• CERN

• "Big Bang“ Experiment

• 10 September 2008

• Gravitons and Bosons "Missing Dark Matter“

• Higgs particles

IPTS 2008

Pharmaceutical Patents

Dr.Ecz. PINAR BULUT

FarmaPatent Limitedhttp://www.farmapatent.com.tr

PatentNo

PatentExpiration

Drug Substance

Claim

Drug ProductClaim

Patent UseCode

4687777 Jan 17, 2011 Y

6150383 Jun 19, 2016 U-753

6211205 Jun 19, 2016 U-753

6303640 Aug 9, 2016 U-753

6329404 Jun 19, 2016 Y U-753

Patent Data *

Exclusivity DataThere is no unexpired exclusivity for this product.

Electronic Orange Book

* GLIMEPIRIDE; PIOGLITAZONE HYDROCHLORIDE

The patents that FDA regards as claiming these drug patents are: 1) Patents that claim the active ingredient(s)

2) Drug product patent, which include formulation/composition patents

3) Use patents for a particular approved indication or method of using the product.

Marketing Exclusivity Codes:

New CombinationNew Chemical EntityNew Dosage FormNew Ester or Salt of an Active IngredientNew ProductNew RouteNew Strength

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 a basic patent in force;

Article 1 . Definitions For the purposes of this Regulation:

(a)'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;

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)

SPC number: SPC/GB01/053 Patent No: EP 0397831 (Treatment of Obesity )Community authorisation: Germany (14 January 1999) Product description: Sibutramine hydrochloride monohydrate

Supplementary Protection Certificate

Claims

1. 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.

2. 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.

CAUTION ! *

For most Generic Drug Developments, Molecule Patent

expiry dates are the

‘Tip of the Iceberg’

* Presented by Leighton Howard – ICSE2005 , Madrid

Secondary Patents (Evergreening)

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

Drug Product• Formulation / Composition

• Combination

• Manufacturing method

• Excipients

• Packaging

• Medical Use

• Route of Administration

• Dosing Regimen

POLYMORPH PATENTS (Donepezil – EISAI)

Claims

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

POLYMORPH PATENTS (Rosiglitazone – SKB)

Claims

1.A polymorphic form of …… maleic acid salt (the Polymorph) characterised in that it provides:(i)an infrared spectrum containing peaks at ………. ; and/or(ii)a Raman spectrum containing peaks at ………. ; and/or(iii) a solid-state 13C NMR spectrum containing peaks at ……; and/or(iv)an XRPD pattern ……………

PSEUDOPOLYMORPH (Hydrate) - (Rosiglitazone – SKB)

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 USP although 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

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 bioequivalent to 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

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:

RANITIDINE: Patents and Generics

Patent No. Coverage Expiry Date

US 4128658 Ranitidine Form I 25/07/1997

US 4521431 Ranitidine Form II 09/08/2002

Product Approval Date

Zantac 150 mg Tablet (GLAXO)Zantac 300 mg Tablet (GLAXO)

09/06/198309/12/1985

TEVA Ranitidine Tablets 31/07/1997

SANDOZ Ranitidine Tablets 29/08/1997

TORPHARM Ranitidine Tablets 12/09/1997

WATSON Ranitidine Tablets 20/10/1997

INVENTIONS NOT PATENTABLE

3. What are not inventions

PATENT ACT (INDIA) Amendment (5th April 2005)

“(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.”

Search International Patent Applications

RESULT LIST Approximately 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

EuropeanPatent Office

Results of searching in PCT for:

ABSTRACT: POLYMORPH OR POLYMORPHS OR POLYMORPHISM PRIORITY COUNTRY: INDIA IPC: C07D 99 records

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

Search International Patent Applications

Results of Search in US Patent Collection db for:

(ACLM/(crystalline AND form) AND a61k): 184 patents.

ISOMERIC FORM, SALT and HYDRATE

Claims

1. The magnesium salt of S-omeprazole trihydrate

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)

IMPURITY

Claims1. Use of escitalopram comprising less than 3% w/w of R-citalopram for the preparation of a pharmaceutical composition.

METABOLITES

TERFENADINE(SELDANE)

FEXOFENADINE(ALLEGRA)

Patent No. US 3878217 US4254129

Filed: July 12, 1973 Apr. 10, 1979

Publication : Apr. 15, 1975 Mar. 3, 1981

Expiry Date: Apr. 15, 1994 (Extended) Feb. 17, 2001 (Extended)

Approval Date: Jul 25, 1996 (60 mg Cap)

CHO NH2C

H2C CH2 C

H

OH

C

CH3

CH3

COOHCHO NH2C

H2C CH2 C

H

OH

C

CH3

CH3

CH3

FDA TALK PAPER

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).

Feb. 27, 1998

SUBSTANTIALLY PURE

13. An HPLC method comprising the steps of:

(a) 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-Tolterodine tartrate having less than about 0.5% area by HPLC of total impurities.

FORMULATIONS – COMPOSITIONS - EXCIPIENTS

Clopidogrel bisulfate tablet formulation

1. A pharmaceutical tablet which comprises clopidogrel bisulfate and a lubricant selected from the group consisting of zinc stearate, sodium stearyl fumarate and stearic acid.

Dry Mix Formulation for Bisphosphonic acids

1. A pharmaceutical composition comprising from 0.5 to 40% by weight of 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid or a pharmaceutical acceptable salt thereof and from 60 to 99.5% by weight of excipients, said excipients comprising a diluent selected from anhydrous lactose or hydrous fast flow lactose, a dry binder, a disintegrant, and a lubricant.

COMBINATIONS

1. Pharmaceutical composition which comprises an insulin sensitivity enhancer selected from pioglitazone or a pharmaceutically acceptable salt thereof in combination with methormin.

1. Pharmaceutical composition which comprises an insulin sensitivity enhancer selected from pioglitazone or a pharmaceutically acceptable salt thereof in combination with the insulin secretion enhancer glimepiride.

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).

DOSE / USE

BONIVA Tablet 2.5 mg, 150 mg - ROCHE

Claims1.Use of ibandronic acid of pharmaceutical acceptable salt thereof for the manufacture of a medicament for the prevention or the treatment of disorders characterized by pathological increased bone resorption wherein the medicament

a)comprises at least 120% of the expected efficacious daily dose, i.e. 50 – 250 mg of ibandronic acid or a pharmaceutical acceptable salt thereof and one of more pharmaceutical acceptable excipients thereof; and

b)the medicament is orally administered on one day per month.

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-diphosphonic acid to a patient in need of bisphosphonate treatment comprising intravenously administering4 mg of2-(imidazol-1yl)-1-hydroxyethane-1, 1-diphosphonic acid or a pharmaceutical acceptable

salt thereof over a period of 15 minutes to a patient in need of said treatment.

Zometa(zoledronic acid) Injection Concentrate for Intravenous Infusion

Method of AdministrationDue 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

SPC number: SPC/GB93/141Maximum expiry date: 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

CASE 2: PERINDOPRIL Erbumine

Patent No. Coverage

1 EP 0049658 B1 Expiry date (SPC): 21.06.2003 (UK)

2 EP 1296947 B1 Alpha polymorph of perindopril erbumine

3 EP 1294689 B1 Beta polymorph of perindopril erbumine

4 EP 1296948 B1 Gamma polymorph of perindopril erbumine

5 EP 1354873 B1 Perindopril arginine (new salt)

6 EP 1032414 B1 Medical usage (perindopril and indapamide)

7 EP 1467750 B1 Orodispersible tablet

8 EP 1345605 B1 CR formulation

9 EP 0308340 B1 Process for preparing perindopril

10 EP 0308341 B1 Process for preparing perindopril

……………….. ……………………………..

37 EP 1272454 B1 Process for preparing perindopril

38 EP 1268398 B1 Process for preparing perindopril

PERINDOPRIL PATENTS (SERVIER)

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

Country, Dosage(s) Launch DateHungary 4MG 8MG

31 Oct 200531 Jan 2007

Poland 2MG 4MG 30 Jun 2006Slovakia 4MG 31 Dec 2006Slovenia 4MG 8MG

31 Jan 200630 Sep 2006

Czech Republic 4MG 31 Mar 2006Marketing Authorisation in UK (mutual recognition procedure - reference state: Hungary )

May 2006

KRKA / SERVIERPrenessa Tablet (Perindopril erbumine)

KRKA / SERVIER

Unaudited Interim Report for the Krka Company and the Krka Group for January – September 2006

Based on the settlement the companies will withdraw all legal actions filed against each other in various countries.

Based on settlement, Krka will market a product with the active ingredient perindopril in alpha-crystalline form on the markets of Slovenia, Czech Republic, Hungary, Latvia, Lithuania, Poland and Slovakia.

APOTEX / SERVIER

APOTEX / SERVIER

Decision:

1. This is an appeal from one of the last first instance decisions of the late

Lord Justice Pumfrey. He held that Servier’s EP (UK) 1296947 was

invalid for lack of novelty and obviousness, but that if patent had been

valid, Apotex’s product would have infringed.

* Basic patent ** Process patent

Perindopril tert-butyl amine polymorph patent held invalid by UK Supreme Court (Generic Pharmaceuticals and Patents, 14 May 2008)

In the patent spat between Servier (innovator) and Apotex (Generic), UK supreme court held the patent (EP1296947), covering crystalline polymorphic form α of perindopril tert-butylamine salt,invalid over the prior art patents i.e. EP0049658 * and EP0380341 **

Trade Name Dosage(s) Holder Launch Date

Coversyl 2, 4, 8 mg Servier 31/01/199031/12/2002 (8 mg)

2, 4, 8 mg Apotex 31/08/2006

Perindopril Teva 2, 4, 8 mg Teva 31/07/2007

Coversyl Arginine 2.5, 5, 10 mg Servier 31/03/2008

Perindopril Products in UK SPC Expiry Date: 21 June 2003

LUPIN / SERVIER

PERINDOPRIL PROCESS PATENTS

Title Patent No. Applicant

PROCESS FOR PREPARATION OF PERINDOPRIL AND SALTS THEREOF

WO-2004075889 LUPIN

NOVEL METHOD FOR PREPARATION OF CRYSTALLINE PERINDOPRIL ERBUMINE

WO-2005037788 LUPIN

LUPIN / SERVIER

Title Patent No. Patent Holder

PROCESS FOR PREPARATION OF PERINDOPRIL AND SALTS THEREOF

WO-2004075889

EP1603558 B1

LUPIN

SERVIER

NOVEL METHOD FOR PREPARATION OF CRYSTALLINE PERINDOPRIL ERBUMINE

WO-2005037788

EP1675827 A1

LUPIN

SERVIER

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

LUPIN / SERVIER

THANKS

Pharmaceutical Patents

Dr.Ecz. PINAR BULUTpbulut@farmapatent.com.tr

FarmaPatent Limitedhttp://www.farmapatent.com.tr