CERN

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FarmaPatent Limited http//www.farmapatent.com.tr
IPTS 2008 Pharmaceutical Patents Dr.Ecz.
PINAR BULUT

• CERN
• "Big Bang Experiment
• 10 September 2008
• Gravitons and Bosons "Missing Dark Matter
• Higgs particles

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Electronic Orange Book
Patent Data
PatentNo PatentExpiration Drug SubstanceClaim 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
Exclusivity Data There is no unexpired
exclusivity for this product.
GLIMEPIRIDE PIOGLITAZONE HYDROCHLORIDE
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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
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.
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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
• '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

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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)
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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
• The use of N,N-dimethyl-1-1-(4-chlorophenyl)cyclo
  butyl-3-methylbutylamine hydrochloride in the
  manufacture of a medicament for the treatment of
  obesity.
• The use of N,N-dimethyl-1-1-(4-chlorophenyl)cyclo
  butyl-3-methylbutylamine hydrochloride
  monohydrate in the manufacture of a medicament
  for the treatment of obesity.

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CAUTION !

• For most Generic Drug Developments, Molecule
  Patent expiry dates are the
• Tip of the Iceberg

Presented by Leighton Howard ICSE2005 , Madrid
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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

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

• Claims
• A polymorphic form of maleic acid salt (the
  Polymorph) characterised in that it provides
• an infrared spectrum containing peaks at .
  and/or
• a Raman spectrum containing peaks at .
  and/or
• a solid-state 13C NMR spectrum containing peaks
  at and/or
• an XRPD pattern

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PSEUDOPOLYMORPH (Hydrate) - (Rosiglitazone SKB)
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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

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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

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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

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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) 09/06/1983 09/12/1985

TEVA Ranitidine Tablets 31/07/1997
SANDOZ Ranitidine Tablets 29/08/1997
TORPHARM Ranitidine Tablets 12/09/1997
WATSON Ranitidine Tablets 20/10/1997
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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.
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EuropeanPatent Office
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
Search International Patent Applications

Results of searching in PCT for ABSTRACT
POLYMORPH OR POLYMORPHS OR
POLYMORPHISM PRIORITY COUNTRY INDIA IPC
C07D
99 records
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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.
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ISOMERIC FORM, SALT and HYDRATE
Claims 1. The magnesium salt of
(-)-5-methoxy-2-(4-methoxy-3,5-dimethyl-2-pyridi
nyl)methyl)sulfinyl-1H-benzimidazole (Mg-salt of
the (-) enantiomer of omeprazole)
Claims 1. The magnesium salt of S-omeprazole
trihydrate
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IMPURITY
Claims 1. Use of escitalopram comprising less
than 3 w/w of R-citalopram for the preparation
of a pharmaceutical composition.
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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)
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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-containi
ng 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).
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SUBSTANTIALLY PURE
I . R-Tolterodine tartrate having less than about
0.5 area by HPLC of total impurities.

• 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 ..

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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-b
isphosphonic 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.
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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.
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SECOND MEDICAL USE SWISS CLAIM
Claims 1. Use of tomoxetine for the manufacture
of a medicament for treating attention-deficit/hyp
eractivity disorder.
Indications STRATTERA is indicated for the
treatment of Attention-Deficit/Hyperactivity
Disorder (ADHD).
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DOSE / USE BONIVA Tablet 2.5 mg, 150 mg -
ROCHE

• Claims
• 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
• 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
• the medicament is orally administered on one day
  per month.

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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-hydrox
yethane-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
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
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CASE 2 PERINDOPRIL Erbumine
SPC number SPC/GB93/141 Maximum 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
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PERINDOPRIL PATENTS (SERVIER)
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
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1. a 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
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KRKA / SERVIER Prenessa Tablet (Perindopril
erbumine)
Country, Dosage(s) Launch Date
Hungary 4MG 8MG 31 Oct 2005 31 Jan 2007
Poland 2MG 4MG 30 Jun 2006
Slovakia 4MG 31 Dec 2006
Slovenia 4MG 8MG 31 Jan 2006 30 Sep 2006
Czech Republic 4MG 31 Mar 2006
Marketing Authorisation in UK (mutual recognition procedure - reference state Hungary ) May 2006
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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.
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APOTEX / SERVIER
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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 Serviers EP (UK)
1296947 was invalid for lack of novelty and
obviousness, but that if patent had been valid,
Apotexs product would have infringed.
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 a of perindopril tert-butylamine
salt,invalid over the prior art patents i.e.
EP0049658 and EP0380341
Basic patent Process patent
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Perindopril Products in UK SPC Expiry Date 21
June 2003
Trade Name Dosage(s) Holder Launch Date
Coversyl 2, 4, 8 mg Servier 31/01/1990 31/12/2002 (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
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LUPIN / SERVIERPERINDOPRIL 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
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LUPIN / SERVIER
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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
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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
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FarmaPatent Limited http//www.farmapatent.com.tr
Pharmaceutical Patents Dr.Ecz. PINAR
BULUT pbulut_at_farmapatent.com.tr

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