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 document3. ALENDRONATE
View the document4. CLARITHROMYCIN
View the document5. OMEPRAZOLE
View the document6. FLUCONAZOLE
View the document8. FEXOFENADINE
View the documentCONCLUSIONS
View the documentABBREVIATIONS
View the documentREFERENCES


Paroxetine is a antidepressant compound through its inhibiting effect on uptake of the 5-hydroxy-triptamine neurotransmitter. Chemically, the product is identified as (3S-trans)-3-[(1,3-benzodioxol-5-yloxy)methyl]-4-(4-fluorophenyl) piperidine.

The compound has been known both in its basic form and in the form of its pharmaceutically acceptable salts since at least 1977 with the publication of United States patent 4,007,196 (which invokes United Kingdom application priority No. 4496/73 of 30 January 1973), belonging to the Danish company A/S Ferrosan. The patent makes explicit reference to the paroxetine base and to its maleate, but the other salts with a pharmaceutically acceptable acid are covered by reference in the general formula. Although the patent gives no example of the preparation of paroxetine hydrochloride, it does refer to a procedure for preparing N-methyl paroxetine hydrochloride using a widespread general technique for preparing hydrochlorides.

During the period 1979-1985, the Ferrosan company supplied paroxetine hydrochloride to numerous research groups working on the biochemistry and pharmacology of antidepressants; the supplies were public, as is indicated by several articles, of which at least 11 were published by the research groups in scientific journals. For example, in 1979, Ferrosan’s own investigators published a paper on the pharmacokinetics of paroxetine in humans, which referred to the administration of oral doses of paroxetine hydrochloride (Acta Pharmacolo et Toxicol., 44, 289-295 (1979)).

In May 1984, a licensing agreement was signed between Ferrosan and SmithKline Beecham (at the time Beecham). Subsequently, and with the expiry date for the Ferrosan paroxetine patent not far off (United Kingdom priority, 1973), Beecham attempted to extend the protection for paroxetine by means of several patents, including:

1) With 1985 UK priority, Beecham applied and obtained patent EP 233.403 claiming crystalline paroxetine hydrochloride hemihydrate. The product patent was granted without it being clear in what way it was different from the already known paroxetine hydrochloride or what the benefits of the allegedly new product were in comparison with that already known.

2) With 1995 GB priority, Beecham requested protection through application WO 96/24595 for four different forms of paroxetine hydrochloride anhydrate, and for various paroxetine hydrochloride solvates.

3) With 1997 GB priority documents, Beecham requested protection under WO 98/31365 for free-flowing paroxetine hydrochloride obtained using the “spray-dried” technique.

4) With 1998 GB priority documentation, SmithKline Beecham requested protection, through WO 99/47519, for a crystalline form of paroxetine free base, paroxetine free base in substantially pure form and paroxetine free base which is substantially solvent free.

5) With prior 1998 GB documentation, SmithKline Beecham requested protection through WO 99/40084, for salts of paroxetine with various acids selected from the group consisting of sulfuric, oxalic, fumaric, propionic, formic, glutamic, succinic, benzoic, citric, nitric, phosphoric, tartric, 4-methylbenzenesulfonic, hypophosphorous, lactic and mandelic acids and glycine.

In addition to endeavouring to protect every possible form of paroxetine base and of paroxetine salts with different acids in various forms (free-flowing, crystalline, hydrates, anhydrates and solvates, including different polymorphs of some of these), SmithKline attempted to block other alternatives to the use of the product as a pure solid, by applying for protection of the use of paroxetine in liquid form or as a solid absorbed in or by another solid.

Thus, in WO 99/26625 (invoking 1997 priority) the company attempted to patent an oral swallow capsule containing paroxetine as the free base or a pharmaceutically acceptable salt or solvate thereof in solution in a carrier, while in WO 99/48499 (invoking 1998 priority) it claimed paroxetine or a pharmaceutically acceptable derivative thereof adsorbed on or absorbed by a solid carrier. Finally, SmithKline Beecham rounded off the circle by claiming paroxetine maleate, a product which had been explicitly described in Ferrosan’s expired patent US 4,007,196.

In SmithKline Beecham’s application WO 99/52901, the authors claim that although example 2 in US 4,007,196 describes treatment of the paroxetine base dissolved in ether with a solution of maleic acid in ether to produce a crystalline product which is recrystallized from ethanol-ether to give paroxetine maleate with a melting point of 136-138°C, the patent gives no further data that allow the structure to be determined unambiguously.

In this way, they claim “surprisingly” to have discovered “novel” maleate salts of paroxetine.

Although paroxetine maleate and paroxetine hydrochloride were known from the description in US 4,007,196 and from the samples made by Ferrosan itself between 1979 and 1985 respectively, SmithKline Beecham has deployed a barrage of patents which for the moment prevent paroxetine hydrochloride from being marketed until EP 223 403 expires, i.e. at least until 2006 in the European designated countries without SPC13 (Belgium, Germany, Greece, Spain, Luxembourg, the Netherlands, Sweden and The United Kingdom) or until June 2008 in Switzerland and Liechtenstein, October 2009 in France and December 2012 in Italy, where SPCs were granted.

13 “Special Protection Certificate”.

It should be borne in mind that Ferrosan’s basic patents claiming paroxetine and its pharmaceutically acceptable salts, equivalent to US 4,007,196, have already expired or are about to expire in those European Countries. For example, in Belgium, Luxembourg, the Netherlands, Switzerland, the United Kingdom, Spain and Germany, the equivalent patents expired between 1992 and 1999, depending on the country (in some of them, SPCs were granted, extending the patent until 1999). In France the patent expires in January 2001 and in Sweden in April 2002.

Because all the methods of producing paroxetine hydrochloride by crystallization of the salt in not completely dry solvents produce in any case the hemihydrate crystalline form, to prevent competition from generic drugs using distinct forms of it, Beecham has blocked the amorphous or anhydrate forms of paroxetine hydrochloride.

Finally, anticipating action by more intrepid competitors who might had imagined to market paroxetine salts other than hydrochloride (HCL), Beecham patented other salts even though they had no benefits other than those already known, and again patented the maleate salt, first described by Ferrosan.

In short, this case illustrates how it may be possible to extend the patent protection for an active ingredient, through processes for producing salts that add little or nothing in terms of innovation, occasionally resorting to well-known techniques.

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