The rise of "obvious to try" is over as Court of Appeal finds CIALIS dosage regimen patent obvious

Although it was obvious for the AmeriKat
to try being nice to Merpel, she knew
there was little expectation of success...

Unpredictable. Through the ages, humans and Kats have had to deal with the unpredictable, random and the volatile nature of life and, in particular, human behavior.  After the events of 2016/7, many of us may instituted more robust psychological tools to deal with unpredictable times - with varying degrees of success.  But an area where you cannot employ such tools is in patent litigation, where the fate of your patent or your defence depends on an inherently unpredictable fictional character/s - the skilled person/team - viewed through the prism of expert evidence and weighted with the perception of whatever judge you are before.  The Court of Appeal's decision last week in Actavis v ICOS [2017] EWCA Civ 1671 is a reminder that the uncertainty that can plague this and the resulting outcome of a court hearing, may not extend to the skilled team embarking on a routine clinical trial program.

The Court of Appeal consisting of Lord Justice Kitchin, Lord Justice Floyd and Lord Justice Lewison overturned Mr Justice Birss' first instance decision (handed down last August - see here) that the '181 Patent was valid and infringed.  The '181 Patent covers the dosage regimen for tadalafil - a PDE5 inhibitor - sold under the brand name CIALIS (for male erectile dysfunction) and ADCIRCA (for pulmonary arterial hypertension).  The 2014 market for CIALIS in the UK amounted to $99 million and ADRICA amounted to $1 million.  Actavis and Teva appealed the decision on the '181 Patent on five grounds - construction/infringement, lack of entitlement to priority, added matter, novelty and obviousness. The Court of Appeal held that the '181 Patent was invalid for obviousness.  Birss J had held that the other patent at issue in the first instance proceedings - the '092 Patent - which covered the formulation was invalid.  ICOS (patent owner)/Lilly (exclusive licencee) did not appeal that decision.

This is a decision about obviousness and, in particular, the role of obviousness and the "obvious to try" when the skilled person/team embarks upon a routine clinical trial program.   Although there is some nice Kitchin LJ dicta to digest in relation to the other appeal grounds (all which were ultimately dismissed) this post will look at the obviousness attack. However, the AmeriKat includes a link to a (ever color-coded) table she pulled together which sets out the key extracts on the other grounds, summary of the arguments and legal tests.

Given the scale of the first instance and Court of Appeal judgment on this issue, the AmeriKat is splitting the post into two.  This first post will quickly summarize the facts and pull out the key extracts.  A longer, more analytical post will follow about what it means in terms of what is left of the "obvious to try" case law and what it practically means for innovators who are faced with defending their so-called follow-on patents.

The Claims

Claims 7 and 10 are the relevant claims at issue.  The claims are as follows:

1.         A pharmaceutical unit dosage composition comprising 1 to 5mg of a compound having the structural formula:            

          said unit dosage form suitable for oral administration up to a maximum total dose of 5 mg per day.

2.          The dosage form of claim 1 comprising 2.5mg of the compound in unit dosage form.

3.          The dosage form of claim 1 comprising 5mg of the compound in unit dosage form.

4.          The dosage form of any one of claims 1 through 3 wherein the unit dose is in a form selected from a liquid, a tablet, a capsule, or a gelcap.

5.         The dosage form of any one of claims 1 through 3 wherein the unit dose is in the form of a tablet.

6.          The dosage form of any of claims 1 through 3 for use in treating a condition where inhibition of PDE5 is desirable.

7.         The dosage form of claim 6 wherein the condition is a sexual dysfunction.

10.      Use of a unit dose containing 1 to 5mg of a compound having the structure [of tadalafil] for the manufacture of a medicament for administration up to a maximum total dose of 5mg of said compound per day in a method of treating sexual dysfunction in a patient in need thereof.”

Daugan prior art

The prior art for the purposes of obviousness was citation called Daugan - a patent application published on 6 February 1997 (before the earliest priority date of the '181 Patent) that teaches the use of PDE5 inhibitors for the treatment of  erectile dysfunction.  Compound A - tadalafil - is specifically disclosed.  It also discloses tadalfil's  IC₅₀ against PDE5.  IC₅₀ is the measure of the potency of a drug inhibiting a specific function.  It describes the in vitro concentration of a drug that is required for 50% inhibition.   Examples of a tablet containing a 50mg dose are described in Daugan and it explains that doses of tadalafil will generally be in the range of 0.5mg to 800 mg/day for the average adult patient.  The difference of Daugan and Claim 1 is that it does not specifically disclose a tablet containing 5mg of tadalafil and, similarly, with Claims 7 and 10, as well as not stating that such a dose will be an effective treatment for sexual dysfunction.  

The parties arguments 

Actavis/Teva argued that at the priority date it would have been obvious for the skilled team, given Daugan, to take tadalfil forward into a routine pre-clinical and clinical trail program to assess its use as an oral treatment for sexual dysfunction.  In the course of this exercise, a 5mg/day dose of tadalafil would be used in patients and would reveal the invention (i.e. its safe, tolerable and effective).

Lilly argued that this argument was really an "obvious to try" case.  An invalidity finding could only be arrived at if the skilled team would consider the program had a fair prospect of success.  There is no way the skilled team could have thought so given, on the basis of Daugan, the team would have no idea whether a 5mg/day dose would be safe, tolerable or efficacious (with minimal PDE5 related side effects) in the treatment of sexual dysfunction.  It was, therefore, not obvious.

The skilled team's steps at first instance 

Birss J agreed - it was not obvious. As a whole, the judge commented, a clinical progam has many routine and obvious steps.  In this case the skilled team had two avenues to explore - on demand dosing and daily dosing.  Fast forwarding to the daily dosing avenue (although the skilled team would purse the on demand dosing first), although a 25mg/day dose would be obvious, a 5mg/day dose was not.  This was because it was so much lower than the 50mg disclosed in the prior art and the marketed doses of sildenafil.  It was on this basis that it would not be chosen in the routine first dosing range.   The team would have, in the earlier dosing studies, found that 10mg was effective and safe.  The drive to go lower than 10mg would be reduced but not eliminated.  They would eventually try 5mg/day but would have no reasonable expectation of success and indeed would be surprised that it was useful with reduced side effects (see the conclusions of the judge at [343(iv)-(vi)].

The parties' arguments

Actavis/Teva argued that the judge having found that the skilled team would take tadalafil into a clinical testing program where they would, eventually, test a dose of 5mg and would find it to be safe and efficacious, was "irrational and wrong" to conclude that the 5mg/day dose claim was still inventive.  Much reliance was placed by Actavis' counsel on the Court of Appeal in Actavis v Merck [2008] EWCA Civ 444 which stated that:

“32. So holding is far from saying that in general just specifying a new dosage regime in a Swiss form claim can give rise to a valid patent. On the contrary, nearly always such dosage regimes will be obvious – it is standard practice to investigate appropriate dosage regimes. Only in an unusual case such as the present (where, see below, treatment for the condition with the substance had ceased to be worth investigating with any dosage regime) could specifying a dosage regime as part of the therapeutic use confer validity on an otherwise invalid claim.”

Lilly argued that was not the right question - the evidence established the team would have "no expectation that a dose of 5mg/day wold be efficacious" and they would have been "surprised to find that a dose of 5mg was both efficacious and had reduced side effects".  Expectation of success argued Lilly, was a "critical consideration in all "obvious to try" cases."

The Law

The question of obviousness is, in light of all the relevant evidence:

was it obvious to the skilled but unimaginative addressee in light of the prior art and the common general knowledge to make a product or carry out a process falling within the claim?  (see MedImmune v Novartis [2012] EWCA Civ 1234)

Whether it was obvious to try a particular route with a fair expectation of success can be considered "where appropriate".  This and what these terms mean will depend on the circumstances and will vary from case to case.  In Novartis AG v Generics (UK) Ltd (trading as Mylan) [2012] EWCA Civ 1623 the Court explained:

"Sometimes, as in Saint Gobain, it may be appropriate to consider whether it is more or less self-evident that what is being tested ought to work. So, as this court explained in that case, simply including something in a research project in the hope that something might turn up is unlikely to be enough. But I reject the submission that the court can only make a finding of obviousness where it is manifest that a test ought to work. That would be to impose a straightjacket upon the assessment of obviousness which is not warranted by the statutory test and would, for example, preclude a finding of obviousness in a case where the results of an entirely routine test are unpredictable.” 

On Robin LJ's dicta in Actavis v Merck it is "important" but it should not be taken too far, held Kitchin LJ.  In particular:

"It does not establish that investigations into appropriate dosage regimens cannot yield patentable inventions. Indeed, Jacob LJ made it clear at [29] of his judgment that research into new and better dosage regimens is clearly desirable and that there is no policy reason why the discovery of a novel and non-obvious dosing regimen should not be rewarded by a patent." 

The Court of Appeal

It all fell down at the Phase IIb study.  Lord Justice Kitchin found that this was not a case in which the skilled team would be faced with a series of parallel avenues of study, with no expectation that any of those avenues would be fruitful/more fruitful than any other.  It was a case of two avenues - daily and on demand - with both avenues revealing tadalafil's half life and where each would lead the skilled team to the invention.   He continued:

"Rather than focussing on these important points, as I believe he should have done, the judge has instead attached weight to the fact that a dose of 5mg is considerably less than the 50mg dose which would be used in Phase IIa efficacy test, and to the fact that a dose of 5mg would not be chosen for the routine first dose ranging study in Phase IIb. It is of course true that a dose of 5mg is considerably less than a dose of 50mg but it must also be borne in mind that the two parts of Phase II have different purposes. Phase IIa is designed to provide proof of concept and is generally carried out at one dose selected to be high enough to provide the best chance of showing a positive effect while not causing serious side effects. Phase IIb is carried out at different doses chosen to provide an understanding about the dose response relationship. It is also true that a dose of 5mg would not be chosen for the first study in Phase IIb. However, as the judge himself found, the skilled but uninventive team would very likely investigate it thereafter."

 He concluded:

"Drawing the threads together, I am satisfied that Mr Speck has made good his criticisms of the judge’s reasoning. The judge has lost sight of the fact that, on his own findings, the claimed invention lies at the end of the familiar path through the routine pre-clinical and clinical trials’ process. The skilled but non-inventive team would embark on that process with a reasonable expectation of success and in the course of it they would carry out Phase IIb dose ranging studies with the aim of finding out, among other things, the dose response relationship. It is very likely that in so doing they would test a dose of 5mg tadalafil per day and, if they did so, they would find that it is safe and efficacious. At that point they would have arrived at the claimed invention. In my judgment claims 7 and 10 are therefore invalid."

Lord Justice Floyd, agreeing with Kitchin LJ, continued:

"I think that it was in these final steps in his reasoning that the judge fell into error.  The whole purpose of embarking on the routine Phase IIb dose ranging study was to identify a dose response. The discovery of a plateau indicated that the routine study would have to be repeated at a lower dose, because it was not complete.  Completion of the study would inevitably lead the skilled team to test 5 mg/day, whether that dose was still on the plateau, or in a region of the curve where a dose effect is observed.  Which it is does not matter, because the result is that the skilled person would at this stage have arrived at a dosing regimen within the claim.

Whilst the existence of value judgments on the road to the invention are of course highly material, the judgments identified by the judge in this passage of his reasoning were collateral ones which had no impact on the decision to complete the Phase IIb study, or were not true value judgments at all.  ... "

Floyd LJ also provided an excellent summary of the case law and its bounds from [156]-[162] and in particular warned of extending the "obvious line of enquiry" principle too far:

"It is important not to let this approach to obviousness extend beyond its proper bounds.  There will hardly ever be an invention for which it is not possible to “show how it might be arrived at by starting from something known, and taking a series of apparently easy steps”: see per Moulton LJ in British Westinghouse v Braulik (1910) 27 RPC 209 at 230.  Nearly 100 years later, Moulton LJ’s view that this approach was “not countenanced by English law” was said by Jacob LJ (with whom Mummery and Pill LJJ both agreed) in Technip France’s SA’s Patent [2004] RPC46 at [112] to be “as true today as when it was first said”.

I said something about the dangers of too relentless an approach to the “obvious line of enquiry” principle in Gedeon Richter v Bayer Schering [2011] EWHC 583 (Pat), in the context of experimentation. "

Lord Justice Lewison put the "obvious to try" case law firmly back in its box stating that "it is not the law" that "an expectation of success is an integral component of an "obvious to try" case "some tests are taken in ignorance of the results (see Gedeon Richter v Bayer Schering).  Although whether a skilled person/team has an expectation of success can be relevant to whether or not they undertake such a test/experiment, it is not a precondition (see Novartis AG v Generics).   With a final blow at[180] he concluded that:

"This court has been at pains to warn against the over-elaboration of the “obvious to try” line of cases. While there are a number of factors which, depending on the circumstances, may bear on the question it is not always necessary for all of them to be ticked off as if on a checklist. As Kitchin and Floyd LJJ have demonstrated, in a case which involves routine pre-clinical and clinical trials, what would be undertaken as part of that routine is unlikely to be inventive."

Well then...