INNsight articles by Duncan Curley

The ACE inhibitor Coversyl® first received marketing authorisation in Europe in the late 1980s.  The API is well known as the tertiary butylamine salt of perindopril, often referred to as perindopril erbumine or simply just “perindopril”.  With UK sales of approximately £72 million in 2005 it is not surprising that the drug has attracted a great deal of generic interest.  Although the launch of generic perindopril has been anticipated in the UK for a number of years, the innovator, Les Laboratoires Servier (“Servier”), has (until recently) managed by an ingenious combination of patent litigation and strategic settlement deals to preserve their market exclusivity. 

In anticipation of the expiry of the original patent to the compound itself - in Europe, European Patent No. 0,049,658 – Servier put in place a veritable thicket of secondary patents, claiming (for example) various crystalline forms of perindopril and processes for their manufacture.  The UK SPC based on the original patent expired on 21 June 2003, but since then Servier has deployed (to great effect) the other secondary patents in their stack and kept generic competition at bay, whilst continuing to grow the UK sales for Coversyl® at a significant rate (22% in 2006).

Servier has profited in particular from the somewhat controversial (and arguably harsh) ruling in the paroxetine litigation from a number of years ago, when a senior Patents Court Judge (Jacob, J. – now Lord Justice Jacob sitting in the Court of Appeal) held that the apparent weakness of a secondary patent was not the primary factor in deciding whether to grant an interim injunction against a threatened generic entrant.   In the UK, generic manufacturers now bear the responsibility for “clearing the way” of patent obstacles, or else face the likelihood of an interim injunction. 

In 2006, both Apotex and KRKA were caught out by this rule after intimating an intention to Servier to launch generic perindopril.  In Apotex’s case, generic perindopril was actually launched and sold for a few days in August 2006, before they were sued by Servier on one of their secondary patents: European Patent (UK) No. 1,296,947 (“New a crystalline form of perindopril tert-butylamine salt, a process for its preparation and pharmaceutical compositions containing it”).  Servier subsequently obtained an injunction against Apotex and KRKA then suffered the same fate, even though the Judge (Kitchin, J.) conceded that KRKA had “powerful evidence” that Servier had themselves sold the patented product – the a crystalline form of perindopril – before the priority date of the patent. 

In the meantime, other generic manufacturers lay waiting in the wings.  Eventually, the case proceeded to trial with Servier alleging infringement and defending the a crystalline form patent against attacks on validity by Apotex, KRKA and Lupin.   Before the trial (which took place in March 2007), Servier managed to settle both KRKA and Lupin out of the litigation, but Apotex stayed the course.  Finally, on 11 July 2007, Pumfrey, J. handed down a judgment containing his decision to revoke the patent.   

In the patent in suit, the a crystalline form of perindopril was characterised by powder X-ray diffraction.  In particular, one of the contested claims contained a tabulated version of the X-ray diffraction spectrum.  There was no real dispute in the case on infringement.  Expert witnesses for both sides agreed that there were no material differences between the X-ray diffraction data for Apotex’s product and the X-ray diffraction data in the claim that defined Servier’s patent monopoly. 

On the issue of validity, the Judge decided not to deal with the “difficult question” of whether Servier’s prior sales of Coversyl® (which was in the a crystalline form) invalidated the patent.  Instead, he confined himself (in a relatively short judgment) to an alternative case that was run by Apotex, which was as follows.   A prior art Servier patent – European Patent No. 0,308,341 – described a process for the industrial synthesis of perindopril.  Apotex alleged that if the skilled person put this process into effect, the a crystalline form of perindopril would inevitably be produced, thereby rendering the later patent to the a crystalline form invalid for lack of novelty.   Apotex therefore repeated the process described in the prior art patent and obtained X-ray diffraction spectra of the crystalline perindopril that was obtained. 

One of the main issues in contention in the case was whether it was legitimate for Apotex to perform a laboratory scale “litigation experiment” of the industrial synthetic process described in the prior art document, i.e. was the crystal structure of the product obtained by a laboratory scale repeat (done for the purpose of the litigation) representative of the result that would be obtained by carrying out the prior art industrial scale synthesis?   To meet this objection, Apotex carried out the process described in the prior art on both a laboratory scale and in a pilot plant and produced X-ray diffraction data on the products of both processes. 

Apotex compared the X-ray diffraction spectra for their laboratory scale product and the pilot plant product with the spectra for the a crystalline form of perindopril referred to in the patent in suit.   Servier accepted that the laboratory scale material obtained by Apotex was the same as that claimed in the patent in suit.  However, they alleged that the material produced by the synthesis in the pilot plant was different to that claimed in the patent.   But did the differences matter?  Were the differences enough to persuade the Judge (as Servier hoped) that if the synthetic procedure described in the prior art document was followed on an industrial scale, it did not inevitably result in a crystalline perindopril (as required for a case on anticipation)? 

The Judge heard expert evidence from both sides on the appearance and interpretation of X-ray diffraction spectra and data.  In the end, he was not convinced that the differences in the X-ray diffraction spectra were enough to satisfy him that Apotex’s pilot plant experimental repeat had in fact produced something other than a crystalline perindopril: “While the detailed analysis of the results undoubtedly revealed differences, it was not convincingly demonstrated [by Servier] that the differences represented a different crystalline form”.  The product claim (claim 1) was therefore anticipated and was invalid.  As for the process claims (2 to 7), these were “merely a recital of typical process conditions” and were invalid for lack of inventive step. 

It is not yet known whether there will be an appeal, but one outstanding question that will likely follow the decision of Pumfrey, J. is the measure of compensation that Servier will now presumably have to pay to Apotex for preventing them from launching generic perindopril last year (by obtaining an interim injunction in August 2006 on the strength of an invalid patent).   The way that the UK court ordinarily protects a company that is subject to an interim injunction is to require the patentee to give a cross undertaking in damages to the court, i.e. a binding undertaking to compensate the company that suffers the injunction, if it later transpires (after a full trial on the merits) that the injunction should not have been granted. 

Apotex’s previous attempt (after the paroxetine litigation) to force a payment from an innovator under the terms of a cross undertaking as to damages had failed, because the cross undertaking that was given when the interim injunction was granted did not cover the company in the Apotex group that had suffered the loss.  If the damages assessment proceeds in the perindopril case (i.e. if it is not settled beforehand), it will be particularly fascinating to see how it pans out.  For example, in deciding how much loss Apotex has suffered, the court will be required to speculate how much money Apotex would have made, had it not been stopped from selling generic perindopril following the abortive launch in August last year. Apotex apparently sold generic perindopril to the value of £4 million in the short period before the interim injunction was granted, and on that basis, Servier’s payout under its cross undertaking could be huge.  However, Servier will no doubt contend that many other generic companies would have entered the market - if the injunction against Apotex had not been granted - and this would have driven the price down, which would of course have affected the money that Apotex might have made on their generic product.   

Following the publication of the judgment of Pumfrey, J., Apotex immediately announced that they would launch generic perindopril on to the UK market.  This was followed in quick succession by an announcement from Teva.   Whilst there may be more interesting legal developments in the UK litigation on the question of damages under the cross undertaking, it seems that for Servier the UK perindopril party is well and truly over.