(12) United States Patent
`US 9,439,906 B2
`(10) Patent N0.:
`Vermeulen et al.
`
`(45) Date of Patent: Sep. 13, 2016
`
`US009439906B2
`
`(54) DOSING REGIMEN ASSOCIATED WITH
`LONG ACTING INJECTABLE
`PALIPERIDONE ESTERS
`
`(75)
`
`Inventors: An Vermeulen, Beerse (BE); Alfons
`Wouters, Beerse (BE)
`
`(73) Assignee: Janssen Pharmaceutica NV (BE)
`J
`y
`*
`Notice:
`Sub'ect to an disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 770 days.
`
`(21) Appl. No.: 12/337,144
`
`(22)
`
`(65)
`
`Filed:
`
`Dec. 17, 2008
`
`Prior Publication Data
`
`US 2009/0163519 A1
`
`Jun. 25, 2009
`
`Related US. Application Data
`
`(60) Provisional application No. 61/014,918, filed on Dec.
`19, 2007, provisional application No. 61/120,276,
`filed on Dec. 5, 2008.
`
`(51)
`
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`(2006.01)
`
`Int. C1.
`0070 471/04
`A61K 31/445
`A61K 31/41
`A61K 31/42
`A61K 31/519
`(52) us. Cl.
`CPC ................................... A61K 31/519 (2013.01)
`(58) Field of Classification Search
`CPC .A61K 31/519; A61K 9/0019; A61K 9/0024
`USPC ................................. 514/257, 323, 360, 379
`See application file for complete search history.
`
`(56)
`
`References Cited
`U.S. PATENT DOCUMENTS
`
`4,804,663 A
`5,158,952 A
`5,254,556 A
`5,453,425 A
`5,612,346 A
`6,077,843 A
`6,555,544 B2
`6,577,545 B2
`2002/0082245 A1
`2003/0157180 A1
`2007/0197591 A1
`2009/0163519 A1
`2011/0105536 A1
`2012/0263795 A1
`
`2/1989 Kennis et al.
`10/1992 Janssen et al.
`10/1993 Janssen et al.
`9/1995 Francois et al.
`3/1997 Mesens et al.
`6/2000 Francois et al.
`4/2003 Francois et al.
`6/2003 Kim et al.
`6/2002 Yelle
`8/2003 Francois et al.
`8/2007 Boom et a1.
`6/2009 Vermeulen et al.
`5/2011 Lewyn-Briscoe et al.
`10/2012 Francois et al.
`
`FOREIGN PATENT DOCUMENTS
`
`WO
`W0
`WO
`WO
`WO
`WO
`WO
`
`2004/010981
`WO 2006/114384
`2008/021342
`2009/025859
`2009/047499
`2009/080651
`2011/053829
`
`2/2004
`11/2006
`2/2008
`2/2009
`4/2009
`7/2009
`5/2011
`
`OTHER PUBLICATIONS
`
`Alphs L, Bossie C, Sliwa JK, Ma YW, Haskins T Tolerability 0f
`Paliperidone Palmitate Initiation Doses in Subjects With Recently
`
`Diagnosed Schizophrenia. Poster N0. NR6-21 at the 163rd Annual
`Meeting of the American Psychiatric Association (APA), New
`Orleans, Louisiana, USA, May 22-26, 2010.
`Alphs L, Haskins, Bossie C, Sliwa JK, Gopal S, Hough D, Davis J
`Long-term Metabolic Outcomes With Paliperidone Palmitate, A
`Once-Monthly Long-Acting Inj ectable Antipsychotic Agent, in the
`Treatment of Subjects With Schizophrenia. Poster N0. 204 at the
`48th Annual Meeting
`of
`the American
`College
`of
`Neuropsychopharmacology (ACNP), Hollywood, Florida, USA,
`December 6-10, 2009.
`Cleton A, Rossenu S, Crauwels H, Berwaerts J, Hough D, Gopal S,
`Eerdekens M, Vandebosch A, Rosso Fernandez C Assessment of the
`Dose Proportionality 0f Paliperidone Palmitate 25, 50, 100 and 150
`mg eq., A New Long-Acting Injectable Antipsychotic, Following
`Administration in the Deltoid 0r Gluteal Muscles. Poster at the 2008
`Annual Meeting of the American Society for Clinical Pharmacology
`and Therapeutics (ASCPT), Orlando, Florida, USA, Apr. 2-5, 2008.
`Coppola D, Liu Y, Gopal S, Remmerie B, Samtani M, Pandina G,
`Hough D, Nuamah I, Sulaiman A Long-Term Safety, Tolerability
`and Pharmacokinetics of Paliperidone Palmitate 234 mg (150 mg
`eq.), The Highest Marketed Dose: A One-Year Open-Label Study in
`Patients With Schizophrenia. Poster N0. PI-49 at the 2010 Annual
`Meeting of the American Society for Clinical Pharmacology and
`Therapeutics (ASCPT), Atlanta, Georgia, USA, Mar. 17-20, 2010.
`Gopal S, Berwaerts J, Nuamah I, Akhras K, Coppola D, Daly E,
`Hough DW, Palumbo JM Efficacy and Safety of Long-Acting
`Injectable Paliperidone Palmitate Relative
`to Long-Acting
`Haloperidol, Bromperidol and Fluphenazine Decanoate for Long-
`Term Treatment
`in Patients With Schizophrenia Using Number
`Needed to Treat and Number Needed to Harm. Poster at the 65th
`Annual Convention and Scientific Program of the Society of Bio-
`logical Psychiatry (SOBP), New Orleans, Louisiana, USA, May
`20-22, 2010.
`Gopal S, Gassmann-Mayer C, Palumbo J, Samtani MN, Shiwach R,
`Alphs L, Practical Guidance for Dosing and Switching Paliperidone
`Palmitate Treatment in Patients with Schizophrenia, Current Medi-
`cal Research and Opinion 26 (2), p. 377-387, 2010.
`Gopal S, Hough DW, Xu H, Lull JM, Gassmann-Mayer C, Rem-
`merie BM, Eerdekens MH, Brown DW, Eificacy and Safety of
`Paliperidone Palmitate in Adult Patients with Acutely Symptomatic
`Schizophrenia: A Randomized, Double-Blind, Placebo-Controlled,
`Dose-Response Study, International Clinical Psychopharmacology,
`pp. 247-256 (2010).
`Gopal S, Lindenmayer JP, Hough D, Melkote R, Lim P, Eerdekens
`M, Safety and Tolerability 0f the Investigational Antipsychotic
`Paliperidone Palmitate Injected in the Deltoid 0r Gluteus Muscle in
`Patients with Schizophrenia, 63rd Annual Convention and Scientific
`Program of the Society of Biological Psychiatry (SOBP), Washing-
`ton, DC, USA, May 1-3, 2008, Biological Psychiatry 63 (7, Suppl.
`7), p. 285S, 2008.
`Gopal S, Vijapurkar U, Lim P, Morozova M, Eerdekens M Long-
`Term Eflicacy, Safety and Tolerability 0f Paliperidone Palmitate in
`Patients with Schizophrenia. Poster N0. 20 at the 12th Annual
`Meeting of the College of Psychiatric and Neurologic Pharmacists
`(CPNP), Jacksonville, Florida, Apr. 19-22, 2009.
`(Continued)
`
`Primary Examiner 7 Sreeni Padmanabhan
`Assistant Examiner 7 Jody Karol
`
`(57)
`
`ABSTRACT
`
`The present invention provides a method of treating patients
`in need of treatment with long acting inj ectable paliperidone
`palmitate formulations.
`
`21 Claims, 3 Drawing Sheets
`
`Mylan v. Janssen (IPR2020-00440) EX. 1001 p. 001
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1001 p. 001
`
`

`

`US 9,439,906 B2
`Page 2
`
`(56)
`
`References Cited
`
`OTHER PUBLICATIONS
`
`Haskins JT, Sliwa JK, Ma YW, Pandina GJ, Palumbo J Elficacy and
`Safety of 234 mg Initation Dose and 3-Fixed Maintenance Doses of
`Paliperidone PalmitateiA Once-Monthly Injectable Atypical
`Antipsychotic. Poster No. 123 at the 22nd US Psychiatric and
`Mental Health Congress (USPMHC), Las Vegas, Nevada, USA,
`Nov. 2-5, 2009.
`Hough D, Gopal S, Vijapurkar U, Lim P, Morozova M, Eerdekens
`M Paliperidone Palmitate, an Atypical Injectable Antipsychotic, In
`Prevention of Symptom Recurrence in Patients with Schizophrenia:
`A Randomized, Double-Blind, Placebo Controlled Study. Poster at
`the 63rd Annual Convention and Scientific Program of the Society
`of Biological Psychiatry (SOBP), Washington, DC, USA, May 1-3,
`2008.
`Hough D, Gopal S, Vijapurkar U, Lim P, Morozova M, Eerdekens
`M, Paliperidone Palmitate in Prevention of Symptom Recurrence in
`Patients with Schizophrenia: A Randomized, Double-Blind, Pla-
`cebo-Controlled Study, l6lst Meeting of the American Psychiatric
`Association (APA), Washington, DC, USA, May 3-8, 2008, Pro-
`ceedings/AbstractBook, p. 173, No. NR4-029, 2008.
`Hough D, Lindenmayer JP, Gopal S, Melkote R, Lim P, Herben V,
`Yuen E, Eerdekens M, Safety and Tolerability of Deltoid and
`Gluteal Injections of Paliperidone Palmitate in Schizophrenia, Prog-
`ress in Neuro-Psychopharmacology and Biological Psychiatry 33
`(6), p. 1022-1031, 2009.
`Kozma C, Dirani R, Nicholl D, Akhras K Evaluation of the
`Relationships Among Change in Function, Symptoms, and Duration
`of Schizophrena. Poster No. NR6-4 at the 163rd Annual Meeting of
`the American Psychiatric Association (APA), New Orleans, Loui-
`siana, USA, May 22-26, 2010.
`Kramer M, Litman R, Hough D, Lane R, Lim P, Eerdekens M A
`9-Week, Placebo-Controlled Study in Schizophrenia Patients: Elfi-
`cacy and Safety of the Long-Acting Injectable Agent, Paliperidone
`Palmitate. Poster No. 4-072 at the l6lst Meeting of the American
`Psychiatric Association (APA), Washington, DC, USA, May 3-8,
`2008.
`Kramer M, Litman R, Lane R, Lim P, Hough D, Palumbo J,
`Eerdekens M Efficacy and Tolerability of Two Fixed Dosages of
`Paliperidone Palmitate in the Treatment of Schizophrenia: Results
`of a 9-Week Placebo-Controlled Trial. Poster at
`the 20th US
`Psychiatric and Mental Health Congress (USPMHC), Orlando,
`Florida, USA, Oct. 11-14, 2007.
`Pandina G, Lane R, Gopal S, Gassmann-Mayer C, Hough D,
`Remmerie B, Simpson G A Randomized, Double-Blind, Compara-
`tive Study of Flexible Doses of Paliperidone Palmitate and
`Risperidone Long-Acting Therapy in Patients with Schizophrenia.
`Poster at
`the 48th Annual Meeting of the American College
`Neuropsychopharmacology (ACNP), Hollywood, Florida, USA,
`Dec. 6-10, 2009.
`Pandina GJ, Lindenmayer JP, Lull J, Lim P, Gopal S, Kusumakar V,
`Yuen E, Palumbo J A Randomized, Placebo-Controlled Study to
`Assess the Efiicacy and Safety of Three Doses of Paliperidone
`Palmitate in Adults with an Acute Exacerbation of Schizophrenia.
`Poster at
`the 12th International Congress on Schizophrenia
`Research (ICOSR), San Diego, California, USA, Mar. 28-Apr. 1,
`2009.
`Pandina GJ, Lindenmayer JP, Lull J, Lim P, Gopal S, Kusumakar V,
`Yuen E, Palumbo J A Randomized, Placebo-Controlled Study to
`Assess the Efiicacy and Safety of Three Doses of Paliperidone
`Palmitate in Adults with an Acute Exacerbation of Schizophrenia.
`Poster at the 12th Annual Meeting of the College of Psychiatric and
`Neurologic Pharmacists (CPNP), Jacksonville, Florida, Apr. 19-22,
`2009.
`Samtani MN, Gopal S, Kern Sliwa J, Haskins JT, Alphs L,
`Stuyckens K, Vermeulen A Management of Missed Paliperidone
`Palmitate Doses Based on Pharmacokinetic Modeling and Simula-
`tion. Poster at the 49th Annual Meeting of the New Clinical Drug
`Evaluation Unit (NCDEU) of the National Institute of Mental
`Health (NIMH), Hollywood, Florida, USA, Jun. 29-Jul. 2, 2009.
`
`Samtani MN, Gopal S, Kern Sliwa J, Haskins JT, Alphs L,
`Stuyckens K, Vermeulen A, Switching to Paliperidone Palmitate
`From Other Antipsychotics: Guidance Based on Pharmacokinetic
`Modeling and Simulation, 49th Annual Meeting of the New Clinical
`Drug Evaluation Unit (NCDEU) of the National Institute of Mental
`Health (NIMH), Hollywood, Florida, USA, Jun. 29-Jul. 2, 2009,
`Proceedings/AbstractBook, p. 68, 2009.
`Samtani MN, Gopal S, Kern Sliwa J, Haskins T, Alphs L, Stuyckens
`K, Vermeulen A Paliperidone Palmitate Dosing in Special Patient
`Populations Including the Elderly and Those With Renal Impair-
`ment or Differing Body Mass
`Index: Guidance Based on
`Pharmacokinetic Modeling and Simulation. Poster at the American
`Conference on Pharmacometrics, Mashantucket, Connecticut, USA,
`Oct. 4-7, 2009.
`Samtani MN, Haskins JT, Alphs L, Sliwa JK, Stuyckens K, Herben
`V, Vermeulen A Maintenance Dosing of Once-Monthly (4-Weekly)
`Paliperidone Palmitate in Schizophrenia: Pharmacokinetic Ratio-
`nale Based on Population Simulations. Poster No. 21 at the 12th
`Annual Meeting of the College of Psychiatric and Neurologic
`Pharmacists (CPNP), Jacksonville, Florida, Apr. 19-22, 2009.
`Samtani MN, Haskins JT, Gopal S, Sliwa JK, Alphs L, Stuyckens
`K, Vermeulen A Dosing Information for Paliperidone PalmitateiA
`Once-Monthly Injectable Atypical AntipsychoticiBased on Popu-
`lation Pharmacokinetic Analysis. Poster No. 310 at the 22nd US
`Psychiatric and Mental Health Congress (USPMHC), Las Vegas,
`Nevada, USA, Nov. 2-5, 2009.
`Samtani MN, Sliwa JK, Haskins JT, Alphs L, Stuyckens K, Herben
`V, Vermeulen A Initiation Dosing of Deltoid Intramuscular
`Paliperidone Palmitate in Schizophrenia: Pharmacokinetic Ratio-
`nale Based on Modeling and Simulation. Poster No. 19 at the 12th
`Annual Meeting of the College of Psychiatric and Neurologic
`Pharmacists (CPNP), Jacksonville, Florida, Apr. 19-22, 2009.
`Samtani MN, Vermeulen A,
`Stuyckens K,
`Population
`Pharmacokinetics of
`Intramuscular Paliperidone Palmitate in
`Patients with Schizophrenia A Novel Once-Monthly, Long-Acting
`Formulation of an Atypical Antipsychotic, Clinical Pharmacokinet-
`ics 48 (9), p. 585-600, 2009.
`Sikirica M, Crivera C, Dirani R, Cost-Effectiveness of Paliperidone
`Palmitate Versus Oral Atypicals in the US. Poster No. NR6-5 at the
`163rd Annual Meeting of the American Psychiatric Association
`(APA), New Orleans, Louisiana, USA, May 22-26, 2010.
`Turner N, Bossie CA, Haskins JT, Kern Sliwa J, Ma YW, Alphs L
`Effects of Paliperidone Palmitate in Acutely ill Subjects With a
`Marked to Severe Exacerbation of Schizophrenia. Poster No. NR6-
`26 at
`the 163rd Annual Meeting of the American Psychiatric
`Association (APA), New Orleans, Louisiana, USA, May 22-26,
`2010.
`Alphs et al., “Are the Long-Acting Intramuscular Formulations of
`Risperidone or Paliperidone Palmitate Associated with Post-Injec-
`tion Delirium/Sedation Syndrome? An Assessment of Safety Data-
`bases”, Current Drug Safety, 2011, 6, 43-45.
`Alphs et al., “Paliperidone Palmitate Versus Risperidone Long-
`Acting Therapy in Markedly to Severely ill Subjects With Schizo-
`phrenia”, Poster presented at the 23rd Annual US Psychiatric and
`Mental Health Congress; Supported by Ortho-McNeil Janssen Sci-
`entific Affairs, LLC Nov. 18-21, 2010; Orlando, FL, USA.
`Alphs et al., “Tolerability of Paliperidone Palmitate Initiation Doses
`in Subjects with Recently Diagnosed Schizophrenia”, Poster hand-
`out presented at The Scientific Program of XXVII CINP Congress,
`Hong Kong. Jun. 6-10, 2010.
`Alphs et al., “Tolerability of Paliperidone Palmitate Initiation Doses
`in Subjects with Recently Diagnosed Schizophrenia”, Poster pre-
`sented at The Scientific Program of XXVII CINP Congress, Hong
`Kong. Jun. 6-10, 2010.
`Cleton et al., Clinical Pharmacology & Therapeutics, Mosby-Year
`Book, St. Louis, MO, US, vol. 81, No. Suppl. 1, p. S63 (2007).
`Cockcroft et al., Prediction of creatinine clearance from serum
`creatinine, Nephron, 16:31-41, 1976.
`“A randomized trial of
`Fleischhacker, W. Wolfgang et
`al.,
`paliperidone palmitate and risperidone long-acting injectable in
`schizophrenia”, International Journal of Neuropsychopharmacol-
`ogy, pp. 1-12, CINP 2011.
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1001 p. 002
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1001 p. 002
`
`

`

`US 9,439,906 B2
`
`Page 3
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Gopal et al., “A 52-week open-label study of the safety and
`tolerability of paliperidone palmitate in patients with schizophre-
`nia”, JPsychopharmacol. 2010; First View: 1-13.
`Gopal et al., “Dosing Information for Paliperidone PalmitateiA
`Once-Monthly Injectable Atypical AntipsychoticiBased on Popu-
`lation Pharmacokinetic Analysis”, Poster presented at The Scientific
`Program of XXVII CINP Congress, Hong Kong. Jun. 6-10, 2010.
`Gopal et al., “Elficacy and safety of paliperidone palmitate in adult
`patients with acutely symptomatic schizophrenia: a randomized,
`double-blind, placebo-controlled, dose-response study”,
`Interna-
`tional Clinical Psychopharmacology 2010, vol. 25 No. 5, pp.
`247-256.
`Gopal et al., Risk of Cardiovascular Morbidity and Sudden Death
`with Risperidone and Paliperidone Treatment: Analysis of 64 Ran-
`domized, Double-Blind Trials, NR 10-24 Presented at the 164th
`Annual MeetingiAmerican Psychiatric Association, May 14-18,
`2011; Honolulu, Hawaii.
`Hough et al., “Paliperidone palmitate maintenance treatment in
`delaying the time-to-relapse in patients with schizophrenia: A
`randomized, double-blind, placebo-controlled study”, Schizophre-
`nia Research 116 (2010) 107-117.
`Hough et al., “Safety and tolerability of deltoid and gluteal injec-
`tions
`of paliperidone
`palmitate
`in
`schizophrenia”, Prog
`Neuropsychopharmacol Biol Psychiatry. 2009;33:1022-1031.
`Li et al., “A Comparative Randomized, Open-label, Rater-blinded
`Study of Paliperidone Palmitate and Risperidone Long-Acting
`Injectable Therapy in Patients with Schizophrenia”, Poster No.
`P-11-005 presented at the XXVII CINP Congress, Jun. 6-10, 2010;
`Hong Kong.
`“A Controlled, Evidence-Based Trial of
`al.,
`Nasrallah et
`Paliperidone Palmitate, A Long-Acting Injectable Antipsychotic, in
`Schizophrenia”, Neuropsychopharmacology (2010) 35, 2072-2082.
`Pandina et al., “A double-blind study of paliperidone palmitate and
`risperidone long-acting injectable in adults with schizophrenia”,
`Progress in Neuro-Psychopharmacology & Biological Psychiatry
`2011;35:218-226.
`Pandina et al., “A randomized, placebo-controlled study to assess
`the efficacy and safety of 3 doses of paliperidone palmitate in adults
`with acutely exacerbated schizophrenia”, J Clin Psychopharmacol.
`2010;30:235-244.
`Revill et al., Drugs of the Future, Prous Science, ES, vol. 31, No.
`7, pp. 579-584 (2006).
`Samtani et al., “Dosing and Switching Strategies for Paliperidone
`Palmitate”, CNS Drugs 2011; 25(10): 829-845.
`Samtani et al., “Expansion of Paliperidone Palmitate Day 8 Dose
`Window from t 2 Days to t 4 Days: Model-Based Pharmacokinetic
`Simulation and Safety Data”, Poster presented at the 24th Annual
`U.S. Psychiatric and Mental Health Congress Meeting, Nov. 7-10,
`2011, Las Vegas, Nevada.
`Samtani et al., “Expansion of Paliperidone Palmitate Day 8 Dose
`Window from t 2 Days to t 4 Days: Model-Based Pharmacokinetic
`Simulation and Safety Data”, Poster handout presented at the 24th
`Annual U.S. Psychiatric and Mental Health Congress Meeting, Nov.
`7-10, 2011, Las Vegas, Nevada.
`Samtani et al., “Switching to Paliperidone Palmitatel'2 from Other
`Depot Antipsychotics Guidance Based on Pharmacokinetic Simu-
`lations”, Population Approach Group in Europe, Applicationsi
`CNS (Group IV) Abstr 1839, Berlin, Germany. Jun. 8-11, 2010.
`Samtani, Mahesh N., “Use of Model Based Simulations to Support
`the Paliperidone Palmitate Label”, AAPS Workshop on Facilitating
`Oral Product Development and Reducing Regulatory Burden
`through
`Novel Approaches
`to
`Assess
`Bioavailability/
`Bioequivalence, Oct. 22-23, 2011, Washington.
`Sheehan et al., “The Management of Antipsychotic Treatment
`Discontinuation and Interruptions Using Model-Based Simula-
`tions”, Poster presented at the 5 lst Annual NCDEU New Research
`Approaches for Mental Health Interventions Meeting, Jun. 13-16,
`2011, Boca Raton, Florida.
`
`Sliwa et al., “Tolerability and Elficacy of Paliperidone Palmitate vs
`Risperidone Long-acting Injection in Subjects with Recently Diag-
`nosed Schizophrenia”, Presented at the 13th International Congress
`on Schizophrenia Research; Apr. 2-6, 2011; Colorado Springs,
`Colorado, USA.
`Alen et al., Ansel’s Pharmaceutical Dosage Forms and Drug Deliv-
`ery Systems, 8”“ Edition, 2005; pp. 260-263, 652-653, 682.
`Guidance Document: Patented Medicines (Notice of Compliance)
`Regulations, Health Canada, Nov. 12, 2010.
`New Drug Application (NDA) dated Oct. 25, 2007 submitted under
`section 505(b) of the Federal Food, Drug, and Cosmetic Act for
`Invega Sustenna (paliperidone palmitate) 39mg, 78mg, 117mg,
`156mg, and 234 mg extended-release injectable suspension, date of
`letter is Jul. 31, 2009.
`Supplemental New Drug Application (sNDA) dated Mar. 14, 2011,
`submitted under section 505(b) of the Federal Food, Drug, and
`Cosmetic Act (FDCA) for Invega Sustenna (paliperidone palmitate)
`extended-release injectable suspension, 39 mg, 78 mg, 117 mg, 156
`mg, and 234 mg.
`Alphs et a1. Annals of General Psychiatry 2011, 10:12.
`Altamura et al., Intramuscular preparations of antipsychotics: uses
`and relevance in clinical practice. Drugs. 2003; 63(5): 493-512.
`Berwaerts et al., Journal ofAffective Disorders 138 (2012) 247-258.
`Canuso et al. 2010, Expert Opinion Pharmacother., vol. 11 (15), pp.
`2557-2567.
`the Dose Proportionality of
`al., Assessment of
`Cleton et
`Paliperidone Palmitate 25, 50, 100 and 150 MG EQ., A New
`Long-Acting Injectable Antipsychotic Following Administration in
`the Deltoid or Gluteal Muscles, PI-74, Clinical Pharmacology &
`Therapeutics, vol. 83, Supplement 1, Mar. 2008, S31.
`Ereshefsky L., Pharmacokinetics and drug interactions: update for
`new antipsychotics. J Clin Psychiatry. 1996;57 Suppl 11:12-25.
`Gefvert et a1. Pharmacokinetics and D2 receptor occupancy of
`long-acting injectable risperidone (Risperdal Consta) in patients
`with schizophrenia.
`Int J Neuropsychopharmacol. 2005; 8(1):
`27-36.
`Kane et al., Guidelines for depot antipsychotic treatment in schizo-
`phrenia. European Neuropsychopharmacology Consensus Confer-
`ence in Siena, Italy. Eur Neuropsychopharmacol. 1998; 8(1): 55-66.
`Levron et al., Clinical pharmacokinetics of haloperidol decanoate.
`Comparison with other prolonged-action neuroleptics. Encephale.
`1987; 13(2): 83-7 [see English Summary as provided].
`Markowitz et al., “Benefit-Risk Assessment of Maintenance
`Therapy in Schizophrenia Comparing Long-Acting Injectable (LAI)
`Paliperidone Palmitate with Paliperidone ER”, Presented at the
`164th Annual Meeting of the American Psychiatric Association,
`May 14-18, 2011, Honolulu, HI, USA.
`Mauri et al., Clinical pharmacokinetics of atypical antipsychotics: a
`critical review of the relationship between plasma concentrations
`and clinical response. Clin Pharmacokinet. 2007;46(5):359-88.
`Pandina et al., Progress in Neuro-Psychopharmacology & Biologi-
`cal Psychiatry 35 (2011) 218-226.
`Sheehan et al., Comparison of the Peak-to-trough Fluctuation in
`Plasma Concentration of Long-acting Inj ectable Antipsychotics and
`Their Oral Equivalents, Irmov Clin Neurosci. 2012;9(7-8):17-23.
`Vermeir
`et
`al., Absorption, metabolism,
`and excretion of
`paliperidone, a new monoaminergic antagonist, in humans. Drug
`Metab Dispos. Apr. 2008;36(4):769-79.
`Lewyn-Briscoe et al., US. Appl. No. 13/903,638.
`International Search Report Re: International Application No. PCT/
`US2010/054807 dated Jan. 11, 2011.
`Office Action mailed Feb. 28, 2013 in US. Appl. No. 12/916,910.
`Kazuo Yamada et al., Future Potentiality of Pharmacotherapy for
`Schizophrenia in Acute Phase, Clinical Psychopharmacology, vo. 8,
`No. 10 (2005), pp. 1563-1568.
`Takashi Yoshio, Sustained-release Antipsychotic Drugs (depot
`drugs), Psychiatric Nursing, vol. 33, No. 4 (2006), pp. 64-67.
`Gibaldi’s Drug Delivery Systems in Pharmaceutical Care. edited by
`Mary Lee, Archana Desai, American Society of Health-System
`Pharmacists, Inc. (2007), pp. 103-108.
`Third Party Observations filed during prosecution of corresponding
`EP Appl No. 088635347.
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1001 p. 003
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1001 p. 003
`
`

`

`US 9,439,906 B2
`Page 4
`
`(56)
`
`References Cited
`OTHER PUBLICATIONS
`
`Australian Patent Opposition for AU Patent Appl No. 2008340101
`dated May 20, 2015.
`Statement of Grounds and Particulars dated Aug. 19, 2015 re:
`Australian Patent Opposition for AU Patent Appl No. 2008340101.
`Cleton A, Rossenu S, Crauwels H, et al. A single-dose, open-label,
`parallel, randomized, dose-proportionality study of paliperidone
`after intramuscular injections of paliperidone palmitate in the del-
`toid or gluteal muscle in patients with schizophrenia. J Clin
`Pharmacol. 2014;54(9):1048-1057.
`Cleton A, Rossenu S, Hough D, Crauwels H, Vandebosch A,
`Berwaerts J, Eerdekens M, Francetic,
`I. “Evaluation of the
`pharmacokinetic profile of gluteal versus deltoid intramuscular
`Injections of paliperidone palmitate 100 mg equivalent in patients
`with schizophrenia” Clin.Pharmacal. Therapeutics. Published Mar.
`2008.
`Cockshott WP, Thompson GT, Howlett LJ, Seeley ET. Intramus-
`cular
`or
`intralipomatous
`injections? N Engl
`J Med.
`1982;307(6):356-358.
`Haramati N, Lorans R, Lutwin M, Kaleya RN. Injection granulo-
`mas. Intramuscle or intrafat? Arch Fam Med. 1994;3(2):146-148.
`Janicak, P. G. and Winans, E. A. “Paliperidone ER: a review of the
`clinical trial data” Neuropsychiatr. Dis. Treat. Dec. 3, 2007(6):
`869-897 Published Jan. 15, 2008.
`Rosen, H, and Abribat, T. “The rise and rise of drug delivery” Nat.
`Rev. Drug Discov. May 4, 2005(5): 381-5.
`
`Rossenu S, Cleton A, Hough D, et al. Pharmacokinetic profile after
`multiple deltoid or gluteal intramuscular injections of paliperidone
`palmitate in patients With schizophrenia. Clinical Pharmacology in
`Drug Development. 2015;4(4):270-278.
`Population
`Samtani MN, Vermeulen A,
`Stuyckens K.
`pharmacokinetics of
`intramuscular paliperidone palmitate in
`patients with schizophrenia: a novel once-monthly,
`long-acting
`formulation of an atypical antipsychotic. Clin Pharmacokinet.
`2009;48(9):585-600.
`Synopsis of the Phase III clinical study described at Example 8 of
`the opposed application accessed at http://yoda.yale.edu/sites/de-
`fault/files/nct00590577.pdf on Aug. 17, 2015, Issue Date: Sep. 12,
`2008.
`Yin J, Collier AC, Barr AM, Honer WG, Procyshyn RM.
`Paliperidone Palmitate Long-Acting Injectable Given Intramuscu-
`larly in the Deltoid Versus the Gluteal Muscle: Are They Thera-
`peutically Equivalent? J Clin Psychopharmacol. 2015;35(4):447-
`449.
`Kreyenbuhi, et al., “Adding or Switching Antipsychotic Medica-
`tions in Treatment-Refractory Schizophrenia”, Psychiatr Serv., Jul.
`2007, pp. 983-990, vol. 58(7).
`Third Party Observations dated Jan. 28, 2016 filed during prosecu-
`tion of EP Application No. 107738213.
`Office Action mailed Mar. 24, 2015 in US. Appl. No. 13/903,638.
`Final Office Action mailed Oct. 22, 2015 in US. Appl. No.
`13/903,638.
`Cirincione, et al., “Population pharmacokinetics of paliperidone ER
`in healthy subjects and patients with schizophrenia”, clinical Phar-
`macology & Therapeutics, vol. 81, Issue Supplement SI, P. 819
`(published in Mar. 2007).
`
`Mylan v. Janssen (IPR2020-00440) EX. 1001 p. 004
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1001 p. 004
`
`

`

`U.S. Patent
`
`Sep. 13, 2016
`
`Sheet 1 of3
`
`US 9,439,906 B2
`
`
`
`Piassma Cancentratian
`
`39g} .
`
`40 ..
`
`20 -
`
`75 .
`
`35
`
`ng/mé
`
`0.3 -
`
`”$8
`22
`36
`50 64
`78
`
`03$
`
`
`
`92 ӣ069.20
`
`Days
`
`Mylan V. Janssen (IPR2020-00440) EX. 1001 p. 005
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1001 p. 005
`
`

`

`U.S. Patent
`
`Sep. 13, 2016
`
`Sheet 2 of 3
`
`US 9,439,906 B2
`
`
`
`PQSfixaConcenUafign
`
`nghni
`
`-352
`
`35"
`
`(13 ..
`
`..
`
`..
`
`..
`
`..
`
`.
`
`{3.1
`
`18 22
`
`36
`
`5Q 64
`
`7'8
`
`92 366120
`
`Bay$
`
`Mylan V. Janssen (IPR2020-00440) EX. 1001 p. 006
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1001 p. 006
`
`

`

`U.S. Patent
`
`Sep. 13, 2016
`
`Sheet 3 of 3
`
`US 9,439,906 B2
`
`
`
`Piasma 6011118111218th
`
`250 ..
`
`..
`
`..
`
`..
`
`..
`
`..
`
`..
`
`..
`
`.,
`
`3,5
`
`11113
`
`~~
`
`.
`
`40 N ’
`
`20
`
`7.5
`
`ng/m§
`
`Q3 ..
`
`9.3
`
`1822 36
`
`50
`
`64 78
`
`92 1061211
`
`Days
`
`Mylan V. Janssen (IPR2020-00440) EX. 1001 p. 007
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1001 p. 007
`
`

`

`US 9,439,906 B2
`
`1
`DOSING REGIMEN ASSOCIATED WITH
`LONG ACTING INJECTABLE
`PALIPERIDONE ESTERS
`
`CROSS REFERENCE TO RELATED
`APPLICATIONS
`
`This application claims the benefit of US. Provisional
`Application 61/014,918, filed on Dec. 19, 2007 and US.
`Provisional Application 61/120,276, filed on Dec. 5, 2008.
`
`FIELD OF THE INVENTION
`
`This invention relates to a method of treating patients in
`need of treatment with long acting injectable paliperidone
`palmitate formulations.
`
`BACKGROUND OF THE INVENTION
`
`Antipsychotic medications are the mainstay in the treat-
`ment of schizophrenia, schizoalfective disorder, and schizo-
`phreniforrn disorders. Conventional antipsychotics were
`introduced in the mid-1950s. These typical or first genera-
`tion drugs are usually effective in controlling the positive
`symptoms of schizophrenia, but are less effective in mod-
`erating the negative symptoms or the cognitive impairment
`associated with the disease. Atypical antipsychotics or sec-
`ond generation drugs, typified by risperidone and olanzap-
`ine, were developed in the 1990s, and are generally char-
`acterized by effectiveness against both the positive and
`negative symptoms associated with schizophrenia.
`Paliperidone palmitate is the palmitate ester of paliperi-
`done (9-hydroxy-risperidone), a monoaminergic antagonist
`that exhibits the characteristic dopamine D2 and serotonin
`(5-hydroxytryptamine type 2A) antagonism of the second-
`generation, atypical antipsychotic drugs. Paliperidone is the
`major active metabolite of risperidone. Extended release
`(ER) osmotic controlled release oral delivery (OROS) pali-
`peridone, as a tablet formulation, is marketed in the United
`States (US) for the treatment of schizophrenia and main-
`tenance of effect.
`
`Paliperidone palmitate is being developed as a long-
`acting, intramuscular (i.m.), injectable aqueous nanosuspen-
`sion for the treatment of schizophrenia and other diseases
`that are normally treated with antipsychotic mediations.
`Because of extreme low water solubility, paliperidone esters
`such as paliperidone palmitate dissolve slowly after an i.m.
`injection before being hydrolyzed to paliperidone and made
`available in the systemic circulation.
`Many patients with these mental illnesses achieve symp-
`tom stability with available oral antipsychotic medications;
`however,
`it
`is estimated that up to 75% have difficulty
`adhering to a daily oral treatment regimen, i.e. compliance
`problems. Problems with adherence often result in worsen-
`ing of symptoms, suboptimal treatment response, frequent
`relapses and re-hospitalizations, and an inability to benefit
`from rehabilitative and psychosocial therapies.
`Paliperidone palmitate injection has been developed to
`provide sustained plasma concentrations of paliperidone
`when administered once monthly, which may greatly
`enhance compliance with dosing. Paliperidone palmitate
`was formulated as an aqueous nano suspension as is
`described in US. Pat. Nos. 6,577,545 and 6,555,544. How-
`ever, after the data was analyzed from the clinical trials of
`this formulation it was discovered that the absorption of
`paliperidone from these injections was far more complex
`than was originally anticipated. Additionally, attaining a
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`2
`
`potential therapeutic plasma level of paliperidone in patients
`was discovered to be dependent on the site of injection until
`steady state concentration is reached. Due to the challenging
`nature of ensuring an optimum plasma concentration-time
`profile for treating patients with paliperidone it is desirable
`to develop a dosing regimen that fulfills this goal in patients
`in need of treatment.
`
`SUMMARY OF THE INVENTION
`
`invention there is
`In one embodiment of the present
`provided a dosing regimen for administering paliperidone
`esters to a psychiatric patient in need of treatment compris-
`ing administering intramuscularly in the deltoid a first
`loading dose from about 100 mg-eq. to about 150 mg-eq. of
`paliperidone as a paliperidone palmitate formulated in a
`sustained release formulation on the first day of treatment;
`administering intramuscularly a second loading dose from
`about 100 mg to about 150 mg-eq of paliperidone as a
`paliperidone palmitate formulated in a sustained release
`formulation between about the 6th to 10th day of treatment;
`and administering intramuscularly in the gluteal a mainte-
`nance dose of about 25 to about 150 mg-eq. of paliperidone
`as a paliperidone ester in a sustained release formulation on
`between about the 34th and about the 38th day of treatment.
`In one embodiment of the present
`invention there is
`provided a dosing regimen for administering paliperidone
`esters to a psychiatric patient in need of treatment compris-
`ing administering intramuscularly in the deltoid a first
`loading dose from about 100 mg-eq. to about 150 mg-eq. of
`paliperidone as a paliperidone palmitate formulated in a
`sustained release formulation on the first day of treatment;
`administering intramuscularly a second loading dose from
`about 100 mg to about 150 mg-eq of paliperidone as a
`paliperidone palmitate formulated in a sustained release
`formulation between about the 6th to 10th day of treatment;
`and administering intramuscularly in the gluteal a mainte-
`nance dose of about 25 to about 150 mg-eq. of paliperidone
`as a paliperidone ester in a sustained release formulation
`approximately monthly from the date of the second loading
`dose.
`
`In another embodiment of the present invention there is
`provided a dosing regimen for administering paliperidone
`palmitate to a psychiatric patient
`in need of treatment
`comprising administering intramuscularly in the deltoid of a
`patient in need of treatment a first loading dose from about
`100 mg-eq. to about 150 mg-eq of paliperidone as paliperi-
`done palmitate formulated in a sustained release formulation
`on the first day of treatment; administering intramuscularly
`in the deltoid muscle of the patient in need of treatment a
`second loading dose from about 100 mg-eq. to about 150
`mg-eq. of paliperidone as paliperidone palmitate formulated
`in a sustained release formulation on the eighth day of
`treatment; and administering intramuscularly in the deltoid
`or gluteal muscle of the patient
`in need of treatment a
`maintenance dose of about 25 mg-eq. to about 75 mg-eq. of
`paliperidone as paliperidone palmitate in a sustained release
`formulation on between about the 34th day and the 38th day
`of treatment.
`
`In another embodiment of the present invention there is
`provided a dosing regimen for administering paliperidone
`palmitate to a psychiatric patient
`in need of treatment
`comprising administering intramuscularly in the deltoid of a
`patient in need of treatment a first loading dose of about 150
`mg-eq of paliperidone as paliperidone palmitate formulated
`in a sustained release formulation on the first day of treat-
`ment; administering intramuscularly in the deltoid muscle of
`
`Mylan v. Janssen (IPR2020-00440) Ex. 1001 p. 008
`
`Myl