, vol. 336, No. 9, pp. 605-610.
`
`
`
`
`
`
`Rosales, et al., “Hemodynamic Effects Observed with Inhaled Nitric
`
`
`
`
`
`
`
`Oxide After Surgical Repair of Total Anamolous Pulmonary Venous
`
`
`
`
`
`
`
`Return”, Pediatric Cardiology, 1999, vol. 20, pp. 224-226.
`
`
`
`
`
`
`
`
`Sadiq HF et al., “Inhaled Nitric Oxide in the Treatment of Moderate
`
`
`
`
`
`
`
`
`Persistent Pulmonary Hypertension of the Newborn: A Randomized
`
`
`
`
`
`Controlled, Multicenter Trial”, Journal of Perinatology, 2003; 23:98-
`
`
`
`
`
`
`
`103.
`
`Sehgal A et al., “Experience with Inhaled Nitric Oxide Therapy in
`
`
`
`
`
`
`
`
`Hypoxic Respiratory Failure of the Newborn”, Indian J Chest Dis
`
`
`
`
`
`
`
`
`Allied Sci, 2005; 47:245-49.
`
`
`
`
`Semigran et al., “Hemodynamic Effects of Inhaled Nitric Oxide in
`
`
`
`
`
`
`
`Heart Failure”, Journal of American College of Cardiology (JACC),
`
`
`
`
`
`
`
`vol. 24, No. 4, Oct. 1994, pp. 982-988.
`
`
`
`
`
`
`
`Singh, et al., “Nitric Oxide, the biological mediator of the decade:
`
`
`
`
`
`
`
`
`fact of fiction?”, Eur Respir J 1997; 10: 699-707.
`
`
`
`
`
`
`
`Smyth RL, “Inhaled nitric oxide treatment for preterm infants with
`
`
`
`
`
`
`
`
`
`hypoxic respiratory failure”, Thorax, 2000;55(Suppl 1):S51-S55.
`
`
`
`
`
`
`Steinhorn, RH, “Pulmonary Hypertension, Persistent-Newborn”,
`
`
`
`
`
`Updated Apr.
`19, 2007, http://emedicine.medscape.com/article/
`
`
`
`
`
`898437-overview.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`002
`
`

`
`
`
`US 8,282,966 B2
`Page 3
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Office Action Response to AU 2010202422 OA dated Jul. 9, 2010,
`
`
`
`
`
`
`
`response filed Sep. 1, 2010.
`
`
`
`
`PCT/US2010/038652 Search Report dated Jul. 29, 2010, 16 pages.
`
`
`
`
`
`
`
`
`
`Response filed Aug. 18, 2010 to EP Search Report dated May 10,
`
`
`
`
`
`
`
`
`
`
`2010 for EP09251949.
`
`
`
`Search Report from EP 09251949 dated May 10, 2010.
`
`
`
`
`
`
`
`Towbin, et al.,
`Incidence, Causes, and Outcomes of Dilated
`
`
`
`
`
`
`
`
`
`Cardiomyopathy in Children, JAMA, Oct. 18, 2006—vol. 296, No.
`
`
`
`
`
`
`
`
`15, pp. 1867-1876.
`
`
`
`Yoshida, Kiyoshi, “Well-illustrated Diagnostics and Treatment of
`
`
`
`
`
`
`Heart Failure” Professor of Kawasaki Medical University, cardiovas-
`
`
`
`
`
`
`
`cular internal medicine Circulation Up-to-Date vol. 2, No. 4,
`
`
`
`
`
`
`
`
`2007(343), pp. 23-28.
`
`
`
`Behera, et al., Nesiritide Improves Hemodynamics in Children with
`
`
`
`
`
`
`Dilated Cardiomyopathy: A Pilot Study, Pediatr Cardiol (2009)
`
`
`
`
`
`
`30:26-34.
`
`Bhagavan, et al., Potential role of ubiquinone (coenzyrne Q10) in
`
`
`
`
`
`
`
`
`pediatric cardiomyopathy, Clinical Nutrition (2005) 24, 331-338, pp.
`
`
`
`
`
`
`
`
`331-338.
`
`Bublik, et al., Pediatric cardiomyopathy as a chronic disease: A
`
`
`
`
`
`
`perspective on comprehensive care programs, Progress in Pediatric
`
`
`
`
`
`
`Cardiology 25 (2008) 103-111.
`
`
`
`Cox, et al., Factors Associated with Establishing a Causal Diagnosis
`
`
`
`
`
`
`
`for Children with Cardiomyopathy, Pediatrics vol. 118, No. 4, Oct.
`
`
`
`
`
`
`
`
`2006, pp. 1519-1531.
`
`
`
`Dermatological Cryosurgery in Primary Care with Dimethyl Ether
`
`
`
`
`
`
`
`Propane Spray in Comparison with Liquid Nitrogen, Martinez, et al.,
`
`
`
`
`
`
`
`
`Atnecion Primaria, vol. 18, No. 5, (211, 216), Sep. 30, 1996.
`
`
`
`
`
`
`
`
`
`
`Dronedarone is Less Effective, But Safer Than Amiodarone in Atrial
`
`
`
`
`
`
`
`Fibrillation, Oct. 27, 2009, p. 3, <<http://www.npci.org.uk/blog/
`
`
`
`
`
`?p:778>>.
`
`Early Inhaled Nitric Oxide Therapy in Term and Near Term Infants
`
`
`
`
`
`
`
`
`
`with Respiratory Failure,
`from ClinicalTrials.gov
`archive,
`
`
`
`
`
`NCT00005773, Jun. 23, 2005.
`
`
`
`
`Ehrenkranz RA, “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, 1997, vol. 336, No.
`
`
`
`
`
`
`
`
`
`9, pp. 597-605.
`
`
`
`Elbl, et al., Long-term serial echocardiographic examination of late
`
`
`
`
`
`
`
`anthracycline cardiotoxicity and its prevention by dexrazoxane in
`
`
`
`
`
`paediatric patients, Eur J Pediatr (2005) 164: 678-684.
`
`
`
`
`
`
`
`The Encarta Webster’s Dictionary ofthe English Language (2004) is
`
`
`
`
`
`
`
`the second edition of the Encarta World Dictionary, published 1999,
`
`
`
`
`
`
`
`
`<<http://encarta.msn.com/encnet/features/dictionary/
`
`dictionaryhome.aspx>>; used to look up the definitions of “precau-
`
`
`
`
`
`tion” and “exclusion”.
`
`
`
`Green, “Patent Ductus Aterio sus Demonstrating Shunting of Blood”,
`
`
`
`
`
`
`
`Figure from presentation given Jan. 10, 2011, pp. 1.
`
`
`
`
`
`
`
`
`Harrison’s Principles of Internal Medicine, Fauci, et al., p. 1287-
`
`
`
`
`
`
`
`
`
`1291 and 1360, 12th edition, McGraw Hill, 1998.
`
`
`
`
`
`
`
`
`Huddleston,
`Indications
`for heart
`transplantation in children,
`
`
`
`
`
`
`Progress in Pediatric Cardiology 26 (2009) 3-9.
`
`
`
`
`
`Inhaled Nitric Oxide by Oxygen Hood in Neonates, from ClinicalTri-
`
`
`
`
`
`
`
`
`als.gov, NCT00732537, Aug. 8, 2008.
`
`
`
`
`Inhaled Nitric Oxide in Neonates with Elevated A-a DO2 Gradients
`
`
`
`
`
`
`
`
`Not Requiring Mechanical Ventilation,
`from ClinicalTrials. gov
`
`
`
`
`
`
`archive, NCT00041548, Jun. 23, 2005, 2 pages.
`
`
`
`
`
`
`James, et al., Treatment of heart
`failure in children, Current
`
`
`
`
`
`
`
`
`
`Paediatrics (2005) 15, 539-548.
`
`
`
`
`JP 2009-157623 Office Action dated Feb. 15, 2011, 3 pages.
`
`
`
`
`
`
`
`
`
`Lavigne, et al., Cardiovascular Outcomes of Pediatric Seroreverters
`
`
`
`
`
`Perinatally Exposed to HAART, Cardiovascular Toxicology (2004)
`
`
`
`
`
`04 187-197.
`
`
`injury in
`Lipschultz, The effect of dexrazoxane on myocardial
`
`
`
`
`
`
`
`
`
`doxorubicin-treated children with acute lymphoblastic leukemia,
`
`
`
`
`
`
`New England Journal of Medicine 2004; 35 1 : 145-153.
`
`
`
`
`
`
`Lipshultz, et al., Cardiovascular status of infants and children of
`
`
`
`
`
`
`
`
`
`women infected with HIV-1 (P2C2 HIV): a cohort study, The Lancet,
`
`
`
`
`
`
`
`
`
`
`vol. 360, Aug. 3, 2002, pp. 368-373.
`
`
`
`
`
`
`Lipshultz, et al., Cardiovascular Trials in Long-Term Survivors of
`
`
`
`
`
`
`
`Childhood Cancer, Journal ofClinical Oncology, vol. 22, No. 5, Mar.
`
`
`
`
`
`
`
`
`
`1, 2004, pp. 769-773.
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Steinhorn, et al., “Inhaled nitric oxide enhances oxygenation but not
`
`
`
`
`
`
`
`
`
`survival in infants with alveolar capillary dysplasia”, The Journal of
`
`
`
`
`
`
`
`
`Pediatrics, Mar. 1997, pp. 417-422.
`
`
`
`
`
`“Use of Inhaled Nitric Oxide”, American Academy of Pediatrics—
`
`
`
`
`
`
`
`Committee on Fetus and Newborn, Pediatrics vol. 106, No. 2, Aug.
`
`
`
`
`
`
`
`
`
`2000, pp. 344-345.
`
`
`
`Watson, et al., “Clinical and Economic Effects of iNO in Premature
`
`
`
`
`
`
`
`
`Newborns With Respiratory Failure at 1Year”, Pediatrics 2009; 124;
`
`
`
`
`
`
`
`
`1333-1343.
`Weinberger B et al., “The Toxicology of Inhaled Nitric Oxide”,
`
`
`
`
`
`
`
`Toxicological Sciences, 59, pp. 5-16 (2001).
`
`
`
`
`
`
`Weinberger, et al., “Nitric Oxide in the lung: therapeutic and cellular
`
`
`
`
`
`
`
`
`
`mechanisms of action”, Pharmacology & Therapeutics 84 (1999)
`
`
`
`
`
`
`401-41 1 .
`
`Wessel DL et al., “Improved Oxygenation in a Randomized Trial of
`
`
`
`
`
`
`Inhaled Nitric Oxide for Persistent Pulmonary Hypertension of the
`
`
`
`
`
`
`
`
`Newborn”, Pediatrics, vol. 100, No. 5, Nov. 5, 1997.
`
`
`
`
`
`
`
`AU 2009202685 Office Action dated Jun. 17, 2010 (3 pages).
`
`
`
`
`
`
`
`
`
`AU 2009202685 Office Action Response dated Jul. 29, 2010, 19
`
`
`
`
`
`
`
`
`
`
`pages.
`
`Branson, Inhaled Nitric Oxide in Adults, The Science Journal of the
`
`
`
`
`
`
`
`
`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, 1998, pp. 1287-1291 & 1360.
`
`
`
`
`
`
`
`
`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.
`
`
`
`
`
`
`“Comparison of Supplemental Oxygen and Nitric Oxide for Inhala-
`
`
`
`
`
`
`
`
`tion in the Evaluation of the Reactivity ofthe PulmonaryVasculature
`
`
`
`
`
`During Acute Pulmonary Vasodilator Testing,” ClinicalTrials. gov
`
`
`
`
`
`
`
`archive, updated Jan. 12, 2009, 4 pages, retrieved at <<http://
`
`
`
`
`
`
`
`
`
`clinicaltrials.gov/archive/NCT00626028/2009_01_12
`Jan.
`12,
`
`
`
`2009>>.
`
`Cox, et al., Factors Associated With Establishing a Causal Diagnosis
`
`
`
`
`
`
`
`
`for Chidren With Cardiology, Pediatrics, vol. 118, No. 4, Oct. 4,
`
`
`
`
`
`
`
`
`
`2006, pp. 1519-1531, published online Oct. 2, 2006.
`
`
`
`
`
`
`
`Cuthbertson et al., “UK guidelines for the use of inhaled nitric oxide
`
`
`
`
`
`
`
`
`
`
`therapy in adults ICUs*”, Intensive Care Med (1997), 23, Springer-
`
`
`
`
`
`
`
`
`
`Verlag, 1997, pp. 1212-1218.
`
`
`
`
`Dorland, “The American Illustrated Medical Dictionary”, 7th Edi-
`
`
`
`
`
`
`
`
`tion, W.B. Saunders Company, 1914, pp. 113.
`
`
`
`
`
`
`
`EP 09251949 Office Action dated Oct. 11, 2010, 5 pages.
`
`
`
`
`
`
`
`
`
`Guideline for Industry; Clinical Safety Data Management: Defini-
`
`
`
`
`
`
`
`
`tions and Standards for Expedited Reporting, Mar. 1995, 17 pages.
`
`
`
`
`
`
`
`
`
`
`Headrick, Hemodynamic monitoring of the critically ill neonate, J
`
`
`
`
`
`
`
`Perinat Neonatal Nurs 1992; 5(4): 58-67.
`
`
`
`
`
`
`INO Therapeutics, LLC, “INOflo for Inhalation 800ppm”, package
`
`
`
`
`
`
`
`leaflet, 2010, 2.
`
`
`JP 2009157623 Office Action dated Feb. 23, 2010, 3 pages.
`
`
`
`
`
`
`
`
`
`JP 2009157623 Office Action dated Jul. 30, 2010, 6 pages.
`
`
`
`
`
`
`
`
`
`JP 2009157623 Office Action response filed Jun. 18, 2010, 37 pages
`
`
`
`
`
`
`
`
`
`(no translation).
`
`
`JP 2009157623 request for accelerated exam filed Jan. 15, 2010 (60
`
`
`
`
`
`
`
`
`
`
`
`pages).
`
`JP 2009157623 response filed Nov. 30, 2010, 58 pages.
`
`
`
`
`
`
`
`
`Letter ofAcceptance for AU 2010202422, dated Oct. 7, 2010.
`
`
`
`
`
`
`
`Letter of acceptance of AU application 2009202685, dated Aug. 10,
`
`
`
`
`
`
`2010, 3 pages.
`
`
`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>>.
`NIH Clinical Center Services, retrieved at <http://www.cc.nih.gov/
`
`
`
`
`
`ccmd/clinical_services.html>> on Aug. 18, 2010.
`
`
`
`
`Office Action for AU 2010202422 dated Jul. 9, 2010, 3 pages.
`
`
`
`
`
`
`
`
`Office Action from AU 2009202685 dtd Mar. 15, 2010.
`
`
`
`
`
`
`
`
`Office Action from AU 2010206032 dated Aug. 16, 2010 (3 pages).
`
`
`
`
`
`
`
`
`
`Office Action Response for AU 2009202685 to Mar. 15, 2010 OA,
`
`
`
`
`
`
`
`
`
`filed Jun. 8, 2010 (16 pages).
`
`
`
`
`
`Office Action Response for JP2007157623 filed on Nov. 12, 2009 (no
`
`
`
`
`
`
`
`
`English translation).
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`003
`
`003
`
`

`
`
`
`US 8,282,966 B2
`Page 4
`
`
`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,” Pediatric Cardiol,
`
`
`
`
`
`
`
`vol. 23, pp. 20-26 (2002).
`
`
`
`
`
`Barst eta1., “Vasodilator Testing with Nitric Oxide and/or Oxygen in
`
`
`
`
`
`
`
`
`
`Pediatric Pulmonary Hypertension,” Pediatr. Cardiol., vol. 31, pp.
`
`
`
`
`
`
`
`
`598-606 (2010).
`
`
`Beghetti et al., “Inhaled nitric oxide and congenital cardiac disease,”
`
`
`
`
`
`
`
`
`Cardiol.Young, vol. 11, pp. 142-152 (2001).
`
`
`
`
`
`
`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).
`
`
`
`
`
`
`
`
`
`Dickstein et al., “A theoretic analysis of the effect of pulmonary
`
`
`
`
`
`
`
`
`
`
`vasodilation on pulmonary venous pressure: Implications for inhaled
`
`
`
`
`
`
`
`nitric oxide therapy,” J Heart Lung Transplant, vol. 15, pp. 715-721
`
`
`
`
`
`
`
`
`
`
`(1996).
`
`Haddad et al., “Use of inhaled nitric oxide perioperatively and in
`
`
`
`
`
`
`
`
`intensive care patients,” Anesthesiology, vol. 92, pp. 1821-1825
`
`
`
`
`
`
`
`
`(2000).
`
`Hare et al., “Influence of Inhaled Nitric Oxide on Systemic Flow and
`
`
`
`
`
`
`
`
`
`Ventricular Filling Pressure in Patients Receiving Mechanical Circu-
`
`
`
`
`
`
`
`latory Assistance,” Circulation, vol. 95, pp. 2250-2253 (1997).
`
`
`
`
`
`
`
`
`Hayward et al., “Inhaled Nitric Oxide in Cardiac Failure: Vascular
`
`
`
`
`
`
`
`
`Versus Ventricular Effects,” Journal of Cardiovascular Pharmacol-
`
`
`
`
`
`
`
`ogy, vol. 27, pp. 80-85 (1996).
`
`
`
`
`
`
`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).
`
`
`
`
`
`
`
`
`Kulik, “Inhaled nitric oxide in the management of congenital heart
`
`
`
`
`
`
`
`
`disease,” Current Opinion in Cardiology, vol. 11, pp. 75-80 (1996).
`
`
`
`
`
`
`
`
`
`Madriago et al., “Heart Failure in Infants and Children,” Pediatrics in
`
`
`
`
`
`
`
`
`Review, vol. 31, pp. 4-12 (2010).
`
`
`
`
`
`
`Semigran et al., “Hemodynamic effects of inhaled nitric oxide in
`
`
`
`
`
`
`
`
`heart failure,” J Am Col Cardiol, vol. 24, pp. 982-988 (1994).
`
`
`
`
`
`
`
`
`Steudel et al., “Inhaled nitric oxide,” Anesthesiology, vol. 91, pp.
`
`
`
`
`
`
`
`
`1090-1121 (1999).
`
`
`Wessel et al., “Managing low cardiac output syndrome after congeni-
`
`
`
`
`
`
`
`
`
`tal heart surgery,” Crit. Care Med., vol. 29(10) pp. S220-S230 (2001).
`
`
`
`
`
`
`
`
`
`
`
`OfficeActioninU.S.Appl. No. 12/821,041, mailed Feb. 10, 2012, 34
`
`
`
`
`
`
`
`pages.
`
`Fish & Richardson PC., Supplemental Amendment and Remarks in
`
`
`
`
`
`
`
`U.S. Appl. No. 12/821,041, filed May 11, 2012 (32 pages).
`
`
`
`
`
`
`
`
`
`European Patent Office minutes of oral proceedings in EP 09 251
`
`
`
`
`
`
`
`949.5, with allowable claims (7 pages), dated May, 23, 2012.
`
`
`
`
`
`
`
`
`
`Barst eta1., “Vasodilator Testing with Nitric Oxide and/or Oxygen in
`
`
`
`
`
`
`
`
`
`Pediatric Pulmonary Hypertension,” Received: Sep. 14, 2009 /
`
`
`
`
`
`
`
`Accepted: Jan. 19, 2010 Springer Science + Business Media, LLC,
`
`
`
`
`
`
`
`
`
`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.
`
`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.
`
`
`
`UTMB Respiratory Care Services, “Delivery of Inhaled Nitric Oxide
`
`
`
`
`
`
`
`Therapy through an Adult or Pediatric Nasal Carmula,” (4 pages) Jul.
`
`
`
`
`
`
`
`2003.
`
`Douwes et al., “The Maze of Vasodilator Response Criteria,” Pub-
`
`
`
`
`
`
`
`
`lished online: Nov. 26, 2010, Pediatr Cardiol, (201 1) 32: pp. 245-246.
`
`
`
`
`
`
`
`
`
`
`
`Frai sse et al., “Acute pulmonary hypertension in infants and children:
`
`
`
`
`
`
`
`
`
`cGMP-related drugs,” Pediatric Crit Care Med 2010, vol. 11, No. 2
`
`
`
`
`
`
`
`
`
`
`(Suppl.), 4 pages.
`
`
`Fraisse et al., “Doppler echocardiographic predictors of outcome in
`
`
`
`
`
`
`newborns with persistent pulmonary hypertension,” Cardiol. Young,
`
`
`
`
`
`
`
`vol. 14, pp. 277-283, 2004.
`
`
`
`
`
`Ichinose et al., “Inhaled Nitric Oxide, A Selective Pulmonary
`
`
`
`
`
`
`
`
`Vasodilator: Current Uses and Therapeutic Potential,” Circulation,
`
`
`
`
`
`
`
`vol. 109, pp. 3106-3111, Feb. 11, 2011.
`
`
`
`
`
`
`
`INOmax (nitric oxide) for inhalation 100 and 800 ppm (parts per
`
`
`
`
`
`
`
`
`
`
`million), drug label insert, 2007, 2 pages.
`
`
`
`