`
`(12) United States Patent
`Scharschmidt et :1].
`
`(10) Patent No.:
`(45) Date of Patent:
`
`US 9,095,559 B2
`Aug. 4, 2015
`
`(54)
`
`(71)
`
`(72)
`
`METHODS OF THERAPEUTIC
`MONITORING OF NITROGEN SCAVENGING
`DRUGS
`
`Applicant: Horizon Therapeutics, Inc., Palo Alto,
`CA (US)
`
`(58) Field of Classification Search
`CPC ............. .. A61K 31/216: GOlN 31/221; YIOT
`436/ 175383
`USPC ........... 424/92; 514/432, 433, 544, 570, 533;
`436/4, 113
`See application file for complete search history.
`
`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. 154(b) by 230 days.
`
`(21)
`
`Appl. No.: 13/775,000
`
`(22)
`
`Filed:
`
`Feb. 22, 2013
`
`(65)
`
`(62)
`
`(60)
`
`(51)
`
`(52)
`
`Prior Publication Data
`
`US 2013/0210914Al
`
`Aug. 15, 2013
`
`Related U.S. Application Data
`
`Division of application No. 13/417,137, filed on Mar.
`9, 2012, now Pat. No. 8,404,215.
`
`Provisional application No. 61/542,100, filed on Sep.
`30, 2011, provisional application No. 61/564,668,
`filed on Nov. 29, 2011.
`
`Int. Cl.
`A61K 49/00
`A 611’ 13/00
`A 61K 31/216
`G01N 31/22
`U.S. Cl.
`CPC .......... .. A61K3M16 (2013.01); G01N31021
`(2013.01); Y1 0T 436/1 75383 (2015.01)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006001)
`
`4,284,647 A
`4,457,942 A
`5.654.333 A
`5,968,979 A
`6.050.510 A
`
`8/1981 Brusilow ct 81.
`7/1984 Brusilow
`8/1997 Samid
`10/ 1999 Brusilow
`4/2000 Bonnewitz
`
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`W0
`W0
`
`WO94/22494
`WO 2005/053607 A1
`
`10/1994
`6/2005
`
`(Continued)
`OTHER PUBLICATIONS
`
`Batshaw, ML. et al. (Aug. 1981 ) “New Approaches to the Diagnosis
`and Treatment of Inborn Errors of Urea Synthesis.” Pallarrlcs
`68(2):290-297.
`
`(Continued)
`
`Primary Examiner — Savitha Rao
`
`ABSTRACT
`(57)
`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
`
`mama».-
`as: _ sutwkib‘rk‘flfl
`
`~10"
`.
`\
`‘-~71-.1‘v9.v:. :3,
`u-‘~,-fi>‘x-Vv' r
`
`
`
`
`Page 1 of 22
`
`Horizon Exhibit 2005
`
`Horizon Exhibit 2005
`Lupin v. Horizon
`Lupin v. Horizon
`IPR2017-01159
`IPR2017-01159
`
`Page 1 of 22
`
`
`
`US 9,095,559 B2
`Page 2
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`6,083,984 A
`6,219,567 Bl
`8.094,521 B2
`8,404,215 Bl
`8,642,012 BZ
`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
`
`712000 Brusilow
`4/2001 Eggers
`1/2012 Levy
`3/2013 Scharschmidtetal.
`2/2014 Scharschmidt
`10/2003 Summar
`11/2004 Summaretal.
`12/2005 Young
`6/2006 Ferrante
`5/2008 Jalanetal.
`1/2010 Scharschmidt
`1/2010 Wurtmanetal.
`1/2012 Scharschmidt
`8/2012 lee
`8/2013 Scharschmidt
`10/2013 Scharschrnidtetal.
`5/2014 Scharschmidtetal.
`
`FOREIGN PATENT DOCUMENTS
`
`W0 W0 2006/056794
`W0
`WO 2007/005633
`W0
`WO 2009/087474
`W0
`WO 2009/134460 A1
`W0
`WO 2010/025303 A1
`W0
`WO 2012/028620
`W0
`WO2013/048558
`W0
`W02013/158145
`
`6/2006
`1/2007
`7/2009
`11/2009
`3/2010
`3/2012
`4/2013
`10/20 13
`
`OTHER PUBLICATIONS
`
`Brahe. C., et al.. (2005) “Pherylbutyrate Increases SMN Gene
`Expression in Spinal Muscqu Atrophy Patients," Eur JHum Genet
`13:256-259.
`Brunetti-Pien'i, N., et 211., (201 l) “Phenylbutyrate Therapy for Maple
`Syrup Urine Disease." Hum Mol Gare! 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 Rm 6: 1452-1458.
`Cudkowicz, ALS (2009) “Phase 2 Study ofSodium Phenylbutyrate in
`ALS." Amyotrophic Lateral Sclerosis 10:99-106.
`Diaz, G.A.. et al.. “Phase 3 Blinded. Randomized, Crossover Com-
`parison of Sodium Phenylbutyrme
`(NaPBA) and Glycerol
`Phenylbutyrate (GPB): Ammonia (NT-13) Control in Adults with Urea
`Cycle Disorders (UCDs),” Mol. Genet. Metab. 1022276, Society of
`Inherited Metabolic Disease (SMID) Abstract.
`Enns. G.M., et
`a1..
`(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 Maab 100:520-S30.
`Hines. P.. et
`a1..
`(2008) "Pulsed-Dosing with Oral Soditu'n
`Phenylbutyrate Increases Hemoglobin F in a Patient with Sickle Cell
`Anemia.” Pediatr Blood Cancer 50:357-359.
`Hogarth, P.. et a1., (2007) “Sodium Phylbutyrme in Huntington’s
`Disease: A Dose-Finding Study," Mov Disord 22(13): 1962-1964.
`Huang, H.H., et a1., (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 ofGT4P in Patients
`with Urea Cycle Disorders” Announcement, 1 page (Oct. 23, 2007).
`Mercuri. E... et a1., (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
`Metal) 105:342.
`Moldave, K.. et a1., (1957) “Synthesis of Phenylacetylglutamine by
`Human Tissue,” J. Biol. Chem. 229:463-476.
`
`Patent Application No.
`
`Monteleone, IPR. et a1., (2012) “Population pk Analysis ofGlycerol
`Phenylbutyrate (GPB) and Sodium Phenylbutyrate(NAPBA) in
`Adult and Pediatric Patients with Urea Cycle Discorders,"Mol Genet
`Metab 105:343.
`0113, J. 13., et al., (2003) "Correlation Between Ammonia Levels and
`the Severity of Hepatic Farcephalopathy," Am. J. Med. 114:188-193.
`Pen-inc, S. P., (2008) “Fetal Globin Stimulant Therapies in the Beta-
`Hemoglobinopathies: Principles and Current Potential," PediatrAnn
`37(5):339-346.
`Ryu, 11., et a1., (2005) “Sodium Phenylbutyrate Prolongs Survival
`and Regulates Expression of Anti-Apoptotic Genes in Transgenic
`Amyotrophic Lateral Sclerosis Mice,”JNeurocIrem 93: 1087-1098.
`Stauch. et al., (1998) "Oral L-omithine-L-aspartate therapy of
`chronic hepatic encephalopathy: results of a placebo-controlled
`double-blind study" J Hepatology 28(5):856-864.
`Xie, G., et a1., (2012) “Role of Differentiation of Liver Sinusoidal
`Endothelial Cells in Progression and Regression of Hepatic Fibrosis
`in Rats,” Gartroemerology 1422S918.
`European Patent Ofiice. Extended European Search Report for
`EP09739263 completed Nov. 2, 2011.
`European Patent Oflice, International Search Report and Written
`Opinion for PCT/[1520091055256 completed Dec. 18, 2009 and
`mailed Dec. 30, 2009.
`for British
`Examination Report
`6310134682 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 Patentahility (Ch 11) for PCT/
`U82012/028620. complded Aug. 22. 2013 and mailed Sep. 4. 2013.
`United States Patent and Trademark Ofice, International Search
`Report andWritten Opinion for PCT/U520091030362 mailed Mar. 2.
`2009.
`United States Patent and Trademark Oflice. International Search
`Report and Written Opinion for PCT/[1820121028620 mailed Jun.
`20, 2012.
`United States Patent and Trademark Ofl‘ice. International Search
`Report and Written Opinion for PCT/U820 12/54673 mailed Nov. 20,
`2012.
`United States Patent and Trademark Office. International Search
`Report ande'tten Opinion for PCT/USZOI3/71333 mailed Mar. 28,
`2014.
`Ambrose, A.M. et a1. ( 1933). “Further Studies on the Detoxification
`of Phenylacetic Acid," J. Bio. Chem. 101 :669-675.
`Batshaw, ML. et a1. (Dec. 1980). “Treatment of Hyperarrunonemic
`Coma Caused by inborn Errors of Urea Synthesis," J. Pediatr.
`97(6):893-900.
`Batshaw, ML. et al. (Aug. 1981). “New Approaches to the Diagnosis
`and Treatment of lnborn Errors of Urea Synthesis." Pediatrics
`68(2):290-297.
`Batshaw ML. et a1. (Jun. 10, 1982). “Treatment of lnborn Errors of
`Urea Synthesis: Activation of Alternative Pathways of Waste Nitro-
`gen Synthesis and Excretion,” N. Engl. J. Med. 306(23): 1387-1392.
`Batshaw, ML. (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) 138:856-861.
`Brusilow. S., et al., “Amino Acid Acylation: A Mechanism ofNitro-
`gen Excretion in lnborn Errors of Urea Synthesis," Science 207:659-
`661 (1980).
`Brusilow. S. W.. a al.. “Phenylacetylglutamine May Replace Urea as
`a Vehicle for Waste Nitrogen Excretion," Pediatr. Res. 29:147-150
`(1991).
`Brusilow. S.w. et a1. (Sep. 1. 1979). “New Pathways of Nitrogm
`Excretion in lnborn Errors of Urea Synthesis,” Lancet 2(8140):452-
`454.
`Brusilow. S.w. (Jun. 21, 1984). “Treatment of Episodic Hyperam-
`monemia in Children With lnborn Errors ofUrea Synthesis,” N.
`.1. Med. 3 10(25): 1630-1634.
`Brusilow. S.w. (Amendment Dated Jul. 25, 1994). “Protocols for
`Management ofIntercurrent Hyperammonemia 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.
`
`Page 2 of 22
`
`Page 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. RJ. et al. eds.
`Churchill Livingstone, New York, New York, pp. 79-94.
`Brusilow, S.W. et a1. (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, New York. PP. 1187-
`1 232.
`Brusilow, S.W., et a1. (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 Hyperammonemic Enecphalopathy,” Progress in Liver Dis-
`eases (1995) 12:293-309.
`Brusilow, S. W., et al., "Restoration of Nitrogen Homeostasis in a
`Man with Omithine 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 101:775-786.
`Galloway. D.H. et a1. (1971). “Variation in Endogenous Nitrogen
`Excretion and Dietary Nitrogen Utilization as Determinants of
`Human Protein Requirements," J. Nutrition [01:205-216.
`Camacho. LH. 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 ofNCT0055 1200 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. 10134682, filed on Aug. 27,
`2009, six pages.
`Combined Search and Examination Report mailed on Oct. 9, 2009,
`for Great Britain Patent Application No. GB09 l 5545 .8, filed on Aug.
`27, 2009, eight pages.
`Comte. B.. et al.. “Identification of Phenylhrtyrylglutamine. 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. 102:276 (2011).
`Examination Report mailed on Oct. 27. 2010. for United Kingdom
`Patent Application No. 61309155458, filed on Aug. 27, 2009. two
`pages.
`Examination Report mailed Feb. 5. 2010, for United Kingdom Patent
`Application No. 6309155453, filed on Aug. 27, 2009. two page.
`Examination Report mailed May 11. 2010. for United Kingdom
`Patent Application No. 6309155453, filed on Aug. 27, 2009, one
`page.
`FDA. (Aug. 2003). “Buphenyl® (Sodium Phenyllaityrate) label”
`nine pages.
`FDA Label for Buphenyl. 6 pages.
`Gargosky. S. (2006). “High Ammonia Levels Are Associated With
`Increased Mortality and Coma,” Ucyclyd Phanna. Inc.. one page.
`Gargosky. S. et al. (Oct. 14, 2005). “Results of a Twenty-two Year
`Clinical Trial: Actue. Adjunctive Pharmacological Treatment of
`Hyperanu'noncmic Episodes
`in Patients with Deficiencies
`in
`Enzymes ofthe UreaCycle." poster. Ucyclyd Pharma. Inc.. one page.
`Gargosky, S. (Aug. 2, 2005). “Improved Survival of Neonates Fol-
`lowing Administration of Ammonul® (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., “ll-l MRS Allows Brain Phenotype Differen-
`tiation in Sisters with Late Onset Omithine Transcarbamylase Defi-
`ciency (01'CD) and Discordant Clinical Presentations.” Mol. Genet.
`Metab. 94(1):52-60 (2008).
`Gropman. A.L., et al.. “ll-1 MRS Identifies Symptomatic and
`Asyrrptomatic Subjects with Partial Ornithine Transcarbamylase
`Deficiency,” Mol. Genet. Metal). 95:21-30 (2008).
`Hyperion Therapartics. (Mar. 30. 2009). “Hyperion Therapeutics
`Announces Results for Phase II Study in Urea Cycle Disorders,”
`located
`at
`<http://www.hyperiontx.com/pressr’release/pr
`1238518388,> last visited on Apr. 27, 2011. three pages.
`Hyperion Therapeutics. (Jun. 2. 2009.) “Hyperion Therapeutics
`Announces Results ofPhase [Study in Patients with Liver Cirrhosis"
`located
`at<http:l/wwwhyperiontx.com’press/release/pr
`1243891161>, last visited on Apr. 27, 2011. three pages.
`International Preliminary Report on Patentability mailed on Mar. 1.
`201 1, for PCT Application No. PCT/US2009/030362. filed on Jan. 7.
`2009, seven pages.
`International Preliminary Report on Patentability mailed on Mar. 1.
`201 l, for PCT Application No. PCT/U82009/055256. filed on Aug.
`27, 2009, six pages.
`James, MO. et a1. (1972). “The Conjugation of Phenylacetic Acid in
`Man. Sub-Human Primates and Some Other Non-Primates Species,”
`Proc. R. Soc. London 182:25-35.
`John, BA et al. (Mar. 2009). “The Disposition of HPN-IOO, A Novel
`Pharmaceutical Under Development for Potential Treatment of
`Hyperammonemia, in Cynomologus Monkeys.” abstract presented at
`ACMG 2009. one page.
`John. BA et al. (Mar. 2009). “The Disposition of HPN-IOO, A Novel
`Pharmaceutical Under Development for Potential Treatment of
`Hyperammonemia, 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):]0-19.
`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 IClEM 2009. San Diego. CA. one
`page.
`Lee, B. et al. (Aug. 2009). “Dosing and Therapeutic Monitoring of
`Ammona 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 Anunonia 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-Pheny1butyrate)
`[HPN- 100].
`to Buphenyl® (Sodium
`Phenylbutyrate [PBA].” presented at SSIEM 2008. Lisbon, Portugal.
`Poster. one page.
`Lee. B.. et al.,“Phase 2 Comparison ofa Novel Ammonia Scavenging
`Agart with Sodium Phenylbutyrate in Patients with Urea Cycle Dis-
`orders: Safety. Pharmacokinetics and Ammonia Control," Mol.
`Genet. Metal). 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-
`
`Page 3 of 22
`
`Page 3 of 22
`
`
`
`US 9,095,559 B2
`Page 4
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Phenylbutyrate) (HPN-IOO). to Buphenyl (Sodium Phenylbutyrate
`(PBA))." J. Inherit. Metab. Dis. 31(Suppl. l):9l (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
`:225-231.
`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).
`MacArthur, R. 13., et al .. "Pharmacokinetics ofSodium Phenylacetate
`and Sodium Benzoate Following Intravenous Administration as Both
`a Bolus and Continuous Infusion to Healthy Adult Volunteers.” Mol.
`Genet. Metab. 81:867-873 (2004).
`Mansour. A. et al. (Oct. 1997). “Abdominal Operations in Patients
`with Cirrhosis: Still a Major Surgical Challenge." Surqerv
`122(4):730-735. (Abstract Only).
`Masetri. N.E. et al. (Aug. 1992). “Plasma Glutamine Conctmtion:
`A Guide in the Management ofUrea Cycle Disorders.” J. Pediatr. l 2 1
`(2);259-251.
`McGuire. B. M.. et al.. “Pharmacology and Safety of Glycerol
`Phenylbutyrale in Healthy Adults and Adults with Cirrhosis."
`Hepatol. 51:2077-2085 (2010).
`McGuire. BM. et al. (2009). “Pharmacokinetic (PK) and Safety
`Analyses of a Novel Ammonia-Reducing Agent in Healthy Adults
`and Patients with Cirrhosis." Hyperion Therapeutics. poster. one
`page.
`McGuire, B.M. et al. (May 2009). “Pharmacokinetic (PK) and Safety
`Analyses of a Novel Ammonia-Reducing Agent in Healthy Adults
`and Patients with Cirrhosis." abstract presented at DDW. May 2009,
`two pages.
`McGuire. 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).
`McGuire, B. et al. (Apr. 2008). “Pharmacokeinetic (PK) Safdy Study
`of Sodium Phenylacetate and Sodium Benmate Administered to
`Subjects with Hepatic Impairment.” abstract ofThe 1 3th International
`Symposium. Abano (Padova). Italy. Apr. 28-May 1. 2008. two pages.
`McQuade RS. (1984). “Analysis and the Effects of Some Drugs on
`the Metabolism of Phenylethylamine and Phenylacetic Acid."
`Neuropsychopharmacol. Bioi. Psychiat. 8:607-614.
`Piscitelli. SC. et al. (1995). "Disposition of Phenyl hutyrate and its
`Metabolites. Phenylacetete and Phenylaeetylglutamine." 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. IR. et al. (Nov. 15. 2001). “Preventive Strategies in Chronic
`Liver Disease: Part II. Cirrhosos.“ Am Fam. Physician 64(10): 1735-
`1740. (Abstract Only).
`Rudman. D.. et al.. “Maximal Rates of Excretion and Synthesis of
`Urea in Nomial and Cirrhotic Subjects." J. Clin. Invest. (1973)
`52:2241-2249.
`Shiple. 6.]. et al. (1922). “Synthesis of Amino Acids in Animal
`Organisms. 1. Synthesis of Glycocoll and Glutamine in the Human
`Organism.” J. Am. Chem. Soc. 44:618-624.
`Simell. 0.. et al.. ‘WVaste Nitrogen Excretion Via Amino Acid Acyla-
`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) l38(l):Sl-SS.
`Summer. M.L. et al. (Oct. 2008. e—pub. Jul. 17. 2008). “Diagnosis.
`Symptoms. Frequency and Mortality of260 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 3 16 Urea
`Cycle Patients From a 21-Year, Multicenter Study of Acute
`Hyperammonemic Episodes," Abstract, presented at Annual Sympo-
`sium CCH—Congress Centre Hamblng, 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 1 and Pharmacokinetic Study of Intra-
`venous Phenylncdate in Patients with Cancer.” Cancer Res. 54: 1690-
`1694 (1994).
`Thibaull. 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, PL. et al. (Jul. 2002). “Evidence ofCFI'R Function in Cystic
`Fibrosis After System Administration of 4-Phenylbutyrate." Mol.
`Therapy 6(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; US.
`Pat. No. 8.404.215 and US. 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 Pharmacol Ther. 33 (‘7):739-747 (2011).
`Barsotti. Measurement of Ammonia in Blood. 138 J. Pediatrics.
`s11-szo (2001).
`Batshaw. et al.. Treatment of Carbamyl Phosphate Synthetase Defi-
`ciency with Keto Analogues ofEssential Amino Acids. 292 The New
`
`England J. Medicine, 1085390 (1975).
`Batshaw. M. L. et. al.. Alternative Pathway Therapy for Urea Cycle
`Disorder: Twenty Years Later. 138 J. Pediatrics S46 (2001).
`Blau. Duran. Blasknvics. Gibson (editors). Physician's Guide to the
`Laboratory Diagnosis ofMetabolic Diseases. 261-276 (2d ed. 1996).
`Blei. A. T.. eta1.. “Hepatic Encephalopathy,” Am. J. Gastroenterol.
`96(7):]968-1976 (2001 ).
`Burlina. A.B.
`et
`al., Long-Tenn Treatment with Sodium
`Phenylbutyrate in Omithine 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 1 Clinical and Pharmacological Evalu-
`ation of Sodium Phenylbutyrate on an l20-h Infusion Schedule. 7
`Clin. Cancer Res. 3047 (2001).
`Center for Drug Evaluation and Research. Clinical Pharmacology
`and Biopharrnaceutics Review for New Drug Application No. 20-645
`(Ammonul®) (2005).
`Center for Drug Evaluation and Research. labeling for New Drug
`Application No. 20-645 (Ammonul®) (2005).
`Center for Drug Evaluation and Research. Medical Review for New
`Drug Application No. 20-645 (Ammonul®) (2005).
`Chen. Z. eta1.. Tributyrin: A Prodrug of Butyric Acid for Potential
`Clinical Application in Difierentmfion Therapy. 54 Cancer Research
`3494 (1994).
`Clay. A. et. a1, Hyperammonemia in the ICU. 132 Chest 1368 (2007).
`Collins. A.F. et al.. Oral Sodium Phenylbutyrate Therapy in
`Homozygous Beta Thalassernia: A Clinical Trial. 85 Blood 43
`(1995).
`
`Page 4 of 22
`
`Page 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
`ofHepatology 54: 1030-1040(2011 ).
`Darmaun. D. et al.. Phenylbutyrate-Induced Glutamine Depletion in
`Humans: Efi‘ect 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 Ieonard. J.V.. lntercurrent Illness in lnborn 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 16058 (2004).
`European Medicines Agency, Annex I: Summary of Product Charac-
`teristics for Ammonaps.
`European Medicines Agency. European Public Assessment Report:
`Summary for the Public for Ammonaps (2009).
`European Medicines Agency. Scientific Discussion for Ammonaps
`(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
`Inbom Errors ofUrea Synthesis: Effect on Camitine Metabolism and
`Ammonia Nitrogen Removal, 57 Biochemical and Molecular Medi-
`cine 31 (1996).
`Ferenci, P.. etal.. “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 ofthe Urea Cycle, in
`Liver Disease in Children 827 (El. 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 Efi‘ect on Venous Ammonia Concentration." Clinical Phannacol-
`ogy in Drug Development 2(3): 278-284 (2013).
`Gilbert. J. et al.. A Phase 1 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 ofthe Putative Difi‘erentiating Agent Sodium
`Phenylbutyrate on Myelodysplastic Syndromes and Acute Myeloid
`Leukemia, 7 Clin. Cancer Res. 2330 (2001).
`Gropman. A.L. et al.. Neurological Implications ofUrea Cycle Dis-
`orders, 30 J. Inherit Metal: Dis. 865 (2007).
`Hassanein, T.
`1., et al.. “Randomized Controlled Study of
`Extracorporeal Albumin Dialysis for Hepatic Encephalopathy in
`Advanced Cirrhosis,” Hepatology 46: 1853-1 862 (2007).
`Hassanein. T. 1.. et al.. “Introduction to the Hepatic flicephalopathy
`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.. Successfirl Treatment of Severe Hyperammonemia
`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/USZOO9/
`055256. mailed Dec. 30. 2009. 13 pages.
`Kleppe. S. et al.. Urea Cycle Disorders, 5 Current Treatment Options
`in Neurology 309-319 (2003).
`Kubota, K. and lshizaki. '11. Dose-Dependent Pharmacokinetics of
`Benznic Acid Following Oral Administration ofSodium Benzoate to
`Humans, 41 Eur. J. Clin. Pharmacol. 363 (1991).
`Lee. B. and Goss, J.. Long-Tenn Correction ofUrea Cycle Disorders.
`[38 J. Pediatrics 562 (2001).
`Lee. B. et al.. Considerations in the Difficult-to-Manage Urea Cycle
`Disorder Patient. 21 Crit. Care Clin. $19 (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 Disorda's. 7 Serrlin. Nenatol. 27 (2002).
`Lizardi-Cervera. J. et al.. Hepatic Encephalopathy: A Review. 2
`Annals of Hepatology 122-120 (2003).
`Maestri NE, et al.. Prospective treatment of urea cycle disorders. J
`Paediatr 1991;119:923-928.
`Maestri, N.E.. et al.. Long-Tenn Survival of Patients with
`Argininosuccinate Synthetase Deficiency. 127 J. Pediatrics 929
`(1993).
`Maestri, N.E., Long-Term Treatment of Girls with Omithine
`Transcarbamylase Deficiency. 355 N. Engl. J. Med. 855 (1996).
`Majeed. K.. Hyperammonemia. eMedicine.com (Dec. 2001).
`Marini. J.C. et a] ., Phenylbutyrate Improves Nitrogen Disposal via an
`Alternative Pathway without Eliciting an Increase in Protein Break-
`down and Catabolism in Control and Omithine Transcarbamylase-
`Deficient Patients. 93 Am. J. Clin. Nutr. 1248 (201 l).
`Matsuda, 1.. Hyperammonemia in Pediatric Clinics: A Review of
`Omithine Transcarbarrrylase Deficiency (0TCD) Based on our Case
`Studies. 47 JMAJ 160 (2004).
`McGuire. BM. et al.. Pharmacokinetic (PK) and Safety Analyses of
`a Novel Ammonia-Reducing Agent in Healthy Adults and Patients
`with Cirrhosis. Hyperion Therapeutics. poster. one page (2009).
`Mizutani. N. et al.. Hyperargininemia: Clinical Course and Treat-
`ment with Sodium Berzoate and Phenylacetic Acid. 5 Brain and
`Development 555 (I983).
`Mokhtarani. M.. et al., (2013) “Elevated Phenylacetic Acid Levels Do
`Not Correlate with Adverse Evts in Patients with Urea Cycle Dis-
`orders 0 rHepatic Encephalopathyand Can Be Predicted Based onthe
`Plasma PAA to PAGN Ratio,” Mol Genet Metal) 110(4):446-453.
`Mokhtarani. M.. et al.. (2012) “Urinary Phenylacetylglutamine as
`Dosing Biomarker for Patients with Urea Cycle Disorders.” Mol
`Genet Metab lO7(3):308-3l4.
`Monteleonc. JPR, et al.. (2013) “Population Phamracokinctic 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. l. “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 ofMetabolic Programs. Acute Illness Pro-
`tocol: Urea Cycle Disorders: The Infant/Child with Argininosuc-
`cinate Lyase Deficiency. adapted from Summar. M and Tuchman. M.
`Proceedings of a Consensus Conference for the Management of
`Patients with Urea Cycle Disorders. 138 J. Pods. Suppl. 86 (2001).
`New England Consortium ofMetabolic Programs. Acute Illness Pro-
`tocol: Urea Cycle Disorders: The lnfanUChild with Citrullinemia.
`adapted from Summar. M and Tuchrnan, M. Proceedings of 3 Con-
`sensus Conference for the Management of Patients with Urea Cycle
`Disorders, 138 J. Peds. Suppl. SS (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., et 511., “Development ofaClinical Hepatic Encephalopathy
`Staging Scale." Aliment Pharrnacol Ther 26:859-867 (2007).
`
`Page 5 of 22
`
`Page