(S)-Omeprazole magnesium trihydrate: Lack of inventive step / preliminary injunction denied

Case No. S2012_011 ¦ Decision of 21 November 2012 ¦ “Abweisung des Gesuchs um Erlass vorsorglicher Massnahmen wegen fehlender erfinderischer Tätigkeit”

First patent applications on the blockbuster drug Omeprazole date back to 1978; cf. the review of Correa, Trends in Drug Patenting – Case Studies, 2001, WHO, Medicines Documentation. Upon synthesis, the proton pump inhibitor Omeprazole is a racemic mixture of two mirror-imaged molecules, the so-called R- and S-enantiomers. Both enantiomers are converted to the same active molecule in the body, but since some people metabolise (R)-Omeprazole only slowly, medication with pure (S)-Omeprazole purportedly results in higher dose efficiency and less interindividual variation. The present case pertains to a specific pharmaceutical form of Omeprazole, i.e. (S)-Omeprazole magnesium trihydrate. The structural formula of this compound is as follows:

The plaintiff requested (i) preliminary injunctive relief on the basis of a European patent; and (ii) that the defendant be obliged to recall already delivered items. Moreover, the plaintiff requested the grant of both interim measures without prior hearing of the defendant (according to Art. 265 CPC). The FPC did not grant interim measures without hearing the defendant. Unfortunately, the decision is silent about the reasoning (emphasis added):

[…] wurde der Beklagten in sinngemässer Abweisung des Gesuchs um Erlass superprovisorischer Massnahmen Frist angesetzt, um das Massnahmegesuch zu beantworten, […].

With respect to the allegedly infringing product, the plaintiff presented an analysis report showing that it contained not only the dihydrate form, but rather also a high amount of the trihydrate form — contrary to the published admission to the market; cf. Swissmedic Journal 12/2011. Note that due to the entry into the market of the allegedly infringing product in suit, the plaintiff’s own product came under pricing pressure: The Federal Office of Public Health informed the plaintiff that it intends to increase the deductible from 10% to 20% if the sales price of the plaintiff’s product was not lowered voluntarily.

As to the merits of the patent in suit, the plaintiff essentially argued as follows: It had surprisingly been found that the magnesium salt of (S)-Omeprazole also exists in the form of a trihydrate (i.e. not only as a dihydrate or in amorphous form). This trihydrate form is more stable and thus easier to store and handle. The defendant presented several lines of defence:

1. Non-infringement
   It was contested that the allegedly infringing product contained the trihydrate form.
2. Novelty
   It was argued that the patent in suit on the one hand claims (S)-Omeprazole magnesium trihydrate, but on the other hand admits in the introductory section that this compound is prior art. The defendant argued, that the claimed subject-matter was thus not novel.
3. Inventive step
   As a last line of defence, it was argued that the claimed subject-matter lacked an inventive step over
   (i) WO 94/27988 A1; or
   (ii) WO 96/01623 A1 in view of Byrn et al., Pharmaceutical Research, 1995, Vol. 12, No. 7, 945-954.¹

The decision does not expand further on the question of whether or not the allegedly infringing product in fact contained the trihydrate form (cf. 1., above). With respect to the questions pertaining to validity of the patent in suit (cf. 2. and 3., above), the reporting judge provided an opinion as follows:

Novelty (opinion of the reporting judge)

The mere fact that the trihydrate form is described as prior art in the patent in suit does not take away novelty of the claimed subject-matter. This statement in the patent in suit could also have occured erroneously, and there was no other prima facie evidence on file that the trihydrate form was not novel. Novelty of claim 1 of the patent in suit was thus acknowledged by the reporting judge.

Inventive step (opinion of the reporting judge)

In accordance with the so-called problem-and-solution approach, the closest prior art was identified in a first step. While both WO 94/27988 A1 and WO 96/01623 A1 disclose magnesium salts of (S)-Omeprazole and their medical use, only the latter explicitly discloses crystalline forms of magnesium salts of (S)-Omeprazole. The reporting judge thus identified WO 96/01623 A1 as the closest prior art. The distinguishing feature (the magnesium salt of (S)-Omeprazole being in the form of a trihydrate) led the reporting judge to formulate the objective technical problem to be solved as to provide new and advantageous forms of the magnesium salt of (S)-Omeprazole:

Bereitstellung neuer vorteilhafter Formen von (S)-Omeprazol Magnesiumsalz.

The reporting judge then assessed the publication of Byrn et al. as general knowledge of the person of routine skill in the art. As a matter of routine, such person would thus have analyzed the crystalline forms of the magnesium salt of (S)-Omeprazole in the expectation to find solid forms with improved properties. Moreover, the reporting judge referred to the reasoning of an EPO Board of Appeal in decision T 0777/08: It could not be considered inventive to provide a hydrate form of an already known pharmaceutical compound, unless there is a technical prejudice to be overcome. Such a prejudice had not been evidenced by the plaintiff. The reporting judge thus concluded that the claimed subject-matter does not involve an inventive step.

Comments of the plaintiff on the opinion of the reporting judge ¦ Decision of the FPC

The plaintiff objected that both the formulation of the objective technical problem and the choice of WO 96/01623 A1 as closest prior art is based on an undue ex-post-facto analysis. The magnesium salt should not be included in the objective technical problem to be solved. Taken as a whole, WO 94/27988 A1 would be more appropriate as closest prior art, the plaintiff argued. The FPC held that the prominent example of the crystalline magnesium salt of (S)-Omeprazole in WO 96/01623 A1 indeed can be considered as the closest prior art. Even if one were to consider WO 94/27988 A1 as closest prior art, this would not have changed the game: Since claim 1 of the patent in suit does not claim crystallinity, it is of no relevance whether there is an explicit teaching in WO 94/27988 A1 of the magnesium salt of (S)-Omeprazole being crystalline.

(Author’s note: This is not fully self-explanatory just from the decision as such. It would be interesting to understand the underlying claim construction of the FPC in view of the description of the patent in suit. The decision suggests that a trihydrate is claimed. It is the author’s understanding that the term hydrate describes a compound with associated water of crystallization, and thus crystallinity might well be implied.)

With reference to Byrn et al., the plaintiff outlined that it was explicitly not a routine measure to further investigate hydrate forms of pharmaceuticals. This would only be done as a routine measure when no well described solid forms of the respective compound were available. However, such well described forms were undoubtedly available in the present case. Moreover, Byrn et al. would not provide for any reasonable expectation of improved properties, but rather only states that the properties of different solid forms are not readily predictable. The FPC again referred to Byrn et al. (cf. p. 946, left col., first compl. para.): Even when a well defined solid form of a drug is already known, it is scientifically advisable to do further testing.

[…] from a regulatory standpoint, if a company can establish a specification/test to ensure production of a well defined solid form of the drug substance, then it is not necessary to do all of the physical/chemical testing outlined in the decision trees. From a scientific standpoint, however, such an approach is risky since new forms may appear unpredictably during various stages of the development process.

The FPC thus held that the person of routine skill in the art would have searched for hydrates of the magnesium salt of (S)-Omeprazole and would have arrived at the trihydrate without inventive merit.

Finally, the plaintiff argued that the trihydrate form was not an arbitrary choice but rather provides for the unexpected advantageous properties set forth above. The FPC held that this is not sufficient to acknowledge an inventive step. The decisive criterion is that the person of routine skill in the art was incited by Byrn et al. to search for hydrates of the magnesium salt of (S)-Omeprazole and would have arrived at the trihydrate without inventive merit — irrespective of additional advantageous properties to be expected or not.

(Author’s note: This reasoning of the FPC is quite similar to the case law of the EPO Boards of Appeal on bonus effects. However, this case law frequently refers to “one-way-street” situations; cf. e.g. T 0192/82, headnote II:

[…] The lack of alternatives in this respect might therefore create a “one-way-street” situation leading to predictable advantages which remained obvious in spite of the existence of some unexpected “bonus” effect.

Without in-depth knowledge of the details of the case, it is hard to judge whether the general teaching of Byrn et al. might indeed have created a clear-cut “one-way-street” situation for the person of routine skill in the art to arrive at the trihydrate of the magnesium salt of (S)-Omeprazole or not.

Noteworthy, the FPC did not further assess the advantageous properties of the trihydrate form — contrary to the EPO Board of Appeal decision T 0777/08 referred to by the FPC. According to this decision (p. 11, first para., last sentence),

[i]t must therefore be decided whether there was an incentive for the skilled person to arrive at the present solution in the expectation of achieving these improved characteristics […]

and there was a specific pointer from yet another document that these improved characteristics could be obtained by means of the alleged invention.)

In sum, the FPC dismissed the request for interim measures for reasons of lack of inventive step of the allegedly infringed patent.

Reported by Martin WILMING

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BIBLIOGRAPHY

Case No. S2012_011 ¦ Decision of 21 November 2012 ¦ “Abweisung des Gesuchs um Erlass vorsorglicher Massnahmen wegen fehlender erfinderischer Tätigkeit”

(not identified) ./. (not identified)

Subject(s):

• Patent infringement
• Preliminary injunction

Composition of the Board of the FPC:

• Dr. iur. Dieter BRÄNDLE (President)
• Prisca von BALLMOOS (Reporting Judge)
• Emmanuel JELSCH (Judge)
• Lic. iur. Susanne ANDERHALDEN (Court Secretary)

Representative(s) of Plaintiff:

• (not identified)

Representative(s) of Defendant:

• (not identified)

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¹ Note that this document is hyperlinked here to the freely accessible online file inspection service of the European Patent Office (EPO) in opposition/appeal proceedings T 0777/08. This decision and the publication of Byrn et al. were referred to in the present decision.