Trends in Drug Patenting - Case Studies
(2001; 78 pages) [Spanish]
Table of Contents
View the documentINTRODUCTION
Close this folderTHE CASES
View the document1. PAROXETINE
View the document2. AMLODIPINE/AMLODIPINE BESYLATE
View the document3. ALENDRONATE
View the document4. CLARITHROMYCIN
View the document5. OMEPRAZOLE
View the document6. FLUCONAZOLE
View the document7. OFLOXACIN/LEVOFLOXACINE
View the document8. FEXOFENADINE
View the document9. RECOMBINANT ERYTHROPOIETIN
View the documentCONCLUSIONS
View the documentABBREVIATIONS
View the documentREFERENCES
 

5. OMEPRAZOLE

Omeprazole, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl)methyl]sulfinyl]-1H-benzimidazole is an inhibitor of secretion of gastric acid, developed by the Swedish firm Aktiebolaget Hassle.

The product patent family for omeprazole belongs to the Haessle company, and invokes priority SE 78-4231 (14 April 1978) in Europe. In Europe, Haessle protected the invention through patent EP 005 129, in which it protected, among other claims, omeprazole or its pharmaceutically acceptable salts and pharmaceutical preparations containing them. The United States equivalents to EP 005 129 are US 4,255,431, US 4,337,257 and US 4,508,905.

The expiry date of EP 005 129 in each country, and of the equivalent patents in the same family are shown in a table below.

Although the description and claims describe omeprazole, there are no examples of salts of the compound.

The compound is very labile and decomposes easily, especially in an acid environment. This is why, when it is administered orally, it needs to be protected from the stomach’s highly acid environment. For this reason, Astra developed and patented under EP 247 903, a colour-stable oral pharmaceutical preparation containing omeprazole as an active ingredient; the preparation is characterized by being formed of a core, in the form of a small pill or tablet containing omeprazole with an alkaline reacting substance or alkaline reacting salt of omeprazole, optionally with an alkaline reacting substance. The core is covered with one or more inert separating layers containing excipients that are water soluble or rapidly disintegrating in water or water-soluble polymers used for film-coating applications, which may optionally contain pH buffering compounds between the alkaline reacting core, and an outer enteric coating.

This patent was applied for on 16 April 1987 and granted on 7 January 1993. It designates Austria, Belgium, Switzerland, Germany, Spain, France, the United Kingdom, Greece, Italy, Liechtenstein, Luxembourg, the Netherlands and Sweden.

Equivalents exist in Australia, Canada, the Czech Republic, China, Korea, Denmark, the United States, Finland, Hungary, Israel, Japan, Norway, Portugal, Russia, Singapore and South Africa.

The expiry date of EP 247 983 in each country, and of the equivalent patents of the same family, are given below.

Germany was one of the first countries in which the patent for omeprazole expired, in April 1999, and in which generic versions of Astra’s Prilosec or Mopral have been put on the market. Astra had applied for and obtained an SPC extending the patent until 21 March 2003. However, the SPC was subsequently revoked and declared null and void by a decision of the German Patent Court, dated June 1997. An appeal against the decision was lodged with the German Court of Appeal, which recently referred the case to the European Court of Justice.

The company has requested, and in some cases secured, protective measures to halt the sale of these generic versions, for alleged infringement of EP 247 983.

Astra is not only the holder of the above patents, but of many others relating to this product.

A telling example is patent EP 124 495, which invokes 1983 priority, claiming omeprazole salts per se.

Patent EP No.:

124 495 B

Application No.:

84850066.6

Application date:

28 February 1984

Date granted:

14 January 1987

Approx. expiry date:

28 February 2004

Priorities:

SE 83-8301182 (4 March 1983)

Designated States:

AT, BE, CH, DE, FR, GB, IT, LI, LU, NL, SE

Inventor:

Brändström A. E.

Assignee:

Aktiebolaget Hässle

International class.:

C 07 D 401/12

Patent family:

 

AT

24,907

IL

70,985

AU

563,842

JP

03/013233

BG

44,538

KR

87/01005

BG

60,837

LT

2,253

CA

1,264,751

NO

160,204

CS

241,150

NZ

207,348

DD

221,459

PH

21,352

DE

3,462,036

PL

142,748

DK

160,044

PT

78,191

ES

530,242

RO

88,721

FI

83,649

RU

1,314,953

GB

2,137,616

SI

84/10397

GR

79,828

SG

90/00014

HK

90/135

HU

193,557

US

4,738,974

   

HR

93/0428

YU

43,345

IE

57,326

ZA

84/01202

The patent claims the lithium, sodium, potassium, magnesium, calcium salts of omeprazole, a process for their manufacture, the pharmaceutical salts containing it, and its use to inhibit gastric acid secretion, to provide gastrointestinal cytoprotective effects and to treat gastrointestinal inflammatory diseases in humans and mammals and in humans.

According to the authors’ description in the patent, these novel alkaline salts of omeprazole are more stable during storage than the corresponding neutral form of omeprazole; they state, for example, that the magnesium salts are specially preferred for the preparation of tablets, while the sodium salts are preferred for the formulation of liquid pharmaceutical preparations.

This European patent and its equivalents were submitted 5 years after omeprazole or its pharmaceutically acceptable salts had been patented under EP 005 129.

Not only are separate claims made for omeprazole and its sodium or magnesium salts, but Astra again attempted to patent, under WO 99/08500 (November 1998 priority), WO 99/00380 (June 1997 priority) and WO 95/01977 (July 1993 priority), specific polymorphic forms of omeprazole, sodium omeprazole and magnesium omeprazole, respectively, characterized by having a degree of crystallinity which is higher than 70%, many years after the products had become known.

A further front in this vast field of omeprazole patents involves a push towards the development of enantiomerically pure forms of the compound or of its salts.

For example, Astra is currently in the process of registering the drug perprazole, which is an optical isomer of omeprazole. Omeprazole is a sulfoxide, and consequently a chiral compound, since sulfur is a stereogenic centre; it is a racemic mixture and perprazole is one of the two isomers of the racemic mixture.

In this case, perprazole was not patented by Astra itself but by another firm, Byk Gulden, which described and patented (+)-omeprazole and (-)-omeprazole through WO 92/08716. Although through WO 98/54171, (Swedish priority of December 1986), Astra claims S-omeprazole in a neutral form, characterized by being in a solid state.

Astra has done the same with the (+) and (-) isomers of omeprazole salts, which are protected under Astra’s PCT application relating to WO 94/27988, invoking 1993 priority. This strategy of extending product life by means of new patents continued with the submission of WO 98/54171, which describes and claims the magnesium salt of the S-enantiomer of omeprazole trihydrate or omeprazole (-)-enantiomer.

Lastly, it should be mentioned that Astra has patented new oral pharmaceutical formulations of omeprazole. Omeprazole pellets, protected by patent EP 247 983 are dosed and administered in capsule form. Astra has now designed a new form known as “MUPS” (multiunit pellet system) whereby the pellets are dosed and administered in tablet form.

In: WO 96/01623, Astra claims an oral pharmaceutical multiple unit tableted dosage form comprising tablet excipients and pellets formed by core material containing omeprazole or one of its single enantiomers or an alkaline salt of omeprazole or one of its single enantiomers, optionally mixed with alkaline compounds, covered with one or more layers, at least one of which is an enteric coating layer, whereby the enteric coating layer has mechanical properties such that the compression of the individual units mixed with the tablet excipients into the multiple unit tableted dosage form does not significantly affect the acid resistance of the individually enteric-coating layered units. A specific claim is made where the active substance is a magnesium salt of omeprazole having a degree of crystallinity which is higher than 70% as determined by X-ray powder diffraction, and where the active substance is an alkaline salt of (+) omeprazole or (-) omeprazole, preferable a magnesium salt.

This patent, which was applied for on 7 June 1995, designates, inter alia, Australia, Brazil, Canada, the Slovak Republic, the Czech Republic, China, Korea, the United States (US 5,817,338), Finland, Hungary, Japan, Mexico, Norway, Russia and Singapore. There is also an equivalent in South Africa.

In Europe, an application has been made under EP 723 436 A, designating Austria, Belgium, Switzerland, Germany, Denmark, Spain, France, the United Kingdom, Greece, Ireland, Italy, Liechtenstein, Luxembourg, Monaco, the Netherlands, Portugal and Sweden.

The new pharmaceutical form presents no tangible advantage. Its purpose is probably to eliminate competition from alternative products produced by competitors.

In Germany and in some 20 other countries, Astra has already withdrawn the capsules containing omeprazole pellets from the market and has replaced them with the MUPS tablets. As a result, when the product patent for omeprazole expires, the generic products will have no reference on the market; this hinders or may hinder the processing and/or approval of the generic product by the relevant health authority. Some health authorities have already declared that they will not authorize generic versions of products the original form of which is no longer on the market, even if it has been present recently.

AstraZeneca itself has stated, according to the journal Scrip (issue No. 2497 of 10 December 1999) that the launch of the new MUPS formulation has led to a revitalization of the Losec brand, and was a further barrier to generic entry. Losec MUPS has been launched in around 20 countries.

In practice, this strategy is also designed to prevent parallel imports. It is common for Losec to be introduced into northern Europe from other cheaper markets in southern Europe. For example, withdrawing Losec in the United Kingdom and replacing it with MUPS prevents parallel imports of Losec, because the code of ethics of British pharmaceutical chemists stipulates that unless a prescription indicates the generic name of the compound, a chemist will not dispense an imported medicament if the name is different from that on the prescription (see, Scrip, No. 2494, 1 December 1999).

OMEPRAZOLE

COUNTRY

Product patent or patent for the equivalent process
Expiry date

Pellets Patent Expiry date

Germany

EP 005.129 a
03/04/1999
21/03/2003*

EP 247.983; EP 496.437 2
16/04/2007

Argentina

Unpatented

AR 240.250
30/03/2005

Austria

AT 389.995 b
14/08/2007

EP 247.983
16/04/2007

Austria

AT 375.365 c
14/12/2001

EP 496.437
16/04/2007

Austria

AT 374.471 d
14/09/2001 **

 

Australia

AU 529.654
10/04/95***

AU 601.974
22/04/2007

Belgium

EP 005 129
16/11/2002*

EP 247 983; EP 496 437
16/04/2007

Brazil

Unpatented

Unpatented

Bulgaria

Unpatented

Unpatented

Canada

CA 1,127,158
06/07/99

CA 1,292,693
03/12/2008

China

Unknown

CN 1,020,852
30/04/2002

Cyprus

CY 1,232
03/04/99

CY 1,810
16/04/2007

Korea

Unknown

KR 91/4579
29/04/2007

Croatia

Unknown

HR 92/0854
01/01/2002

Cuba

Unpatented

Unpatented

Denmark

DK 150,510
(11/04/99)****

DK 169,988
28/04/2007

Egypt

Unpatented

Unpatented

Spain

Unpatented,

ES 2,006,457; ES 2,091,971
16/04/2007

Finland

FI 65,067
21/03/2003*

FI 90.393
29/04/2007

Philippines

Unpatented

Unpatented

France

EP 005 129
14/04/2004*

EP 247 983; EP 496 437
16/04/2007

United Kingdom

EP 005 129
14/04/2002*

EP 247 983; EP 496 437
16/04/2007

Greece

Unpatented

EP 247 983; EP 496 437
16/04/2007

Hong Kong

HK 84/00152
03/04/99

HK 94/1352
16/04/2007

Honduras

Unknown

Unknown

Netherlands

EP 005 129
15/11/2002*

EP 247 983; EP 496 437
16/04/2007

Hungary

HU 179,022
13/04/99

HU 196,708
29/04/2007

India

Unpatented

Unpatented

Indonesia

Unknown

Unknown

Ireland

IE 48,370
15/04/2002*

IE 61,416
27/04/2007

Israel

Unpatented

IL 82,911
18/06/2007

Italy

EP 005129
01/03/2010*

EP 496 437
16/04/2007

Italy

 

EP 247 983
01/03/2010*

Japan

JP 60/034956; JP 63/053191
03/01/2004;
14/04/99***

JP 05/069807
30/04/2007

Latvia

LV 93/853; LV 93/883;
LV 93/881; LV 93/882 13/04/99

LV 10.357
29/04/2007

Liechtenstein

Unpatented

EP 247.983; EP 496.437
16/04/2007

Lithuania

Unknown

LT 3,699
28/12/2008

Luxembourg

EP 005.129
16/11/2002*

EP 247 983; EP 496 437
16/04/2007

Malaysia

MY 85/74
03/04/99

Unpatented

Morocco

Unknown

Unknown

Mexico

MX?
03/04/99

Unpatented

Norway

NO 152,216
10/04/99

NO 174,239
29/04/2007

New Zealand

NZ 190,203
17/04/99

NZ 220,096
26/04/2007

Poland

Unpatented

PL 151.631
29/04/2002

Portugal

Unpatented

PT 84785
29/04/2007

Czech Republic

CZ 261,851; CZ 261,872
CZ 261,873; CZ 261,874
13/04/94

Unpatented

Slovak Republic

SK 261,851; SK 261,872
SK 261,873; SK 261,874
13/04/94

Unpatented

Romania

Unpatented

Unknown

Singapore

SG 83/00633
03/04/99

SG 94/1542
16/04/2007

Sweden

EP 005 129
04/02/2003 *

EP 247 983; EP 496 437
16/04/2007

Switzerland

EP 005 129
03/04/99

EP 247 983; EP 496 437
16/04/2007

South Africa

ZA 79/01586
02/04/99

ZA 87/2378
31/03/2007

Turkey

Unpatented

Unpatented

Soviet Union

SU 873,879; SU 873,880;
SU 878,196; SU 895,292
13/04/99

SU 1,820,837
29/04/2007

Ukraine

UA 4909; UA 4910;
UA 4776; UA 4908
13/04/99

 

USA

US 4,255,431
05/04/2001

US 4,786,505
20/04/2007

Yugoslavia

Unpatented

YU 46,192
01/01/2002

 

Notes: The data for the table are taken from data bases (WPI, INPADOC, CIBEPAT, NEW PORT and DRUGPAT) which do not cover 100% of the patent data for the countries listed; these data need to be reconfirmed by patent data from the countries themselves. Moreover, the expiry dates for the patents are simply indicative, and also need to be confirmed by data from the countries.

* SPC extension

** SPC requested

*** Possible extension

**** SPC refused

a SPC for sodium omeprazole, 21 March 2003; SPC for omeprazole refused and under appeal.

b Patent AT 389,995 claims a specific use for omeprazole.

c Patent AT 375,365 claims a generic process for synthesizing omeprazole.

d Patent AT 374,471 claims a specific process for synthesizing omeprazole.

e EP 496 437 is a divisional patent of EP 247 983.


To sum up, this case illustrates the use of a wide range of methods for broadening and extending patent protection, including the use of patent protection for polymorphs, isomers and pharmaceutical formulations.

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