INNsight articles by Duncan Curley, July 09

Significant growth is anticipated in the global antibacterial market to 2011, even though it is already highly genericised.  In particular, levofloxacin - a quinolone antibiotic - is an important on-patent medicine, which is marketed in Europe as the product Tavanic®.  In October 2008, the English Patents Court handed down a decision comprehensively rejecting all of the attacks mounted by Generics [UK] on the validity of European Patent (UK) No. 0,206,283 B1 (“the Patent”) and supplementary protection certificate SPC/GB97/085 (“the SPC”) that protects levofloxacin from generic competition.   

Generics [UK] had initially challenged the validity of the SPC by mounting no less than nine separate attacks on the validity of the basic patent (it will be recalled that an SPC depends for its life on valid patent claims that protect the API).  The tenth attack was based on a stand-alone issue, to the effect that the SPC should not have been granted, because the application for the SPC did not comply with the requirements set out in Article 3 of Council Regulation (EEC) No. 1768/92 (“the SPC Regulation”).  

Generics [UK] appealed the first instance decision, although they narrowed their appeal down to only two issues: a point of invalidity of the basic patent over a single piece of prior art and the SPC stand-alone invalidity point.  The appeal by Generics [UK] was heard early in June 2009 and on 2 July 2009, the appeal court handed down its decision.  Generics [UK] suffered another defeat, with the appeal court upholding both aspects of the first instance decision. 

As discussed in a previous edition of INNform (see http://www.genericsweb.com/index.php?object_id=719), the first instance Judge had found that the quinolone field was unusual, in that the medicinal chemists researching this field at the relevant time were more intent on developing new chemical entities, rather than examining the relative activities of enantiomers of existing chiral molecules.   This evidence of the skilled person’s “mindset” or motive to resolve proved to be critical in the Judge’s assessment of obviousness.  Since it was a finding of fact, it was unlikely to be overturned on appeal. 

The single piece of prior art relied upon by Generics [UK] in their appeal specifically described how to make the enantiomeric forms of another antibiotic, flumequine.  In the prior art method, an intermediate for flumequine was resolved.  The resolved enantiomers of this intermediate were then used to make each of the enantiomers of flumequine.  The argument put forward by Generics [UK] was that the skilled person seeking the separate enantiomers of ofloxacin would consider using the same method of resolution to obtain enantiomerically pure forms of the intermediate of ofloxacin.  The Judge at first instance had not been satisfied that the skilled person would have analogised with the flumequine disclosure and would therefore have attempted to resolve one of the intermediates of ofloxacin in the same way.  The Judge said that the skilled man “would have considered it worthwhile exploring whether ofloxacin could be resolved, but only to a point”. 

In rejecting Generics [UK]’s argument on this point, the appeal court endorsed the first instance Judge’s approach: it was “...a perfect example of a Judge properly carrying out the balancing task of forming an overall value judgment which it is so often the task of a first instance Judge to perform” (per Lord Justice Jacob, giving the leading judgment of the three Court of Appeal judges). 

That left the stand-alone attack on the levofloxacin SPC.   The argument mounted by Generics [UK] was that levofloxacin did not comply with Article 3(d) of the SPC Regulation, which required the marketing authorisation for the medicinal product (Tavanic®) that was submitted with the application for the SPC to be the first authorisation to place the API (levofloxacin) on the market as a medicinal product.  Generics [UK] maintained that a previous marketing authorisation to sell ofloxacin - the racemate - was effectively the first authorisation to sell levofloxacin, because levofloxacin was present (albeit only as a component) of ofloxacin. 

Despite caselaw from the field of SPCs that requires the term “product” in the SPC Regulation to be strictly construed (so as to rule out further SPCs for minor variants of an active substance), the Court of Appeal robustly rejected this argument too.  The Court of Appeal refused to accept that ofloxacin should be regarded simply as levofloxacin with an impurity (the R(+) enantiomer of ofloxacin).    The Court of Appeal held that levofloxacin was a novel and inventive improvement over ofloxacin.  Levofloxacin has its own distinct activity, bioavailability and toxicity that are different from ofloxacin.    As such, levofloxacin was not a minor variant of ofloxacin and it was entitled to its own SPC. 

The appeals by Generics [UK] against the first instance rejection of the attacks on the validity of the Patent and the SPC therefore failed.  The SPC for levofloxacin will now remain in place in the UK until expiry on 19 June 2011.