Review Article | Published:

Putting chirality to work: the strategy of chiral switches

Nature Reviews Drug Discovery volume 1, pages 753768 (2002) | Download Citation



Most of the new drugs reaching the market today are single enantiomers, rather than the racemic mixtures that dominated up to ten years ago. Many of the new single-enantiomer drugs were developed as such, but there are also important examples of new single-enantiomer drugs derived from 'chiral switches' of established racemates. Indeed, a well-timed chiral switch can offer enhanced therapy and further profitability as a 'line extension' of a major racemic drug with patents that are expiring.

Key points

  • Chiral switches are chiral drugs that have already been claimed, approved and marketed as racemates or as mixtures of stereoisomers, but have since been redeveloped as single enantiomers. The essential criterion of a chiral switch is a change in the status of chirality. There are still a significant proportion of racemic drugs among the recently approved new molecular entities.

  • The patentability of single enantiomers in a chiral switch is an extreme case of a selection patent. The novelty of a single enantiomer is not negated by the prior-art disclosure of its racemate. The strategy of enantiomeric pairs of patents of single enantiomers — E1 and E2 — in a chiral switch consists of two patents claiming simultaneously that E1 and E2 are pharmacologically superior to the racemic drug E1,2. This strategy has been questioned.

  • According to the US FDA, single enantiomers in chiral switches are not new molecular entities, and are therefore barred from five-years exclusivity. Such new products are treated as new derivatives of existing drugs or new formulations, on a case-by-case basis.

  • Despite the regulatory acceptance of 'bridging strategies' from racemate to single enantiomer, only a few successful switches have emerged from this route.

  • Successful chiral switches emerge from racemic drugs that have efficacy and/or safety that can be enhanced, leading to significantly superior single enantiomers that are patentable and compete effectively with cheaper generic versions of the racemates.

  • Chiral switches are also eligible in cases in which the mechanisms of action of the single-enantiomer drugs involve achiral intermediates — for example, esomeprazole magnesium — and/or racemization.

  • Paradoxically, a chiral switch can result in the increased use of the racemate, this being a feature of the failure of the chiral switch of fenfluramine to dexfenfluramine and the 'fen–phen' fiasco.

  • The timing of chiral switches of blockbuster drugs is crucial. The new single enantiomer should be launched ideally before the expiration of the patents that cover the racemate, with extended exclusivity and before the incursions of the respective generic drugs.

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  1. 1.

    & Stereochemical aspects of drug action and disposition. Adv. Drug Res. 28, 1–64 (1996).An excellent, authoritative review that focuses on the relative contributions of different stereoisomers to drug action.

  2. 2.

    Chirality and the Biological Activity of Drugs (CRC Press, Boca Raton, Florida, 1995).This book brings together the theoretical, commercial and practical aspects of chirality and biological activity of drugs and acts as a reference for the effects of enantiomers of drug substances.

  3. 3.

    & (eds) The Impact of Stereochemistry on Drug Development and Use (Chemical Analysis Vol. 142) (Wiley, New York, 1997).

  4. 4.

    Stereoselectivity of drug action. Drug Discov. Today 2, 138–147 (1997).

  5. 5.

    Through the looking glass in chiral drug development. Modern Drug Discov. 2, 51–60 (1999).A review of the opportunities for chiral drugs and the global regulatory environment that influences their development.

  6. 6.

    (ed.) Chiral Drugs (Ashgate, Burlington, Vermont, 2001).

  7. 7.

    , & (eds) Stereochemical Aspects of Drug Action (Springer, Heidelberg, 2002).

  8. 8.

    in Chirality in Industry II: Development in the Commercial Manufacture and Application of Optically Active Compounds (eds Collins, A. N., Sheldrake, G. N. & Crosby, J.) 11–18 (Wiley, New York, 1997).

  9. 9.

    & Intellectual property and chirality of drugs. Drug Discov. Today 4, 313–321 (1999).The first review to analyse the legal state-of-the-art of the patentability of chiral switches as derived from US and European precedents.

  10. 10.

    Chiral roundup. Chem. Eng. News 80, 43–50 (2002).

  11. 11.

    Chiral chemistry. Chem. Eng. News 79, 45–56 (2001).

  12. 12.

    Chiral switches. Lancet 355, 1085–1087 (2000).

  13. 13.

    Technology Catalyst International Corporation. Racemic Switch Update. World Market and Technology Assessment: Optically Active Chemical Compound Report 11th edn (Technology Catalyst International Corporation, Falls Church, Virginia, 2001).

  14. 14.

    , & Stereochemistry of Organic Compounds (Wiley, New York, 1994).A comprehensive, authoritative treatise on stereochemistry.

  15. 15.

    Basic terminology of stereochemistry. Pure Appl. Chem. 68, 2193–2222 (1996).

  16. 16.

    The Ambidextrous Universe: Symmetry and Asymmetry, From Mirror Reflections to Superstrips 3rd edn (W. H. Freeman and Company, New York, 1990).

  17. 17.

    Molecular chirality. Top. Stereochem. 22, 1–82 (1999).

  18. 18.

    Parity violation and the evolution of biomolecular homochirality. Chirality 12, 114–126 (2000).

  19. 19.

    & Introduction. Reflections on chiral discrimination. Enantiomer 1, 249–250 (1996).

  20. 20.

    Stereochemistry: a basis for sophisticated nonsense in pharmacokinetics and clinical pharmacology. Eur. J. Clin. Pharmacol. 26, 663–668 (1984).

  21. 21.

    & The enantiomer debate: realising the potential of enantiomers in pharmacology. Hum. Psychopharmacol. Clin. Exp. 16 (Suppl. 2), S65–S107 (2001).

  22. 22.

    , & Stereochemical origin of some clinically significant drug safety concerns: lessons for future drug development. Adv. Drug React. Toxicol. Rev. 17, 145–190 (1998).This article reviews the cases in which differences in the pharmacology or toxicology of enantiomers of a drug have contributed to safety concerns associated with the clinical use of the drug, and discusses the association of stereochemistry with improved efficacy, adverse drug reactions, drug withdrawals or discontinuations, and drug–drug interactions.

  23. 23.

    & (eds) To Market, To Market in Annual Reports in Medicinal Chemistry Vols 25–36 (Academic Press, San Diego, California, 1990–2001).

  24. 24.

    FDA perspectives on quality control for chiral pharmaceuticals. 13th Int. Symp. Chiral Discrimination Abstract L/316 and lecture (2001).

  25. 25.

    in Chiral Separation Techniques. A Practical Approach 2nd edn (ed. Subramaninn, G.) 317–341 (Wiley–VCH, Weinheim, 2000).This chapter gives the historical background to the regulation of chiral drugs, shows the effect of regulation on increasing the number of enantiomerically pure new drug substances that are being developed, describes the regulations that apply in Europe, the United States and Japan, and includes a discussion of internationally harmonized guidelines that are relevant to the registration of chiral drugs.

  26. 26.

    Regulatory issues and validation in chiral analysis. The Chiral Technology Conference 2000, CPI Worldwide, Milano (2000).

  27. 27.

    Stereochemistry: handling interactions. Drug Discov. Today 2, 127 (1997).

  28. 28.

    & Comments Submitted to the US Food and Drug Administration (FDA) in response to FDA Notice on Policy Period of Marketing Exclusivity for Newly Approved Drug Products With Enantiomer Active Ingredients 62 Fed. Reg. 2167 FDA Dkt No. 97N-0002, Comment No. 7327 (1997).

  29. 29.

    The therapeutic advantages achieved through single-isomer drugs. Pharm. News 6, 11–15 (1999).

  30. 30.

    Racemic switches: historical perspectives and current status. Chem. Oggi/Chem. Today 17, 28–32 (1999).

  31. 31.

    Food and Drug Administration. FDA's policy statement for the development of new stereoisomeric drugs. US Food and Drug Administration [online] (cited 26 Aug 2002) 〈〉 57 Fed. Reg. 22, 249 (1992).

  32. 32.

    Committee for Proprietary Medicinal Products. Working Parties on Quality, Safety and Efficacy of Medicinal Products. Note for Guidance: Investigation of Chiral Active Substances, III/3501/91 (1993).

  33. 33.

    , & Development of stereoisomeric (chiral) drugs: a brief review of scientific and regulatory considerations. Drug Inf. J. 31, 639–646 (1997).

  34. 34.

    FDA policy and regulation of stereoisomers: paradigm shift and the future of safer more effective drugs. Food Drug Law J. 54, 463–487 (1999).An excellent review and analysis of the FDA policy on the regulation of stereoisomers, including a discussion of the five versus three years exclusivity law for single enantiomers of previously approved racemates.

  35. 35.

    Department of Health and Human Services. The International Conference on Harmonization; guidance on Q6A specifications: test procedures and acceptance criteria for new drug substances and new drug products: chemical substances. US Food and Drug Administration〉 (2000).

  36. 36.

    54 Fed. Reg. At 28,898; 59 Fed. Reg. At 50,359.

  37. 37.

    US Food and Drug Administration. FDA Staff Manual Guide 4820.3. Drug Classification and Priority Review Policy (US Food and Drug Administration, 1992).

  38. 38.

    21 USC §355(j)(5)(D) ii (1997).

  39. 39.

    21 USC §355(j)(5)(D) iii (1997).

  40. 40.

    The case against market exclusivity for purified enantiomers of approved drugs. Yale Symp. Law Technol. Vol. 6 (1999).

  41. 41.

    Patents for Chemicals, Pharmaceuticals and Biotechnology (Oxford Univ. Press, Oxford, 1999).This highly acclaimed, informative, updated book guides the reader through the legal and procedural complexities of the British, European, Japanese and US patent systems, focusing on the relevant technology and industry practices.

  42. 42.

    Intellectual Property 2nd edn (Pitman, London, 1994).

  43. 43.

    Patent and Trademark Laws (The Bureau of National Affairs, Washington DC, 1989).

  44. 44.

    European Patent Convention (European Patent Office, Munich, Germany, 1977).

  45. 45.

    Patents for Inventions 5th edn (Stevens & Sons, London, 1983).

  46. 46.

    I. G. Farhenindustrie. [1930] 47 RPC 289–341 (1930).

  47. 47.

    Bayer (Boatz). [1982] RPC 319–324 (EPO/TBA) (1982).

  48. 48.

    duPont (Witsipe). [1982] FRS 303–310 (H.L.) (1982).

  49. 49.

    & P-hydroxyampicillin and salts thereof. GB Patent 1,214,844 (1972).

  50. 50.

    & Penicillins. GB Patent 978,178 (1964).

  51. 51.

    Beacham Group Limited's (Amoxicillin) Application (Court of Appeal). RPC 261–304 (1980).

  52. 52.

    & Methods of using (+)-cisapride for the treatment of gastro-esophageal reflux disease and other disorders. EP Application 93918155.3 (1994).

  53. 53.

    & Methods of using (−)-cisapride for the treatment of gastro-esophageal reflux disease and other disorders. EP Application 93916996.7 (1994).

  54. 54.

    Cisapride litigation: EPO Patent Application 93918153.3 ((+)-cisapride), EPO Application 93916996.7 ((−)-cisapride) (12 Aug 1997).

  55. 55.

    & in Goodman and Gilman'sThe Pharmacological Basis of Therapeutics 10th edn (eds Hardman, J. G., Limbird, L. E. & Gilman, A. G.) 1005–1029 (McGraw Hill, New York, 2002).

  56. 56.

    Gastrointestinal Disorders: New Therapies for the New Millenium (PJB Publications, New York, 2000).A guide to gastrointestinal disorders and their treatments, including gastric antisecretory PPI drugs, such as omeprazole and esomeprazole.

  57. 57.

    , & Esomeprazole magnesium. Drugs Future 24, 1178–1183 (1999).

  58. 58.

    & Esomeprazole. Drugs 60, 321–329 (2000).

  59. 59.

    , & Two of a kind. Chem. Brit. 42–45 (May 2002).

  60. 60.

    & Structural proteomics. Nature Rev. Drug Discov. 1, 175–176 (2002).

  61. 61.

    et al. Omeprazole: the first proton pump inhibitor. Med. Res. Rev. 10, 1–60 (1990).

  62. 62.

    et al. Acid activation of (H+,K+)-ATPase inhibiting 2-(2-pyridylmethyl-sulphinyl)benzimidazoles: isolation and characterisation of the thiophilic 'active principle' and its reactions. J. Chem. Soc. Chem. Commun. 125–127 (1986).

  63. 63.

    Anonymous. US Prilosec patent trial drawing to close. SCRIP 2743, 17 (May 03, 2002).

  64. 64.

    , & Esomeprazole for acid peptic disorders. Ann. Pharmacother. 36, 655–663 (2002).

  65. 65.

    Center for Drug Evaluation and Research. Nexium delayed-release capsules: printed labeling. Center for Drug Evaluation and Research [online] (cited 26 Aug 2002) 〈〉 (2001).

  66. 66.

    & Method for the treatment of gastric acid-related diseases and production of medication using (−)-enantiomer of omeprazole. US Patent 5,877,192 (1999).

  67. 67.

    & Compositions. US Patent 5,714,504 (1998).

  68. 68.

    , , & Method for preparing a pharmaceutically active enantiomeric or enantiomerically enriched sulfoxide compound by enantioselective bioreduction of a racemate sulfoxide compound. US Patent 5,776,765 (1998).

  69. 69.

    Process for preparing pure salts of pyridinylmethyl-sulfinyl-1H-benzimidazole. US Patent 5,693,818 (1997).

  70. 70.

    , , & Form of S-omeprazole. WO Patent 98/54171 (1998).

  71. 71.

    , , & Resolution of the enantiomers of omeprazole and some of its analogues by liquid chromatography on a trisphenylcarbamoylcellulose-based stationary phase; the effect of the enantiomers of omeprazole on gastric glands. J. Chromatogr. B 532, 305–319 (1990).

  72. 72.

    & Enantiomerentrennung. DE Patent 4,035,455 (1992).

  73. 73.

    , , , & Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same. US Patent 6,262,085 (2001).

  74. 74.

    et al. Pharmaceutical unit dosage form. US Patent 6,262,086 (2001).

  75. 75.

    et al. Dry blend pharmaceutical formulations. US Patent 6,268,385 (2001).

  76. 76.

    , , , & Alkoxy substituted benzimidazole compounds, pharmaceutical preparations containing the same, and methods of using the same. US Patent 6,369,087 (2002).

  77. 77.

    et al. Method of improving bioavailability. US Patent 6,312,712 (2001).

  78. 78.

    et al. Pharmaceutical unit dosage form. US Patent 6,312,723 (2001).

  79. 79.

    et al. Pharmaceutical formulations. US Patent 6,316,020 (2001).

  80. 80.

    et al. Dry blend pharmaceutical unit dosage form. US Patent 6,326,384 (2001).

  81. 81.

    & Poster 170. 6th World Congress of Theoretically Oriented Chemists (WATOC 2002), Lugano (2002).

  82. 82.

    Department of Health and Human Services. Electronic Orange Book. Approved Drug Products with Therapeutic Equivalence Evaluations 22nd edn. US Food and Drug Administration [online] (cited 26 Aug 2002) 〈〉 (2002).

  83. 83.

    , & Levalbuterol hydrochloride. Expert Opin. Inv. Drugs 7, 2027–2042 (1998).

  84. 84.

    Cardiac and CNS toxicity of levobupivacaine: strength of evidence for advantage over bupivacaine. Drugs Saf. 25, 153–163 (2002).

  85. 85.

    & Levobupivacaine: a new safer long acting local anaesthetic agent. Expert Opin. Inv. Drugs 8, 861–876 (1999).

  86. 86.

    & The metabolic chiral inversion pf 2-arylpropionic acids — a novel route with pharmacological consequences. J. Pharm. Pharmacol. 35, 693–704 (1983).

  87. 87.

    & Pharmacodynamics pharmacokinetics and toxicology of ibuprofen enantiomers. Drugs Future 22, 1347–1366 (1997).

  88. 88.

    S(+)-Ibuprofen/STERLING EPO/TBA. T 0315/98 – 3.3.2 (1999).

  89. 89.

    , & Clinical pharmacokinetics of Dexketoprofen. Clin. Pharmacokinet. 40, 245–262 (2001).

  90. 90.

    Aminorex to Fen/Phen: an epidemic foretold. Circulation 99, 156–161 (1999).

  91. 91.

    US Department of Health and Human Service. Cardiac valvulatory associated with exposure to fenfluramine or dexfenfluramine. US Department of Health and Human Service Interim Public Health Recommendations, November 1997. Morbid. Mortal. Weekly Rep. 46, 1061–1066 (1997).

  92. 92.

    (ed.) Obesity Management of Redux™ (Academic, San Diego, California, 1997).

  93. 93.

    & d-Fenfluramine for modifying feeding behavior. US Patent 4,309,445 (1982).

  94. 94.

    & Method of utilizing d,l-fenfluramine for modifying feeding behavior. US Patent 4,452,815 (1984).

  95. 95.

    Public Law 98-417. Drug Price Competition and Patent Term Restoration Act: Amendment of the Federal Food, Drug and Cosmetic Act (Hatch–Waxman Amendment) (1984).

  96. 96.

    Anonymous. Redux slated for US patent extension. SCRIP 2191, 19 (1996).

  97. 97.

    , , & A double-blind clinical trial in weight control: use of fenfluramine and phentermine alone and in combination. Arch. Intern. Med. 144, 1143–1146 (1984).

  98. 98.

    et al. Long-term weight control study. Clin. Pharmacol. Ther. 51, 581–646 (1992).

  99. 99.

    et al. Valvular heart disease associated with fenfluramine–phentermine. N. Engl. J. Med. 337, 581–588 (1997).

  100. 100.

    et al. Appetite-suppressant drugs and the risk of primary pulmonary hypertension. N. Engl. J. Med. 335, 609–616 (1996).

  101. 101.

    , , , & A selective inhibition of serotonin uptake: Lilly 11040, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamine. Life Sci. 15, 471–479 (1974).

  102. 102.

    in Goodman and Gilman's The Pharmacological Basis of Therapeutics 10th edn (eds Hardman, J. G., Limbird, L. E. & Gilman, A. G.) 447–483 (McGraw Hill, New York, 2002).

  103. 103.

    , , & Absolute configurations and pharmacological activities of the optical isomers of fluoxetine, a selective serotonin-uptake inhibitor. J. Med. Chem. 31, 1412–1417 (1998).

  104. 104.

    & Method for treating migraine headaches using optically pure S-(+)-fluoxetine. US patent 5,589,511 (1996).

  105. 105.

    , & Methods for treating depression and other disorders using optically pure R-(−)-fluoxetine and monoamine oxidase inhibitor. US patent 5,648,396 (1997).

  106. 106.

    , & (S)-Norfluoxetine in method of inhibiting serotonin uptake. US patent 5,250,571 (1993).

  107. 107.

    & (R)-Norfluoxetine in method for occupying serotonin IC receptors. US patent 5,250,572 (1993).

  108. 108.

    Anonymous. Lilly Sepracor deal on R-fluoxetine. SCRIP 2395, 8 (1998).

  109. 109.

    & Treatment of obesity with aryloxyphenylpropylamines. US patent 4,626,549 (1986).

  110. 110.

    & Aryloxyphenylpropylamines in treating depression. US patent 4,018,895 (1977).

  111. 111.

    US Court of Appeals Federal Circuit, 99-1262-1263-1265-1303. Eli Lilly and Company versus Barr Laboratories and others. First judgement dated 09 Aug 2000. Validated judgement dated 30 May 2001.An important judgement, including the majority and dissent opinions, that invalidates a Prozac 'mechanism-of-action' patent for obviousness-type double patenting, thereby shortening Prozac's protection by almost three years.

  112. 112.

    & Arloxyphenylpropylamines. US patent 4,314,081 (1982).

  113. 113.

    Anti-anxiety method. US patent 4,590,213 (1986).

  114. 114.

    US Food and Drug Administration. Modernization Act 1997 Pub. L No. 105–115 (1997).

  115. 115.

    Sepracor: skating on 'ICE'. Chem. Eng. News 76, 11–13 (1998).

  116. 116.

    & in Goodman and Gilman's The Pharmacological Basis of Therapeutics 10th edn (Hardman, J. G., Limbird, L. E. & Gilman, A. G.) 1059–1095 (McGraw Hill, New York, 2002).

  117. 117.

    et al. The total synthesis of strychnine. Tetrahedron 19, 247–288 (1963).

  118. 118.

    in Goodman and Gilman's The Pharmacological Basis of Therapeutics 10th edn (Hardman, J. G., Limbird, L. E. & Gilman, A. G.) 933–970 (McGraw Hill, New York, 2002).

  119. 119.

    , , , & On the botanical distribution of chiral forms of gossypol. Planta Med. 58, 454–458 (1992).

  120. 120.

    Prospects for pharmacological male contraception. Drugs 48, 851–863 (1994).

  121. 121.

    & Effects of gossypol on cultured TM3 leydig and TM4 sertoli cells: 31P and 23Na NMR Study. Nucl. Magnet. Reson. Biomed. 9, 72–78 (1996).

  122. 122.

    et al. The (−)-enantiomer of gossypol possesses higher anticancer potency than racemic gossypol in human breast cancer. Anticancer Res. 22 (Suppl. 1A), 33–38 (2002).

  123. 123.

    , & Synthesis of ent-19-nortestosterone from its naturally occuring antipode. Tetrahedron Lett. 42, 2869–2871 (2001).

  124. 124.

    , , , & Recent development in structure–activity relationships for steroid modulators of GABAA receptors. Brain Res. Rev. 37, 91–97 (2001).

  125. 125.

    & Dexanabinol (HU-211): a nonpsychotropic cannabinoid with neuroprotective properties. Drug Dev. Res. 50, 211–215 (2000).

  126. 126.

    et al. Dexanabinol (HU-211) in the treatment of severe closed head injury: a randomized, placebo-controlled, Phase II clinical trial. Crit. Care Med. 30, 548–554 (2002).

  127. 127.

    Department of Health and Human Services. Lexapro approval letter. US Food and Drug Administration [online] (cited 26 Aug 2002) 〈〉 (2002).

  128. 128.

    & Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans. US Patent 4,136,193 (1979).

  129. 129.

    & Anti-depressive substituted 1-dimethylaminopropyl-1-phenyl phthalans. GB Patent 1,526,331 (1979).

  130. 130.

    in X-Ray Crystallography and Drug Action (eds Horn, A. S. & De Ranter, C. J.) 3–4 (Clarendon, Oxford, 1984).

  131. 131.

    The Nobel Prize in Chemistry 2001 — presentation speech. The Royal Swedish Academy of Science [online] (cited 26 Aug 2002) 〈http//〉 (2001).

  132. 132.

    , , & Chromatographic separation of racemic thalidomide and teratogenic activity of its enantiomers. Arzneimittelforschung 29, 1640–1642 (1979).

  133. 133.

    , & Toxicity and teratogenicity of optical isomers of thalidomide. Nature 215, 296–297 (1967).

  134. 134.

    , , & Chiral inversion and hydrolysis of thalidomide: mechanisms and catalysis by bases and serum albumin, and chiral stability of teratogenic metabolites. Chem. Res. Toxicol. 11, 1521–1528 (1998).

  135. 135.

    , , , & Stereospecific determination, chiral inversion in vitro and pharmacokinetics in humans of the enantiomers of thalidomide. Chirality 7, 44–52 (1995).

  136. 136.

    Re: May and Eddy. US Court of Customs and Patent Appeals. US CCPA 574F.2d1082, 197 USPQ 601 (1978).

  137. 137.

    Eli Lilly and Company versus Generix Drug Sales Inc. et al. 460F. 2nd 1096, US Court of Appeals for the Fifth Circuit. 174 USPQ (BNA) 65 (1972).

  138. 138.

    Enantiomers/HOECHST. European Technical Board of Appeals Decision. T 296/87 — 3.3.1 (1988).

  139. 139.

    SEPRACOR. European Technical Board of Appeals Decision. T 1031/00 — 3.3.2 (2002).

  140. 140.

    & Methods of using (+)-cisapride for the treatment of gastro-esophageal reflux disease and other disorders. WO Patent 94/01111 (1994).

  141. 141.

    & Methods of using (−)-cisapride for the treatment of gastro-esophageal reflux disease and other disorders. WO Patent 94/01112 (1994).

  142. 142.

    Levofloxacin. Expert Opin. Pharmacother. 1, 109–120 (1999).

  143. 143.

    , & Comparison of the effects of Levocetirizine and Loratadine on histamine-induced wheal, flare, and itch in human skin. Allergy 56, 985–988 (2001).

  144. 144.

    US Department of Health and Services. Approval Package. Focalin (dexmethylphenidate HCl) tablets. Company: Celgene. App. No. 21-278 〈〉 (2001).

  145. 145.

    & Enantiomeric antidepressant drugs should be considered on individual merit. Hum. Psychopharmacol. Clin. Exp. 16, S85–S92 (2001).

  146. 146.

    in Optimising the Treatment of Mood and Anxiety Disorders 13–17 (Lundbeck, Copenhagen, 2002).

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We thank S. K. Branch (Medicines Control Agency, London, UK), R. Perry (Gill, Jenning & Every, London, UK), S. P. Miller (Office of New Drug Products, FDA, Rockville, USA), P. Lindberg (AstraZeneca, Mulndal, Sweden), B. G. Larsson (AstraZeneca, Sodertalje, Sweden), J. Senn-Bilfinger (ALTANA Pharma, Konstanz, Germany), J. P. Leeds (Eli Lilly and Company, Indianapolis, USA) and J. W. Jaroszewski (Royal Danish School of Pharmacy, Copenhagen, Denmark) for enlightening discussions. I.A. became interested in chiral switches in 1996 as a Fellow of the Institute for Advanced Studies at The Hebrew University of Jerusalem, where he directed a research group on Chirality of Drugs and Chiral Recognition: New Challenges.

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  1. Division of Biomedical Sciences, Imperial College Faculty of Medicine, Sir Alexander Fleming Building, London SW7 2AZ, United Kingdom.

    • Israel Agranat
    •  & John Caldwell
  2. Department of Organic Chemistry, The Hebrew University of Jerusalem, Jerusalem 91904, Israel.

    • Israel Agranat
    •  & Hava Caner


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Corresponding author

Correspondence to Israel Agranat.



The geometric property of a rigid object (or spatial arrangement of points or atoms) of being non-superimposable on its mirror image; such an object has no symmetry elements of the second kind (a mirror plane, σ = S1; a centre of inversion, i = S2; or a rotation–reflection axis, S2n). If an object is superposable on its mirror image, it is described as being achiral.


The spatial arrangement of the atoms affording distinction between stereoisomers, which can be interconverted by rotations about formally single bonds. A conformer is one of a set of stereoisomers, each of which is characterized by a conformation that corresponds to a distinct potential energy minimum.


In the context of stereochemistry, the term is restricted to the arrangements of atoms of a molecular entity in space that distinguishes stereoisomers, the isomerism between which is not due to conformational differences. The absolute configuration is the spatial arrangement of the atoms of a chiral molecular entity (or group) and its stereochemical description — for example, R or S (for chiral centres) and M or P (for chiral axes).


An equimolar mixture of a pair of enantiomers. It does not have optical activity. The chemical name or formula of a racemate is distinguished from those of the enantiomers by the prefix (±)- or rac- (or racem-), or by the symbols RS and SR.


A grant by the state of exclusive rights for a limited time (in most jurisdictions 20 years from filing date) in respect of a new and useful invention. The patentable invention must be new, it must involve an inventive step and it must be capable of industrial application.


(Chirality centre). An atom that holds a set of ligands in a spatial arrangement, which is not superimposable on its mirror image. A chiral centre is, therefore, a generalized extension of the concept of the asymmetric carbon atom to central atoms of any element.


Configurational descriptors for carbohydrates and α-amino acids.


The preferential formation in a chemical reaction of one stereoisomer over another. When the stereoisomers are enantiomers or diastereomers, the phenomenon is known as enantioselectivity or diastereoselectivity, respectively.


The part of a patent specification that defines the scope of protection.


Diastereomers that have the opposite configuration at only one of two or more tetrahedral stereogenic centres that are present in the respective molecular entities.


The basic conditions of patentability, which an application must meet if granted, are that the invention must be novel, contain an inventive step, be capable of industrial application and not be in one of several exluded fields.


The essential condition for patentability that what is claimed is new.


An invention is taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter that forms part of the state of the art, but not including matter from a patent application with an earlier priority date that is published later then the priority date of the invention (European Patent Convention, Section 3). The state of the art is the total information in the relevant field known to the hypothetical person skilled in the art.


A ground of invalidity of a patent, if the description does not allow the skilled reader to work the invention.


The description of the identity and connectivity (and corresponding bond multiplicities) of the atoms in a molecular entity (omitting any distinction that arises from their spatial arrangement).


The date on which an invention was first disclosed to a patent office in a patent application or in an earlier application from which it validly claims priority.


An area of the law that concerns legal rights that are associated with creative effort or commercial reputation and goodwill.


Capable of being preformed by the average skilled person in possession of the prior art.


(Chirality axis). An axis about which a set of ligands is held so that it results in a spatial arrangement that is not superimposable on its mirror image.


A sample of material that can rotate the plane of polarization of a beam of transmitted plane-polarized light is said to have optical activity (or to be optically active). This optical rotation is the classical distinguishing characteristic (which is sufficient but not necessary) of systems that contain unequal amounts of corresponding enantiomers. An enantiomer that causes rotation in a clockwise direction (when viewed in the direction that faces the incoming light beam) under specified conditions is called dextrorotatory and its chemical name or formula is designated by the prefix (+)-; one causing rotation in the opposite sense is laevorotatory and is designated by the prefix (−)-. Materials that have optical activity also have other chiroptic phenomena.


All public knowledge before the priority date that could be relevant to the novelty or unobviousness of an invention.

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