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Thursday, 21 February 2013

Something Wellcome didn't welcome: loss of the Malarone patent

Definitely not a generic ...
The prefix "Glen-" means only one thing to this Kat: a decent single malt whisky. Glenlivet, Glenmorangie, Glen Scotia, Glenfiddich, Glen Garioch. Sadly, the list is not actually endless, but it is no less dear for all that.  Anyway, spotting a recent decision from the Patents Court, England and Wales, by the name of Glenmark Generics (Europe) Limited & others v The Wellcome Foundation Limited &  and Glaxo Group Ltd [2013] EWHC 148 (Pat), his first thought was that it must have something to do with alcohol.  Was this not after all a judgment from the pen of Mr Justice Arnold, the man who taught our discerning palates to distinguish vodka from Vodkat?  But no: this was only a pharmaceutical patent spat after all. It was however a most interesting one. Here Simon Spink (CMS Cameron McKenna LLP) takes up the tale:
"The dispute concerns Wellcome's European Patent (UK) No. 0 670 719 which relates to an anti-malarial pharmaceutical composition comprising a combination of atovaquone and proguanil in the ratio 5:2.  Glenmark challenged the patent on the basis of obviousness over two pieces of prior art: a presentation by Dr David Hutchinson and an abstract from a plenary lecture by Dr A T Hudson.  Dr Hutchinson was also one of inventors named in the patent; both he and Hudson worked at Wellcome.  The patent protected the medicinal product sold by Wellcome under the trade name Malarone.  Glenmark wanted to sell a generic version of Malarone, while Wellcome counterclaimed for infringement on a quia timet basis.  There was no dispute between the parties that Glenmark's product would infringe the patent.  Glenmark gave undertaking not launch a generic product pending trial and Wellcome gave a corresponding cross-undertaking in damages.

It is of note that Wellcome made an unconditional application to amend the patent and to delete claim one as granted.  Claim 1 as granted was to a method of treatment using a combination of atovaquone and proguanil (in any ratio).  The application was granted and the trial was heard on a expedited basis.

Arnold J summarised in the technical background to malaria and its treatment with anti-malarial drugs with the degree of thoroughness we have become accustomed to in his judgments.  There was little difference between the parties in relation to constitution of the skilled team, both envisaging a team consisting of a clinician and a pharmacologist with the appropriate experience with malarial infections.  In setting out the law as to the common general knowledge, the judge referred to his decision in KCI Licensing Inc v Smith & Nephew plc [2010] EWHC 1487 (Pat) as approved by the Court of Appeal [2010] EWCA Civ 1260.  However, as could be expected in obviousness-only proceedings, there were certain areas of dispute as to what fell within the common general knowledge.  Most of these disputes came down to the strength of the evidence adduced by the parties.  However, the dispute concerning the common general knowledge in relation to combinations, and in particular the circumstances in which the skilled team would regard it as appropriate to combine two drugs, is likely to be of wider interest. 

Glenmark's expert, Prof Molyneux gave evidence as to the benefit of additive combinations of drugs in where there is some resistance to one or both drugs and in the absence of any synergy [82].  He added that there are different uses for drugs, including limiting the spread of resistance . Accordingly there is nothing irrational about using an additive combination in the appropriate circumstances.  Counsel for Wellcome put an article to Prof Molyneux which stated that the main advantage of additive combinations was the prevention of spasmodic resistance, and their use for strains that were already resistant to the more active drug was ostensibly irrational [84].  Prof Molyneux did not agree with that proposition.  Arnold J did not consider the article to be well-known and in conclusion agreed with Prof Molyneux  in relation to the benefit of additive combinations [86].

With regard to synergistic combinations the judge found that in the field of malaria research it was generally believed that, for a combination to be synergistic, the two drugs needed to act at consecutive points on the same pathway.  More generally he found that a combination which was shown to be significantly synergistic in vitro would encourage the skilled team to go forward to in vivo trials [88].

The first piece of prior art was a presentation by Dr Hutchinson scientists which detailed the history of the clinical trials atovaquone and the decision to trial it as part of a combination.  There were a number of sources of evidence as to what was disclosed in the presentation which included an abstract, the presentation slides, the speaker's notes, notes of those attending the presentation and several published summaries of the presentation.  The audience were told how tetracycline and proguanil were selected to be used in the combination with atovaquone.  Dr Hutchinson's notes stated that this selection was on the basis of in vitro potentiation studies.  However, the abstract merely stated that the combination was additive.  The judge concluded, that although the words actually used by Dr Hutchinson were those used in his notes, he was understood by his audience to mean that combinations of atovaquone with tetracycline and proguanil gave the best in vitro potentiation of the combinations studied.  Dr Hutchinson also gave the efficacy results of the combination clinical trials -- atovaquone/tetracycline effected a cure in all 25 of the patients treated while atovaquone/proguanil effected a cure in 20 of the 25 patients treated.  He recalled that he was disappointed with how his presentation was received, there being a number of challenges to his conclusions, and also to the rationale of combining atovaquone and proguanil.

The second piece of prior art was an abstract of a lecture given by Dr A T Hudson also of Wellcome.  The abstract disclosed the chemistry of atovaquone, its high potency against the malaria parasite, its metabolic stability, its good tolerability and its efficacy in clearing initial parasitemia.  It also disclosed the combination of atovaquone and proguanil, the fact that the combination had produced a cure rate of 100% in clinical trials against P. falciparum infections and that clinical trials of the combination were continuing.  No other data from the clinical trials was disclosed.

Arnold J set out the law on obviousness by reference to the restatement of the Windsurfing test in Pozzoli v BDMA SA [2007] EWCA Civ 588 and by reference to the consideration of that restated test in MedImmune Ltd v Novartis Pharmaceuticals Ltd [2012] EWCA Civ 1234.  He also cited Hallen Co v Brabantia (UK) Ltd [1991] RPC 195 and Dyson Appliances Ltd v Hoover Ltd [2002] RPC 22, both in relation to the relevance of commercial considerations to obviousness.   

He then applied the test to claims.  For claim 1 he found that there was no technical significance in the 5:2 ratio and that accordingly the correct question was whether it would be obvious to proceed with the combination of atovaquone and proguanil at all [116].  As the Hutchinson presentation disclosed the combination for treatment of malaria and encouraging clinical trials results, Wellcome was required to show that the skilled team would not proceed with the development of the combination of atovaquone and proguanil [118].  In the judge's opinion Wellcome was unable to establish through the expert evidence that sufficient technical considerations existed that would lead the skilled team not to pursue the combination [139], nor was the secondary evidence relating to the audience's reaction to the presentation and commercial success sufficiently persuasive to get them home.  The judge concluded at [144] that against the background of an urgent need for new anti-malarials, the skilled team would have reached the conclusion that the combination was well worth taking forward and that a Phase 2b trial was justified.  That would have led them to an appropriate ratio of the two drugs, accordingly, claim was obvious.  The Hudson abstract contained the same disclosure as the Hutchinson presentation bar the clinical data.  However, that was not sufficient to save it as the experts agreed that the skilled team would still consider the project for further development, thus it followed that claim 1 was also obvious over the Hudson abstract [153]. 

Glenmark asserted independent validity in claim 9, a claim to the co-formulation of atovaquone and proguanil.  However, the judge found on the evidence that once efficacy had been shown in clinic that the skilled team would consider co-formulating the combination, thus it was obvious to develop a pharmaceutical composition containing a combination of atovaquone and proguanil for the treatment and/or prophylaxis of malaria.  It followed that claim 9 also also invalid over both the Hutchinson presentation [146] and also the Hudson abstract [155].

This decision by Arnold J is another black mark on the checked fortunes of combination patents before the Patents Court for England and Wales.  We wait to discover how the Court would treat a combination where the patent disclosed a synergy which was not disclosed in the prior art.  Combination products are widespread across the healthcare industry, so this decision will not be welcomed by those companies owning patents relating to combination products (especially where they have no other patent protection for those products)".  
A well deserved katpat goes to Simon for this stupendous effort.

5 comments:

Anonymous said...

The case is a learning lesson for inventors. It should be part and parcel of does and don't.

Anonymous said...

I thought the patentee's strategy was a bit odd here. The feature that gives novelty (the ratio of 5:2) was assumed to not contribute to inventive step, and no attempt was made to use synergy at this ratio to argue inventive step. I agree that it is not clear the strategy would have succeeded, but it might have led to the judge seeing the case with a different perspective.

Mr Justice Arnold is presently using his 'let's decide it on the facts' test from Medimmune v Novartis to strike down biotech/pharma patents for inventive step, which he ends up turning into an 'obvious to try' test. In view of that as the patentee one needs to develop legal reasoning that will make it more likely the advantageous properties of the product will be an important determinant of inventive step. At the EPO of course being able to define the technical problem as providing a product with X, Y, Z advantageous properties makes it more likely properties of the product will contribute to inventive step.

Someone needs to stop Mr Arnold doing what he is doing on inventive step. I thought Conor v Angiotech was the point at which the UK courts would start to make a serious effort at including expectation of success in their analysis. Alas that has not happened, and that basically means the UK is going to continue to find a high proportion of pharma/biotech patents granted by EPO invalid for inventive step.

Anonymous said...

Great article. A very small point though, the writer says claim 1 as granted was not restricted by a ratio. It was restricted by a ratio range though. The ratio was 1:1 to 3:1 (as written in a way that corresponds to the 5:2 ratio quoted in the decision. The claims have the ratios written the other way). I suspect the writer made the same mistake as I have done in the past, if the claims are not available for a B spec at the EPO, the webpage will helpfully give the A spec claims telling you only in small print that it is doing so!

Anonymous said...

There's not much difference between a ratio of 5:2 and a 5¼ inch plate....

Anonymous said...

To Anon @ 09:58:00

At least Floyd J is giving expectation of success a bit of a fairer crack of the whip - see Regeneron/Bayer v Genentech for example.

At the moment it really is a coin-toss for patentees. Get Arnold J and you're probably in trouble, get Floyd J and you've got a fighting chance.

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