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Monday, 3 August 2015

Taking the pH? Trial judge's decision on psoriasis patent doesn't come up to scratch

Taking the pH? No, just
enjoying a drop of H2O
Last week a judgment from Sir Robin Jacob plopped into Merpel's inbox which caused more than a slight tremor of her whiskers.  At the invitation of Lord Justice Kitchin, veteran British IP judge Sir Robin came back from retirement to give the first judgment in Leo's appeal against the decision of Mr Justice Birss last October [noted by the IPKat here] that its patents -- EP (GB) 1 178 808 and 2 455 083 -- were invalid for obviousness over US Patent 4,083,974  ("Turi").  In Teva UK Ltd & Another v Leo Pharma A/S [2015] EWCA Civ 779 (28 July 2015), the Court of Appeal granted Leo's appeal, deciding that Leo's patents were not quite so obvious after all.

Background and the problem

The patents at issue covered formulations for Leo's ointment treatment to alleviate the symptoms of psoriasis, an inflammatory skin disease without a cure.  When psoriasis is mild and reasonably contained, there is a greater risk that a patient will not comply with the instructions for treatment.  This is especially the case where treatment is unpleasant, has adverse side effects or is simply annoying.  Patient compliance is thus an important factor for the treatment of the condition.

The claims of the patents, as amended, were for an ointment consisting of
Both active ingredients were known before the priority date as the sole active ingredient in ointments and, given their own individual benefits, they were often prescribed together to patients.  However, they could not be applied at the same time because each was unstable except for in a narrow pH range in which the two did not overlap with one other (calcipotriol being an alkali and betamethasone being an acid).  Since it could be tricky to get patients to comply by using one cream in the morning and another in the evening, clinicians wanted an ointment that contained both ingredients.  This, the Court of Appeal stated, could be somewhat discounted because "clinicians are not formulators. What cannot be discounted is that formulators must have known of the desire -– the want –- of clinicians for a combination product."

Things are rarely so simple in the world of pharmaceutical inventions, especially as it was "far from established that any non-aqueous non-toxic solvent would produce a stable ointment".  At trial Mr Justice Birss commented at [39] and [40] that there was no proper evidence either way to establish whether or not such solvents would work, or that a skilled team would expect that it would work.

In theory there was a simple solution.  pHs are only possible if water is present.  Thus, just get rid of water.  All you would need to solve the problem is to find a non-aqueous non-toxic solvent.  Pick one of those and it will surely work (albeit it would be a mere arbitrary, non-inventive selection of the type discussed in Actavis v Novartis [2010]). The Court of Appeal commented that this was an important finding: it could not then be said that any particular non-aqueous solvent selected by a formulator would result in a product stable for both active ingredients, since the opposite is true: the formulator would have to undergo a research project starting with non-aqueous solvents that were already established and which had been used in other pharmaceutical topical formulations.  At the priority date, the formulator may have started with propylene glycol as it was used in a third of marketed corticosteriod formulations and had a water content of 0.2%.  However, that did not work -- as LEO discovered.  In cross-examination, Teva's expert conceded that trying to find a solution for the incompatibility of the two active ingredients required a lot of work.  

It was here that the Court of Appeal considered that the judge missed the significance of this evidence, which Sir Robin summarised as follows:   
"It was that to the skilled person, identifying a non-aqueous solvent which would actually work to produce a stable ointment, was not easy. Having the property of being non-aqueous was a necessary, but well short of sufficient, condition. Finding one was a research project. And that was because there was no sufficient expectation of success. Yes, a particular candidate might work, but it was far from certain that it would.
Indeed the formulator experts agreed that one would test a number of solvents. The Judge found “about 10-20” – again by implication it is clear that the expectation of success with any one of them was not high. The Judge said such testing “was entirely routine” but that does not alter the expectation. It was not even proved that there was a good expectation that if you did try 20 one of them would work. "
The Solution

The solution was Arlamol E, which was disclosed in Turi as a solvent for a corticosteriod back in 1978.  In the real world, although it had been used for cosmetics, it had not been significantly used for topical pharmaceuticals and did not thus form part of the common general knowledge of the formulator.  However, Mr Justice Birss held it would have been obvious to use it at the priority date, despite it not being one of the 10-20 solvents which a real formulator would have tried.

At paragraph 79 of his judgment, Mr Justice Birss stated:
"The notional skilled formulator would test some familiar compounds but, subject to the regulatory point considered below, would not be put off from including unfamiliar compounds merely because of their unfamiliarity. The question is primarily a technical one and would be decided based on consideration of the known properties and desired characteristics of the compound."
This, the Court of Appeal stated, was rather odd in that the judge is saying that the notional skilled persons are different from the real skilled persons.  The law of obviousness attributes the real prejudices and practices of persons skilled in the art to the notional person (see Dyson v Hoover [2002]).

Birss J had concluded that, since Arlamol E had the desired characteristics, there were grounds to include the compound in pre-formulation tests.  The Court of Appeal did not agree.  There were many non-aqueous solvents that may have had the desired characteristics, including the ill-fated propylene glycol.  But the Turi disclosure did not say anything about Arlamol E that made it "anything like an outstanding candidate".    Birss J also held that there was "sufficient prospect of a positive result" to make Arlamol E worth testing.   The Court of Appeal commented that this would have been equally true with any non-aqueous solvent, but that would not mean it would have necessarily solved the pH problem.

The Court of Appeal held:
"In effect the Judge was saying that the idea of including this solvent as part of a research project amounted to obviousness. The “obvious to try” standard requires a higher expectation of success than that. Otherwise, as I observed in St Gobain at [35]: 
"Mere possible inclusion of something within a research programme on the basis you will find out more and something might turn up is not enough. If it were otherwise there would be few inventions which were patentable. The only research which would be worthwhile (because of the prospect of protection) would be in areas totally devoid of prospect.” 
Putting this point into a Pozzoli structured analysis, the difference between the prior art (Turi) and the invention was that Turi was a mono active product using Arlamol E. The invention is a double active product. Turi would be seen as using one of a large number of possible non-aqueous solvents. It might provide stability for the two actives, just as any of the others might. But there was no reasonably optimistic expectation that it would. Finding that it really did was an invention and an advance in human knowledge. 
So I think the judge did err in principle and we are obliged and entitled to revisit the question of obviousness de novo."
To find comfort in this conclusion Sir Robin turned to the fact that although the active ingredients, the fact that clinicians wanted a dual active product to solve the patient compliance problem and the pH issue were all known well before and at the priority date, no solution had ever been achieved.  No-one found a way to put the actives together in an an ointment until LEO did it with the present invention.  As the Court concluded at [36] to [38]:
"When the dual active product came onto the market in 2002 it was a success. The experts on both sides were agreed that it was a significant advance in the treatment of patients. That was not because of a synergistic effect (at least the Judge did not find there was one) but because of the much better patient compliance – something desired since at least 1995. 
Mr Alexander suggested that there was no long-felt want, that the combination product came about exactly when you would expect, especially from LEO. They were really only undertaking a brand extension of their still patented calcipotriol. That simply does not square up with the dates and the facts that a combination product was wanted from at least the mid-1990s and, when achieved, was a real advance.  
So we have here the classic sort of case where the courts have found invention over the years, a long-felt want, the desired solution and no explanation of why that solution was not done before when it could have been. The Judge’s failure to consider this seems to me to be another error of principle – he missed a relevant circumstance. "
The Court of Appeal reversed the first instance decision on obviousness.

Added-Matter & Insufficiency

No "pick'n'mix" holds
the Court of Appeal
In relation to added-matter and insufficiency, the Court of Appeal had little to add.  Teva argued that the proposed amended claims formed a subset of the claims in the application as filed.  The technical narrowing from a very wide disclosure in the application amounted to a post-hoc "pick and mix" operation which added new information by discarding much that would not work or might not work.  The Court of Appeal dismissed the "pick and mix" argument as it cannot be said to be an intermediate generalisation that was not disclosed in the application:
"Betamethasone and calcipotriol are singled out as among the most appropriate actives, the solvent is said to be preferably non-aqueous, Arlamol E is the first example of a solvent in a specific list of solvents. Moreover Example 1 is an ointment with these two actives using Arlamol E as the solvent. True it is that it also includes an anti-oxidant but it is pushing one’s luck too far to say that omitting the necessity for this amounts to adding matter when the specification itself says “The composition may also contain other commonly used additives such as anti-oxidants.” 
So there is nothing in this point. As to insufficiency, it was but faintly argued and really only as some sort of support for the main obviousness argument. Clearly the patents contain instruction which would enable a person skilled in the art to make the ointment now claimed."
Merpel's mewsings

This decision is good news for Leo, says Merpel.  The main theme of the Court of Appeal's decision seems to be to caution against the hindsight explanation of the invention, especially where known matters have been well established before and by the priority date, but no solution had been advanced (see paragraph [38]).  Merpel also notes the Court of Appeal's comments on the skilled person -- or "nerd" as Sir Robin is fond of calling him (or her). On occasion, both the parties and the court can fall into a trap where the skilled person is suddenly emancipated from the constraints and prejudices with which the real skilled person would be imbued, with the effect that the notional skilled person has more scope for creativity (and perhaps invention in the extreme cases) than the legal construct actually permits.  With so many juicy points of law, Merpel will keep an eye out for Teva's potential appeal to the Supreme Court.


Suleman Ali said...

A welcome decision from the Court of Appeal, that will hopefully lead the UK courts to start considering reasonable expectation of success properly in pharma cases. Until now 'obvious to try' has been too dominant as a test.

Barbara Cookson said...

A wonderful example of a court judgement written for the benefit of students. The condoning of pick and mix is something I find worrying. It's all very convenient, but it sanctions the idea that you file the application then make the invention and then cut out all the rubbish that you told the world would work. Is this really the way we want it to work?

Anonymous said...

"(calcipotriol being an alkali and betamethasone being an acid)"

Really? Truly? Honestly?

Darren Smyth said...

To the last anonymous commenter, please be kind to Merpel who is a Kat not a chemist. What she intended to write, I discern, was "calcipotriol being stable in alkali and betamethasone being stable in acid". But you probably knew that already.

Best wishes


MaxDrei said...

What interests me here is the difference (if any) between the notional skilled addressee and the real person of skill in the art. According to Robin Jacob:

"...the judge is saying that the notional skilled persons are different from the real skilled persons"

So is Robin Jacob disagreeing? For the sake of objectivity, I had thought, the notional addressee has to be different from any real person. But perhaps Robin Jacob is telling us that this is so, but only to the extent needed for objectivity. As far as prejudices are concerned, there is no need to subtract them from the mental furniture of the notional addressee.

For novelty, the notional addressee cannot real, because he/she knows all the art yet is devoid of any scintilla of inventive capability. What real person fits that definition?

Even though it might not be the same person for insufficiency, it must surely be the same person for obviousness as for novelty. mustn't it? Presumably though, prejudices don't matter, in the assessment of novelty.

MaxDrei said...

I must say, reading this Decision, one wonders how Colin Birss could have got to the opposite conclusion. I guess i must read his judgement once again, to remind myself how he got there.

Anonymous said...

My take on Birss J.'s decision is that the "skilled formulator" wishing to implement the known desire of a medicament combining both "actives" and having the understanding that a non-aqueous solvent would be a "good thing" together with a knowledge of Turi as prior art in which the solvent of the claim was used with one of the actives would consider it blindingly obvious to try the claimed composition. He was, after all, the one who heard the expert testimony.

Anonymous said...

Darren, I know many things and many things I do not know. One thing I know, being a chemist, is that many non-chemists make incorrect statements regarding chemistry. In itself that is not a problem, but when it comes to the patent field there are many non-chemists practising chemistry and making an absolute hash of things.

As for your re-writing of the statement, it is still not scientifically correct. One substance may be more stable at one pH than another, but that does not make it stable per se.

Darren Smyth said...

Dear Anon, now you are just being picky. The term "stable" by itself is perfectly acceptable in scientific, including chemical, discourse, and chemists use it all the time. The implied degree is by reference to what you are doing. If it will sit in a container on a shelf for a reasonable amount of time, then it is "stable".
Best wishes

Anonymous said...


I find your reply to Anon to be a bit too prickly.

His point was that the words fail the art. That is NOT being "picky" when it comes to patents. It very much matters being "picky" in such regards.

I do not think that you can take the luxury of even saying "the implied degree" because then you are saying that the words don't matter when clearly the point being made is that the words very much matter. You cannot say "well, it's implied, just figure it out" because that is the issue with the words being so loosely chosen in the first place.

In other words, your defense of shabby language only proves his point.

Darren Smyth said...

Dear Anon at 12:18

I am sorry if you find me prickly. But to clarify, we are not talking about the patent, we are talking about the reporting of a judgment describing the underlying issue to the claimed invention. The previous Anon's allegation was that the wording used was not "scientifically correct". That is wrong in general, and is particularly wrong in the context of the reporting of the judgment, which uses "stable" and "unstable" throughout without limitation, entirely in accordance with normal usage. I think you have completely missed the point.


Anonymous said...

and Darren, you have completely missed both mine and the other Anonymou's.

Again - you prove our point.


Anonymous said...

Plutonium 239 is stable

Gold is unstable.

Suleman Ali said...

MaxDrei, I think Birss went wrong at the point when he assumed:

'40. However in the end the skilled formulator is an empiricist. Exactly how these various considerations will play out in practice is hard to predict in advance and always requires testing. For example that is why pre-formulation compatibility studies are always carried out.'

His 'skilled person' was too real, and did not reflect the skilled person as required for inventive step. Birss was right in the scientists would have got to the invention doing what they normally do, but that is not the inventive step test.

MaxDrei said...

Thank you Suleman Ali. One reason I like EPO-PSA is that (whatever R Jacob contends) the debate between the parties at the EPO squeezes out ex post facto reasoning. One reason I have reservations about assessing evidence obtained by x-examining tech experts on their respective reports is that all the evidence is created for the first time long after the priority date of the claim.

Anonymous said...

"This decision is good news for Leo, says Merpel." Surely this must count as the most inane commentary ever?

"This decision is [good/bad] news for the [winning/losing party], says [thought-leader X]."

Merpel McKitten said...

Fair comment, Anon @08:20. I should have added why it's good news. Leo, like most other pharma companies, does not trade in a single jurisdiction. Leo's products are sold on over 100 countries and, when a respected appellate court upholds a patent against a strong challenge from a legally savvy generics company with a deep pocket, this makes any corresponding patents elsewhere look a good deal more secure. Good news, at least if it's your patent.

Anonymous said...

Plutonium 239 is not stable. I had a bottle on a shelf and when MI5 knocked my door down it fell off.

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