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`US009326966B2
`
`c12) United States Patent
`Scharschmidt et al.
`
`(IO) Patent No.:
`(45) Date of Patent:
`
`US 9,326,966 B2
`*May 3, 2016
`
`(54) METHODS OF THERAPEUTIC
`MONITORING OF NITROGEN SCAVENGING
`DRUGS
`
`(71) Applicant: Horizon Therapeutics, Inc., Deerfield,
`IL (US)
`
`(72)
`
`Inventors: Bruce Scharschmidt, San Francisco,
`CA (US); Masoud Mokhtarani, Walnut
`Creek, CA (US)
`
`A61K31/235
`A61K9/00
`(52) U.S. Cl.
`CPC ............. A61K 311235 (2013.01); A61K 910053
`(2013.01)
`
`(2006.01)
`(2006.01)
`
`(58) Field of Classification Search
`CPC ............... A61K 31/216; GOIN 31/221; YlOT
`436/175383
`See application file for complete search history.
`
`(73) Assignee: Horizon Therapeutics, Inc., Lake
`Forest, IL (US)
`
`( *) Notice:
`
`Subject to any disclaimer, the term ofthis
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 0 days.
`
`This patent is subject to a terminal dis(cid:173)
`claimer.
`
`(21) Appl. No.: 14/958,259
`
`(22) Filed:
`
`Dec. 3, 2015
`
`(65)
`
`Prior Publication Data
`
`US 2016/0081969 Al
`
`Mar. 24, 2016
`
`Related U.S. Application Data
`
`(63)
`
`(60)
`
`(51)
`
`Continuation of application No. 14/816,674, filed on
`Aug. 3, 2015, now Pat. No. 9,254,278, which is a
`continuation of application No. 13/775,000, filed on
`Feb. 22, 2013, now Pat. No. 9,095,559, which is a
`continuation 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 49100
`A61P 13100
`
`(2006.01)
`(2006.01)
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`4,284,647 A
`4,457,942 A
`
`8/1981 Brusilow et al.
`7/1984 Brusilow
`(Continued)
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`
`10/1994
`W094/22494
`6/2005
`W02005/053607
`(Continued)
`
`OTHER PUBLICATIONS
`
`Ahrens, M. et al. (Jan. 2001). "Consensus Statement From a Confer(cid:173)
`ence for the Management of Patients With Urea Cycle Disorders."
`Supp. Journal of Pediatrics 138(1):Sl-S5.
`(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(cid:173)
`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
`
`1 of 22
`
`

`

`US 9,326,966 B2
`Page 2
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`5,654,333 A
`5,968,979 A
`6,060,510 A
`6,083,984 A
`6,219,567 Bl
`8,094,521 B2
`8,404,215 Bl
`8,642,012 B2
`9,078,865 B2
`2003/0195255 Al
`2004/0229948 Al
`2005/0273359 Al
`2006/0135612 Al
`2008/0119554 Al
`2010/0008859 Al
`2010/0016207 Al
`2012/0022157 Al
`2012/0220661 Al
`2013/0210914 Al
`2013/0281530 Al
`2014/0142186 Al
`2015/0094278 Al
`2015/0105469 Al
`
`8/1997 Samid
`10/1999 Brusilow
`512000 Brusilow
`712000 Brusilow
`4/2001 Eggers et al.
`112012 Levy
`3/2013 Scharschmidt et al.
`2/2014 Scharschmidt
`7/2015 Lee
`10/2003 Summar
`1112004 Summar et al.
`12/2005 Young
`612006 Ferrante
`5/2008 Jalan et al.
`112010 Scharschmidt
`112010 Wurtman et al.
`112012 Scharschmidt
`8/2012 Lee
`8/2013 Scharschmidt et al.
`10/2013 Scharschmidt et al.
`5/2014 Scharschmidt et al.
`4/2015 Scharschmidt et al.
`4/2015 Scharschmidt et al.
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`WO
`
`W02006/056794
`W02007 /005633
`W02009/087474
`W02009/134460
`W02010/025303
`W02012/028620
`W02013/048558
`W02013/158145
`
`612006
`112007
`712009
`1112009
`3/2010
`3/2012
`4/2013
`10/2013
`
`OTHER PUBLICATIONS
`
`Ambrose, A.M. et al., "Further Studies on the Detoxification of
`Phenylacetic Acid", 101 J. Bio. Chem. 669 (1933).
`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 Therapeu(cid:173)
`tics, inc .. Re: Glycerol Phenylbutyrate 1.1 gm/ml oral liquid; U.S.
`Pat. Nos. 8,404,215 and 8,642,012 Notice of Paragraph IV Certifi(cid:173)
`cation Mar. 12, 2014.
`Anda Notice Letter, Lupin Ltd. to Horizon Therapeutics, Inc .. Re:
`Notification of Invalidity, Unenforceability, and/or N oninfringement
`for U.S. Pat. Nos. 8,404,215 and 8,642,012 Pursuant to §
`505(j)(2)(B)(ii) and (iv) of the Federal Food, Drug, and Cosmetic
`Act, Sep. 4, 2015.
`Anda Notice Letter, Lupin Ltd. to Horizon Therapeutics, Inc .. Re:
`Notification of Invalidity, Unenforceability, and/or N oninfringement
`for U.S. Pat. No. 9,095,559 Pursuant to§ 505(j)(2)(B)(ii) and (iv) of
`the Federal Food, Drug, and Cosmetic Act, Nov. 6, 2015.
`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,
`Sll-S20 (2001).
`Batshaw, M.L. et al., "Treatment oflnborn Errors of Urea Synthesis:
`Activation of Alternative Pathways of Waste Nitrogen Synthesis and
`Excretion", 306 N. Engl. J. Med. 1387 (1982).
`Batshaw, M.L. et al., "New Approaches to the Diagnosis and Treat(cid:173)
`ment oflnborn Errors of Urea Synthesis", 68 Pediatrics 290 (1981).
`Batshaw, M.L. et al., "Treatment of Carbamyl Phosphate Synthetase
`Deficiency with Keto Analogues of Essential Amino Acids", 292 The
`New England J. Medicine, 1085 (1975).
`
`Batshaw, M.L. et al., "Treatment ofHyperammonemic Coma Caused
`by Inborn Errors of Urea Synthesis", 97 J. Pediatrics 893 (1980).
`Batshaw, M.L., "Hyperammonemia," Current Problems in Pediat(cid:173)
`rics, vol. 14, Issue 11, p. 6-69 (1984).
`Batshaw, M. L. et. al., "Alternative Pathway Therapy for Urea Cycle
`Disorder: Twenty Years Later", 138 J. Pediatrics S46 (2001).
`Berry, G. T. et al., "Long-Term Management of Patients with Urea
`Cycle Disorders", 138 J. Pediatrics S56 (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," Arn. J. Gastroenterol.
`96(7):1968-1976 (2001 ).
`Brahe, C., et al., (2005) "Phenylbutyrate Increases SMN Gene
`Expression in Spinal Muscular Atrophy Patients," Eur J Hum Genet
`13:256-259.
`Brunetii-Pierri, N., et al., (2011) ""Phenylbutyrate Therapy for
`Maple Syrup Urine Disease"," Hum Mo! Genet 20(4):631-640.
`Brusilow, S.W. et al., "New Pathways of Nitrogen Excretion in
`Inborn Errors of Urea Synthesis", 2 Lancet 452 (1979).
`Brusilow, S.W. et al., "Amino Acid Acylation: A Mechanism of
`Nitrogen Excretion in Inborn Errors of Urea Synthesis", 207 Science
`659 (1980).
`Brusilow, S.W., "Treatment of Episodic Hyperammonemia in Chil(cid:173)
`dren With Inborn Errors of Urea Synthesis", 310 N. Engl. J. Med.
`1630 ( 1984).
`Brusilow, S.W. Phenylacetylglutamine May Replace Urea as a
`Vehicle for Waste Nitrogen Excretion, Pediatric Research, vol. 29,
`No. 2, 147-150 (1991).
`Brusilow, S.W. et al, "Treatment of Urea Cycle Disorders", in Treat(cid:173)
`ment of Genetic Diseases 79 (R.J. Desnik. et al., eds.1991 ).
`Brusilow, S.W. et al., "Restoration ofNitrogen Homeostasis in a Man
`with Ornithine Transcarbamylase Deficiency", 42 J. Metabolism
`1336 (1993).
`Brusilow, S.W., "Protocols for Management of Intercurrent
`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 (Amendment Dated Jul. 25,
`1994).
`Brusilow, S.W. et al., "Urea Cycle Disorders: Clinical Paradigm of
`Hyperammonemic Encephalopathy", 12 Progress in Liver Diseases
`293 (1995).
`Brusilow, S.W. et al., "Urea Cycle Enzymes", in the Metabolic and
`Molecular Bases oflnherited Diseases 1187 (C.R. Scriver et al. eds.
`1995).
`Brusilow, S.W. et al., "Urea Cycle Disorders: Diagnosis,
`Pathophysiology, and Therapy", 43 Adv. Pediatr. 127 (1996).
`Burlina, A.B. et al., "Long-Term Treatment with Sodium
`Phenylbutyrate in Ornithine Transcarbamylase-Deficient Patients",
`72 Molecular Genetics and Metabolism 351-355 (2001).
`Calloway, D.H. et al., "Sweat and Miscellaneous Nitrogen Losses in
`Human Balance Studies", 101 J. Nutrition 775 (1971).
`Calloway, D.H. et al., "Variation in Endogenous Nitrogen Excretion
`and Dietary Nitrogen Utilization as Determinants of Human Protein
`Requirements", 101 J. Nutrition 205 (1971).
`Camacho, L.H. et al., "Phase I Dose Escalation Clinical Trial of
`Phenylbutyrate Sodium Administered Twice Daily to Patients With
`Advanced Solid Tumors", 25 Invest. New Drugs 131 (2007, e-pub.
`Oct. 20, 2006).
`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
`Evaluation of Sodium Phenylbutyrate on an 120-h Infusion Sched(cid:173)
`ule", 7 Clin. Cancer Res. 3047 (2001).
`Center for Drug Evaluation and Research, Clinical Pharmacology
`and Biopharmaceutics Review for New Drug Application No. 20-645
`(Arnmonul®) (2005).
`Center for Drug Evaluation and Research, Labeling for New Drug
`Application No. 20-645 (Arnmonul®) (2005).
`Center for Drug Evaluation and Research, Medical Review for New
`Drug Application No. 20-645 (Arnmonul®) (2005).
`Chang, J.-G., et al., "Treatment of Spinal Muscular Atrophy by
`Sodium Butyrate", 98 PNAS USA 9808 (2001).
`
`2 of 22
`
`

`

`US 9,326,966 B2
`Page 3
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Chen, Z. et al., "Tributyrin: A Prodrug of Butyric Acid for Potential
`Clinical Application
`in Differentiation Therapy", 54 Cancer
`Research 3494 (1994).
`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 EBY-Targeted
`Therapy," Clin Cancer Res 6: 1452-1458.
`Clay, A. et. al, "Hyperammonemia in the ICU", 132 Chest 1368
`(2007).
`Clinica!Trials.Gov/Archive View of NCT00551200 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.
`Collins, A.F. et al., "Oral Sodium Phenylbutyrate Therapy in
`Homozygous Beta Thalassemia: A Clinical Trial'', 85 Blood 43
`(1995).
`Combined Search and Examination Report mailed on Oct. 9, 2009,
`for Great Britain Patent Application No. GB0915545.8, filed on Aug.
`27, 2009, eight pages.
`Combined Search and Examination Report mailed on Sep. 9, 2010,
`for Great Britain Patent Application No. 1013468 .2, filed on Aug. 27,
`2009, six pages.
`'Complaint for Patent Infringement', Hyperion Therapeutics, Inc. v.
`Par Pharmaceuticals, Inc. Filed in U.S. District Court for the Eastern
`District of Texas, Apr. 23, 2014.
`'Complaint for Patent Infringement', Horizon Therapeutics, Inc. v.
`Lupin Ltd. and Lupin Pharmaceuticals Inc. Filed in U.S. District
`Court for the District of New Jersey, Oct. 19, 2015.
`Comte, B., et al., "Identification of Phenylbutyrylglutamine, A New
`Metabolite of Phenylbutyrate Metabolism in Humans", 37 J. Mass
`Spectrometry 581 (2002).
`Conn, H. 0., et al., "Liver Physiology and Disease: Comparison of
`Lactulose and Neomycin in the Treatment of Chronic Portal-Sys(cid:173)
`temic Encephalopathy. A Double Blind Controlled Trial," Gastroen(cid:173)
`terology 72(4):573-583 (1977).
`Cordoba, J., "New Assessment of Hepatic Encephalopathy," Journal
`ofHepatology 54: 1030-1040 (2011 ).
`Cudrowicz (2009) "Phase 2 Study of Sodium Phenylbutyrate in
`ALS," Amyotrophic Lateral Sclerosis 10:99-106.
`Darmaun, D. et al., "Phenylbutyrate-InducedGlutamine Depletion in
`Humans: Effect on Leucine Metabolism", 5 Am. J. of Physiology:
`Endocrinology and Metabolism E801 (1998).
`Darzens, G.
`et al.:
`"Preparation de quelques glycerides
`phenylaliphatiques et leur reduction en alcools
`", Comptes
`Rendus Hebdomadaires Des Seances De L' Academie Des Sciences.,
`vol. 205, Oct. 18, 1937, pp. 682-684.
`Deferrari, G. et al., "Brain Metabolism of Amino Acids and Ammonia
`in Patients with Chronic Renal Insufficiency", 20 Kidney Interna(cid:173)
`tional 505 (1981).
`Diaz, G.A. et al., "Phase 3 Blinded, Randomized, Crossover Com(cid:173)
`parison of Sodium Phenylbutyrate
`(NaPBA) and Glycerol
`Phenylbutyrate (GPB): Ammonia (NH3) Control in Adults with Urea
`Cycle Disorders (UCDs)", 102 Mo!. Genet. Metab. 276 (1981), Soci(cid:173)
`ety of Inherited Metabolic Disease (SMID) Abstract, (2011 ).
`Diaz G.A.et al, "Ammonia (NH3) control and improved neurocogni(cid:173)
`tive outcome among urea cycle disorder (UCD) patients treated with
`glycerol phenylbutyrate (GPB)." Mo!. Genet. Metab. 2012, 105, 311,
`SIMD Abstract 24.
`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
`oflntermediary Metabolism, 67 Archives of Disease in Childhood",
`1387 (1992).
`Dover, G. et al, "Induction of Fetal Hemoglobin Production in Sub(cid:173)
`jects with Sickle Cell Anemia by Oral Sodium Phenylbutyrate", 54
`Cancer Research 3494 ( 1994).
`
`Endo, F. et al., "Clinical Manifestations oflnborn Errors of the Urea
`Cycle and Related Metabolic Disorders During Childhood", 134 J.
`Nutrition 1605S (2004).
`Enns, G. M., et al., "Survival After Treatment with Phenylacetate and
`Benzoate for Urea-Cycle Disorders", 356 N. Eng. J. Med. 2282
`(2007).
`European Medicines Agency, Annex I: Summary of Product Charac(cid:173)
`teristics for Arnmonaps.
`European Medicines Agency, European Public Assessment Report:
`Summary for the Public for Arnmonaps (2009).
`European Medicines Agency, Scientific Discussion for Arnmonaps
`(2005).
`European Medicines Agency, Scientific Discussion for Carbaglu
`(2004).
`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.
`Examination Report mailed Feb. 5, 2010, for United Kingdom Patent
`Application No. GB0915545.8, filed on Aug. 27, 2009, two pages.
`Examination Report mailed May 11, 2010, for United Kingdom
`Patent Application No. GB0915545.8, filed on Aug. 27, 2009, one
`page.
`Examination Report mailed on Oct. 27, 2010, for United Kingdom
`Patent Application No. GB0915545.8, filed on Aug. 27, 2009, two
`pages.
`for British Patent Application No.
`Examination Report
`GB1013468.2 dated Oct. 28, 2011.
`FDA Label for Arnmonul®, sixteen pages (Feb. 2005).
`FDA Label for Buphenyl, six pages.
`FDA Buphenyl® (Sodium Phenylbutyrate) Label, nine pages. (Aug.
`2003).
`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 of Urea Synthesis: Effect on Carnitine Metabolism and
`Ammonia Nitrogen Removal", 57 Biochemical and Molecular Medi(cid:173)
`cine 31 (1996).
`Ferenci, P., et al., "Hepatic Encephalopathy-Definition, Nomencla(cid:173)
`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).
`Gargosky, S. "Improved Survival of Neonates Following Adminis(cid:173)
`tration of Arnmonul® (Sodium Phenyl acetate & Sodium Benzoate)
`10% 110% Injection", SSIEM Poster, six pages (Aug. 2, 2005).
`Gargosky, S. et al., "Results of a Twenty-two Year Clinical Trial:
`Acute, Adjunctive Pharmacological Treatment ofHyperammonemic
`Episodes in Patients with Deficiencies in Enzymes of the Urea
`Cycle", poster, Ucyclyd Pharma, Inc., one page (Oct. 14, 2005).
`Gargosky, S., "High Ammonia Levels are Associated With Increased
`Mortality and Coma", Ucyclyd Pharma, Inc., one page (2006).
`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 (GPB) Administration in
`Patients with Cirrhosis and Episodic Hepatic Encephalopathy (HE),
`accepted for presentation at Digestive Disease Week (2012).
`Ghabril, M. et al., "Glycerol Phenylbutyrate in Patients with Cirrho(cid:173)
`sis and Episodic Hepatic Encephalopathy: A Pilot Study of Safety
`and Effect on Venous Ammonia Concentration," Clinical Pharmacol(cid:173)
`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 DifferentiatingAgent 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
`Disorders", 30 J. Inherit Metab Dis. 865 (2007).
`
`3 of 22
`
`

`

`US 9,326,966 B2
`Page 4
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Gropman, A. L. et al., lH MRS Allows Brain Phenotype Differen(cid:173)
`tiation in Sisters with Late Onset Ornithine Transcarbamylase Defi(cid:173)
`ciency (OTCD) and Discordant Clinical Presentations, 94 Mo!.
`Genet. Metab. 52 (2008).
`lH MRS Identifies Symptomatic and
`Gropman, A.L. et al.,
`Asymptomatic Subjects With Partial Ornithine Transcarbamylase
`Deficiency, 95 Mo!. Genet. Metab. 21(Sep.-Oct.2008, e-pub. Jul. 26,
`2008).
`Gropman, A. (2010) "Brain Imaging in Urea Cycle Disorders," Mo!
`Genet Metab 100:S20-S30.
`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).
`Hines, P., et al., (2008) "Pulsed-Dosing with Oral Sodium
`Phenylbutyrate Increases Hemoglobin Fin 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.
`Honda, S. et al., "Successful Treatment of Severe Hyperammonemia
`Using Sodium Phenylacetate Power Prepared in Hospital Phar(cid:173)
`macy", 25 Biol. Pharm. Bull. 1244 (2002).
`Huang, H.H., et al., (2012) "Cannabinoid Receptor 2 Agonist Ame(cid:173)
`liorates Mesenteric Angiogenesis and Portosystemic Collaterals in
`Cirrhotic Rats," Hepatology 56:248-258.
`Hyperion Therapeutics. "Hyperion Therapeutics Announces Enroll(cid:173)
`ment of First Patient in Phase 112 Clinical Trial of GT 4P in Patients
`with Urea Cycle Disorders" Announcement, 1 page (Oct. 23, 2007).
`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.
`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/
`prl238518388,> 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.
`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.
`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.
`Inter Partes Review of U.S. Pat. No. 8,404,215.
`Inter Partes Review of U.S. Pat. No. 8,642,012.
`James, M.O. et al., "The Conjugation of Phenylacetic Acid in Man,
`Sub-Human Primates and Some Other Non-Primates Species", 182
`Proc. R. Soc. London 25 (1972).
`John, B.A. et al., "The Disposition of HPN-100, A Novel Pharma(cid:173)
`ceutical Under Development for Potential Treatment of Hyperam(cid:173)
`monemia, in Cynomolgus Monkeys", ACMG 2009 ADME, poster,
`two pages (Mar. 2009).
`John, BA et al. (Mar. 2009). "The Disposition ofHPN-100, A Novel
`Pharmaceutical Under Development for Potential Treatment of
`Hyperammonemia, in Cynomologus Monkeys," abstract presented at
`ACMG 2009, one page.
`
`Kasumov T., et al., "New Secondary Metabolites of Phenylbutyrate
`in Humans and Rats", 32 Drug Metabolism and Disposition 10
`(2004).
`Kleppe, S. et al., "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).
`Lea et al., "Butyramide and Monobutyrin: Growth Inhibitory and
`Differentiating Agents", Anticancer Res., 13: 145-150 (1993).
`Lee, B. and Goss, J., "Long-Term Correction of Urea Cycle Disor(cid:173)
`ders", 138 J. Pediatrics S62 (2001).
`Lee, B. et al., "Considerations in the Difficult-to-Manage Urea Cycle
`Disorder Patient", 21 Crit. Care Clin. Sl9 (2005).
`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., "Dosing and Therapeutic Monitoring of Ammonia
`Scavenging Drugs and Urinary Phenylacetylglutamine (PAGN) as a
`Biomarker: Lessons From a Phase 2 Comparison of a Novel Ammo(cid:173)
`nia Scavenging Agent with Sodium Phenyl butyrate (NAPBA)", pre(cid:173)
`sented atICIEM 2009, San Diego, CA, poster, one page. (Aug. 2009).
`Lee, B. et al., "Phase 2 Study ofa Novel Ammonia Scavenging Agent
`in Adults With Urea Cycle Disorders (UCDs )", abstract presented at
`ACMG 2009, one page. (Mar. 2009).
`Lee, B. et al., "Phase 2 Study ofa Novel Ammonia Scavenging Agent
`in Adults with Urea Cycle Disorders (UCDs)", presented at ACMG
`2009, seventeen pages (Mar. 2009).
`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-Phenylbutyrate)
`[HPN-100],
`to
`Buphenyl®
`(Sodium
`Phenylbutyrate [PBA ])", abstract presented at SSIEM 2008, Lisbon,
`Portugal, one page. (Aug. 2008).
`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-Phenylbutyrate)
`[HPN-100],
`to
`Buphenyl®
`(Sodium
`Phenylbutyrate [PBA])", presented at SSIEM 2008, Lisbon, Portu(cid:173)
`gal, Poster, one page (Sep. 2008).
`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-
`Phenylbutyrate) (HPN-100), to Buphenyl (Sodium Phenylbutyrate
`[PBA ])", 31 J. Inherit. Metab. Dis. 91 (2008).
`Lee, B., et al., Phase 2 Comparison of a Novel Ammonia Scavenging
`Agent with Sodium Phenylbutyrate in Patients with Urea Cycle Dis(cid:173)
`orders: Safety, Pharmacokinetics and Ammonia Control, 100 Mo!.
`Genet. Metab. 221 (2010).
`Lee, B., et al., "Optimizing Ammonia (NH3) Control in Urea Cycle
`Disorder (UCD) Patients: A Predictive Model," Oral Abstract Plat(cid:173)
`form Presentations, Biochemical Genetics, Phoenix, AZ, Mar. 22,
`2013.
`Leonard, J.V., "Urea Cycle Disorders", 7 Semin. Nenatol. 27 (2002).
`Levin, B. et al. "Hyperammonaemia: A Variant Type of Deficiency of
`Ornithinine Transcarbamylase." Arch. Dis. Childhd. 1969, 44, 162-
`169.
`Lewis, H.B., "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", 18 J. Biol. Chem. 225
`(1914).
`Liang, K.Y., et al., "Longitudinal Data Analysis Using Generalized
`Linear Models", 73 Biometrika 13 (1986).
`Lichter-Konecki, U., et al., "Ammonia Control in Children with Urea
`Cycle Disorders (UCDs); Phase 2 Comparison of Sodium
`Phenylbutyrate and Glycerol Phenylbutyrate", 103 Mo!. Genet.
`Metab. 323 (2011).
`Lizardi-Cervera, J. et al., "Hepatic Encephalopathy: A Review", 2
`Annals ofHepatology 122-120 (2003).
`
`4 of 22
`
`

`

`US 9,326,966 B2
`Page 5
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Macarthur, H B., et al., "Pharmacokinetics of Sodium Phenylacetate
`and Sodium Benzoate Following Intravenous Administration as Both
`a Bolus and Continuous Infusion to Healthy Adult Volunteers", 81
`Mo!. Genet. Metab. S67 (2004).
`Maestri, N.E., et al., "Prospective treatment of urea cycle disorders",
`JPaediatr 1991;119:923-928.
`Maestri, N.E. et al., "Plasma Glutamine Concentration: A Guide in
`the Management of Urea Cycle Disorders", 121 J. Pediatrics 259
`(1992).
`Maestri, N.E., et al., "Long-Term Survival of Patients with
`Argininosuccinate Synthetase Deficiency", 127 J. Pediatrics 929
`(1993).
`Maestri, N.E., "Long-Term Treatment of Girls with Ornithine
`Transcarbamylase Deficiency", 355 N. Engl. J. Med. 855 (1996).
`Majeed, K., "Hyperammonemia", eMedicine.com (Dec. 2001).
`Mansour, A. et al., "Abdominal Operations in Patients with Cirrhosis:
`Still a Major Surgical Challenge", 122 Surgery 730 (1997) (Abstract
`Only).
`Marini, J.C. et al., "Phenylbutyrate Improves Nitrogen Disposal via
`an Alternative Pathway without Eliciting an Increase in Protein
`Breakdown
`and Catabolism
`in Control
`and Ornithine
`Transcarbamylase-Deficient Patients", 93 Am. J. Clin. Nutr. 1248
`(2011).
`Matsuda, I., "Hyperammonemia in Pediatric Clinics: A Review of
`Ornithine Transcarbamylase Deficiency (OTCD) Based on our Case
`Studies", 47 JMAJ 160 (2004).
`McGuire, B. et al., "Pharmacokinetic (PK) Safety Study of Sodium
`Phenylacetate and Sodium Benzoate Administered to Subjects with
`Hepatic Impairment", abstract of the 13th International Symposium,
`Abano (Padova), Italy, Apr. 28-May 1, 2008, two pages (Apr. 2008).
`McGuire, B. et al., "Pharrnacokinetic Safety Study of Sodium
`Phenylacetate and Sodium Benzoate Administered to Subjects With
`Hepatic Impairments", 28 Liver International 743 (2008) (Abstract
`Only).
`McGuire, B.M. et al., "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
`(May 2009).
`McGuire, B.M. 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).
`McGuire, B. M., et al., "Pharmacology and Safety of Glycerol
`Phenylbutyrate in Healthy Adults and Adults with Cirrhosis", 51
`Hepatol. 2077 (2010).
`McQuade, P.S., "Analysis and the Effects of Some Drugs on the
`Metabolism of Phenylethylamine and Phenylacetic Acid", 8
`Neuropsychopharrnacol. Bio. Psychiat.607 (1984).
`Mercuri, E., et al., (2004) "Pilot Trial of Phenylbutyrate in Spinal
`Muscular Atrophy," Neuromuscul Disord 14: 130-135.
`Mizutani, N. et al., "Hyperargininemia: Clinical Course and Treat(cid:173)
`ment with Sodium Benzoate and Phenylacetic Acid", 5 Brain and
`Development 555 (1983).
`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," Mo! Genet
`Metab 105:342.
`Mokhtarani, M., et al., (2013) "Elevated Phenylacetic Acid Levels Do
`Not Correlate with Adverse Events in Patients with Urea Cycle Dis(cid:173)
`orders o rHepatic Encephalopathy and Can Be Predicted Based on the
`Plasma PAA to PAGN Ratio," Mo! Genet Metab 110(4):446-453.
`Mokhtarani et al., (2012) "Urinaryphenylacetylglutamine appears to
`be a more useful marker than metabolite blood levels for therapeutic
`monitoring of phenylacetic acid (PAA) prodrugs." Mo! Genet Metab
`105, 312, SIMD Abstract 78.
`Mokhtarani, M., et al., (2012) "Urinary Phenylacetylglutamine as
`Dosing Biomarker for Patients with Urea Cycle Disorders," Mo!
`Genet Metab 107(3):308-314.
`Moldave, K., et al., (1957) "Synthesis of Phenylacetylglutamine by
`Human Tissue," J. Biol. Chem. 229:463-476.
`
`Monteleone, JPR, et al., (2012) "Population pk Analysis of Glycerol
`Phenylbutyrate (GPB) and Sodium Phenylbutyrate(NAPBA) in
`Adult and Pediatric Patients with Urea Cycle Discarders," Mo! Genet
`Metab 105:343.
`Monteleone, JPR, et al., (2013) "Population Pharmacokinetic Mod(cid:173)
`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(cid:173)
`tocol: Urea Cycle Disorders: The Infant/Child with Argininosuc(cid:173)
`cinate Lyase Deficiency, adapted from Summar, Mand 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(cid:173)
`tocol: Urea Cycle Disorders: The Infant/Child with Citrullinemia,
`adapted from Summar, Mand Tuchman, M, Proceedings of a Con(cid:173)
`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).
`Ong, J.P., et al., (2003) "Correlation Between Ammonia Levels and
`the Severity of Hepatic Encephalopathy," Am. J. Med. 114:188-193.
`Ortiz, M., et al., "Development of a Clinical Hepatic Encephalopathy
`Staging Scale," Aliment Pharrnacol Ther 26:859-867 (2007).
`PAR Pharmaceutical, Inc. 'S Initial Invalidity Contentions and Non(cid:173)
`Infringement Contentions for U.S. Pat. Nos. 8,404,215 and
`8,642,012.
`Parsons-Smith, B. G., et al., "The Electroencephalograph in Liver
`Disease," Lancet 273:867-871 (1957).
`Perrine, S. P., (2008) "Fetal Globin Stimulant Therapies in the Beta(cid:173)
`Hemoglobinopathies: Principles and Current Potential," Pediatr Ann
`37(5):339-346.
`Phuphanich, S. et al., "Oral Sodium Phenylbutyrate in Patients with
`Recurrent Malignant Gliomas: A Dose Escalation
`and
`Pharmacologic Study", Neuro-Oncology 177 (2005).
`Piscitelli, S.C. et al., "Disposition of Phenyl butyrate and its Metabo(cid:173)
`lites, Phenylacetate and Phenylacetylglutamine", 35 J. Clin. Pharma(cid:173)
`cology 368 (1995).
`Praphanproj, V. et al., "Three Cases oflntravenous Sodium Benzoate
`and Sodium Phenylacetate Toxicity Occurring in the Treatment of
`Acute Hyperammonemia," 23 J. Inherited Metabolic Disease 129
`(2000).
`Propst, A. et al., "Prognosis and Life Expectancy in Chronic Liver
`Disease", 40 Dig Dis Sci 1805 (1995) (Abstract Only).
`Riley, T.R. et al., "Preventive Strategies in Chronic Liver Disease:
`Part II", Cirrhosis, 64 Am. Earn. Physician 1735 (2001). (Abstract
`Only).
`Rockey, D. C., et al., "Randomized, Controlled, Double Blind Study
`of Glycerol Phenylbutyrate in Patients with Cirrhosis and Episodic
`Hepatic Encephalopathy," Hepatology 56:248(A) (2012).
`Rudman, D., et al., "Maximal Rates of Excretion and Synthesis of
`Urea in Normal and Cirrhotic Subjects", 52 J.