Edited by
`Janos Fischer and
`C. Robin Canel/in
`
`An alogue-based Drug
`Discovery II
`
`MPI EXHIBIT 1033 PAGE 1
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0001
`
`

`

`Edited by
`Janos Fischer and C. Robin Canel/in
`
`Analogue-based Drug Discovery II
`
`@
`
`WILEY(cid:173)
`VCH
`WILEY-VCH Verlag GmbH & Co. KGaA
`
`MPI EXHIBIT 1033 PAGE 2
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0002
`
`

`

`The Editors
`
`Prof. Dr. Janos Fischer
`Richter Pie
`Cyomroi uL 30
`1103 Budapest
`llungary
`
`Prof. Dr. C. Robin Co"11IJin
`University College London
`Department of Chemistry
`20 Gordon SLCccL
`London WCIH OAf
`United Kingdom
`
`Supported by
`
`The lntcrnational Union of Pure and Applied
`Chemist,y (IUPAC)
`Chemistry and Human Health Devision
`PO Box 13757
`Rcsca,ch Triangle Park, NC 27709-3757
`USA
`
`Ail books published by Wilcy-VCJ·I arc =cfully
`produced. Nevertheless. authors, editors. and
`publisher do not warrant lbe information conlaincd
`in these books, including this book, lo be free of
`errors. Rc,ders ,re advised Lo ke<>p in mind UUL
`statements, data, illustrations, procedural details or
`olbcr items may i!ladvcrtcntly be inaccura Le.
`
`1
`
`Lib,2.ry ofC<>ngn:u::.c C2rd No.~ :.pplicd ror
`
`British Library Cataloguing-in-Publication Data
`A catalogue record for this book is available from lhc
`British fj brary.
`
`Bibliographic in~rmation publi.shed by
`the Deutsche Nationalbibliothek
`The DcuL~chc Nationalbibliolhck lisL, this
`publication in the Deutsche Nationalbibliografic;
`detailed bibliographic data arc available on U1c
`Internet at hLtp://dnb.d-nb.de.
`
`© 2010 WILEY.YCI I Verlag GmbH & Co. KGaA,
`Wcinhcim
`
`All righL~ reserved (including those of translation into
`olbcr languages). No part of this book may be
`reproduced in any form - by photoprinting,
`microftlm. or any other means - nor transmitted or
`translated into a machine language without wriucn
`permission from the publishers. Registered names,
`trademarks, etc.. used in th.is book, even wbcn not
`specifically marked as such, arc not Lo be considered
`unprotected by law.
`
`Cove,- Design Ad.am De:sign. Wc inhcim
`Typesetting Thomson Digital, Noida, India
`Printing and Binding Strauss GmbH, Morlcnbacb
`
`Printed in tl1c Federal Republic of Gcrrnwy
`Printed on acid-free paper
`
`ISBN: 978-3-S27·325~9-8
`
`MPI EXHIBIT 1033 PAGE 3
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0003
`
`

`

`Contents
`
`Preface XV
`Introduction XVII
`Abbreviations XXI
`
`Part I
`
`General Aspects 1
`
`O ptimizing Drug Therapy by Analogues 3
`Janos Fischer, C. Robin Canel/in, john Proudfoot, and Erika M. Alapi
`Introduction 3
`Pharmacodynamic Characteristics 4
`Potency 4
`Improving the Ratio of Main Activity and Adverse Effects 5
`Improving Selectivity Through Receptor Subtypes 6
`Improving Selectivity Through Unrelated Receptors 7
`Improving Selectivity by Tissue Distribution 7
`Improving Selectivity of Nonreceptor-Mediated Effects 10
`Improving the Physicochemical Properties with Analogues 10
`Analogues lo Reduce the Resistance to Anti-Infective Drugs 11
`Antibiotics 11
`Antifungal Drugs 12
`Antiviral Drugs 12
`Analogue Research in Resistance to Drug Therapies in Cancer
`Treatment 15
`Pharmacokinetic Characteristics 15
`Improving Oral Bioavailability 15
`Improving Absorption 16
`Improving Metabolic Stability 16
`Drugs with a Long Duration of Action 17
`Ultrashort-Acting Drugs 18
`Decreasing Interindividual Pharm;;cokinetic Differences 20
`Decreasing Systemic Activity 21
`
`1.1
`1.2
`1.2.1
`1.2.2
`1.2.2.1
`1.2.2.2
`1.2.2.3
`1.2.2.4
`1.2.3
`1.2.4
`1.2.4.1
`1.2.4.2
`1.2.4.3
`1.2.5
`
`1.3
`1.3.1
`1.3.1.1
`1.3.1.2
`1.3.2
`1.3.3
`1.3.4
`1.3.S
`
`A11a/otue-based Dr.g Discovery 11. Edited by Janos Fischer and C . Robin Gancllin
`Copyright© 2010 WII.EY-VCl-1 Vctlag Gmbl-1 & Co. KGaA, Wcinhcim
`ISBN: 978-3-527-32549-8
`
`MPI EXHIBIT 1033 PAGE 4
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0004
`
`

`

`VI I Contents
`
`1.4
`1.4.1
`1.4.2
`1.5
`
`2
`
`2.1
`2.2
`2.3
`2.3.1
`
`2.3.2
`2.3.3
`2.4
`2.5
`2.6
`2.7
`2.8
`2.9
`2.10
`
`3
`
`3.1
`3.2
`3.3
`3.4
`3.5
`3.6
`3.7
`
`4
`
`4.1
`4.2
`4.3
`4.4
`4.5
`4.6
`4.7
`
`Drug Interactions 22
`Decreasing Drug Jnteractions 22
`Increasing Drug Interactions 23
`Summary 23
`References 24
`
`Standalone Drugs 29
`Janos Fischer, C. Robin Canel/in, Arun Ganesan, and John Proudfoot
`Acetaminophen (Paracetamol) 30
`Acctylsalicylic Acid (Aspirin) 33
`Aripiprazolc 35
`First Generation "Typical" Antipsychotic Drugs (Other Names:
`Neuroleptics, Conventional Antipsychotics) 36
`Second-Generali.on "Atypical" Antipsychotic Drugs 37
`A New Approach: Aripiprazole, a Dopamine Partial Agonist 38
`Bupropion 39
`Ezetimibe 42
`Lamotrigine 46
`Metformin 47
`Topiramate 49
`Valproate 51
`Summary 52
`References 53
`
`Application of Molecular M odeling in Analogue-Based
`Drug Discovery 61
`Cyorgy C. Ferenczy
`Introduction 61
`Cilazapril: An ACE Inhibitor 62
`Atorvastatin: A HMG-CoA Reductase Inhibitor 66
`PDE4 Inhibitors 70
`GPIIb/IIIa Antagonists 73
`HfV Protease Inhibitors 74
`Epilogue 79
`References 79
`
`Issues for the Patenting of Analogues 83
`Stephen C. Smith
`Introduction 83
`Patents: Some Fundamentals 84
`PatentabilHy 85
`Important Elements of the lnternalional Patent System 86
`Priority 87
`Novelty 88
`Inventive Slep: Nonobviousness 90
`
`MPI EXHIBIT 1033 PAGE 5
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0005
`
`

`

`Contents I VII
`
`4.8
`4.9
`4.10
`4.11
`4.12
`4.12.1
`4.12.2
`4.12.3
`4.12.4
`4.12.5
`4.12.6
`4.12.7
`4.12.8
`4.12.9
`4.12.10
`4.13
`
`U tilily. Industrial Application 93
`Selection Inventions 93
`Enantiomers 94
`Prodrugs and Active Metabolites 95
`The Patenting Process from the !mentor's Standpoint 97
`Inventorsh.ip 98
`The Priority Patent Application 98
`Prior Art Disclosure 98
`Patent Specification Review 99
`"Best Mode" of Carrying Out the Invention 99
`Foreign Patent Applications 99
`Patent Application Publication 100
`Patent Examination 100
`Opposition to Grant 101
`Patent Litigation 102
`Pilf::uk for the Unwary: Cr::mted Versus Published P::itents,
`Scientific Publications 102
`References 105
`
`Part II
`
`Analogue Classes 107
`
`5
`
`5.1
`5.2
`
`5.3
`5.4
`5.5
`5.6
`5.7
`
`6
`
`6.1
`6.2
`6.2.1
`6.2.2
`6.2.3
`6.2.4
`6.3
`6.3.1
`6.3.2
`
`Dipeptidyl Peptidase IV Inhibitors for the Treatment
`ofType 2 Diabetes 109
`Jens-Uwe Peters and Patrizio Mattei
`Introduction 109
`In Vitro Assays and Animal Models for the Assessment
`ofDPP-IV Inhibitors 110
`Substrate-Based DPP-IV Inhibitors 110
`Sitagliptin and Analogues 119
`Xanthines and Analogues 122
`Pharmacological Comparison ofDPP-IV Inhibitors 125
`Concluding Remarks 127
`References 128
`
`135
`
`Phosphodiesterase 5 Inhibitors to Treat Erectile Dysfunction
`Nils Griebenow, Helmut Haning, and Erwin Bischoff
`Introduction 135
`Pharmacology of Phosphodiesterases 136
`The Phosphodiesterase Family 136
`Pharmacological Effects of cGMP 137
`PDES: Regulation, Activation, and Structure 138
`PDES Inhibitors and Erectile Dysfunction 143
`Pyrimidinone PDES Inhibitors H7
`Xanthines and cGMP Analogues 147
`PDES Inhibitors Incorporating Lhe Purinone Nucleus 150
`
`MPI EXHIBIT 1033 PAGE 6
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0006
`
`

`

`VIII I Contents
`
`6.3.2.1
`6.3.2.2
`6.3.3
`6.3.3.1
`6.3.3.2
`6.3.4
`6.3.5
`6.3.6
`6.3.7
`6.4
`6.4.1
`6.5
`
`Zaprinast 150
`Purinones 150
`Pyrazolopyrimidinone PDE5 Inhibitors 151
`Pyrazolo[3,4-d)Pyrimidin-4-0ne PDE5 Inhibitors 151
`1,6-Dihydro-7H-Pyrazolo(4,3-d)Pyrimidin-4-0ne PDES Inhibitors 152
`Irnidazotriazinone PDES Inhibitors 154
`Irnidazoquinazolinones 155
`Pyrazolopyridopyrimidines 156
`Miscellaneous Heterocylic-fused Pyrimidinone PDES Inhibitors 156
`Nonpyrimidone PDES Inhibitors 160
`Hexahydro pyrazino-Pyrido-lndole-1, 4-D ion es 160
`Conclusions 162
`References 162
`
`7
`
`7.1
`7.2
`7.3
`
`7.4
`7.5
`7.6
`7.7
`7.8
`7.9
`7.10
`7.11
`7.12
`7.13
`
`8
`
`8.1
`8.2
`
`8.2.1
`8.2.1.1
`8.2.2
`8.2.3
`8.2.3.1
`8.2.3.2
`8.3
`8.3.1
`
`Rifamycins, Antibacterial Antibiotics and Their New Applications 173
`Enrico Selva and Giancarlo Loncini
`Discovery of the Pioneer Drug 173
`Clinically Used Rifamycins 173
`Mode of Action ofRifamycins and Slructural Requirements
`for Activity 174
`Modulation of Chemotherapeutic Properties 177
`Profiles of Rifamycins Targeted at Tuberculosis Treatment 177
`Rifarnpicin (INN), Rifampin (USAN) 178
`Rifapentine 180
`Rifabutin 181
`Rifarnycins Beyond Tuberculosis 181
`Rifarnycin SV and Rifamide 182
`Rifaximin 182
`Trials for Other Therapeutic Indications 183
`Summary 183
`References 184
`
`Monoterpenoid lndole Alkaloids, CNS and Anticancer Drugs 189
`Andras Nemes
`Introduction 189
`Vincamine and Derivatives: Cerebrovascular and Neuroprolective
`Agents 190
`Medicinal Chemistry of Vincarnine Derivatives 190
`Structure- Activity Relationships 192
`Synthesis ofVincamine Derivatives 193
`Pharmacological Properties of Vincamine Derivatives 193
`Mechanism of Action
`I 93
`Clinical Pharmacology
`194-
`Antitumor Dimeric Vinca PJ.kaloids 195
`Medicinal Chemistry of Dimeric Vi.nca Alkaloid Derivatives 195
`
`MPI EXHIBIT 1033 PAGE 7
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0007
`
`

`

`Contents I ix
`
`8.3.1.1
`8.3.2
`8.3.3
`8.3.3.1
`8.3.3.2
`8.4
`8.4.1
`8.4.1.1
`8.4.2
`8.4.3
`8.4.3.1
`8.4.3.2
`8.5
`
`Structure-Activity Relationships 196
`Synthesis of Dimeric Vinca Alkaloid Derivatives 198
`Ph armacological Properties ofDimeric Vinca Alkaloid Derivatives 199
`Mechanism of Action 199
`Clinical Pharmacology 199
`Antitumor Camptothecin Derivatives 201
`Medicinal ChernisLry of Carnptothecin Derivatives 201
`Slructure-Activily Relationships 202
`Synthesis of Camptothecin Derivatives 203
`Pharmacological Properties of Camptothcein Derivatives 204
`Mechanism of Action 204
`Clinical Pharmacology 205
`Summary and Conclusions 207
`References 207
`
`9
`
`9.1
`9.2
`9.3
`9.4
`9.5
`9.6
`9.7
`
`10
`
`10.1
`10.2
`10.3
`10.4
`10.5
`10.6
`
`10.7
`10.8
`10.9
`
`11
`
`11.1
`11.2
`
`Anthracyclinei:, Optimizing Anticancer An:aloguai: 217
`Federico-Maria Arcamone
`Introduction: Biosynthetic Antitumor Anlhracyclines 217
`Analogues with Mod ification of the Aminosugar Moiety 219
`Analogues with Modifications in the Anthraquinone Moiety 223
`Analogues Modified on Ring A of the Aglycone 226
`Disaccharide Analogues 229
`Other Compounds 232
`Summary and Final Remarks 233
`References 234
`
`Paclitaxel and Epothilone Analogues, Anticancer Drugs 243
`Paul W. Erhardt and Mohammad EI-Dakdouki
`Introduction 243
`Discovery and Development of Paclitaxel 243
`Clinical Success and Shortcomings of Paclitaxel 245
`ABDO Leading to Docetaxel 247
`Additional Structural Analogues 249
`The Pursuit of Microtubule-Stabilizing Pharmacological
`Analogues 250
`The Epothilones 252
`ABDO and Development Leading to lxabepilone 258
`Conclusions 260
`References 263
`
`Selective Serotonin Reuptake Inhibitors for the Treatment
`of Depression 269
`Wayne E. Childers Jr. and David P. Rotella
`[ntroduclion 269
`Neurochemistry and Mechanism or Action 270
`
`MPI EXHIBIT 1033 PAGE 8
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0008
`
`

`

`xi Contents
`11.3
`11.3.1
`11.3.2
`11.3.3
`11.3.4
`11.3.5
`11.4
`11.4.l
`11.4.2
`11.4.3
`11.4.4
`11.4.5
`11.S
`11.6
`
`12
`
`12.1
`12.2
`12.3
`12.3.1
`12.3.2
`12.3.3
`12.3.4
`
`12.4
`
`12.4.1
`
`12.4.2
`12.5
`12.6
`
`12.7
`
`13
`
`13.1
`13.2
`13.3
`
`13.4
`
`Preclinical Pharmacology 271
`Sertraline 271
`Escitalopram 272
`Fluvoxarnine 273
`Fluoxetine 274
`Paroxetine 275
`Medicinal Chemistry 276
`Serlrali11e 276
`Escilalopram 278
`Fluvoxaminc 279
`Fluoxetine 281
`Paroxetine 284
`Comparison of SSRis and Other Uses 285
`Summary 288
`References 288
`
`Muscarinic Receptor Antagonists in the Treatment of CO PD 297
`Matthias Crauert, Michael P. Pieper, and Paola Casarosa
`fntroduction 297
`Muscarinic Receptor Subtypes 298
`Structures of Muscarinic Agonists and Antagonists 299
`Muscarinic Agonists 299
`Antimuscarinics 300
`Discovery of Quaternary Antimuscarinics 303
`Once-Daily Quaternary Antimuscarinics: Tiotropium Bromide
`as the Gold Standard 305
`Preclinical Pharmacology: Comparison of Ipratropium
`and Tiotropium 309
`Bronchoconstriction in Conscious Guinea Pigs According
`to the Method of Kallos and Pagel 310
`Bronchoconstriction in Anaesthetized Dogs 310
`Clinical Pharmacology 31!
`Antimuscarinics in dinical Development for the Treatmenf
`ofCOPD 313
`Summary 313
`References 314
`
`l}-Adrenoceptor Agonists and Asthma 319
`Giovanni Gaviraghi
`Introduction 319
`First-Generation f3i-Agonists: The Short-Aeling Bronchodilators 319
`Second-Generation f3i-Ago.t1isLs: Further Derivalives
`of Salbutarnol 321
`Third-Generation f3i-Agonisls: The Long-Acting
`Bronchodilalors 321
`
`MPI EXHIBIT 1033 PAGE 9
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0009
`
`

`

`Contents I XI
`
`13.5
`13.6
`
`Combination Therapy with LABA and Corticosteroids 326
`Future Directions: Once-a-Day Therapy and Bifunctional Muscarinic
`Antagonist- /h-Agonist (MABA) 327
`References 329
`
`Part Ill
`
`Case Histories 333
`
`14
`
`14.1
`14.2
`14.2.1
`14.2.2
`14.2.3
`14.2.4
`14.3
`
`15
`
`15.1
`15.2
`15.3
`15.4
`15.5
`15.6
`15.7
`
`16
`
`16.1
`16.1.1
`16.2
`16.2.1
`16.2.2
`16.3
`16.4
`16.4.1
`16.5
`16.6
`16.7
`16.8
`16.9
`16.9.1
`
`Liraglutide, a GLP-1 Analogue to Treat Diabetes 335
`Lotte B. Knudsen
`Introduction 335
`Discussion 338
`Physiology of Native GLP-1 338
`Development ofLiraglutide: A GLP-1 Analogue 339
`The Pharmacology of Liraglutide 346
`Clinical Evidence with Liraglutide 349
`Summary 350
`References 351
`
`Eplerenone: Selective Aldosterone Antagonist 359
`Jaros/av Kalvoda and Marc de Gasparo
`Introduction 359
`Development of a Specific and Selective Aldosterone Antagonist 360
`Eplerenone: Selectivity and Specificity 367
`Preclinical Development ofEplerenone: From Animal to Man 373
`Further Development of Eplerenone 375
`Conclusions 376
`Epilogue 376
`References 377
`
`Clevudine, to Treat Hepatitis B Viral Infection 383
`Ashoke Sharon, Ashok K. Jha, and Cnung K. Chu
`Current Status of Anti-HBV Agents 383
`Nucleoside Reverse Transcriptase Inhibitors 386
`Chemical Evolution of Clevudine 387
`Development of Synthetic Routes 387
`Structure-Activity Relationships 388
`Metabolism and Mechanism of Action 390
`Pharmacokinetics 392
`Woodchuck Studies 393
`Clinical Studies 394
`Drug Resistance 396
`Toxicity and Tolerability 398
`Dosage and Administration 399
`Combination Therapy 399
`Combination of Clevudine v.<ilh Other Agents 399
`
`MPI EXHIBIT 1033 PAGE 10
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0010
`
`

`

`XII I Contents
`
`16.9.2
`16.10
`
`17
`
`17.1
`17.2
`17.2.1
`17.2.2
`17.2.3
`17.3
`17.3.1
`
`17.3.2
`
`17.3.3
`17.3.4
`17.4
`17.5
`17.6
`17.7
`
`18
`
`18.1
`18.2
`18.2.1
`18.3
`18.3.1
`18.3.2
`18.3.3
`18.3.3.1
`18.3.3.2
`18.3.3.3
`18.4
`18.4.1
`18.4.2
`18.4.3
`18.5
`18.6
`
`Combination of Clevudine with Vaccine 400
`Summary 400
`References 401
`
`Rilpivirine, a Non-nucleoside Reverse Transcriptase Inhibitor
`to Treat HIV-1 409
`Jerome Guillemont, Luc Geeraert, Jan Heeres, and Paul j. Lewi
`Introduction 409
`Chemistry 412
`Synthesis ofTMC278 and Close Analogues 412
`Modulation oflhe Central Heterocycle Core 418
`C-5 Substitution of the Pyrimidine Core 419
`Structure- Activity Relationships 420
`Introduction of G Spacer Between the Aryl Ring
`and the Cyano Group 421
`Modulation of Su bstituents at C-2 :md C-6 on the Left Wing
`and of the linker Between Left Wing and Pyrimidine Core 423
`Subsitution a l C-5 Position of the Pyrimjdine Heterocycle 424
`Modification of the Central Heterocycle Core 426
`TMC278: PhysicochemicaJ Properties 429
`Modeling ofTMC278 and Crystal SITucture 430
`Pharmacokinetic and Phase II Studies ofTMC278 431
`Conclusions 434
`References 434
`
`Tipranavir, a Non-Peptidic Protease Inhibitor for Multi-drug
`Resistant HIV 443
`Suvit Thaisrivongs, Joseph W. Strohbach, and Steve R. Turner
`Human Immunodeficiency Virus 443
`HIV Protease 443
`HfV Pis 444
`Approaches to Identifying and Developing PI Leads 446
`Focused Screening 446
`Broad Screening for Nonpeptidic Leads 447
`Structure-Based Drug Design 448
`PNU-96988, A First-Generation Clinical Candidate 449
`PN U-103017, A Second-Generation Clinical Candidate 450
`Tipranavir, The Third Generation 453
`Characteristics ofTipranavir 454
`ln Vitro Activity
`454
`Pharmacokinelics 455
`Highlights of Clinical Data 456
`Fragment-Based Lead Development? 457
`Summary 458
`References 459
`
`MPI EXHIBIT 1033 PAGE 11
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0011
`
`

`

`Contents I XIII
`
`19
`
`19.1
`19.2
`19.3
`
`19.4
`19.4.1
`19.4.2
`19.4.3
`19.5
`19.6
`19.7
`
`20
`
`20.1
`20.2
`20.3
`
`Lapatinib, an Anticancer Kinase Inhibitor 465
`Karen Lackey
`Introduction 465
`Aims 467
`Chemical Evolution and Proof-of-Mechanistic Approach
`Using Small Molecules 469
`Final Set of Analogues that Led to ihe Discovery ofl.apatinib 474
`6-Furanyl Quinazoline Series 474
`6-Thiazolylquinazoline Series 479
`Alkynylpyrirnidinc Series 480
`Final Selection Criteria and Data 482
`Early Clinical Results 487
`Prospects for Kinase Inhibitors 489
`References 490
`
`Da,atinib, a Kin:u;o Inhibitor to Treat Chronic M yaloganou,
`l eukemia 493
`Jagabandhu Das and Joel C. Barrish 493
`Tnlroduction 493
`Discussion 494
`Clinical Findings and Summary 502
`References 503
`
`21
`
`21.1
`21.2
`21.3
`21.4
`21.4.1
`21.4.2
`21.4.3
`21.4.4
`21.5
`21.6
`21.7
`
`Venlafaxine and Desvenlafaxine, Selective Norepinephrine
`and Serotonin Reuptake Inhibitors to Treat Major
`Depressive Disorder 507
`Magid Abou-Charbia and Wayne E. Childers Jr.
`Introduction 507
`Major Depressive Disorder 510
`MDD Pharmacotherapy 511
`The Discovery ofVenlafaxine 511
`Identification of an Early Lead (WY-44362) 511
`Structure-Activity Relationship Studies 512
`In Vivo Animal Model,; of Preclinical Efficacy 514
`Selection ofWY-45030 for Clinical Trials 514
`Clinical Efficacy ofEffexol'" 515
`An Extended Release Formulation - Effexor XR119 516
`Discovery of a Second-Generation SN RI -
`O-Desmethylvanlafaxine 516
`21.8
`Effexor and Prisliq - Additional Considerations 518
`21.8.1
`Effexor 518
`21.8.1.1 Onset of Action 518
`21.8.1.2 TreatmenL of Some Anxiety Disorders 519
`21.8.1.3
`Painful Somatic Symptoms 519
`21.8.2
`Pristiq 519
`
`MPI EXHIBIT 1033 PAGE 12
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0012
`
`

`

`XIV I Contents
`
`21.8.2.l Anxiety and Painful Symptoms 519
`21.8.2.2 Symptoms Associated with Menopause 519
`21.9
`Conclusions 520
`References 520
`
`Index 525
`
`MPI EXHIBIT 1033 PAGE 13
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0013
`
`

`

`I XXI
`
`Abbreviations
`
`ABC
`ABDD
`ABPM
`ACAT
`ACE
`ACTH
`ADMET
`AFC
`AIDS
`ALT
`ALL
`AMP
`cAMP
`ANDA
`a -APA
`APV
`AR
`ATP
`AUC
`AZT
`BBB
`Bcr-Abl
`BG
`b.i.d.
`BOC
`CBF
`CCso
`J3-CCE
`CGI
`CHB
`CK
`CL
`CLR
`
`ATP binding cassette
`analogue-based drug discovery
`ambulatory blood pressure monitoring
`acyl-CoA:cholesterol ~cylt1.1t1sfense
`angiotensin-converting enzyme
`adrenocorticotropic hormone
`absorption, distribution, metabolism, excretion and toxicity
`7-amino-4-trilfoorome thylcoumarin
`acquired immunodeficiency syndrome
`alanine aminotransferase
`acute lymphoblastic leukemia
`amprenavir
`cyclic 3' ,5'-adenosine mono phosphate
`Abbreviated New Drug Application
`rx-anilinophenylacetamide
`amprenavir
`androgen receptor
`adenosine triphosphale
`area under the curve
`azidothymidine
`blood-brain-barrier
`Breakpoint cluster region - Abelson
`blood glucose
`twice a day (from Latin bis in die)
`l-butoxycarbonyl
`cerebral blood flow
`50% cytotoxic concentration
`ethyl J3-carboline-3-carboxtlate
`Clinical Global Impressions Scale
`chronic hepatitis B
`creatine kinase
`clearance
`renal clearance
`
`Analogue-basal Drug Disco""ry U. Edited by finos Fischer and C. Robin Gancllin
`Copyright © 2010 WILEY-VCI-I Verlag GmbH & Co. KGaA, Wcinhcim
`ISBN: 978-3-527-32549-8
`
`MPI EXHIBIT 1033 PAGE 14
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0014
`
`

`

`XXII I Abbreviations
`
`CLr
`CLV
`CLV-TP
`CML
`CMRglc
`CNS
`COBP
`COPD
`COX-1
`COX-2
`CPl/r
`CPT
`CRC
`CYP
`DA
`10-DAB
`DAPY
`DATA
`dCK
`DNA
`cDNA
`cccDNA
`mtDNA
`DOC
`DOCA
`DPP-4
`DSM-HI
`
`EBV
`ECso
`ED
`EFS
`EGFR
`EMEA
`EPA
`EPO
`EPS
`Erk
`ETC
`FAAH
`FBDD
`FDA
`L-FEAU
`FEY
`L-FMAU
`
`total clearance
`devudine
`devudine triphosphate
`chronic myelogenogenous leukemia
`cerebral metabolic ra te of glucose
`central nervous system
`duonic obstructive broncho-pnewnopathies
`chronic obstructive pulmonary disease
`cyclooxygenase-1
`cyclooxygcnasc-2
`comparator prolea,e inhibitor boosted with rilonavir
`camptothecin
`coloreclal cancer
`cytochrome P4S0 isoenzyme
`dopamine
`10-de:ice ty l-b:icc:itin
`diarylpyrimidine
`diaryltriazine
`deoxycytidine kinase
`desoxyribonucleic acid
`complementary deoxyribonucleic acid
`covalently closed circular DNA
`mitochondrial DNA
`deoxycorticosterone
`deoxycorticosterone acetate
`dipeptidyl peptidase 4
`Diagnostic and Statistical Manual of Mental Disorders,
`third edition
`Epstein-Barr virus
`effective concentration 50
`erectile dysfunction
`electric field stimulation
`epidermal growth factor receptor
`European Medicines Agency
`Environmental Protection Agency
`European Patent Office
`exprapyramidal side effect
`extracellularly regulated kinase
`emlTiciLabine
`fatty acid amide hydrolase
`fragment-based drug design
`Food and Drug Administration
`1-(2' -deoxy-2' -fluoro-~-L-arabinofuranosyl)-5-ethyluridine
`forced expiratory volume
`L-2' -fluoro-5-melhyl-~-L-arabinofuranosyluracil
`
`MPI EXHIBIT 1033 PAGE 15
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0015
`
`

`

`Abbreviations I XXIII
`
`GABAA
`GAD
`GI
`GIP
`GLP-1
`cGMP
`GPilb/IIIa
`HA
`HAART
`HA/ACTH
`HAM-A
`HAM-D
`HbA1c
`HBV
`HBcAg
`HBeAg
`HbsAg
`HCC
`HCV
`HDV
`hERG
`HFB
`HIAA
`HIV
`HIV PR
`HMG-CoA
`5-HT
`5-HTP
`HTS
`IBMX
`ICso
`p!Cso
`res
`IDR
`IDV
`i.m.
`l ND
`l NN
`lOPY
`i.p.
`i.v.
`Ki
`LABA
`Lek
`hLck
`
`gamma-aminobulyric acid A
`generalized anxiety disorder
`growth inhibition
`glucose-dependenL insulinotropic polypeptide
`glucagon-like peptide-1
`cyclic 3' ,S'-guanosine mono phosphate
`glycoprotein IIb/ IIIa
`heavy atom
`Highly Active Antiretroviral Therapy
`h.islaminc-induccd adrcnocorticotropic hormone
`Hamilton Anxiety Taring Scale
`Hamilton Depression Rating Scale
`glycosylated haemoglobin
`hepatitis B virus
`hepatitis B core antigen
`hepatitis B e :i.ntigen
`hepatitis B surface antigen
`hepatocellular carcinoma
`hepatitis C virus
`hepatitis del ta virus
`human ether-a-go-go-related gene
`human foreskin fibroblast
`5-hydroxy-indole acetic acid
`human immunodeficiency virus
`HIV protease
`3-hydroxy-3-methylglutaryl coenzyme A
`5-hydroxytryptamine {serotonin)
`5-hydroxytryptophan
`high-throughput screening
`isobut:ylmethylxanthine
`inhibitory concentration SO
`- log ICso
`inhaled corticosteroids
`idarubicin
`indi.navir
`intramuscular
`lnvestigational New Drug
`International Nonproprietary Name
`iodophenoxypyridone
`intra peritoneal
`intravenous
`inhibitory constant
`long-acting fu-agonist
`lymphocyte specific kinase
`human Lek
`
`MPI EXHIBIT 1033 PAGE 16
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0016
`
`

`

`XXIV I Abbreviations
`
`mLck
`LDL-C
`LE
`LPV
`LVEF
`MADRS
`MAOI
`M1
`MAP
`rMD
`MOD
`MOR
`MED
`MES
`MIC
`MR
`MRP
`MTD
`NAPQI
`NCE
`NCI
`NDA
`NE
`NMR
`NNRTI
`NO
`NPs
`NPClLl
`NR!s
`NRTI
`NSA!Ds
`NSCLC
`OADs
`oc
`OCD
`OGIT
`PCA
`PCF
`PCT
`PDEs
`PDGFR
`PEP
`PGE1
`PGE2
`P-gp
`
`murine Lek
`low-density lipoprotein-cholesterol
`ligand efficiency
`lopinavir
`left ventricular ejection fraction
`Montgornery-Asberg Depression Rating Scale
`monoarnine oxidase inhibitor
`muscarinic receptor M1 subtype
`mitogen-activated protein
`restrained molecular dynamics
`major depressive disorder
`multidrug resistance
`minimal effective dose
`maximal electroshock seizure
`minimal inhibitory concentration
`mineralocorticoid receptor
`mu.ltidrug resistance-associated protein
`maximum tolerated dose
`N-acetyl-p-benzoquinone imine
`New Chemical Enrity
`National Cancer Institute
`New Drug Application
`norepinephrine
`nuclear magnetic resonance
`nonnucleoside reverse transcriptase inhibitor
`nitric oxide
`natural products
`Niemann-Pick Cl-Like-1
`norepinephrine reuptake inhibitors
`nucleoside reverse transcriplase inhibitor
`nonsteroidal anti-inflammatory drugs
`non-small cell lung cancer
`oral antidiabetic drugs
`ovarian cancer
`obsessive-compulsive disorder
`oral glucose tolerance test
`p-ch.loroamphetamine
`plant cell fermentation
`Patent Cooperation Treaty
`phosphodiesterases
`platelet derived growth factor receptor
`prolyl endopeptidase
`prostaglandi.r1 E1
`prostaglandi.t1 E2
`permeability glyocoprotein
`
`MPI EXHIBIT 1033 PAGE 17
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0017
`
`

`

`Abbreviations I XXV
`
`Ph(+)
`PK
`PKG
`POMS
`PPCE
`PR
`QSAR
`q.d. or QD
`RBA
`RGD
`RNA
`RNApol
`mRNA
`RT
`RTV
`SAR
`SBDD
`s.c.
`SCIO
`SCLC
`SEDDS
`SEF
`SI
`SIV
`SMC
`SNRI
`SQV
`Src
`SRI
`SSR!s
`TCR
`TDF
`TGfa
`TI
`TIBO
`
`t.i.d.
`TK
`TMPK
`TPV
`TPV/r
`TPT
`TRIPs
`TIP
`UDP
`
`Philadelphia chromosome positive
`pharmakokine tic
`protein kinase G
`profile of mood stale
`postproline cleaving enzyme
`progesterone receptor
`q uantilative structure-acti-1ity relationship
`once a day (from Latin quaque die)
`relative binding affinity
`argininc-glycinc-aspartic acid
`ribonucleic acid
`RNA polymerase
`messenger RNA
`reverse transcriptase
`ritonavir
`st-ructure-:1ctivity rehtioncliip
`structure-based drug design
`subcutaneous
`severe combined immunodeficient
`small-cell lung cancer
`self-emulsifying drug delivery system
`sodium excreting factor
`selectivity index
`simian immunodeficiency virus
`smooth muscle cell
`serotonin/norepinephrine reuptake inhibitor
`saquinavir
`sarcoma
`serotonin reuptake inhibitor
`selective serotonin reuptake inhibitors
`T-cell antigen receptor
`tenofovir disoproxil fumarate
`tansforming growth factor-ct
`tumor inhibition
`4,5,6,7-tetrahydro-5-methylimidazo[4,5,1-jk)benzodiazepin-2
`(lH)-one
`three times daily
`thymidine kinase
`thymidylate kinase
`lipranavir
`lipranavir/ritonavir combination
`topotecan
`Trade-related Aspects of Intellectual Property Rights
`time lo progression
`uridine diphosphate
`
`MPI EXHIBIT 1033 PAGE 18
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0018
`
`

`

`XXVI I Abbreviations
`
`UGT
`USAN
`VEGFR
`VMS
`VSMC
`Yss
`WBC
`WI-lcAg
`WI-lsAg
`WHV
`WTO
`
`uridine diphosphate glucuronyl transferase
`United Slates Adopted Names
`vascular endothelial growth faclor receptor
`vasomotor symptoms
`vascular smooth muscle cell
`s teady-state vol ume
`white blood cell
`woodchick hepatitis virus core antigen
`woodchuck hepalilis virus surface antigen
`woodchuck hepatitis virus
`World Trade Organization
`
`MPI EXHIBIT 1033 PAGE 19
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0019
`
`

`

`14
`Liraglutide, a CLP-1 Analogue to Treat D iabetes
`Lotte B. Knudsen
`
`14.1
`Introduction
`
`The therapeutic potential of glucagon-like peptides (GLPs), particularly glucagon-like
`peptide-1 (GLP-1), is onJy now beginning to be realized at the start of the twenly-fust
`century. IL was, however, the cLiscovery of secretin in 1902 by Bayliss and Starli.ng (1]
`that initiated interest in Lhe endocrine function of the gut and pancreas. These
`scientists speculated that signals arising from the gut could elicit an endocrine
`response affecting carbohydrate disposal. In 1929, Zunz and LaBarre described an
`intestinal extract that could produce hypoglycemia (2], and in a separate paper,
`LaBarre used the term "increlin" to describe activity in the gut that might stimulate
`pancreatic endocrine secretions [3]. Despite initial interest in "incretin," research
`virtually slopped in this area due to the outbreak of World War II and the publication
`of several negative papers by Ivy and colleagues [4-6]. Twenty-five years later,
`McIntyre suggested that a bu.moral substance was released from the jejunum during
`glucose absorption, acting in concert with glucose lo stimulate insulin release from
`pancreatic ~-cells (7]. In 1969, Unger and Eisentraut referred lo the gut- pancreas
`association as the enteroinsular axis (8], and this axis was subsequently described as
`involving nutrient, neural, and hormonal sigmls from the gut to Lhe pancreatic islet
`cells. To be termed an "incretin," any substance acting on this pathway must be
`secreted in response lo nutrient stimuli and must stimulate glucose-dependent
`insulin secretion (9].
`A second incretin hormone, following the discovery of glucose-dependent in(cid:173)
`sulinotropic polypeptide (GlP), was postulated lo exist as a consequence of the
`cloning of cDNAs encoding the preproglucagon gene in anglerfish pancreas [10-12].
`Habener and colleagues conducted some of the very early work to characterize
`preproglucagon, but il was Bell who first identified GLP-1(1-37) (13]. In 1986/ 1987, il
`was discovered that the truncated forms, GLP-1(7-37) and (7-36)amide, were the
`active insulinottopic isoforms of GLP-1 (14, 15]. Lowering of blood glucose with GLP-
`1 was first shown in three studies by Nathan, Nauck, and Kreyrnann (16-18), with the
`
`Analogue-basal Drug Disco""ry U. Edited by finos Fischer and C. Robin Gancllin
`Copyright © 2010 WILEY-VCl-1 Verlag GmbH & Co. KGaA, Wcinhcim
`ISBN: 978-3-527-32549-8
`
`MPI EXHIBIT 1033 PAGE 20
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0020
`
`

`

`336114 Lirog/utide, a GLP- l Analogue lo Treat Diabeus
`
`Proglv agon
`
`Pancrea
`
`GRPP
`1
`
`Glucag<m rM MaJorproglucagon fragm nt
`I I JI
`l I
`6164 69 71
`30 33
`
`Gut/Brain
`
`GlP-1
`
`IM
`
`·Gl.P-
`
`I
`69
`
`t
`78
`
`I '
`I
`,
`107N II 11} 1Z3 l26
`
`I I
`159 160
`
`I
`1S8
`
`' 158
`
`GRPP
`
`011Vnl 1110(jijliu
`
`H
`JO 33
`
`I
`69
`
`Figure 14.l Differential post.tra nslational
`processing of progiucagon in 1he pancreas and
`In the gut and brain. The numbers indicate
`amino acid positions in the 160-amino acid
`proglucagon sequence. The vertical hnes
`
`Indica te positions of bask.amino ac.id residues,
`typica l cleavage sites. GRPP glicentin-related
`pancreatic polypeptide; IP- l, intervening
`peptide-7: IP-2, i ntervening peptide-2.
`Reproduced with permission from Holst et al. [19].
`
`lherapeulic application o[ GLP-1 realized in 1993 wilh Lhe observation Lhal GLP-1
`could normalize blood glucose levels.in patients sulfering from Lype 2 dia.beLes [17].
`The GlP-1(7-37) isoforms, Logetherwith the GLP-1(7-36)am.ide, are the insulino(cid:173)
`Lropic peptides deri ed from the preproglucagon gene, products of Lhe post-trans(cid:173)
`lational processing of proglucagon (Figure 14.1).
`The amino acid sequence of GlP-1 is highly conserved across animal species (20].
`This shows not only how important this hormone is but also how ital the particular
`amino acid sequence is (Figure 14.2).
`
`Figure 14.2 Amino acid sequence of native, truncated GLP-l (7-37) .
`
`MPI EXHIBIT 1033 PAGE 21
`
`Apotex v. Novo - IPR2024-00631
`Petitioner Apotex Exhibit 1033-0021
`
`

`

`14. 1 Introduction 1337
`
`The binding affinity and biological activity are particularly affected by His on
`position 7, Glyon position 10, Phe on position 12, 1br on position 13, Asp on position
`15 (all directly involved in receptor interaction), Phe on position 28, and Ile on
`position 29 [21 ). The conformation of G LP-1 in dudes an N-terminal random coil and
`two helical segments joined by a linker region; this closely resembles the structure of
`glucagon [22).
`The preproglucagon gene is expressed in several cell types in th e body. The
`pancreas contains a - and 13-cells: a -cells process proglucagon and therefore secrete
`glucagon. Only small quantities of G LP-1 have been found secreted from pancreatic
`a -cells [23). Proglucagon and its fragments arc furthermore secreted in the small and
`large bowei'l. Intestinal L-cells that process proglucagon are the major source of GLP-
`1; these are mainly situated in the distal jejunum and ileum and also throughout the
`whole intestine. Proglucagon processing occurs in the central nervous system: GLP-1
`is therefore an important neurotransmitter in the brain [24).
`GLP-1 activity is mediated by the GLP-1 receptor, a class 2, G-protein-coupled
`receptor [25]. This receptor is found in m:iny org:ms including the p ancrea£,
`s tomach, intestines, and parts of the peripheral and central nervous systems, and
`these are the main therapeutic targets [26, 27). GLP-1 receptors have been found in
`other tissues that may be relevant for its therapeutic effect, namely, the kidneys,
`endothelium, small blood vessels, and heart [28-31). Due to the organ systems that
`GLP-1 acts on, it is an attractive therapeutic target for Lype 2 diabetes mellitus
`and obesity.
`For example, in pancreatic ~-cells, GLP-1 receptor activation increases adenylate
`cyclase