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
 

3. ALENDRONATE

Alendronate, or alendronate sodium, or 4-Amino-1-hydroxybutane-1,1-diylbis(phosphonic acid), is a product used to treat and prevent osteoporosis.

The product has no patent protection and was described for the first time by M. I. Kabachnik and collaborators in Izv Akad. Nauk. SSR, Ser. Khim (1978), 2, 433-7.

Subsequently, the Italian company Instituto Gentili discovered that certain diphosphonic acids, including alendronic acid and its alkaline metal salts are useful for treating urolithiasis and as inhibitors of bone resorption.

With a 1982 priority, it patented the pharmaceutical compounds containing alendronic acid and its salts (GB 2,118,042) or the pharmaceutical compounds containing alendronic acid and its salts to inhibit bone resorption (DE 3,313,049), and a method of treatment of urolithiasis and inhibiting bone resorption which consists of administering to a patient in need thereof an effective amount of alendronic acid (US 4,621,077).

There are equivalents for this patent in Belgium (expires on 14 April 2008), France (expires on 10 April 2008), Hong Kong (expires with the UK patent), Italy (expires on 15 April 2007), Japan (expires on 13 April 2003), Luxembourg (expires on 13 April 2008), the Netherlands (expires on 15 April 2003, SPC requested), Sweden (expires on 15 April 2008), Switzerland (expires on 25 March 2003, SPC requested) the United Kingdom (expires on 29 March 2008), the United States (expires on 4 August 2007) and Germany (expires on 12 April 2003, SPC requested).

The company granted a world-wide licence to develop the product to Merck & Co.

Even though the preparation of this alendronic acid compound by treatment of 4-aminobutyric acid with phosphorous acid (H3PO3) and phosphorous trichloride (PCl3), phosphorous pentachloride (PCl5), or phosphorous oxychloride (POCl3), had already been described by M. I. Kabachnik and Collaborators in Izv Akad. Nauk. SSR, Ser. Khim (1978), 2, 433-7, and by Henkel Koffman in European patent EP 039 033, and in equivalents such as US4,407,761 (all of which invoked German priority of 28 April 1980), the firms Instituto Gentili and Merck & Co. took out new patents to protect procedures for the preparation of this compound. These include:

US patent No.:

4,705,651

Application No.:

786815

Application date:

11 October 1985

Date granted:

10 November 1987

Approx. exp. date:

10 November 2004

Priorities:

IT 23362, A784 (29 October 1984)

Inventors:

Giorgio Staibano

Assignee:

Instituto Gentili

International class.

C O7F 009/38

Patent family:

   

AT

391,702

IT

1,196,315

BE

903,5

JP

61/109794

Ch

663,791

LU

86,133

DE

3,535,404

NL

85/02949

FR

2,572,406

SE

464,084

HK

9100128

GB

2,166,741

This patent protects an improved process for the preparation of alendronic acid which consists of reacting 4-aminobutyric acid, H3PO3 and PCl in a molar ratio of 1:1.25:2, and in the absence of solvents. This patent will not expire until 11 October 2005.

According to the authors, the molar ratio of the components allows the reaction mixture to be kept fluid, and the product is recovered by dilution with C1-C3 alcohol.

However, according to Gentili itself, the procedure described is unsuitable to an industrial scale application, because of the problem presented by the viscosity of the reaction mixture, which poses problems of stirring and hydrolysis. To resolve them, Gentili applied for an improvement on US patent 4,705,651 via the following European patent:

EP patent No.:

0494 844

Application No.:

92830001.1

Date of filing:

2 January 1992

Date of pub. of appl.

15 July 1992

Date granted:

19 April 1995

Approx. exp. date:

2 January 2012

Designated

 

contracting States:

AT, BE, CH, DE, DK, ES, FR, GB, GR, LI, LU, MC, NL.PT, SE

Priorities:

IT 080191 F191000003 (8 January 1991)

Inventor:

Guaianai-Ricci,G.

Assignee:

Instituto Gentili

International class.:

C07F9/38

Patent family:

 

CA

2,058,905

ES

2,072,126T

JP

04/342596

IT

1,246,992

This patent claims an improved process for the preparation of diphosphonic acids having the formula 2 wherein n is comprised between 2 and 8, and of its alkaline salts in mono or bi-basic form (see figure 1).


Figure 1

The process comprises the following stages a) melting a mixture of aminocarboxylic acid and phosphorous acid in the absence of a solvent; b)adding dropwise phosphorous trihalidide; c) addition of an hydrolyzing agent selected between water and a strong, not oxydizing acid, and d)recovering the diphosphonic acid thus produced. The process is characterized in that the molar ratio between aminocarboxylic acid, phosphorous acid and phosphorous trihalidide in the reaction mixture is comprised between 1:3:2 and 1:20:6.

Claim No. 7 protects the process where the aminodiphosphonic acid produced is alendronic acid. Example No. 4 of the description sets out the preparation of alendronic acid by reaction of 4-aminobutyric acid, phosphorous trichloride and phosphorous acid.

This patent will not expire until January 2002 in all the designated European States, which include Spain, Austria, Germany, Belgium, Denmark, France, the United Kingdom, Greece and Portugal. Equivalents have been found in Canada and Japan.

Merck & Co. also possesses patents covering the preparation of this compound:

EP patent No.

402 152

Application No.:

19900306238

Application date:

8 June 1990

Date appl. published

12 December 1990

Date granted:

2 November 1995

Approx. date of expiry:

8 June 2010

Designated States:

AT, BE, CH, DE, DK, ES, FR, GB, GR, IT, LI, LU, NL. SE

Priorities:

US 363820 (9 June 1989)

Inventors:

Kieczykowski G., Jobson R.

Assignee:

Merck & Co.

International class.

CO7F9/38

Patent family:

 

AU

625,704

NO

902,559

CA

2,018,477

NZ

233,972

FI

902,845

PT

94,306

IL

94,612

US

4,922.007

JP

03/101684

ZA

90/04446

LV

11472

ES

2,080,116T

IE

69564

KH

9600695

HU

211908

 

In this European patent, Merck not only claims a process for the preparation of alendronate, but the product itself, in its crystalline trihydrate form of monosodium alendronic acid salt.

This European patent claims for Austria, Germany, Belgium, Switzerland, Denmark, France, the United Kingdom, Italy, Liechtenstein, Luxembourg, the Netherlands and Sweden, but not for Spain or Greece, alendronic acid monosodium salt trihydrate.

It also claims for these countries, and for Spain and Greece, a procedure for obtaining this compound, comprising:

a) Reacting 4-aminobutyric acid with a mixture of HP3PO3 and PCL3 in the presence of CH3SO3H at a temperature below 85°C;

b) Treating it with water;

c) Cooling to 0 - 5°C;

d) Recovering the compound by filtration, washing with water and 95% ethanol and air drying (see figure 2).


Figure 2

According to the authors, the methane sulfonic acid ensures the homogeneity of the reaction mixture, increases the yield of the process and allows the salt to be obtained without the need to isolate the acid. Claims 4 and 5, protect the process when the compound recovered is alendronic acid monosodium salt trihydrate and alendronic acid respectively.

Equivalents to the European patent have been presented in many countries, such as Canada, Japan, Australia, Norway, Portugal, Finland, South Africa, Israel, Ireland, New Zealand, Latvia and the United States.

The equivalent United States patent, number 4,922,007, claims only the process for the preparation of 4-amino-1-hydroxybutylidene-1,1-biphosphonic acid or salts thereof, but NOT alendronic acid monosodium salt trihydrate itself. The process comprises:

a) reacting 4-aminobutyric acid with a mixture of HP3PO3 and PCl in the presence of CH3SO3H;

b) recovering the acid or salt.


Merck subsequently presented a variant of the process claimed in the earlier European patent EP 402 152:

EP patent No.:

462 663

Application No.:

91201490.9

Date of filing:

14 June 1991

Date of pub. of appl.:

27 December 1991

Date granted:

27 September 1995

Approx. date of expiry:

14 June 2011

Designated States:

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

Priority:

US540997 (20 June 1990)

Inventor:

Kieczykowski G

Assignee:

Merck & Co.

Patent family:

 

AU

642,264

NO

91/02395

CA

2,044,923

PT

97,963

FI

9103008

US

5,019,651

JP

05/132492

ZA

91/04708

LV

11471

ES

2,079,026

NZ

238,493

IL

98462

IE

69171

HK

9600644

RO

112355

 

The patent claims a process for preparing alendronic acid or its salts:

a) reacting 4-aminobutyric acid with a mixture of phosphorous acid and PCl3 in the presence of methanesulfonic acid;

b) contacting the mixture from step a) with an aqueous hydrolysis mixture;

c) recovering said acid or salts thereof; which is characterized by the maintenance of the pH in the range of 4 to 10 during step b).


This patent will remain in force until June 2011 in all the designated States, which include Austria, Belgium, Switzerland, Germany, Spain, France, the United Kingdom, Greece, Italy, Liechtenstein, Luxembourg, the Netherlands and Sweden. Equivalents have also been found in Australia, Canada, Finland, Japan, Norway, Portugal, South Africa, Latvia New Zealand, Israel, Ireland, Hong Kong and Romania.

The equivalent US patent, No. 5,019,561 runs until 20 June 2010. It claims a process for preparing 4-amino-1-hydroxybutylidene-1,1-bisphosphonic acid (ABP) or salts thereof, comprising:

a) reacting 4-aminobutyric acid with a mixture of phosphorous acid and PCl3 in the presence of methanesulfonic acid;

b) contacting the mixture from step (a) with an aqueous hydrolysis mixture, wherein the pH is maintained in the range of 4 to 10 during the contacting;

c) recovering said acid or salts thereof.


A claim is also made for the process comprising:

a) reacting 4-aminobutyric acid with a mixture of H3PO3 and PCl3 in the presence of CH3SO3H at a temperature of about 65°C;

b) contacting the resulting mixture from Step (a) with an aqueous phosphate buffer at a temperature in the range of 0-20° C, and maintaining the pH between 6-8 during the contacting;

b-2) heating the resulting mixture from Step (b) at the boiling point; and


c) recovering said acid or salts thereof.


In addition to claiming the product in its crystalline alendronic acid monosodium salt trihydrate form and/or processes for its preparation, Merck attempts to protect the galenical composition of the tablets marketed under the Fosfamax trade name, through application PCT WO 94/12200. This application designates, inter alia, Spain, Japan, the United Kingdom, France, Germany, Portugal, Italy, Ireland and the United States.

This PCT application claims a pharmaceutical composition comprising between 0.5 and 40% by weight of alendronic acid or its salts and between 60 and 95% by weight of processing aids, essentially consisting of anhydrous lactose, microcrystalline cellulose, croscarmallose sodium and magnesium stearate. It also claims a composition comprising about 0.5 to 40% by weight of alendronic acid or its salts, 10 to 80% by weight of anhydrous lactose, 5 to 50% by weight of microcrystalline cellulose, 0.5 to 10% by weight of croscarmallose sodium and 0.1 to 5% by weight of magnesium stearate. It further claims a process for the preparation of a tablet containing alendronic acid or its salts which involves forming a mixture containing alendronic acid and a diluent selected from anhydrous lactose, a dry binder, a disintegrant and optionally one or more additional ingredients selected from the group consisting of compression aids, flavours, flavour enhancers, sweeteners and preservatives, lubricating the mixture with a lubricant and compressing the lubricated mixture. The method claimed is a direct dry mix compression process.

The application for PCT WO 94/12200 in other countries has been studied; it is being examined as EP 690 719 in Europe.

In the United States, Merck’s PCT application has given rise to three patents: US 5,358,941, US 5,681,590 and US 5,882,656.

In claim 1, US 5,358,941 which is in force until December 2012, describes a composition comprising about 0.5 to 40% by weight of alendronic acid or its salts and from about 60 to 99.5% by weight of excipients consisting essentially of anhydrous lactose, microcrystalline cellulose, croscarmallose sodium and magnesium stearate. It also claims the pharmaceutical composition comprising about 0,5 to 40% by weight of alendronic acid or its salts, about 10 to 80% by weight of anhydrous lactose, about 5 to 50% by weight of microcrystalline cellulose, about 0.5 to 10% by weight of croscarmallose sodium; and about 0.1 to 5% by weight of magnesium stearate.

United States patent No. 5,681,590, which is in force until December 2012, claims a process for the preparation of a tablet containing alendronic acid or its salts, comprising forming a mixture by mixing the active ingredient with a diluent, selected from anhydrous lactose, or hydrous fast flow lactose, a dry binder, a disintegrant, and optionally one or more additional ingredients selected from the group consisting of compression aids, flavours, flavour enhancers, sweeteners and preservatives, lubricating the mixture with a lubricant; and compressing the resultant lubricated mixture into a desired tablet form. The method claimed is a dry mix formulation.

Finally, patent US 5,882,656 claims, in the United States, a pharmaceutical composition comprising by weight, about 0.5 to 40% of alendronic acid and its salts and from about 60 to 99.5% by weight of excipients comprising a diluent, a binder, a disintegrant, and a lubricant.

The PCT has also given rise to patents or equivalent applications in Mexico, Australia, Norway, New Zealand, Bulgaria, Slovakia, Finland, Hungary, Israel, the Czech Republic, South Africa, Canada, Romania and Japan.

To sum up: alendronic acid was a product that became known through a description made in 1978. The Italian firm Instituto Gentili discovered that alendronic acid and its alkaline metal salts are useful in treating urolithiasis and in inhibiting bone resorption. It patented, with 1982 priority, the pharmaceutical compositions containing alendronic acid and its salts in US patent 4,621,077 and equivalents. These patents should originally have remained in force in Europe and in the United States until 2003, but extensions of the deadline have been obtained until 2007-2008, depending on the country.

It should be emphasized that the Gentili patents do not claim only the pharmaceutical compositions containing alendronic acid, but also those containing its salts. Example three describes the preparation of alendronic acid using the method patented by Henkel, while example five describes the preparation of the sodium salt of a product analogous to alendronic acid by treating the corresponding acid with NaOH.

Gentili granted a licence to Merck, who took advantage of the fact that sodium alendronate had not been identified in the Gentili patents; seven years after the Gentili discovery, Merck patented as a product, under patent EP 402 152 (and equivalents) the self-evident result of treating alendronic acid with an alkaline metal base; of course, the product launched on the market as “FOSAMAX” is nothing else than alendronic acid monosodium salt trihydrate; this resulted in an additional two to three years protection beyond the expiry date of the patents for the Gentili pharmaceutical preparations.

In addition to this extended protection, Merck made separate patent claims invoking a 1992 priority, as in application WO 94/12200, for the galenical composition (conventional tablets produced by dry mix using common techniques) contained in the FOSAMAX specialty which had been on the market since November 1993. If these are granted, as they have been in the United States, they will enjoy patent protection until 2012 or 2013.

When the Gentili patents expire between 2007-2008, the generic product will still have to contend with at least two Merck product patents covering monosodium trihydrate (2010) and the tablets containing it (2012-2013).

The case of alendronic acid is illustrative of the simultaneous use of a variety of means - including salts, procedures and formulations- to achieve broad protection and to extend it for more than 30 years after the basic product was first described.

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