UNNATURAL AMINO ACIDS MIR027 A MARKET INSIGHT REPORT– JULY 2010

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1. SCOPE AND METHODOLOGY ...... 1 2. REPORT SYNOPSIS ...... 4 Unnatural Amino Acids – An Introduction ...... 4 Amino Acids ...... 5 Types of Amino Acids ...... 6 Essential Amino Acids ...... 6 Non‐Essential Amino Acids ...... 6 Proteinogenic Amino Acids ...... 6 Non‐Proteinogenic Amino Acids...... 6 Non‐Standard Amino Acids ...... 6 Synthetic Unnatural Amino Acids ...... 7 Amino Acids Analogs ...... 7 Tyrosine Analogs ...... 7 Glutamine Analogs ...... 7 Phenylalanine Analogs ...... 7 Synthesis Applications of Amino Acids ...... 7 Use of Optically Pure Amino Acids ...... 8 Segmentation of Unnatural Amino Acids ...... 9 Exhibit 1: Segmentation of Unnatural Amino Acids Market by Type and Application ...... 9 Unnatural Amino Acids ‐ Definitions, Important Facts & Figures ...... 9 β‐Amino Acids & Derivatives ...... 9 β‐Amino acids ...... 9 β‐Alanine ...... 9 β‐Methylphenylalanine ...... 10 β‐Amino Alcohols ...... 11 Cyclic Amino Acids & Derivatives ...... 11 Cyclic β‐Amino Acids ...... 11 Cyclic Unnatural α‐Amino Acids ...... 11 D‐Cycloserine ...... 11 D‐Amino Acids & Derivatives ...... 12 D‐Phenylglycine ...... 13 D‐Cysteine ...... 14 D‐Serine ...... 15 D‐Proline ...... 16 D‐Valine ...... 17 D‐Alanine ...... 18 D‐Phenylalanine ...... 19 D‐Citrulline /D‐Citrulene ...... 21 D‐Tryptophan ...... 21

MIR027‐Unnatural Amino Acids – A Market Insight Report, July 2010 © RI Technologies, www.researchimpact.com ‐ i ‐ UNNATURAL AMINO ACIDS MIR027 A MARKET INSIGHT REPORT– JULY 2010

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D‐Lysine ...... 23 D‐Leucine ...... 23 D‐Histidine ...... 24 D‐Glutamic Acid ...... 25 D‐Methionine ...... 26 D‐Aspartic Acid ...... 27 D‐Tyrosine ...... 28 D‐Arginine ...... 30 D‐p‐Hydroxyphenylglycine ...... 30 D‐Penicillamine ...... 31 DL‐Amino Acids & Derivatives ...... 32 DL‐Alanine ...... 32 DL‐Methionine...... 33 DL‐Phenylalanine ...... 34 L‐Amino Acid Derivatives ...... 35 L‐Homophenylalanine ...... 35 L‐Dopa ...... 36 Lp‐Hydroxyphenylglycine ...... 37 Other ...... 37 Gamma‐Amino Butyric Acid (GABA) ...... 37 Gamma‐Amino‐Beta‐Hydroxybutyric Acid (GABOB) ...... 38 Synthetic α‐Amino Acids ...... 38 Boc‐Protected Amino Acids ...... 38 Fmoc‐Protected Amino Acids ...... 38 Synthetic Biology – An Overview ...... 38 Unnatural Amino Acids and Biochemistry ...... 42 Unnatural Amino Acids and Chirality...... 45 Protein and Peptide Overview ...... 47 Global Market Analysis ...... 49 Exhibit 2: Unnatural Amino Acids ‐ Global Value Market Estimations and Predictions (2005‐2015) in US$ Billion (Graphical Representation Included) ...... 50 List of Global Major Companies ...... 51 Exhibit 3: Unnatural Amino Acids ‐ Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 53 Exhibit 4: Unnatural Amino Acids ‐ Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 54 Unnatural Amino Acids – Type ...... 55 Exhibit 5: Unnatural Amino Acids by Type ‐ Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 55

MIR027‐Unnatural Amino Acids – A Market Insight Report, July 2010 © RI Technologies, www.researchimpact.com ‐ ii ‐ UNNATURAL AMINO ACIDS MIR027 A MARKET INSIGHT REPORT– JULY 2010

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Exhibit 6: Unnatural Amino Acids ‐ Global Market Shares by Type (2008 & 2015) for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐ Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 57 Unnatural Amino Acids ‐ Application Areas ...... 58 Exhibit 7: Unnatural Amino Acids by Application ‐ Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 59 Exhibit 8: Unnatural Amino Acids ‐ Global Market Shares by Application (2008 & 2015) for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 60 Unnatural Amino Acids ‐ Disease Treatment ...... 61 Exhibit 9: Unnatural Amino Acids by Disease Treatment ‐ Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for Neurological Disorders, Cardiovascular, Diabetes, Arthritis, Cancer and Other (Graphical Representation Included) ...... 61 Exhibit 10: Unnatural Amino Acids ‐ Global Market Shares by Disease Treatment (2008 & 2015) for Neurological Disorders, Cardiovascular, Diabetes, Arthritis, Cancer and Other (Graphical Representation Included) ...... 62 Peptides ‐ Future of Pharmaceutical Industry ...... 63 Peptide Synthesis ...... 63 Exhibit 11: Peptide Synthesis – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 64 Exhibit 12:Peptide Synthesis – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐ Pacific and Rest of World (Graphical Representation Included) ...... 65 Process involved in the Fmoc solid‐phase peptide synthesis...... 66 Process involved in the t ‐Boc solid‐phase peptide synthesis ...... 66 Comparison of Boc and Fmoc Solid‐Phase Peptide Synthesis ...... 67 Application of Protecting Groups in Peptide Synthesis ...... 68 Various Testing Methods of Peptides ...... 69 Mass Spectrometry (MS) ...... 69 Amino Acid Analysis (AAA) ...... 69 Protein Sequence Analysis (PSA) ...... 70 Peptide Drugs ...... 70 Exhibit 13: Peptide Drugs – Global Value Market Estimations and Predictions (2005‐2015) in US$ Billion (Graphical Representation Included) ...... 73 Exhibit 14: Peptide Drugs – Global Value Market Estimations and Predictions (2005‐2015) in US$ Billion for Cancer, Diabetes, Neurological Disorders, Cardiovascular, Pain/Inflammation, Arthritis and Other (Graphical Representation Included) ...... 74

Unnatural Amino Acids ‐ Major Companies – Brief Profiles ...... 75 Abbott Laboratories ...... 75 Aminologics Co., Ltd ...... 78 AnaSpec, Inc...... 78 Biological E Ltd...... 82 China Pharmaceutical Group Limited ...... 83

MIR027‐Unnatural Amino Acids – A Market Insight Report, July 2010 © RI Technologies, www.researchimpact.com ‐ iii ‐ UNNATURAL AMINO ACIDS MIR027 A MARKET INSIGHT REPORT– JULY 2010

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DSM Pharma ...... 85 Genzyme Pharmaceuticals ...... 90 Harbin Pharmaceutical Group Co., Ltd...... 92 IRIS Biotech GmbH ...... 93 Kyowa Hakko Bio Co., Ltd...... 95 Mimotopes Pty Ltd...... 97 NAGASE & Co., Ltd...... 98 PolyPeptide Group ...... 101 Shanghai Hanhong Chemical Co., Ltd...... 104 Sigma‐Aldrich Corporation ...... 105 Unibiochem Co., Ltd...... 108 United Laboratories International Holdings Limited (The) ...... 109 Venus Remedies Ltd...... 109 Wellmark International ...... 110 45 more…...... 110

3. PRODUCT TECHNOLOGY RESEARCH ...... 112 Amino Acids ...... 112 Amino Acids – Building Blocks of Proteins ...... 112 Essential and Non‐essential Amino Acids ...... 112 Importance of Amino Acids ...... 113 Chiral Molecules ...... 114 The First Catalytic Asymmetric Synthesis for Disease Treatment ...... 114 Medical Background ...... 115 Chiral Intermediates’ Application in the Pharmaceutical Industry ...... 116 Chiral Amino Acids ...... 117 Isomerism ...... 118 Chiral Technology in Therapeutics ...... 119 Diabetes‐ Phenomenon of Chiral Mutagenesis of Insulin ...... 119 The Emergence of Chiral Drugs ...... 120 Anticancer Activity of Beta‐l‐Dioxolane‐Cytidine Containing Unnatural Configuration ...... 121 Uses of Chiral Technology in Biotechnology ...... 121 Significance of Unnatural Amino Acids as Chiral Raw Materials ...... 122 Deracemization of Amino Acids ...... 122 Ingenza’s Chemoenzymatic Deracemization Technology ...... 123 Oxidase Biocatalysts ...... 124 Biocatalyst ‐ D‐Amino Acid Oxidase ...... 125 Deracemization of dl‐2‐aminobutyric acid using Pd/C and DAAO ...... 125

MIR027‐Unnatural Amino Acids – A Market Insight Report, July 2010 © RI Technologies, www.researchimpact.com ‐ iv ‐ UNNATURAL AMINO ACIDS MIR027 A MARKET INSIGHT REPORT– JULY 2010

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Facilitating Technologies ...... 126 Importance of Biocatalysis ...... 126 Fabrication of Multipurpose Catalysts ...... 126 Unnatural Amino Acids – Few Facts ...... 127 Unnatural Amino Acids ‐ Historic Overview ...... 129 Amino Acids ‐ A Historical Chronological Overview ...... 130 Occurrence of Unnatural Amino Acids in Nature ...... 132 Specific Plant Vegetation by Employing D‐Amino Acids...... 132 Occurrence of D‐amino Acids in Nature ...... 133 Marine Invertebrates ...... 134 Global Market Analysis ...... 136 Exhibit 15: Unnatural Amino Acids ‐ Global Value Market Estimations and Predictions (2005‐2015) in US$ Billion (Graphical Representation Included) ...... 136 Amino Alcohols ...... 137 Exhibit 16: List of Amino Alcohols ...... 137 Amino Alcohols ‐ Types and Applications ...... 138 Ethanolamines ...... 138 Heptaminol ...... 139 Isoetarine ...... 139 Norepinephrine ...... 139 Propanolamines ...... 141 Sphingosine ...... 141 Amino Alcohol Derivatives and Their Applications ...... 141 As Chemical Intermediates ...... 141 As Emulsifiers ...... 142 As Coating Substance ...... 142 As Inhibitors of Corrosion ...... 142 As Catalysts...... 142 As Biochemicals ...... 142 Derivatives of Chiral Amino Alcohols ...... 143 Carbodiimide ...... 143 Dicyclohexylcarbodiimide ...... 143 DIC (N,N'‐diisopropylcarbodiimide) ...... 144 Piperacillin ...... 144 More About Unnatural Amino Acids ...... 145 Unnatural Amino Acids as Metabolic Intermediates ...... 145 Protection of Unnatural Amino Acids ...... 145 t‐Boc Protecting Group ...... 146

MIR027‐Unnatural Amino Acids – A Market Insight Report, July 2010 © RI Technologies, www.researchimpact.com ‐ v ‐ UNNATURAL AMINO ACIDS MIR027 A MARKET INSIGHT REPORT– JULY 2010

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Fmoc Protecting Group ...... 146 Z‐ Protecting Group ...... 146 Kinetic Resolution of Racemic Unnatural Amino Acids ...... 146 Production of Unnatural Amino Acids ...... 147 Synthesis of Unnatural Amino Acids ...... 148 Synthesis of D‐amino acids ...... 150 Enzymatic synthesis ...... 150 D‐Amino Acids & Escherichia Coli ...... 150 Synthesis of D‐Amino Acids from an L‐Serine‐Derived Aziridine ...... 151 Recombinant Technology ...... 152 Synthesis by Deracemation ...... 152 Lybradyn’s Technology ...... 152 Microbial Synthesis of D‐Amino Acids ...... 153 Synthesis of ß‐amino acids ...... 154 Stereoselective Synthesis ...... 154 Direct Homologation ...... 155 Michael Addition Reactions ...... 155 Wolff Rearrangement ...... 155 Synthesis of Substituted Amino Acids ...... 156 Stereoselecive Enzymatic Hydrolysis ...... 156 Strecker’s Synthesis ...... 156 Bromination Method ...... 156 Transmination ...... 156 Maruoka Catalysts® Method ...... 156 Meta‐substitution ...... 157 Synthesis of Unnatural α‐amino Acids ...... 157 Synthesis of Non‐proteinogenic L‐amino Acids ...... 157 Reductive Amination ...... 157 Fermentation Approach ...... 157 Synthesis of Amino Acid Analogs ...... 158 Synthesis of Glutamine Analogs ...... 158 Synthesis of Tyrosine Analogs ...... 158 Synthesis of Novel Unnatural Amino Acids ...... 158 Synthesis of Bioactive Peptides Containing Unnatural Amino Acids ...... 158 In vivo Peptide Synthesis ...... 159 Non‐sense Codon Suppression ...... 159 Kluger and Lisa Cameron Method ...... 160 Microinjection Method ...... 160

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Expression Systems ...... 160 In vitro Peptide Synthesis ...... 161 SPPS ...... 161 ReCode Technology ...... 164 Incorporation of Selenocysteine and Pyrrolysine ...... 164 Selenocysteine ...... 165 Pyrrolysine ...... 165 Peptide Synthesis ‐ Market Analysis ...... 166 Exhibit 17: Peptide Synthesis – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 166 Super yeasts ...... 167 Insect cells ...... 167 Peptide Hormones ...... 168 Bradykinin...... 168 Angiotensin ...... 168 Oxytocin ...... 169 Heptapeptide Oxytocin Analogues ...... 170 Cetrorelix – a Gonadotropin releasing hormone antagonist ...... 170 Octreotide ...... 170 Pharmaceutical Effects ...... 171 Uses ...... 171 Peptide Drugs ...... 171 Peptides in Cardiovascular Therapies ...... 172 PTM [Post Translational Modification] ...... 172 Peptide Research ...... 173 Exhibit 18: List of Peptide Types ...... 174 Unnatural Amino Acids – by Type ...... 175 β‐Amino Acids and Derivatives ...... 175 β‐Amino Acids ...... 175 Exhibit 19: β‐Amino Acids – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 175 Exhibit 20: β‐Amino Acids – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 176 β‐Amino Acid Derivatives ...... 177 Exhibit 21: β‐Amino Acid Derivatives – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 177 Exhibit 22: β‐Amino Acid Derivatives – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 178 Naturally found β‐Amino acids ...... 179

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β‐Alanine ...... 180 β‐Peptides ...... 180 Antibiotics ...... 180 Exhibit 23: HPLC Analysis of Unprocessed Market Milk Samples (+ve in Screened Test) for Antibiotics in Hyderabad, Pakistan ...... 181 Cyclic Amino Acids & Derivatives ...... 182 Exhibit 24: Cyclic Amino Acids & Derivatives – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) . 182 Exhibit 25: Cyclic Amino Acids & Derivatives – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 183 D‐Amino Acids and Derivatives ...... 184 D‐Amino Acids ...... 184 Exhibit 26: D‐Amino Acids – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 184 Exhibit 27: D‐Amino Acids – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 185 Applications of D‐Amino Acids ...... 186 Exhibit 28: Antibacterial Peptides & Respective D‐Amino Acids Present ...... 186 2,3‐Diamino Acids ...... 187 D‐Amino Acid Oxidase and its Properties ...... 189 D‐Amino Acid Oxidase Reaction ...... 190 Production of D‐Amino Acid Using Composite Immobilized Enzyme Preparations ...... 192 Synthesis of D‐Amino Acid Oxidase Apoprotein ...... 192 D‐Amino Acid Dehydrogenase Synthesis ...... 192 Evaluation of D‐Amino‐Acid Oxidase Activity Using Different Methods ...... 192 Stereo Selective D‐Amino Acid Dehydrogenase for the One‐Step Synthesis of D‐Amino Acids ...... 193 Synthesis and Characterizations of D‐Amino Acid‐Based Oligopeptides ...... 193 D‐Amino Peptides ...... 195 D‐Amino Acid Oxidase and D‐Aspartate Oxidase Antagonists ‐ CNS Disorder Treatment...... 200 Anti‐Diabetic Effects of D‐Amino Acids ...... 201 D‐Phenylalanine ...... 203 Methods of Preparation of DPA ...... 203 Enzymatic Hydrolysis of Benzylhydantoins ...... 203 Biological Synthesis of DPA from Phenylpyruvic Acid ...... 204 Preparation of DPA by Asymmetric Transformation ...... 204 Therapeutic Values of DPA ...... 204 Pain ...... 204 Depression ...... 207 Stress ...... 207

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ADD and ADHD ...... 208 Memory and Learning Behaviors ...... 208 Parkinson’s Disease ...... 209 Multiple Sclerosis ...... 209 Type II Diabetes ...... 210 D‐Lysine ...... 210 Water‐Soluble Lysine Salts ...... 211 Preparation of D‐Lysine ...... 211 Ligand‐Exchange with Zinc (Ii)‐L‐Lysine Complex ...... 211 D‐Valine ...... 212 Tau‐Fluvalinate ...... 212 Dermorphin ...... 214 Lp‐Hydroxyphenylglycine ...... 215 D‐Amino Acid Derivatives ...... 215 Exhibit 29: D‐Amino Acid Derivatives – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 215 Exhibit 30: D‐Amino Acid Derivatives – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 216 DL‐Amino Acids ...... 217 Exhibit 31: DL‐Amino Acids – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 217 Exhibit 32: DL‐Amino Acids – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 218 DL‐Amino Acid Derivatives ...... 219 Exhibit 33: DL‐Amino Acid Derivatives – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 219 Exhibit 34: DL‐Amino Acid Derivatives – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 220 DL‐alanine (racemic compound) ...... 220 DL Phelylalanine (DLPA) ...... 222 L‐Amino Acid Derivatives ...... 224 Exhibit 35: L‐Amino Acid Derivatives – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 224 Exhibit 36: L‐Amino Acid Derivatives – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 225 L Amino Acids Derivatives ...... 225 L‐Dopa ...... 225 Exhibit 37: L Dopa Global Market (2005‐2015) in US$ Billion ...... 226 Lp‐hydroxyphenylglycine ...... 226 L‐Homophenylalanine ...... 226

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Other Unnatural Amino Acids ...... 228 Exhibit 38: Other Unnatural Amino Acids – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included)...... 228 Exhibit 39: Other Unnatural Amino Acids – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 229 GABA – Gamma Amino Butyric acid ...... 229 Unnatural Amino Acids – Applications ...... 230 Research & Development ...... 231 Exhibit 40: Unnatural Amino Acids in R&D Applications – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 231 Exhibit 41: Unnatural Amino Acids in R&D Applications – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 232 Pharmaceutical Applications ...... 233 Exhibit 42: Unnatural Amino Acids in Pharmaceutical Applications – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 234 Exhibit 43: Unnatural Amino Acids in Pharmaceutical Applications – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included)...... 234 ß‐lactams Antibiotics ...... 234 Synthesis of β‐lactams ...... 235 Mode of Action of Antibiotics ...... 236 Bacterial Resistance ...... 236 Types of ß‐lactams Antibiotics ...... 237 Penicillins ...... 237 Production of Penicillin ...... 238 Penicillin binding proteins ...... 238 Functioning of PBPs ...... 238 Development of Penicillin Derivatives ...... 239 Types of Penicillins ...... 239 Narrow‐Spectrum‐ Beta‐lactamase Sensitive ...... 239 Benzathine Penicillin ...... 239 Benzylpenicillin (Penicillin G) ...... 239 Phenoxymethylpenicillin (Penicillin V) ...... 239 Procaine Penicillin ...... 239 Penicillinase‐Resistant Penicillins ...... 240 Oxacillin (Brand Name: Bactocill) ...... 240 Methicillin ...... 240 Mode of Action and Working Pattern ...... 240 Applications...... 241 Dicloxacillin ...... 241

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Function and Reactions ...... 241 Applications...... 241 Recommended Application of Dicloxacillin ...... 242 Flucloxacillin ...... 242 Function and Features ...... 242 Application of Flucloxacillin ...... 243 Co‐Fluampicil ‐ To Combat Streptococcal Infection ...... 243 Functions ...... 244 β‐Lactamase‐Resistant Penicillins ...... 244 Temocillin ...... 244 Moderate‐Spectrum ...... 244 Amoxicillin ...... 244 Antibiotic Reaction Mechanism ...... 245 Product in Market ...... 245 Ampicillin – Penicillin Derivative ...... 245 Ampicillin manufacturing process ...... 246 Research and development in Ampicillin ...... 247 Reaction Mechanism ...... 247 Uses ...... 248 Broad‐Spectrum ...... 249 Co‐Amoxiclav ...... 249 Extended‐Spectrum ...... 249 Azlocillin ...... 249 Carbenicillin ...... 250 Ticarcillin ...... 250 Mezlocillin ...... 251 Piperacillin ...... 251 Cephalosporins ...... 252 Mode of Action ...... 252 Uses ...... 253 Classification of Cephalosporins ...... 254 First generation cephalosporins ...... 254 Cefalexin ...... 255 Cephalothin ...... 256 Cefazolin ...... 256 Second generation cephalosporins ...... 257 Cefotetan ...... 257 Cefoxitin ...... 257 Cefaclor ...... 257 Cefuroxime ...... 259 Third generation cephalosporins ...... 259 Ceftriaxone ...... 261 Cefotaxime ...... 261

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Cefpodoxime ...... 261 Broad Spectrum with Anti‐Pseudomonas Activity ...... 262 Ceftazidime ...... 262 Fourth generation cephalosporins ...... 262 Cefepime ...... 263 Cefpirome ...... 264 Fifth generation cephalosporins ...... 264 Carbapenems ...... 264 Applications...... 265 Types ...... 265 Imipenem ...... 265 Meropenem ...... 265 Ertapenem...... 266 Faropenem ...... 266 Doripenem ...... 267 Monobactams ...... 267 Aztreonam ...... 267 Immunoassays...... 268 Peptide Antibiotics ...... 269 Polypeptide Antibiotics and Application in the Treatment of Infections ...... 270 Gramicidin ...... 271 Gramicidin‐S ...... 272 Bacitracin ...... 273 Actinomycin D ...... 275 Enramycin ...... 276 Cycloserine ...... 277 Polymyxin B ...... 278 Desmopressin Acetate ...... 279 Clinical Pharmacology ...... 280 Human Pharmacokinetics ...... 281 Indications ...... 281 Hemophilia A ...... 281 Von Willebrand’s Disease (Type I) ...... 281 Diabetes Insipidus ...... 282 Unnatural amino acids for the treatment of diseases ...... 282 Treatment of arthritis ...... 282 Treatment of Parkinson’s disease ...... 282 Treatment of Alzheimer’s disease ...... 282 Treatment of cancer ...... 283 Control of diabetes mellitus ...... 283 Treatment of cardiovascular diseases ...... 284 Treatment of other disorders ...... 286 Exhibit 44: Therapeutic Products Containing Unnatural Amino Acids ...... 289

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Pharmaceutical Intermediates ...... 290 Applications of D‐Amino Acids ...... 291 D–Valine ...... 292 D‐Aspartic Acid ...... 292 N‐Methyl‐D‐Aspartic Acid ...... 293 D‐Aspartic Acid Β‐Hydroxamate in the Therapy of Viral Infections and Tumors ...... 293 D‐Glutamic ...... 293 Manufactured Free Glutamic Acid ...... 294 D‐Arginine ...... 294 D‐Methionine ...... 295 Glycine ...... 295 Glycine as a D‐Amino Acid Surrogate in the K+‐Selectivity Filter ...... 295 D‐Proline Reductase ...... 295 Pharmaceutical/Cosmetic Compositions Comprising Lysine‐D‐Proline‐Valine Tripeptide ...... 296 Immuno Diagnostics ...... 296 Cardiac Biomarkers ...... 296 Immuno Diagnostics Kits ...... 296 Therapeutic Formulations ...... 296 Production of Novel Drugs ...... 298 Unnatural Amino Acids ‐ Building Blocks of New Peptidomimetics ...... 299 Unnatural Amino Acids in Anti‐infective Drugs ...... 300 Anti‐viral Drugs ...... 300 Antibiotics [Antibacterial Drugs] ...... 300 Bio‐techniques for Development of Antibiotics ...... 300 Fed‐Batch Culture Technique ...... 300 Directed‐Evolution Techniques ...... 301 Antibiotic Testing in Milk ...... 301 Antibiotic Test Kits ...... 301 Penzym® kit ...... 301 SNAP MRL Beta‐Lactam Test Kit ...... 303 CHARM II Kit ‐ β‐lactams ...... 303 Screening Plus Kit ...... 303 Charm ROSA® MRL‐3 Test ...... 303 Food & Feed ...... 306 Exhibit 45: Unnatural Amino Acids in Food& Feed Applications – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 306 Exhibit 46: Unnatural Amino Acids in Food& Feed Applications – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included)...... 307 Artificial Sweeteners ...... 308 Alitame ...... 311 Exhibit 47: Global Market for Alitame (2009‐2015) in US$ million ...... 312

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Exhibit 48: Global Market Shares for Alitame (2009‐2015) ...... 312 Flavor Enhancers ...... 315 D‐Glutamate ...... 315 DL‐Alanine ...... 316 Sugar Substitutes ...... 316 Veterinary Feed ...... 317 Nutritional Requirements for Swine ...... 317 Three most crucial amino acids for proper nutrition of pigs ...... 317 D‐Lysine ...... 317 D‐Methionine ...... 317 D‐Tryptophan ...... 318 Nutritional Requirements for Silkworms ...... 318 DL‐Methionine‐ Pet Food ...... 319 Agrochemicals ...... 319 Insecticides ...... 319 Fluvalinate ...... 320 Plant related proteins and enzymes ...... 321 Exhibit 49: Unnatural Amino Acids in Agrochemicals – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 322 Exhibit 50: Unnatural Amino Acids in Agrochemicals – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 323 Arsenal Herbicide ‐ α‐methylamine ...... 323 Fenamidone – l‐α‐methylphenylglycine ...... 325 Other Applications ...... 326 Exhibit 51: Unnatural Amino Acids in Other Applications – Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 326 Exhibit 52: Unnatural Amino Acids in Other Applications – Global Market Shares by Region (2008 & 2015) for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 327 Plant Biomarkers ...... 327 Biosensors ...... 327 Deodorants ...... 327 Unnatural Amino Acids ‐ Research Studies ...... 330 4. MARKET DYNAMICS ...... 338 Global Market Analysis ...... 338 Exhibit 53: Unnatural Amino Acids ‐ Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 339 Exhibit 54: Unnatural Amino Acids ‐ Global Market Shares by Region (2008 & 2015)for North America, Europe, Asia‐Pacific and Rest of World (Graphical Representation Included) ...... 340

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Unnatural Amino Acids by Type ...... 340 Exhibit 55: Unnatural Amino Acids by Type ‐ Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 341 Exhibit 56: Unnatural Amino Acids ‐ Global Market Shares by Type (2008 & 2015) for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included)...... 342 Exhibit 57: List of Unnatural Amino acids and Application Areas ...... 343 Exhibit 58: Global Production of D‐amino acids and Derivatives in Tons (2005‐2015) ...... 345 Exhibit 59: Global Production of D‐ phenylglycine and p‐hydroxy‐D‐phenyl glycine in Tons (2005‐2015)...... 345 Unnatural Amino Acids by Application ...... 346 Exhibit 60: Unnatural Amino Acids by Application ‐ Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 347 Exhibit 61: Unnatural Amino Acids ‐ Global Market Shares by Application (2008 & 2015) for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 348 R&D Applications ...... 349 Pharmaceutical Applications ...... 349 By Disease Treatment ...... 352 Exhibit 62: Unnatural Amino Acids by Disease Treatment ‐ Global Value Market Estimations and Predictions (2005‐2015) in US$ Million for Neurological Disorders, Cardiovascular, Diabetes, Arthritis, Cancer and Other (Graphical Representation Included) ...... 353 Exhibit 63: Unnatural Amino Acids ‐ Global Market Shares by Disease Treatment (2008 & 2015) for Neurological Disorders, Cardiovascular, Diabetes, Arthritis, Cancer and Other (Graphical Representation Included)...... 354 Exhibit 64: Global Market for Cephalosporins (First and Second Generation) in US (2007 and 2008) in US$ Million ...... 354 Pharmaceutical Intermediates Market Driven by Drug Development and Consolidations ...... 355 Regulatory Approval Processes ‐ Driving Down Pharmaceutical Intermediates Market ...... 355 Technology Trends ‐ More Towards Biotechnology ...... 355 Exhibit 65: Global Peptide Therapeutics Market in US$ Billion for the US, Germany, UK, Japan, China, and Rest of World (2005‐2015) ...... 356 Exhibit 66: Global Peptide Therapeutics Market – Market Shares for the US, Germany, UK, Japan, China, and Rest of World (2005‐2015) ...... 357 Exhibit 67: Global Custom Peptide Synthesis Market in US$ Million for North America, Europe, Asia Pacific, and Rest of World ...... 358 Exhibit 68: Global Custom Peptide Synthesis Market by Disease Area in US$ Million for North America, Europe, Asia Pacific, and Rest of World ...... 359 Exhibit 69: Global Custom Peptide Synthesis Market Shares by Disease Area for North America, Europe, Asia Pacific, and Rest of World ...... 360 Exhibit 70: Peptide Therapeutics Market in the US in US$ Billion for 2005‐2015 ...... 361

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Exhibit 71: Peptide Therapeutics Market in Germany and UK in US$ Million for 2005‐2015 ...... 361 Exhibit 72: Peptide Therapeutics Market in Japan and China in US$ Million for 2005‐2015...... 361 Exhibit 73: Antibacterial peptides and the D‐amino acids they contain...... 362 Peptide Drugs – The Challenges ...... 362 Overview of peptide therapeutic market ...... 362 Technology improvements ...... 364 Synthetic therapeutic peptides ...... 365 Limitations to the use of peptides as drug candidates ...... 366 Food and Feed ...... 366 Exhibit 74: Global Alitame Value Market (2009‐2015) in US$ Million for China, Australia and Rest of World .. 367 Sweetener production stopped due to high costs ...... 368 Agrochemicals ...... 369 Tau‐fluvalinate ...... 369 Regional Market Analysis ...... 376 North America ...... 376 Exhibit 75: Unnatural Amino Acids – North American Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 376 Exhibit 76: Unnatural Amino Acids – North American Value Market Estimations and Predictions (2005‐2015) in US$ Million for US and Canada (Graphical Representation Included) ...... 377 Exhibit 77: Unnatural Amino Acids – North American Market Shares by Region (2008 & 2015) for US and Canada) ...... 377 Exhibit 78: Unnatural Amino Acids by Type – North American Value Market Estimations and Predictions (2005‐ 2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 378 Exhibit 79: Unnatural Amino Acids – North American Market Shares by Type (2008 & 2015) for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 379 Exhibit 80: Unnatural Amino Acids by Application – North American Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 380 Exhibit 81: Unnatural Amino Acids – North American Market Shares by Application (2008 & 2015) for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 381 United States ...... 382 Exhibit 82: Unnatural Amino Acids – United States Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 382 Exhibit 83: Unnatural Amino Acids by Type –United States Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐ Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 383

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Exhibit 84: Unnatural Amino Acids by Application – United States Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 385 Canada ...... 386 Exhibit 85: Unnatural Amino Acids – Canadian Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 386 Exhibit 86: Unnatural Amino Acids by Type – Canadian Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐ Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 387 Exhibit 87: Unnatural Amino Acids by Application – Canadian Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 388 Europe ...... 389 Exhibit 88: Unnatural Amino Acids – European Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 389 Exhibit 89: Unnatural Amino Acids – European Value Market Estimations and Predictions (2005‐2015) in US$ Million for United Kingdom, Germany, Switzerland, Italy, The Netherlands and Rest of Europe (Graphical Representation Included) ...... 390 Exhibit 90: Unnatural Amino Acids –European Market Shares by Region (2008 & 2015) for United Kingdom, Germany, Switzerland, Italy, The Netherlands and Rest of Europe (Graphical Representation Included) ...... 391 Exhibit 91: Unnatural Amino Acids by Type – European Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐ Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 392 Exhibit 92: Unnatural Amino Acids – European Market Shares by Type (2008 & 2015) for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 393 Exhibit 93: Unnatural Amino Acids by Application – European Value Market Estimations and Predictions (2005‐ 2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included)...... 394 Exhibit 94: Unnatural Amino Acids –European Market Shares by Application (2008 & 2015) for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 395 United Kingdom ...... 396 Exhibit 95: Unnatural Amino Acids – United Kingdom Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 396 Exhibit 96: Unnatural Amino Acids by Type – United Kingdom Value Market Estimations and Predictions (2005‐ 2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 397 Exhibit 97: Unnatural Amino Acids by Application – United Kingdom Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 398

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Germany ...... 399 Exhibit 98: Unnatural Amino Acids – German Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 399 Exhibit 99: Unnatural Amino Acids by Type – German Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐ Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 400 Exhibit 100: Unnatural Amino Acids by Application – German Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 401 Switzerland ...... 402 Exhibit 101: Unnatural Amino Acids – Swiss Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 402 Exhibit 102: Unnatural Amino Acids by Type – Swiss Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐ Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 403 Exhibit 103: Unnatural Amino Acids by Application – Swiss Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 404 Italy ...... 405 Exhibit 104: Unnatural Amino Acids – Italian Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included)...... 405 Exhibit 105: Unnatural Amino Acids by Type – Italian Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐ Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 406 Exhibit 106: Unnatural Amino Acids by Application – Italian Value Market Estimations and Predictions (2005‐ 2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 407 The Netherlands ...... 408 Exhibit 107: Unnatural Amino Acids – The Netherlands Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 408 Exhibit 108: Unnatural Amino Acids by Type – The Netherlands Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐ Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 409 Exhibit 109: Unnatural Amino Acids by Application – The Netherlands Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 410 Rest of Europe ...... 411 Exhibit 110: Unnatural Amino Acids – Rest of Europe Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 411

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Exhibit 111: Unnatural Amino Acids by Type – Rest of Europe Value Market Estimations and Predictions (2005‐ 2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 412 Exhibit 112: Unnatural Amino Acids by Application – Rest of Europe Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 413 Asia Pacific ...... 414 Exhibit 113: Unnatural Amino Acids –Asia Pacific Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 414 Exhibit 114: Unnatural Amino Acids – Asia Pacific Value Market Estimations and Predictions (2005‐2015) in China, Japan, India, South Korea, Australia, and Rest of Asia‐Pacific US$ Million for (Graphical Representation Included) ...... 415 Exhibit 115: Unnatural Amino Acids – Asia Pacific Market Shares by Region (2008 & 2015) for China, Japan, India, South Korea, Australia, and Rest of Asia‐Pacific (Graphical Representation Included) ...... 416 By Type ...... 417 Exhibit 116: Unnatural Amino Acids by Type – Asia‐Pacific Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐ Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 417 Exhibit 117: Unnatural Amino Acids – Asia‐Pacific Market Shares by Type (2008 & 2015) for β‐Amino Acids, β‐ Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) . 418 By Application ...... 419 Exhibit 118: Unnatural Amino Acids by Application – Asia‐Pacific Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 419 Exhibit 119: Unnatural Amino Acids – Asia‐Pacific Market Shares by Application (2008 & 2015) for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 420 China ...... 421 Exhibit 120: Unnatural Amino Acids – Chinese Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 421 By Type ...... 422 Exhibit 121: Unnatural Amino Acids by Type – Chinese Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐ Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 422 By Application ...... 423 Exhibit 122: Unnatural Amino Acids by Application – Chinese Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 423 Japan ...... 425 Exhibit 123: Unnatural Amino Acids – Japanese Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 425

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By Type ...... 426 Exhibit 124: Unnatural Amino Acids by Type – Japanese Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐ Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 426 By Application ...... 427 Exhibit 125: Unnatural Amino Acids by Application – Japanese Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 427 India ...... 429 Exhibit 126: Unnatural Amino Acids – Indian Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 429 By Type ...... 430 Exhibit 127: Unnatural Amino Acids by Type – Indian Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐ Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 430 By Application ...... 431 Exhibit 128: Unnatural Amino Acids by Application – Indian Value Market Estimations and Predictions (2005‐ 2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 431 South Korea ...... 434 Exhibit 129: Unnatural Amino Acids – South Korean Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 434 By Type ...... 435 Exhibit 130: Unnatural Amino Acids by Type – South Korean Value Market Estimations and Predictions (2005‐ 2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 435 By Application ...... 436 Exhibit 131: Unnatural Amino Acids by Application – South Korean Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 436 Australia ...... 437 Exhibit 132: Unnatural Amino Acids – Australian Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 437 By Type ...... 438 Exhibit 133: Unnatural Amino Acids by Type – Australian Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐ Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 438 By Application ...... 439

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Exhibit 134: Unnatural Amino Acids by Application – Australian Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 439 Rest of Asia‐Pacific ...... 440 Exhibit 135: Unnatural Amino Acids – Rest of Asia‐Pacific Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 440 By Type ...... 441 Exhibit 136: Unnatural Amino Acids by Type – Rest of Asia‐Pacific Value Market Estimations and Predictions (2005‐2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐ Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 441 By Application ...... 442 Exhibit 137: Unnatural Amino Acids by Application – Rest of Asia‐Pacific Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 442 Rest of World...... 443 Exhibit 138: Unnatural Amino Acids – Rest of World Value Market Estimations and Predictions (2005‐2015) in US$ Million (Graphical Representation Included) ...... 443 By Type ...... 444 Exhibit 139: Unnatural Amino Acids by Type – Rest of World Value Market Estimations and Predictions (2005‐ 2015) in US$ Million for β‐Amino Acids, β‐Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included) ...... 444 Exhibit 140: Unnatural Amino Acids – Rest of World Market Shares by Type (2008 & 2015) for β‐Amino Acids, β‐ Amino Acid Derivatives, Cyclic Amino Acids & Derivatives, D‐Amino Acids, D‐Amino Acid Derivatives, DL‐Amino Acids, DL‐Amino Acid Derivatives, L‐Amino Acid Derivatives and Other (Graphical Representation Included)...... 445 By Application ...... 446 Exhibit 141: Unnatural Amino Acids by Application – Rest of World Value Market Estimations and Predictions (2005‐2015) in US$ Million for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 446 Exhibit 142: Unnatural Amino Acids – Rest of World Market Shares by Application (2008 & 2015) for R&D, Pharmaceutical, Food & Feed, Agrochemicals and Other (Graphical Representation Included) ...... 447 Unnatural Amino Acids – A Market Overview ...... 448 Anti‐infectives – Antiviral and Antibacterial drugs ...... 448 Exhibit 143: L Dopa ‐ Global Value Market in US$ Billion ...... 449 Cephalosporins market ...... 450 Regulatory Guidelines for drugs ...... 454 Sweeteners ...... 455 Agrochemicals ...... 455 Major Activities in Unnatural Amino Acids Market ...... 456 Positive Results for Chelsea’s Phase II Clinical Trial of Droxidopa in Fibromyalgia ...... 456

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FDA Approves Hospira’s Generic Version of Antibiotic Merrem…...... 457 Arbuckle’s Planet Rice Record Swelling Sales…...... 457 The US Patent and Trademark Office Issues Notice of Allowance for MultiStat® Group of Compounds of Quick‐Med Technologies…...... 458 Orchid Acquires Karalex Pharma, LLC…...... 458 Low‐cost Drug to Save Thousands of Accident Victims…...... 459 GE Healthcare Announces Prostate Imaging Agent Phase 1 Study Results ...... 459 Ethical Naturals Develops AlphaWave™, a GRAS Approved L‐Theanine…...... 460 US FDA Approves Aurobindo Pharma’s Ceftazidime for Injection…… ...... 460 Strides Arcolab Obtains FDA Approval for Bacitracin Injections…...... 461 First Generic Version of Augmentin XR Launched in the US by Sandoz… ...... 461 Victory Pharma Acquires Assets of MiddleBrook Pharmaceutical for US$ 17.1 Million…...... 461 FDA Approves DUPLEX® System of B.Braun for Administration of Cefepime…… ...... 462 Ceftobiprole Sales to be discontinued in Canada…...... 462 Health Canada Approves Cefprozil Tablets & Powder for Oral Suspension of Aurobindo…...... 463 MDRNA, Inc. and Pfizer in Joint Research Study… ...... 463 Novel Peptide Synthesis and Manufacturing Services Launched by Ajinomoto AminoSciences…… ...... 463 AstraZeneca Acquires Novexel…...... 464 FDA Approves Florida Based Cephalosporin Manufacturing Facility of GeoPharma…...... 465 Pernix Therapeutics Holdings Acquires CEDAX, an Oral Third‐Generation Cephalosporin… ...... 465 Venus Remedies Obtains Patent for SULBACTOMAX…...... 466 Studies Indicate Ineffectiveness of Starlix, the Diabetes Drug of Novartis……...... 467 Hospira Acquires Injectables Formulation Business of Orchid……...... 467 Mefoxin® (cefoxitin injection) Frozen Premix IV Solution Launched by Bioniche Pharma… ...... 468 Antibiotics Prices in India likely to Increase Up to 50%...... 468 Chinese SFDA Approves Penicillin Manufacturing Facility of Suzhou Erye Pharmaceutical ...... 469 Queensland Institute of Medical Research Awards Major Peptide Supply Contract to Mimotopes for Malaria Vaccine Research…… ...... 469 AminoLogics Uses Novel Chiral Technology (ARCA) for Unnatural amino acids ...... 470 Æterna Zentaris Terminates Agreement to Develop, Commercialize and License Cetrorelix in Benign Prostatic Hyperplasia with Sanofi‐Aventis…...... 470 Cubist Pharmaceuticals Formally Acquires Calixa Therapeutics…...... 470 La Jolla Institute Awards Peptide Library Supply Contract to Screen Dengue & Tuberculosis Pathogens to Mimotopes…… ...... 471 Drug Precursor for Cardiovascular Diseases Treatment Developed at USM… ...... 471 Venus Remedies Obtains South African Patent for Potentox…...... 472 AnaSpec Acquired by Eurogentec…… ...... 472 Online Peptide Superstore Launched by Mimotopes…… ...... 473 American Peptide Company Creates Research & Development Division…...... 474

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AnaSpec Appoints Distributor in South Africa……...... 474 Generic Nateglinide for Diabetes Launched in the US by Dr Reddy’s…...... 475 Steri‐Pharma Acquires Cephalosporin Manufacturing Facility from Hanford Pharmaceuticals… ...... 475 Swissmedic Approves Aurobindo Pharma’s Cefepime for Injection…...... 475 AstraZeneca and Forest in Ceftaroline Co‐development and Commercialization agreement ...... 476 FDA Declares Cefepime Appropriate…...... 476 Penicillin G Potassium for Injection, USP, of APP Pharmaceuticals Approved by FDA…...... 477 Generic Version of Vantin® Launched in the US by Sandoz…… ...... 477 Venus Remedies Obtains First Product Patent in South Korea…...... 478 Evonik Plans Substantial Methionine Manufacturing Capacity Expansion…...... 478 AnaSpec Appoints Distributor for Lithuania & Latvia……...... 478 Piperacillin/Tazobactam for Injection Launched in the UK by Hospira…...... 478 ClearPoint™ Peptides of AnaSpec Bestowed Best New Product Award…...... 479 Pfizer and Aurobindo Pharma Expand agreement from 5 Drugs to 44 drugs…...... 479 AnaSpec Offers to Provide Custom Synthesis of Stapled Helical Peptides…...... 480 FIRMAGON® (degarelix) of Ferring Pharmaceuticals Approved by European Commission as Prostate Cancer Treatment…...... 480 Lundbeck Takes Over Ovation Pharmaceuticals...... 481 Sagent Pharmaceuticals Launches Cefazolin for Injection, USP in 500mg Single‐dose Vial to Expand Cefazolin Product Range…...... 481 AnaSpec Appoints BioPike as Distributor for China…...... 482 CPC Scientific and Sigma‐Aldrich in PEPscreen® Custom Peptide Libraries Distribution Agreement……...... 482 AnaSpec Appoints Yope Biotechnology as Distributor……...... 482 FDA Approves Generic Version of Augmentin Suspension… ...... 483 Zevtera Approved in Switzerland as Complicated Skin & Soft Tissue Infection Treatment… ...... 483 Evonik Enhances Methionine Production Capacity…… ...... 484 AnaSpec and Shanghai Universal Biotech in Distribution Agreement……… ...... 484 FDA Grants US Marketing Approval to Ceftazidime Injection of Wockhardt…...... 485 Wockhardt Obtains Marketing Approval for Ceftazidime Injections from FDA…...... 485 Zosyn®, an Injectable Semi‐synthetic Antibiotic & ß‐lactamase Inhibitor Combination Launched in Japan ….. 485 Taisho Launches of Zosyn® in Japan… ...... 486 Merck and Orchid in Anti‐infection Drugs Development Collaboration…...... 486 AnaSpec and Biocore in Distribution Agreement……...... 487 Venus Remedies Launches its Fourth Research Product…...... 487 Injectables Ceftriaxone and Cefuroxime Launched by Sagent Pharmaceuticals…… ...... 487 Cubist to Promote Merrem IV of AstraZeneca in the US…...... 487 Novartis Acquires Protez Pharmaceuticals Along With Rights to Hospital Antibiotic in Clinical Development ...... 488

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Lupin Launches Ramipril Capsules…...... 488 Novartis Acquires Protez Pharmaceuticals…...... 489 Inquiries Follow Nagase in Concurrence with Reinforcement of Unnatural Amino Acids…...... 489 Protez Initiates Phase II Clinical Trials for PZ‐601 in Infectious Diseases… ...... 489 Achillion and FOB Synthesis to Develop Carbapenem Compounds in Collaboration…...... 490 Novartis Acquires Stake in Alcon… ...... 490 Achillion and FOB Synthesis in Carbapenem Compounds Development Collaboration… ...... 490 Strategic Acquisition by Aurobindo Pharma for Expansion in Europe…… ...... 491 AOAC Approves BetaStar® Dairy Antibiotic Test of Neogen…...... 491 FDA Grants Manufacturing & Marketing Approval of Cefuroxime Axetil to Ranbaxy…...... 492 Cefuroxime Axetil for Oral Suspension of Ranbaxy Approved in the US… ...... 492 Amoxicillin of MiddleBrook Approved by FDA for Pharyngitis/Tonsillitis in Adults and Adolescents…...... 492 DSM Anti‐Infectives and Arch Pharmalabs in Partnership Agreement…… ...... 493 US FDA Approves Cefpodoxime Proxetil ANDA of Orchid…...... 493 NeoMPS Acquired by PolyPeptide Group…… ...... 494 Eli Lilly Sells Indian Marketing Rights of Antibiotic Distaclor® (Cefaclor) to Pharmalink… ...... 494 FDA Approves Aurobindo Pharma’s Cefazolin for Injection USP…...... 495 Advancis Pharmaceutical Corporation Renamed MiddleBrook Pharmaceuticals, Inc… ...... 495 Lupin Obtains FDA Approval for Cefdinir for Oral Suspension, 250mg/ 5ml, to Launch Entire Product Range.. 495 Bachem in Expanded Peptide Production Co‐operation with immatics…… ...... 495 Æterna Zentaris Reclaims Exclusive Global Rights (Ex‐Japan) from Solvay for Cetrorelix…...... 496 Charm Sciences Launches ROSA® SL3™…...... 496 FDA Approves Suprax of Lupin Pharmaceuticals…...... 496 FDA Grants US Marketing Approval for Complete Range of Ceftriaxone Antibiotic Injection to Wockhardt..... 497 FDA Grants Marketing Approval to Wockhardt for Complete Range of Ceftriaxone Antibiotic Injections…. .... 497 Cephalosporin Injectable Manufacturing Facility Approved…...... 497 Orchid in Licensing and Distribution Agreement with Actavis for Marketing of Cephalosporin Formulations in Entire Europe…...... 498 FDA Grants Marketing Approval for Amoxicillin and Clavulanate Potassium for Oral Suspension, USP, to Ranbaxy…...... 499 FDA Marketing Approval to Ranbaxy for Amoxicillin and Clavulanate Potassium for Oral Suspension USP…...... 499 FDA Grants Manufacturing and Marketing Approval of Cefprozil Anti‐infective Tablets to Ranbaxy Laboratories…...... 499 Æterna Zentaris Launches Cetrotide® (Cetrorelix) in Japan for In‐Vitro Fertilization… ...... 500 FDA Approves Ceftriaxone 10gm Vials of Lupin……...... 500 FDA Marketing Approval to Wockhardt for Cefotaxime Injection… ...... 500 Advancis Launches Keflex 750mg Capsules…...... 501 Carbapenem Antibiotic Finibax 0.25g IV Solution Kit (Doripenem Hydrate) Launched in Japan by Shionogi….. 501

MIR027‐Unnatural Amino Acids – A Market Insight Report, July 2010 © RI Technologies, www.researchimpact.com ‐ xxiv ‐ UNNATURAL AMINO ACIDS MIR027 A MARKET INSIGHT REPORT– JULY 2010

CONTENTS

Brookwood and Genzyme in an Expansive Drug Delivery Collaboration…...... 501 FDA Approves Cephalexin Capsules of Aurobindo Pharma…...... 502 Polymer Launches New Resin for Solid‐phase Synthesis of Resin‐Bound Unnatural Amino Acids…...... 502 US FDA Approves Ceftriaxone Vials of Orchid…...... 502 FDA Approves Baxter’s Frozen Premixed Ceftriaxone Injection in Ready‐to‐Use Containers… ...... 503 Advancis Launches Keflex® Powder for Oral Suspension in the US…...... 503 Ranbaxy Introduces Chewable Cephalosporin Tablet…...... 503 Unnatural Amino Acids – Major Competitor Profiles ...... 504 Abbott Laboratories ...... 504 ACS Dobfar SpA ...... 505 Æterna Zentaris, Inc...... 508 Ajinomoto Co., Inc...... 509 Amatek Chemical Co., Ltd...... 510 AminoLogics Co...... 511 AnaSpec, Inc...... 511 Aspen Pharmacare Holdings Ltd...... 512 AstraZeneca plc ...... 513 Bajaj Healthcare Ltd...... 514 BASF Corporation ...... 515 Bayer CropScience AG ...... 516 Biological E Ltd...... 517 Biovet SA ...... 518 China Pharmaceutical Group Limited ...... 520 Divis Laboratories Ltd...... 521 Donboo Amino Acid Co., Ltd...... 522 Dragon Pharmaceutical, Inc...... 529 DSM Pharma ...... 532 Elan Corporation plc ...... 534 EMD Chemicals, Inc...... 535 EMD Serono, Inc...... 544 Enzo Life Sciences, Inc...... 545 Evonik Degussa GmbH ...... 546 Genepharm Australasia Limited ...... 548 Genzyme Pharmaceuticals ...... 549 GlaxoSmithKline Plc ...... 552 Hanmi Pharmaceutical Co., Ltd...... 554 Harbin Pharmaceutical Group Co., Ltd...... 556 Hongkong Henry Industry Co., Ltd...... 557 Hovid Berhad ...... 557 IRIS Biotech GmbH ...... 559

MIR027‐Unnatural Amino Acids – A Market Insight Report, July 2010 © RI Technologies, www.researchimpact.com ‐ xxv ‐ UNNATURAL AMINO ACIDS MIR027 A MARKET INSIGHT REPORT– JULY 2010

CONTENTS

Jupiter Bioscience Limited ...... 620 King Pharmaceuticals, Inc...... 621 Kyowa Hakko Bio Co., Ltd...... 622 Lek d.d...... 623 Lunan Pharmaceutical Group Corporation ...... 624 Lupin Pharmaceuticals, Inc...... 626 Mimotopes Pty. Ltd...... 627 MP Biomedicals, LLC ...... 628 Nagase & Co., Ltd...... 641 Norbrook Laboratories Ltd...... 642 Novartis AG ...... 644 Orchid Chemicals & Pharmaceuticals Ltd...... 644 PerkinElmer Life and Analytical Sciences, Inc...... 646 PolyPeptide Group ...... 648 Ranbaxy Laboratories Ltd...... 650 Sandoz International GmbH ...... 651 Sanofi‐Aventis SA ...... 654 Sekisui Medical Co., Ltd...... 654 Shanghai Hanhong Chemical Co., Ltd...... 657 Shanghai Hengbai Biotech Co., Ltd...... 658 Shanghai PanQi Biochem Tech Co., Ltd...... 660 Sigma‐Aldrich Corporation ...... 661 Synthetech, Inc...... 669 Takeda Pharmaceutical Co., Ltd...... 673 Tocris Bioscience ...... 674 Topsun Pharm. & Chem.Trading Co., Ltd...... 674 Unibiochem Co., Ltd...... 676 United Laboratories International Holdings Limited (The) ...... 701 Venus Remedies Ltd...... 703 Wellmark International ...... 705 Xeno Pharmaceuticals Phils, Inc...... 706 Zhangjiagang Huachang Pharmaceutical Co., Ltd...... 707 Unnatural Amino Acids – OUTLOOK ...... 708 Market prospects for peptide drugs ...... 708 Hurdles that may be experienced in marketing novel peptides ...... 708 Challenges ...... 709 Unmet needs ...... 710 5. CORPORATE DIRECTORY ...... 715 PATENTS INFORMATION ...... 716

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