Wednesday, May 15, 2019

Arginine Salt Obvious to Try

Les Laboratoires Servier v Apotex Inc 2019 FC 616 Roy J
            2,423,825 / perindopril arginine / VIACORAM / NOC

The most interesting aspect of this decision concerns overbreadth, which was also raised in another decision released last week, Aux Sable 2019 FC 581. I’ll deal with overbreadth in a subsequent post. This post provides an overview and deals with the finding that the invention was obvious.

Perindopril is used for treating hypertension and related cardiovascular disorders. Servier invented perindopril in the early 1980s, and ultimately received Canadian patent 1,341,196 for the compound per se [9], which it marketed as the erbumine salt under the brand name COVERSYL [10]. The 196 patent expired in March of 2018. The erbumine salt had stability problems, particularly in hot and humid conditions, that adversely affected shelf life [15], [34]. These problems had been raised early on in the development of perindopril. At that time one of the inventors of the 825 patent had suggested pursuing alternative salt forms and did some preliminary experiments with the arginine salt. However, pursuing a different salt form was not a priority for Servier, which initially dealt with the stability problem by using “tropicalized” packaging for some countries [31], and accepting a limited 2 year shelf life. Eventually though, in the late 1990s, Servier decided to pursue a new salt form, and returned to further development of the arginine salt. In 2002 Servier filed the application which matured to the 825 patent. Claim 1 is to the arginine salt of perindopril and its hydrates (“Sel d'arginine de périndopril ainsi que ses hydrates”). Servier markets the arginine salt as VIACORAM. Apotex, wishing to sell a generic version of perindopril arginine, which it concedes will infringe the 825 patent, attacked the validity on a variety of grounds, including obviousness and overbreadth [5]-[6].

The obviousness attack succeeded, on a fairly straightforward application of the obvious-to-try test. There was no real difficulty in testing and making the arginine salt, so the real question was whether selecting it to try involved inventive ingenuity. At the time the inventors had initially suggested the arginine salt, they had never heard of it being used to to form a salt of an active ingredient [31], and Roy J remarked that the decision, at the time, may have involved a spark of ingenuity [244], [252]. However, that was in the early 1980s and salt screen methods had moved on by the claim date in 2002. Roy J accepted the evidence of Apotex’s expert that a routine structured salt screen would have succeeded in identifying perindopril arginine as a suitable salt. In particular, the expert  identified arginine as one of only nine salt formers that would be selected for the initial structured salt screen [286].

One point that I found a bit confusing is that Roy J referred to Apotex’s expert as having been “blinded” [140], [290], and “truly blind” [292], but his expert report appears to take into account the particular properties of perindopril in identifying suitable salt formers for the initial screen [286]. In any event, it appears that by 2002 arginine was fairly commonly used as a salt former [292], [294].

I would also note that Roy J interpreted the principle that it should be “more or less evident that what is being tried ought to work,” as meaning that there should be a high expectation that a salt screen would identify a suitable salt, and not that there should be a high expectation that the arginine salt itself would work [285].

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