`
`(12) United States Patent
`Scharschmidt et al.
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,095,559 B2
`Aug. 4, 2015
`
`(54) METHODS OF THERAPEUTIC
`MONITORING OF NITROGEN SCAVENGING
`DRUGS
`
`(71) Applicant: Horizon Therapeutics, Inc., Palo Alto,
`CA (US)
`
`(58) Field of Classification Search
`CPC ............. .. A61K 31/216; G01N 31/221, YIOT
`436/175383
`USPC ......... .. 424/92, 514/432, 433, 544, 570, 533,
`436/4, 113
`See application file for complete search history.
`
`(72)
`
`Inventors: Bruce Scharschmidt, San Francisco,
`CA (US); Masoud Mokhtarani, Walnut
`Creek, CA (US)
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`(73) Assignee: HORIZON THERAPEUTICS, INC.,
`Deerfield, IL (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. l54(b) by 230 days.
`
`(21) Appl.No.: 13/775,000
`
`(22)
`
`Filed:
`
`Feb. 22, 2013
`
`(65)
`
`Prior Publication Data
`
`US 2013/0210914A1
`
`Aug. 15,2013
`
`Related U.S. Application Data
`
`(62) Division of application No. 13/417,137, filed on Mar.
`9, 2012, now Pat. No. 8,404,215.
`
`(60) Provisional application No. 61/542,100, filed on Sep.
`30, 2011, provisional application No. 61/564,668,
`filed on Nov. 29, 2011.
`
`(51)
`
`Int. Cl.
`A61K 49/00
`A61P 13/00
`A61K31/216
`G01N31/22
`(52) U.S.Cl.
`CPC .......... .. A61K 31/216 (2013.01), G01N31/221
`(2013.01), YIOT436/175383 (2015.01)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`4,284,647 A
`4,457,942 A
`5,654,333 A
`5,968,979 A
`6,050,510 A
`
`8/1981 Brusilow et al.
`7/1984 Brusilow
`8/1997 Samid
`10/1999 Brusilow
`4/2000 Bonnewitz
`
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`W0
`
`WO94/22494
`WO 2005/053607 A1
`
`10/1994
`6/2005
`
`(Continued)
`OTHER PUBLICATIONS
`
`Batshaw, M.L. et al. (Aug. 1981) “New Approaches to the Diagnosis
`and Treatment of Inborn Errors of Urea Synthesis,” Pediatrics
`68(2):290-297.
`
`(Continued)
`
`Primary Examiner — Savitha Rao
`
`(57)
`
`ABSTRACT
`
`The present disclosure provides methods for evaluating daily
`ammonia exposure based on a single fasting ammonia blood
`level measurement, as well as methods that utilize this tech-
`nique to adjust the dosage of a nitrogen scavenging drug,
`determine whether to administer a nitrogen scavenging drug,
`and treat nitrogen retention disorders.
`
`15 Claims, 3 Drawing Sheets
`
`
`
`
`
`LUPIN EX. 1001
`
`1of22
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`1 of 22
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`US 9,095,559 B2
`Page 2
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`6,083,984 A
`6,219,567 B1
`8,094,521 B2
`8,404,215 B1
`8,642,012 B2
`2003/0195255 A1
`2004/0229948 A1
`2005/0273359 A1
`2006/0135612 A1
`2008/0119554 A1
`2010/0008859 A1
`2010/0016207 A1
`2012/0022157 A1
`2012/0220661 A1
`2013/0210914 A1
`2013/0281530 A1
`2014/0142186 A1
`
`7/2000 Brusilow
`4/2001 Eggers
`1/2012 Levy
`3/2013 Scharschmidt et al.
`2/2014 Scharschmidt
`10/2003 Sun1rnar
`11/2004 Sun1rnar et al.
`12/2005 Young
`6/2006 Ferrante
`5/2008 Jalan et al.
`1/20 1 0 Scharschmidt
`1/2010 Wurtrnan et al.
`1/2012 Scharschmidt
`8/2012 Lee
`8/2013 Scharschmidt
`10/20 1 3 Scharschmidt et al.
`5/2014 Scharschmidt et al.
`
`FOREIGN PATENT DOCUMENTS
`
`W0
`W0
`W0
`W0
`W0
`W0
`WO
`WO
`
`WO 2006/056794
`WO 2007/005633
`WO 2009/087474
`WO 2009/134460 A1
`WO 2010/025303 A1
`WO 2012/028620
`WO2013/048558
`WO2013/158145
`
`6/2006
`1/2007
`7/2009
`11/2009
`3/2010
`3/2012
`4/2013
`10/2013
`
`OTHER PUBLICATIONS
`
`Brahe, C., et al., (2005) “Phenylbutyrate Increases SMN Gene
`Expression in Spinal Muscular Atrophy Patients,” Eur JHum Genet
`13:256-259.
`Brunetti-Pierri, N., et al., (201 1) “Phenylbutyrate Therapy for Maple
`Syrup Urine Disease,” Hum Mol Genet 20(4):631-640.
`Chung, Y.L., et al., (2000) “A Novel Approach for Nasopharyngeal
`Carcinoma Treatment Uese Phenylbutyrate as a Protein Kinase C
`Modulator: Implications for Radiosensitization and EBV-Targeted
`Therapy,” Clin Cancer Res 6: 1452-1458.
`Cudkowicz, ALS (2009) “Phase 2 Study of Sodium Phenylbutyrate in
`ALS,” Amyotrophic Lateral Sclerosis 10:99-106.
`Diaz, G.A.. et al.. “Phase 3 Blinded. Randomized, Crossover Com-
`parison of Sodium Phenylbutyrate
`(NaPBA)
`and Glycerol
`Phenylbutyrate (GPB): Ammonia (NH3) Control in Adults with Urea
`Cycle Disorders (UCDs),” Mol. Genet. Metab. 102:276, Society of
`Inherited Metabolic Disease (SMID) Abstract.
`Enns, G.M., et
`al.,
`(2007) “Survival After Treatment with
`Phenylacetate and Benzoate for Urea-Cycle Disorders,” N. Eng J
`Med 356:2282-2292.
`Gropman, A. (2010) “Brain Imaging in Urea Cycle Disorders,” Mol
`Genet Metab 100:S20-S30.
`Hines, P., et al.,
`(2008) “Pulsed-Dosing with Oral Sodium
`Phenylbutyrate Increases Hemoglobin F in a Patient with Sickle Cell
`Anemia,” Pediatr Blood Cancer 50:357-359.
`Hogarth, P., et al., (2007) “Sodium Phenylbutyrate in Huntington’s
`Disease: A Dose-Finding Study,” Mov Disord 22(13): 1962-1964.
`Huang, H.H., et al., (2012) “Cannabinoid Receptor 2 Agonist Ame-
`liorates Mesenteric Angiogenesis and Portosystemic Collaterals in
`Cirrhotic Rats,” Hepatology 56:248-258.
`Hyperion Therapeutics “Hyperion Therapeutics Announces Enroll-
`ment of First Patient in Phase 1/2 Clinical Trial of GT4P in Patients
`with Urea Cycle Disorders” Announcement, 1 page (Oct. 23, 2007).
`Mercuri, E., et al., (2004) “Pilot Trial of Phenylbutyrate in Spinal
`Muscular Atrophy,” Neuromuscul Disord 14: 130-135.
`Mokhtarani, M., et al., (2012) “Elevated Phenylacetic Acid (PAA)
`Levels Appear Linked to Neurological Adverse Events in Healthy
`Adults But Not in Urea Cycle Disorder (UCD) Patients,” Mol Genet
`Metab 105:342.
`Moldave, K., et al., (1957) “Synthesis of Phenylacetylglutamine by
`Human Tissue,” .1. Biol. Chem. 229:463-476.
`
`Patent
`
`Application No.
`
`Monteleone, JPR, et al., (2012) “Population pk Analysis of Glycerol
`Phenylbutyrate (GPB) and Sodium Phenylbutyrate(NAPBA)
`in
`Adult and Pediatric Patients with Urea Cycle Discorders,” Mol Genet
`Metab 105:343.
`Ong, J. P., et al., (2003) “Correlation Between Ammonia Levels and
`the Severity of Hepatic Encephalopathy,” Am. J. Med. 114: 188-193.
`Perrine, S. P., (2008) “Fetal Globin Stimulant Therapies in the Beta-
`Hemoglobinopathies: Principles and Current Potential,” PediatrAnn
`37(5):339-346.
`Ryu, H., et al., (2005) “Sodium Phenylbutyrate Prolongs Survival
`and Regulates Expression of Anti-Apoptotic Genes in Transgenic
`Amyotrophic Lateral Sclerosis Mice,” JNeurochem 93:1087-1098.
`Stauch, et al.,
`(1998) “Oral L-ornithine-L-aspartate therapy of
`chronic hepatic encephalopathy: results of a placebo-controlled
`double-blind study” JHepatology 28(5):856-864.
`Xie, G., et al., (2012) “Role of Differentiation of Liver Sinusoidal
`Endothelial Cells in Progression and Regression of Hepatic Fibrosis
`in Rats,” Gastroenterology 142:S918.
`European Patent Office, Extended European Search Report for
`EP09739263 completed Nov. 2, 2011.
`European Patent Office, International Search Report and Written
`Opinion for PCT/US2009/055256 completed Dec. 18, 2009 and
`mailed Dec. 30, 2009.
`for British
`Examination Report
`GB1013468.2 dated Oct. 28, 2011.
`International Preliminary Report on Patentability (Ch I) for PCT/
`US2012/028620 completed Jun. 4, 2012 and mailed on Apr. 10, 2014.
`International Preliminary Report on Patentability (Ch II) for PCT/
`US2012/028620, completed Aug. 22, 2013 and mailed Sep. 4, 2013.
`United States Patent and Trademark Office, International Search
`Report and Written Opinion for PCT/US2009/030362 mailed Mar. 2,
`2009.
`United States Patent and Trademark Office, International Search
`Report and Written Opinion for PCT/US2012/028620 mailed Jun.
`20, 2012.
`United States Patent and Trademark Office, International Search
`Report and Written Opinion for PCT/US20 12/54673 mailed Nov. 20,
`2012.
`United States Patent and Trademark Office, International Search
`Report andWritten Opinion for PCT/US2013/71333 mailed Mar. 28,
`2014.
`Ambrose, A.M. et al. (1933). “Further Studies on the Detoxification
`of Phenylacetic Acid,” J. Bio. Chem. 101:669-675.
`Batshaw, M.L. et al. (Dec. 1980). “Treatment of Hyperamrnonemic
`Coma Caused by Inborn Errors of Urea Synthesis,” J. Pediatr.
`97(6):893-900.
`Batshaw, M.L. et al. (Aug. 1981). “New Approaches to the Diagnosis
`and Treatment of Inborn Errors of Urea Synthesis,” Pediatrics
`68(2):290-297.
`Batshaw M.L. et al. (Jun. 10, 1982). “Treatment of Inborn Errors of
`Urea Synthesis: Activation of Alternative Pathways of Waste Nitro-
`gen Synthesis and Excretion,” N. Engl. J. Med. 306(23): 1387-1392.
`Batshaw, M.L. (1984). “Hyperammonemia,” in Current Problems in
`Pediatrics, Lockhart, J.D. ed.: Year Book Medical Publishers, pp.
`2-69.
`Berry, G. T., et al., “Long-Term Management of Patients with Urea
`Cycle Disorders,” J. Pediatrics (2001) 138:S56-S61.
`Brusilow, S., et al., “Amino Acid Acylation: A Mechanism of Nitro-
`gen Excretion in Inborn Errors of Urea Synthesis,” Science 207:659-
`661 (1980).
`Brusilow, S. W., et al., “Phenylacetylglutamine May Replace Urea as
`a Vehicle for Waste Nitrogen Excretion,” Pediatr. Res. 29:147-150
`(1991).
`Brusilow, S.w. et al. (Sep. 1, 1979). “New Pathways of Nitrogen
`Excretion in Inborn Errors of Urea Synthesis,” Lancet 2(8140):452-
`454.
`Brusilow, S.w. (Jun. 21, 1984). “Treatment of Episodic Hyperam-
`monemia in Children With Inborn Errors ofUrea Synthesis,” N. Engl.
`J. Med. 310(25):1630-1634.
`Brusilow, S.w. (Amendment Dated Jul. 25, 1994). “Protocols for
`Management ofIntercurrent Hyperamrnonemia in Patients with Urea
`Cycle Disorders,” FDA Application to Market a New Drug for
`Human Use or an Antibiotic Drug for Human Use, Fourteen pages.
`
`20f22
`
`2 of 22
`
`
`
`US 9,095,559 B2
`Page 3
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Brusilow, S.w. et al. (1991). “Treatment of Urea Cycle Disorders,”
`Chapter 5 in Treatment of Genetic Diseases, Desnik, R.J. et al. eds,
`Churchill Livingstone, New York, New York, pp. 79-94.
`Brusilow, S.W. et al. (1995). “Urea Cycle Enzymes,” Chapter 32 in
`The Metabolic and Molecular bases of Inherited Diseases, Scriver,
`C.R. et al. eds., McGraw-Hill, Inc. New York, NewYork, pp. 1187-
`1232.
`Brusilow, S.W., et al. (1996).“Urea Cycle Disorders: Diagnosis,
`Pathophysiology, and Therapy,” Adv. Pediatr. 43:127-170.
`Brusilow, S.W., et al. (1995). “Urea Cycle Disorders: Clinical Para-
`digm of Hyperarnrnonemic Enecphalopathy,” Progress in Liver Dis-
`eases (1995) 12:293-309.
`Brusilow, S. W., et al., “Restoration of Nitrogen Homeostasis in a
`Man with Ornithine Transcarbamylase Deficiency,” J. Metabolism
`(1993) 42: 1336-1339.
`Calloway, D.H. et al. (1971). “Sweat and Miscellaneous Nitrogen
`Losses in Human Balance Studies,” J. Nutrition 1011775-786.
`Calloway, D.H. et al. (1971). “Variation in Endogenous Nitrogen
`Excretion and Dietary Nitrogen Utilization as Determinants of
`Human Protein Requirements,” J. Nutrition 1011205-216.
`Camacho, L.H. et al. (2007, e-pub. Oct. 20, 2006). “Phase I Dose
`Escalation Clinical Trial of Phenyl butyrate Sodium Administered
`Twice Daily to Patients With Advanced Solid Tumors,” Invest. New
`Drugs 25:131-138.
`Chang J.-G., et al., “Treatment of Spinal Muscular Atrophy by
`Sodium Butyrate,” PNAS USA (2001) 98(17):9808-9813.
`ClinicalTrials.Gov/Archive View ofNCT00551200 on Dec. 11, 2007
`“Dose-Escalation
`Safety
`Study
`of
`Glyceryl
`Tri
`(4 -Phenylbutyrate)(GT4P) to Treat Urea Cycle Disorders” [accessed
`Oct. 5, 2009], 4 pages.
`Combined Search and Examination Report mailed on Sep. 9, 2010,
`for Great Britain Patent Application No. 10 13468 .2, filed on Aug. 27,
`2009, six pages.
`Combined Search and Examination Report mailed on Oct. 9, 2009,
`for Great Britain Patent Application No. GB0915 545 .8, filed on Aug.
`27, 2009, eight pages.
`Comte, B., et al., “Identification of Phenylbutyrylglutamine, A new
`Metabolite of Phenylbutyrate Metabolism in Humans,” Journal of
`Mass Spectrometry (2002) 37(6):581-590.
`Deferrari, G. et al. (1981). “Brain Metabolism of Amino Acids and
`Ammonia in Patients with Chronic Renal Insufficiency,” Kidney
`International 20:505-510.
`Diaz, G.A., et al., “Phase 3 Blinded, Randomized, Crossover Com-
`parison of Sodium Phenylbutyrate
`(NaPBA)
`and Glycerol
`Phenylbutyrate (GPB): Ammonia (NH3) Control in Adults with Urea
`Cycle Disorders (UCDs),” Mol. Genet. Metab. 1021276 (2011).
`Examination Report mailed on Oct. 27, 2010, for United Kingdom
`Patent Application No. GB0915545.8, filed on Aug. 27, 2009, two
`pages.
`Examination Report mailed Feb. 5, 2010, for United Kingdom Patent
`Application No. GB0915545.8, filed on Aug. 27, 2009, two page.
`Examination Report mailed May 11, 2010, for United Kingdom
`Patent Application No. GB0915545.8, filed on Aug. 27, 2009, one
`page.
`FDA. (Aug. 2003). “Buphenyl® (Sodium Phenylbutyrate) Label”
`nine pages.
`FDA Label for Buphenyl, 6 pages.
`Gargosky, S. (2006). “High Ammonia Levels Are Associated With
`Increased Mortality and Coma,” Ucyclyd Pharma, Inc., one page.
`Gargosky, S. et al. (Oct. 14, 2005). “Results of a Twenty-two Year
`Clinical Trial: Actue, Adjunctive Pharmacological Treatment of
`Hyperarnrnonemic Episodes
`in Patients with Deficiencies
`in
`Enzymes ofthe Urea Cycle,” poster, Ucyclyd Pharma, Inc ., one page.
`Gargosky, S. (Aug. 2, 2005). “Improved Survival of Neonates Fol-
`lowing Administration of Arr1rnonul® (Sodium Phenyl acetate &
`Sodium Benzoate) 10% 110% Injection,” SSIEM Poster, six pages.
`Gharbril, M., et al., “Glycerol Phenylbutyrate (GPB) Administration
`in Patients with Cirrhosis and Episodic Hepatic Encephalopathy
`(HE),” accepted for presentation at Digestive Disease Week, 2012.
`
`Gropman, A. L., et al., “1H MRS Allows Brain Phenotype Differen-
`tiation in Sisters with Late Onset Ornithine Transcarbamylase Defi-
`ciency (OTCD) and Discordant Clinical Presentations,” Mol. Genet.
`Metab. 94(1):52-60 (2008).
`Gropman, A.L., et al., “1H MRS Identifies Symptomatic and
`Asymptomatic Subjects with Partial Ornithine Transcarbamylase
`Deficiency,” Mol. Genet. Metab. 95:21-30 (2008).
`Hyperion Therapeutics. (Mar. 30, 2009). “Hyperion Therapeutics
`Announces Results for Phase II Study in Urea Cycle Disorders,”
`located
`at
`<http://www.hyperiontx.com/press/release/pr
`1238518388,> last visited on Apr. 27, 2011, three pages.
`Hyperion Therapeutics.
`(Jun. 2, 2009.) “Hyperion Therapeutics
`Announces Results of Phase I Study in Patients with Liver Cirrhosis”
`located
`at<http://www.hyperiontx.com/press/release/pr
`1243891161>, last visited on Apr. 27, 2011, three pages.
`International Preliminary Report on Patentability mailed on Mar. 1,
`2011, for PCT Application No. PCT/US2009/030362, filed on Jan. 7,
`2009, seven pages.
`International Preliminary Report on Patentability mailed on Mar. 1,
`2011, for PCT Application No. PCT/US2009/055256, filed on Aug.
`27, 2009, six pages.
`James, M.O. et al. (1972). “The Conjugation of Phenylacetic Acid in
`Man, Sub-Human Primates and Some Other Non-Primates Species,”
`Proc. R. Soc. London 182125-35.
`John, BA et al. (Mar. 2009). “The Disposition ofHPN-100, A Novel
`Pharmaceutical Under Development for Potential Treatment of
`Hyperarnrnonemia, in Cynomologus Monkeys,” abstract presented at
`ACMG 2009, one page.
`John, BA et al. (Mar. 2009). “The Disposition ofHPN-100, A Novel
`Pharmaceutical Under Development for Potential Treatment of
`Hyperarnrnonemia, in Cynomolgus Monkeys,” ACMG 2009 ADME,
`poster, two pages.
`Kasumov, T., et al., “New Secondary Metabolites of Phenylbutyrate
`in Humans and Rats,” Drug Metabolism and Disposition (2004)
`32(1):10-19.
`Lee, B. et al. (Aug. 2009). “Dosing and Therapeutic Monitoring of
`Ammonia Scavenging Drugs and Urinary Phenylacetylglutamine
`(PAGN) as a Biomarker; Lessons From a Phase 2 Comparison of a
`Novel Ammonia Scavenging Agent With Sodium Phenylbutyrate
`(NaPBA),”.abstract presented at ICIEM 2009, San Diego, CA, one
`page.
`Lee, B. et al. (Aug. 2009). “Dosing and Therapeutic Monitoring of
`Arnrnona Scavenging Drugs and Urinary Phenylacetylglutamine
`(PAGN) as a Biomarker: Lessons From a Phase 2 Comparison of a
`Novel Ammonia Scavenging Agent with Sodium Phenyl butyrate
`(NAPBA),” presented at ICIEM 2009, San Diego, CA, poster, one
`page.
`Lee, B. et al. (Mar. 2009). “Phase 2 Study of a Novel Ammonia
`Scavenging Agent in Adults With Urea Cycle Disorders (UCDs),”
`abstract presented at ACMG 2009, one page.
`Lee, B. et al. (Mar. 2009). “Phase 2 Study of a Novel Ammonia
`Scavenging Agent in Adults with Urea Cycle Disorders (UCDs),”
`presented at ACMG 2009, seventeen pages.
`Lee, B. et al. (Aug. 2008). “Preliminary Data on Adult Patients with
`Urea Cycle Disorders (UCD) in an Open-Label, Switch-Over, Dose-
`Escalation Study Comparing a New Ammonia Scavenger, Glyceryl
`Tri
`(4-Phenylbutyrate)
`[HPN-100],
`to Buphenyl® (Sodium
`Phenylbutyrate [PBAj),” abstract presented at SSIEM 2008, Lisbon,
`Portugal, one page.
`Lee, B. et al. (Sep. 2008). “Preliminary Data on Adult Patients with
`Urea Cycle Disorders (UCD) in an Open-Label, Switch-Over, Dose
`Escalation Study Comparing a New Ammonia Scavenger, Glyceryl
`Tri
`(4-Phenylbutyrate)
`[HPN-100],
`to Buphenyl® (Sodium
`Phenylbutyrate [PBA],” presented at SSIEM 2008, Lisbon, Portugal,
`Poster, one page.
`Lee, B., et al.,“Phase 2 Comparison of aNovel Ammonia Scavenging
`Agent with Sodium Phenylbutyrate in Patients with Urea Cycle Dis-
`orders: Safety, Pharmacokinetics and Ammonia Control,” Mol.
`Genet. Metab. 100:221-228 (2010).
`Lee, B., et al., “Preliminary Data on Adult Patients with Urea Cycle
`Disorders (UCD) in an Open-Label, Switch-Over, Dose-Escalation
`Study Comparing a New Ammonia Scavenger, Glyceryl Tri(4-
`
`30f22
`
`3 of 22
`
`
`
`US 9,095,559 B2
`Page 4
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Phenylbutyrate) (HPN-100), to Buphenyl (Sodium Phenylbutyrate
`(PBA)),” J. Inherit. Metab. Dis. 31(Suppl. 1):91 (2008).
`Lewis, H.B. (1914). “Studies in the Synthesis ofHippuric Acid in the
`Animal Organism. II. The Synthesis and Rate of Elimination of
`Hippuric Acid After Benzoate Ingestion in Man,” J. Bioi. Chem. 18
`2225-23 1.
`Liang, K.Y., et al., “Longitudinal Data Analysis Using Generalized
`Linear Models,” Biometrika 73(1): 13-22 (1986).
`Lichter-Konecki, U., et al., “Ammonia Control in Children with Urea
`Cycle Disorders
`(UCDs); Phase
`2 Comparison of Sodium
`Phenylbutyrate and Glycerol Phenylbutyrate,” Mol. Genet. Metab.
`103:323-329 (2011).
`VIacA1thur, R. B., et al ., “Pharmacokinetics of Sodium Phenylacetate
`and Sodium Benzoate Following Intravenous Administration as Both
`a Bolus and Continuous Infusion to Healthy Adult Volunteers,” Mol.
`Genet. Metab. 81:S67-S73 (2004).
`Vlansour, A. et al. (Oct. 1997). “Abdominal Operations in Patients
`with Cirrhosis: Still
`a Major Surgical Challenge,” Surqerv
`122(4):730-735. (Abstract Only.).
`Vlasetri, N.E. et al. (Aug. 1992). “Plasma Glutamine Concentration:
`A Guide in the Management ofUrea Cycle Disorders,” J. Pediatr. 121
`(2)2259-261.
`\/IcGuire, B. M., et al., “Pharmacology and Safety of Glycerol
`Phenylbutyrate in Healthy Adults and Adults with Cirrhosis,”
`Hepatol. 51:2077-2085 (2010).
`\/IcGuire, B.M. et al. (2009). “Pharmacokinetic (PK) and Safety
`Analyses of a Novel Arr1rnonia-Reducing Agent in Healthy Adults
`and Patients with Cirrhosis,” Hyperion Therapeutics, poster, one
`page.
`\/IcGuire, B.M. et al. (May 2009). “Pharmacokinetic (PK) and Safety
`Analyses of a Novel Arr1rnonia-Reducing Agent in Healthy Adults
`and Patients with Cirrhosis,” abstract presented at DDW, May 2009,
`two pages.
`\/IcGuire, B. et al. (Apr. 2008). Pharmacokinetic Safety Study of
`Sodium Phenylacetate and Sodium Benzoate Administered to Sub-
`jects With Hepatic
`Impairments, Liver
`International 28:743.
`(Abstract Only).
`\/IcGuire, B. et al. (Apr. 2008). “Pharmacokeinetic (PK) Safety Study
`of Sodium Phenylacetate and Sodium Benzoate Administered to
`Subjects with Hepatic Impairment,” abstract ofThe 1 3th International
`Symposium, Abano (Padova), Italy, Apr. 28-May 1, 2008, two pages.
`\/IcQuade P.S. (1984). “Analysis and the Effects of Some Drugs on
`the Metabolism of Phenylethylamine and Phenylacetic Acid,”
`\Ieuropsychopharmaco1. Bioi. Psychiat. 8:607-614.
`Piscitelli, S.C. et al. (1995). “Disposition of Phenyl butyrate and its
`\/Ietabolites, Phenylacetete and Phenylacetylglutamine,” J. Clin.
`Pharmacal. 35:368-373.
`Propst, A. et al. (Aug. 1995). “Prognosis and Life Expectancy in
`Chronic Liver Disease,” Dig Dis Sci 40(8): 1805-1815. (Abstract
`Only).
`Riley, T.R. et al. (Nov. 15, 2001). “Preventive Strategies in Chronic
`Liver Disease: Part II. Cirrhosos,” Am. Fam. Physician 64(10): 1735-
`1740. (Abstract Only).
`Rudrnan, D., et al., “Maximal Rates of Excretion and Synthesis of
`Urea in Normal and Cirrhotic Subjects,” J. Clin. Invest. (1973)
`52:2241-2249.
`Shiple, G.J. et al. (1922). “Synthesis of Amino Acids in Animal
`Organisms. I. Synthesis of Glycocoll and Glutamine in the Human
`Organism,” J. Am. Chem. Soc. 44:618-624.
`Simell, 0., et al., “Waste Nitrogen Excretion Via Amino AcidAcyla-
`tion: Benzoate and Phenylacetate in Lysinuric Protein Intolerance,”
`Pediatr. Res. 20(11):1117-1121 (1986).
`Singh, “Consensus Statement from a Conference for the Manage-
`ment of Patients with Urea Cycle Disorders,” Suppl. to J. Pediatrics
`(2001) 138(1):S1-S5.
`Sun1rnar, M.L. et al. (Oct. 2008, e-pub. Jul. 17, 2008). “Diagnosis,
`Symptoms, Frequency and Mortality of 260 Patients with Urea Cycle
`Disorders From a 21-Year, Multicentre Study of Acute Hyperam-
`monaemic Episodes,” Acta Paediatr. 97: 1420-1425.
`
`Summar, M. et al. (2007). “Description and Outcomes of 316 Urea
`Cycle Patients From a 21-Year, Multicenter Study of Acute
`Hyperarnrnonemic Episodes,” Abstract, presented at Annual Sympo-
`sium CCH—Congress Centre Hamburg, Sep. 4-7, 2007, GSSIEM
`2007, two pages.
`Swedish Orphan International. (Jan. 12, 2007). “Urea Cycle Disor-
`ders an International Perspective,” Poster, Symposium Swedish
`Orphan International, Barcelona, Spain, Jan. 12, 2007, one page.
`Tanner, L. M., et al., “Nutrient Intake in Lysinuric Protein Intoler-
`ance,” J. Inherit. Metab. Dis. 30:716-721 (2007).
`Thibault, A., et al., “A Phase I and Pharmacokinetic Study of Intra-
`venous Phenylacetate in Patients with Cancer,” Cancer Res. 54: 1690-
`1694 (1994).
`Thibault, A., et al., “Phase I Study of Phenylacetate Administered
`Twice Daily to Patients with Cancer,” Cancer 75:2932-2938 (1995).
`Tuchman, M. et al. (2008, e-pub. Jun. 17, 2008). “Cross-Sectional
`Multicenter Study of Patients With Urea Cycle Disorders in the
`United States,” Malec. Genetics Metab. 94:397-402.
`Waterlow, J.C. (Mar. 1963). “The Partition ofNitrogen in the Urine of
`Malnourished Jamaican Infants,” Am. J. of Clin. Nutrition 12:235-
`240.
`Zeitlin, P.L. et al. (Jul. 2002). “Evidence of CFTR Function in Cystic
`Fibrosis After System Administration of 4-Phenylbutyrate,” Mol.
`Therapy 6(1): 1 19-126.
`Amodio, P., et al., “Detection of Minimal Hepatic Encephalopathy:
`Normalization and Optimization of the Psychometric Hepatic
`Encephalopathy Score. A Neuropsychological and Quantified EEG
`Study,” J. Hepatol. 49:346-353 (2008).
`ANDA Notice Letter, Par Pharmaceutical, Inc. to Hyperion Thera-
`peutics, inc.. Re: Glycerol Phenylbutyrate 1.1 gm/ml oral liquid; U.S.
`Pat. No. 8,404,215 and U.S. Pat. No. 8,642,012 Notice of Paragraph
`IV Certification Mar. 12, 2014.
`Bajaj, J. S., et al., “Review Article: The Design of Clinical Trials in
`Hepatic Encephalopathy—An International Society for Hepatic
`Encephalopathy and Nitrogen Metabolism (ISHEN) Consensus
`Statement,” Aliment Pharn1acol Ther. 33 (7):739-747 (2011).
`Barsotti, Measurement of Ammonia in Blood, 138 J. Pediatrics,
`S11-S20 (2001).
`Batshaw, et al., Treatment of Carbamyl Phosphate Synthetase Defi-
`ciency with Keto Analogues of Essential Amino Acids, 292 The New
`England J. Medicine, 1085 90 (1975).
`Batshaw, M. L. et. al., Alternative Pathway Therapy for Urea Cycle
`Disorder: TwentyYears Later, 138 J. Pediatrics S46 (2001).
`Blau, Duran, Blaskovics, Gibson (editors), Physician’s Guide to the
`Laboratory Diagnosis of Metabolic Diseases, 261-276 (2d ed. 1996).
`Blei, A. T., et al., “Hepatic Encephalopathy,” Am. J. Gastroenterol.
`96(7):1968-1976 (2001 ).
`Burlina, A.B.
`et
`al., Long-Term Treatment with Sodium
`Phenylbutyrate in Ornithine Transcarbamylase-Deficient Patients, 72
`Molecular Genetics and Metabolism 351-355 (2001).
`Carducci, M., Phenylbutyrate Induces Apoptosis in Human Prostate
`Cancer and Is More Potent Than Phenylacetate, 2 Clinical Cancer
`Research 379 (1996).
`Carducci, M.A. et al., A Phase I Clinical and Pharmacological Evalu-
`ation of Sodium Phenylbutyrate on an 120-h Infusion Schedule, 7
`Clin. Cancer Res. 3047 (2001).
`Center for Drug Evaluation and Research, Clinical Pharmacology
`and Biopharmaceutics Review for New Drug Application No. 20 -645
`(Arr1rnonul®) (2005).
`Center for Drug Evaluation and Research, Labeling for New Drug
`Application No. 20-645 (Arr1rnonul®) (2005).
`Center for Drug Evaluation and Research, Medical Review for New
`Drug Application No. 20-645 (Arr1rnonul®) (2005).
`Chen, Z. et al., Tributyrin: A Prodrug of Butyric Acid for Potential
`Clinical Application in Differentiation Therapy, 54 Cancer Research
`3494 (1994).
`Clay, A. et. al, Hyperarr1rnonemiain the ICU, 132 Chest 1368 (2007).
`Collins, A.F. et al., Oral Sodium Phenylbutyrate Therapy in
`Homozygous Beta Thalassemia: A Clinical Trial, 85 Blood 43
`(1995).
`
`40f22
`
`4 of 22
`
`
`
`US 9,095,559 B2
`Page 5
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Conn, H. 0., et al., “Liver Physiology and Disease: Comparison of
`Lactulose and Neomycin in the Treatment of Chronic Portal-Sys-
`temic Encephalopathy. A Double Blind Controlled Trial,” Gastroen-
`terology 72(4):573-583 (1977).
`Cordoba, J., “New Assessment of Hepatic Encephalopathy,” Journal
`of Hepatology 54: 1030-1040 (2011 ).
`Darmaun, D. et al., Phenylbutyrate-Induced Glutamine Depletion in
`Humans: Effect on Leucine Metabolism, 5 Am. J. of Physiology:
`Endocrinology and Metabolism E801 (1998).
`Diaz, G. A., et al., “Ammonia Control and Neurocognitive Outcome
`Among Urea Cycle Disorder Patients Treated with Glycerol
`Phenylbutyrate,” Hepatology 57(6):2171-2179 (2013).
`Dixon, M. A. and Leonard, J.V., Intercurrent Illness in Inborn Errors
`of Intermediary Metabolism, 67 Archives of Disease in Childhood
`1387 (1992).
`Dover, G. et al, Induction of Fetal Hemoglobin Production in Sub-
`jects with Sickle Cell Anemia by Oral Sodium Phenylbutyrate, 54
`Cancer Research 3494 (1994).
`Endo, F. et al., Clinical Manifestations of Inborn Errors of the Urea
`Cycle and Related Metabolic Disorders During Childhood, 134 J.
`Nutrition 1605S (2004).
`European Medicines Agency, Annex I: Summary of Product Charac-
`teristics for Arr1rnonaps.
`European Medicines Agency, European Public Assessment Report:
`Summary for the Public for Arr1rnonaps (2009).
`European Medicines Agency, Scientific Discussion for Arr1rnonaps
`(2005).
`European Medicines Agency, Scientific Discussion for Carbaglu
`(2004).
`FDA Label for Carbaglu, seven pages. (Mar. 2010).
`Feillet, F. and Leonard, J.V., Alternative Pathway Therapy for Urea
`Cycle Disorders, 21 J. Inher. Metab. Dis. 101-111 (1998).
`Feoli-Fonseca, M. L., Sodium Benzoate Therapy in Children with
`Inborn Errors ofUrea Synthesis: Effect on Carnitine Metabolism and
`Ammonia Nitrogen Removal, 57 Biochemical and Molecular Medi-
`cine 31 (1996).
`Ferenci, P., eta1., “Hepatic Encephalopathy—Definition, Nomencla-
`ture, Diagnosis, and Quantification: Final Report of the Working
`Party at the 11th World Congresses of Gastroenterology, Vienna,
`1998,” Hepatology 35:716-721 (2002).
`Fernandes, Saudubray, Berghe (editors), Inborn Metabolic Diseases
`Diagnosis and Treatment, 219-222 (3d ed. 2000).
`Geraghty, M.T. and Brusilow, S.W., Disorders of the Urea Cycle, in
`Liver Disease in Children 827 (F.J. Suchy et al., eds. 2001).
`Ghabril, M. et al., “Glycerol Phenylbutyrate in Patients with Cirrho-
`sis and Episodic Hepatic Encephalopathy: A Pilot Study of Safety
`and Effect on Venous Ammonia Concentration,” Clinical Pharmacol-
`ogy in Drug Development 2(3): 278-284 (2013).
`Gilbert, J. et al., A Phase I Dose Escalation and Bioavailability Study
`of Oral Sodium Phenylbutyrate in Patients with Refractory Solid
`Tumor Malignancies, 7 Clin. Cancer Research 2292-2300 (2001).
`Gore, S. et al., Impact of the Putative Differentiating Agent Sodium
`Phenylbutyrate on Myelodysplastic Syndromes and Acute Myeloid
`Leukemia, 7 Clin. Cancer Res. 2330 (2001).
`Gropman, A.L. et al., Neurological Implications of Urea Cycle Dis-
`orders, 30 J. Inherit Metab Dis. 865 (2007).
`Hassanein, T.
`I.,
`et
`al., “Randomized Controlled Study of
`Extracorporeal Albumin Dialysis for Hepatic Encephalopathy in
`Advanced Cirrhosis,” Hepatology 46:1853-1862 (2007).
`Hassanein, T. I., et al., “Introduction to the Hepatic Encephalopathy
`Scoring Algorithm (HESA),” Dig. Dis. Sci. 53:529-538 (2008).
`Hassanein, T., et al., “Performance of the Hepatic Encephalopathy
`Scoring Algorithm in a Clinical Trial of Patients With Cirrhosis and
`Severe Hepatic Encephalopathy,” Am. J. Gastroenterol. 104:1392-
`1400 (2009).
`Honda, S. et al., Successful Treatment of Severe Hyperarr1rnonemia
`Using Sodium Phenylacetate Power Prepared in Hospital Pharmacy,
`25 Biol. Pharm. Bull. 1244 (2002).
`
`International Search Report and Written Opinion for PCT/US09/
`30362, mailed Mar. 2, 2009, 8 pages.
`International Search Report and Written Opinion for PCT/US2009/
`055256, mailed Dec. 30, 2009, 13 pages.
`Kleppe, S. eta1., Urea Cycle Disorders, 5 Current Treatment Options
`in Neurology 309-319 (2003).
`Kubota, K. and Ishizaki, T., Dose-Dependent Pharmacokinetics of
`Benzoic Acid Following Oral Administration of Sodium Benzoate to
`Humans, 41 Eur. J. Clin. Pharmacol. 363 (1991).
`Lee, B. and Goss, J., Long-Term Correction ofUrea Cycle Disorders,
`138 J. Pediatrics S62 (2001).
`Lee, B. et al., Considerations in the Difficult-to-Manage Urea Cycle
`Disorder Patient, 21 Crit. Care Clin. S19 (2005).
`Lee, B., et al., “Optimizing Ammonia (NH3) Control in Urea Cycle
`Disorder (UCD) Patients: A Predictive Model,” Oral Abstract Plat-
`form Presentations, Biochemical Genetics, Phoenix, AZ, Mar. 22,
`2013.
`Leonard, J.V., Urea Cycle Disorders, 7 Semin. Nenatol. 27 (2002).
`Lizardi-Cervera, J. et al., Hepatic Encephalopathy: A Review, 2
`Annals of Hepatology 122-120 (2003).
`\/Iaestri NE, et al., Prospective treatment of urea cycle disorders. J
`Paediatr 1991;119:923-928.
`Vlaestri, N.E., et al., Long-Term Survival of Patients with
`Argininosuccinate Synthetase Deficiency, 127 J. Pediatrics 929
`(1993).
`Vlaestri, N.E., Long-Term Treatment of Girls with Ornithine
`Transcarbamylase Deficiency, 355 N. Engl. J. Med. 855 (1996).
`\/Iajeed, K., Hyperarr1rnonemia, eMedicine.com (Dec. 2001).
`\/Iarini, J.C. et al ., Phenylbutyrate Improves Nitrogen Disposal via an
`Alternative Pathway without Eliciting an Increase in Protein Break-
`down and Catabolism in Control and Ornithine Transcarbamylase-
`Deficient Patients, 93 Am. J. Clin. Nutr. 1248 (2011).
`Vlatsuda, I., Hyperarr1rnonemia in Pediatric Clinics: A Review of
`Ornithine Transcarbamylase Deficiency (OTCD) Based on our Case
`Studies, 47 JMAJ 160 (2004).
`\/IcGuire, B.M. et al., Pharmacokinetic (PK) and Safety Analyses of
`a Novel Arr1rnonia-Reducing Agent in Healthy Adults and Patients
`with Cirrhosis, Hyperion Therapeutics, poster, one page (2009).
`\/Iizutani, N. et al., Hyperargininemia: Clinical Course and Treat-
`ment with Sodium Benzoate and Phenylacetic Acid, 5 Brain and
`Development 555 (1983).
`Vlokhtarani, M., etal., (2013) “Elevated Phenylacetic Acid Levels Do
`\Iot Correlate with Adverse Events in Patients with Urea Cycle Dis-
`orders o rHepatic Encephalopathy and Can Be Predicted Based on the
`Plasma PAA to PAGN Ratio,” Mol Genet Metab 110(4):446-453.
`Vlokhtarani, M., et al., (2012) “Urinary Phenylacetylglutamine as
`Dosing Biomarker for Patients with Urea Cycle Disorders,” Mol
`Genet Metab 107(3):308-314.
`Vlonteleone, JPR, et al., (2013) “Population Pharmacokinetic Mod-
`eling and Dosing Simulations of Nitrogen-Scavenging Compounds:
`Disposition of Glycerol Phenylbutyrate and Sodium Phenylbutyrate
`in Adult and Pediatric Patients with Urea Cycle Disorders,” J. Clin.
`Pharmacol. 53(7): 699-710.
`Munoz, S. J., “Hepatic Encephalopathy,” Med. Clin. N. Am. 92:795-
`812 (2008).
`Nassogne, M.C., Urea Cycle Defects: Management and Outcome, 28
`J. Inherit. Metab. Dis. 407 (2005).
`New England Consortium of Metabolic Programs, Acute Illness Pro-
`tocol: Urea Cycle Disorders: The Infant/Child with Argininosuc-
`cinate Lyase Deficiency, adapted from Sun1rnar, M and Tuchman, M,
`Proceedings of a Consensus Conference for the Management of
`Patients with Urea Cycle Disorders, 138 J. Peds. Suppl. S6 (2001).
`New England Consortium of Metabolic Programs, Acute Illness Pro-
`tocol: Urea Cycle Disorders: The Infant/Child with Citrullinemia,
`adapted from Surnrnar, M and Tuchman, M, Proceedings of a Con-
`sensus Conference for the Management of Patients with Urea Cycle
`Disorders, 138 J. Peds. Suppl. S6 (2001).
`Newmark, H. L. and Young, W. C., Butyrate and Phenylacetate as
`Differentiating Agents: Practical Problems and Opportunities, 22 J.
`Cellular Biochemistry 247 (1995).
`Ortiz, M., eta1., “Development of a Clinical Hepatic Encephalopathy
`Staging Scale,” Aliment Pharn1acol Ther 26:859-867 (2007).
`
`50f22
`
`5 of 22
`
`
`
`US 9,095,559 B2
`Page 6
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Par Pharmaceutical, In