CERN "Big Bang“ Experiment 10 September 2008 Gravitons and Bosons "Missing Dark Matter“

1. FarmaPatentLimited http://www.farmapatent.com.tr • CERN • "Big Bang“ Experiment • 10 September 2008 • Gravitons and Bosons"Missing Dark Matter“ • Higgs particles IPTS 2008 PharmaceuticalPatents Dr.Ecz. PINAR BULUT

2. Electronic Orange Book Patent Data * Exclusivity Data There is no unexpired exclusivity for this product. * GLIMEPIRIDE; PIOGLITAZONE HYDROCHLORIDE

3. Marketing Exclusivity Codes: New Combination New Chemical Entity New Dosage Form New Ester or Salt of an Active Ingredient New Product New Route New Strength Thepatentsthat FDA regards as claimingthesedrugpatentsare: 1)Patentsthatclaimtheactiveingredient(s) 2)Drugproductpatent, whichincludeformulation/compositionpatents 3)Usepatentsfor a particularapprovedindicationormethod of usingtheproduct.

4. Council Regulation (EEC) No 1768/92 of 18 June 1992 concerning the creation of a supplementary protection certificate for medicinal products Article 3 . Conditions for obtaining a certificate A certificate shall be granted if, in the Member State in which the application referred to in Article 7 is submitted and at the date of that application: (a) the product is protected by abasic patent in force; • Article 1 . Definitions For the purposes of this Regulation: • 'medicinal product' means any substance or combination of substances presented for treating or preventing disease in human beings or animals …..; • (b) 'product' means the active ingredient or combination of active ingredients of a medicinal product; • (c) 'basic patent' means a patent which protects a product as defined in (b) as such, a process to obtain a product or an application of a product, and which is designated by its holder for the purpose of the procedure for grant of a certificate;

5. SPC number: SPC/GB02/049 Patent No: EP0347066 (New Enantiomers and Their Isolation )Community authorisation:Sweden (7 December 2001) Product description: Escitalopram oxalate Supplementary Protection Certificate (SPC)

6. SPC number: SPC/GB01/053Patent No: EP 0397831(Treatment of Obesity )Community authorisation:Germany (14 January 1999) Product description: Sibutramine hydrochloride monohydrate Supplementary Protection Certificate • Claims • The use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride in the manufacture of a medicament for the treatment of obesity. • The use of N,N-dimethyl-1-[1-(4-chlorophenyl)cyclobutyl]-3-methylbutylamine hydrochloride monohydrate in the manufacture of a medicament for the treatment of obesity.

7. CAUTION ! * For most Generic Drug Developments, Molecule Patent expiry dates are the ‘Tip of the Iceberg’ * Presented by Leighton Howard – ICSE2005 , Madrid

8. Drug Substance Polymorphs Salt/Hydrate/Solvate Prodrug, Metabolite Impurity Profile, Substantially pure Physicochemical properties Particle size Synthetic Route New intermediates, Starting materials, Catalysts Purification Method Assay Technique DrugProduct Formulation / Composition Combination Manufacturingmethod Excipients Packaging Medical Use Route of Administration Dosing Regimen Secondary Patents (Evergreening)

9. POLYMORPH PATENTS (Donepezil – EISAI) Claims 1. Donepezil hydrochloride ………….. in the form of polymorph (III), being specified ……… X-ray diffraction pattern and ……… infrared absorption spectra ……….

10. POLYMORPH PATENTS (Rosiglitazone – SKB) • Claims • A polymorphic form of …… maleicacid salt (thePolymorph) characterised in that it provides: • an infraredspectrumcontainingpeaks at ………. ; and/or • a Ramanspectrumcontainingpeaks at ………. ; and/or • a solid-state 13C NMRspectrumcontainingpeaks at ……; and/or • an XRPDpattern ……………

11. PSEUDOPOLYMORPH (Hydrate) - (Rosiglitazone – SKB)

12. Scientific Considerations of Polymorphism in Pharmaceutical Solids: Abbreviated New Drug Applications * • POLYMORPHISM IN PHARMACEUTICAL SOLID DRUG SUBSTANCE AND THE ISSUE OF "SAMENESS“ • A drug substance in a generic drug product is generally considered to be the same as the drug substance in the reference listed drug if it meets the same standards for identity. In most cases, the standards for identity are described in the USPalthough FDA may prescribe additional standards when necessary. • Because drug product performance depends on the product formulation, the drug substance in a proposed generic drug product need not have the same physical form (particle size, shape, or polymorph form) as the drug substance in the reference listed drug. * FDA

13. Scientific Considerations of Polymorphism in Pharmaceutical Solids: Abbreviated New Drug Applications * • An ANDA applicant is required to demonstrate that the proposed product meets the standards for identity, exhibits sufficient stability and is bioequivalentto the reference listed drug. • Over the years FDA has approved many generic drug products based upon a drug substance with different physical form from that of the drug substance in the respective reference listed drug (e.g., warfarin sodium, famotidine, and ranitidine). • Also many ANDAs have been approved in which the drug substances differed from those in the corresponding reference listed drugs with respect to solvation or hydration state (e.g., terazosin hydrochloride, ampicillin, and cefadroxil). * FDA

14. CASE 1: RANITIDINE 1. Form 2 ranitidine hydrochloride characterised by an infra-red spectrum as a mull in mineral oil showing the following main peaks:

15. RANITIDINE: Patents and Generics

16. PATENT ACT (INDIA) Amendment (5th April 2005) INVENTIONS NOT PATENTABLE 3. What are not inventions “(d) the mere discovery of a new form of a known substance which does not result in the enhancement of the known efficacy of that substance or the mere discovery of any new property or new use for a known substance or of the mere use of a known process, machine or apparatus unless such known process results in a new product or employs at least one new reactant. Explanation – For the purposes of this clause, salts, esters, ethers, polymorphs, metabolites, pure form, particle size, isomers, mixtures of isomers, complexes, combinations and other derivatives of known substance shall be considered to be the same substance, unless they differ significiantly in properties with regard to efficacy.”

17. RESULT LISTApproximately 662 results found in the Worldwide database for: polymorp* in the title or abstract AND wo as the publication number AND C07D as the IPC classification Search International Patent Applications Results of searching in PCT for: ABSTRACT: POLYMORPH OR POLYMORPHS OR POLYMORPHISM PRIORITY COUNTRY: INDIA IPC: C07D 99 records

18. Search International Patent Applications Results of searching in PCT for: ABSTRACT: POLYMORPH OR POLYMORPHS OR POLYMORPHISM IPC: A61K APPLICANT: TEVA 7 records APPLICANT: PFIZER 12 records APPLICANT: ROCHE 3 records Results of Search in US Patent Collection db for: (ACLM/(crystalline AND form) AND a61k): 184 patents.

19. ISOMERIC FORM, SALT and HYDRATE Claims 1. The magnesium salt of (-)-5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl)sulfinyl]-1H-benzimidazole (Mg-salt of the (-) enantiomer of omeprazole) Claims 1. The magnesium salt of S-omeprazole trihydrate

20. IMPURITY Claims 1. Use of escitalopram comprising less than 3% w/w of R-citalopram for the preparation of a pharmaceutical composition.

21. METABOLITES

22. FDA TALK PAPER Feb. 27, 1998 SELDANE AND GENERIC TERFENADINE WITHDRAWN FROM MARKET Hoescht Marion Roussel and Baker Norton Pharmaceuticals have voluntarily discontinued distribution and marketing of all terfenadine-containing antihistamine product lines in the United States. Terfenadine-containing products, such as Seldane and Seldane-D, have been associated with rare, but serious heart problems when taken with certain other drugs, including certain antibiotics and antifungals. In January 1997, FDA proposed removing all terfenadine products from the marketplace because of the approval of a safer alternative drug: Allegra (fexofenadine hydrochloride).

23. SUBSTANTIALLY PURE 13.An HPLC method comprising the steps of: • combining an R- Tolterodine tartrate sample with a mixture of acetonitrile: water … (b) injecting the solution into a …. column …… (c) gradient eluting the sample from the column at about 8 min using a mixture of …… (d) measuring the impurity content in the relevant sample with a UV detector ….. I . R-Tolterodinetartrate having less than about 0.5% area by HPLC of total impurities.

24. FORMULATIONS – COMPOSITIONS - EXCIPIENTS Clopidogrelbisulfate tablet formulation 1. A pharmaceutical tablet which comprises clopidogrel bisulfate and a lubricant selected from the group consisting of zinc stearate, sodium stearylfumarate and stearic acid. DryMixFormulationforBisphosphonicacids 1. A pharmaceuticalcompositioncomprisingfrom 0.5 to 40% byweight of 4-amino-1-hydroxybutylidene-1,1-bisphosphonicacidor a pharmaceuticalacceptable salt thereofandfrom 60 to 99.5% byweight of excipients, saidexcipientscomprising a diluentselectedfromanhydrouslactoseorhydrousfastflowlactose, a drybinder, a disintegrant, and a lubricant.

25. COMBINATIONS 1. Pharmaceuticalcompositionwhichcomprises an insulinsensitivityenhancerselectedfrompioglitazoneor a pharmaceuticallyacceptable salt thereofin combinationwithmethormin. 1. Pharmaceuticalcompositionwhichcomprises an insulinsensitivityenhancerselectedfrompioglitazoneor a pharmaceuticallyacceptable salt thereofin combinationwiththeinsulinsecretionenhancerglimepiride.

26. SECOND MEDICAL USE – SWISS CLAIM Claims 1. Use of tomoxetine for the manufacture of a medicament for treating attention-deficit/hyperactivity disorder. Indications STRATTERA is indicated for the treatment of Attention-Deficit/Hyperactivity Disorder (ADHD).

27. DOSE / USEBONIVA Tablet 2.5 mg, 150 mg - ROCHE • Claims • Use of ibandronicacid of pharmaceuticalacceptable salt thereofforthemanufacture of a medicamentforthepreventionorthetreatment of disorderscharacterizedbypathologicalincreased bone resorptionwhereinthemedicament • comprises at least 120% of theexpectedefficaciousdailydose, i.e. 50 – 250 mg of ibandronicacidor a pharmaceuticalacceptable salt thereofandone of morepharmaceuticalacceptableexcipientsthereof; and • themedicament is orallyadministered on onedaypermonth.

28. USE / ADMINISTRATION METHOD USE OF ZOLEDRONATE FOR THE MANUFACTURE OF A MEDICAMENT OF BONE METABOLISM DISEASE 1. A method of administering 2-(imidazol-1yl)-1-hydroxyethane-1, 1-diphosphonicacidto a patient in need of bisphosphonatetreatmentcomprisingintravenouslyadministering4 mg of2-(imidazol-1yl)-1-hydroxyethane-1, 1-diphosphonicacidor a pharmaceuticalacceptable salt thereofover a period of 15 minutesto a patient in need of saidtreatment. Zometa (zoledronicacid) InjectionConcentrateforIntravenousInfusion Method of Administration Due to the risk of clinically significant deterioration in renal function, which may progress to renal failure, single doses of Zometa should not exceed 4 mg and the duration of infusion should be no less than 15 minutes

29. CASE 2: PERINDOPRIL Erbumine SPC number: SPC/GB93/141 Maximumexpirydate: 21 June 2003 Product description : Perindopril,….. or an addition salt obtained with a pharmaceutically compatible mineral or organic acid, for example the tert.- butylamine salt

30. PERINDOPRIL PATENTS (SERVIER)

31. 1. α crystalline form of a compound of Formula (I): characterised by the following powder X-ray diffraction diagram, ………. OPPOSITIONS Quimica Sintetica Krka (WITHDRAWN) Norton Healthcare Ltd Lupin Limited (WITHDRAWN ) Glenmark Pharmaceuticals Ltd Niche Generics Limited (WITHDRAWN) Polpharma Hetero Drugs Limited Ratiopharm GmbH

32. KRKA / SERVIER Prenessa Tablet (Perindopril erbumine)

33. KRKA / SERVIER UnauditedInterimReportfortheKrkaCompanyandtheKrkaGroupforJanuary – September 2006 Based on thesettlementthecompanieswillwithdrawall legal actionsfiledagainsteachother in variouscountries. Based on settlement, Krkawill market a productwiththeactiveingredientperindopril in alpha-crystalline form on themarketsof Slovenia, CzechRepublic, Hungary, Latvia, Lithuania, PolandandSlovakia.

34. APOTEX / SERVIER

35. APOTEX / SERVIER Decision: 1. This is an appealfromone of thelastfirstinstancedecisions of thelate LordJusticePumfrey. He heldthatServier’s EP (UK) 1296947 was invalidforlack of noveltyandobviousness, but thatif patent had been valid, Apotex’sproductwouldhaveinfringed. Perindopriltert-butyl amine polymorph patent heldinvalidby UK SupremeCourt(GenericPharmaceuticalsandPatents, 14 May 2008) Inthe patent spatbetweenServier (innovator) andApotex (Generic), UK supremecourtheldthe patent (EP1296947), coveringcrystallinepolymorphic form α of perindopriltert-butylamine salt,invalidovertheprior art patents i.e.EP0049658 * andEP0380341 ** * Basic patent ** Process patent

36. Perindopril Products in UK SPC Expiry Date: 21 June 2003

37. LUPIN / SERVIERPERINDOPRIL PROCESS PATENTS

38. LUPIN / SERVIER

39. LUPIN / SERVIER

40. LUPIN / SERVIER • India's Lupin sells further Perindopril patent rights to Servier for 20 mln eur * • MUMBAI (Thomson Financial) - India's Lupin Ltd said it has earned 20 mln eur by selling additional patent rights of its hypertension drug Perindopril to France-based Laboratoires Servier. • In April this year, Servier had reportedly bought the process patents on the drug -- marketed in Europe as Coversyl -- for 20 mln eur, while Lupin retained other patent rights. * Forbes.com 10.12.2007

41. FarmaPatentLimited http://www.farmapatent.com.tr THANKS PharmaceuticalPatents Dr.Ecz. PINAR BULUT pbulut@farmapatent.com.tr