Second medical use dosage regimen claim successfully traverses both insufficiency and "obvious-to-try" attacks (T 0799/16)

The decision in T 0799/16 is a rare example of dose claim found both sufficient and inventive by the EPO Boards of Appeal.  The claim was found to be sufficiently disclosed over the entire scope of the claim, despite the claimed treatment being shown as non effective in almost two thirds of patients. The Board of Appeal (3.3.01) further found the claim inventive in view of prior art disclosing clinical trial information, information that included the claimed dose itself. The key factor in persuading the Board of Appeal on both counts was the particularly challenging nature of the target indication.    

The case related to Acorda's patent (EP 2377536) relating to a 4-aminopyridine (branded as Fampridine) dosage regime for the treatment of multiple sclerosis (MS). The granted claims specified 4-aminopyridine for use in a method of increasing walking speed of a patient with MS, wherein the 4-aminopyridine was administered as a 10 mg twice daily dose (Bid).

Sufficiency "over the whole scope of the claim" does not require the exclusion of non-responders

Not all patients suffering from a complex disease will respond to treatment. It is not often apparent why some patients respond to therapy, whilst others do not. For a second medical use patent claim, however, Biogen ([1996] UKHL 18) sufficiency requires enablement across the whole scope of the claim (see also T 409/91 Exxon/Fuel oils). This raises the question of whether a claim to "drug X for the treatment of disease Y" is enabled across the whole scope of the claim if drug X only treats disease Y in, for example, 90% of cases. This principle was considered by the UK Supreme Court in Warner Lambert v Actavis [2018] UKSC 56 (IPKat). 

In T 0799/16, the Opponents argued that the use of 4-aminopyridine at a dose of 10 mg Bid (twice daily) for the treatment of MS was not sufficiently disclosed across the whole scope of the claim. The Opponents pointed to evidence in the patent itself that only about one third of MS patients responded to treatment with 4-aminopyridine ("non-responders").

The Board of Appeal dismissed the Opponent's arguments, concluding that "The existence of a substantial proportion of patients who are non-responders is a common phenomenon observed with drugs in many treatment areas [...] If it can be shown that a relevant proportion of patients benefits from a treatment and that it has acceptable safety, the criterion of sufficiency of disclosure is met" (r. 3.5).

Heterogeneous population

In this Kat's view, the Board of Appeal's reasoning on this point is not altogether aligned with that of the UK Supreme Court in Warner Lambert. Lord Sumption found in Warner Lambert that a claim to the use of pregabalin to treat pain was insufficient. Lord Sumption's reasoning was that the patent specification did not plausibly demonstrate that the drug would treat all types of pain. In particular, pain can be caused by a number of different underlying mechanisms, and pregabalin was only demonstrated in the patent application as filed as targeting one of these mechanisms. 

Patients suffering from the different types of pain could be considered as entirely analogous to the "non-responders" discussed in T 0799/16. The patent at issues in T 0799/16 in fact describes the underlying mechanisms of disease thought to distinguish responder and non-responder MS patients: "Only a proportion of MS patients would be expected to possess axons of appropriate functional relevance that are susceptible to these drug effects" (paragraph [0079]). The Board of Appeal none-the-less considered the existence of non-responders as not undermining the sufficiency of a claim to the treatment of "MS patients" as a whole. 

Importantly, the sufficiency point at issue in T 0799/16 was not analogous to the situation in the recent High Court case Ilumina v MGI ([2021] EWHC 57 (Pat) (IPKat), which applied the UK Supreme Court decision in Regeneron v Kymab ([2020] UKSC 27). Ilumina and Regeneron related to the question of whether all of the features in a claim must be enabled across the whole scope of the claim. As summarised by Mr Justice Birss in Illumina, enablement over the whole scope of the claim is only necessary for features relating to "the essence of the invention". However, in T 0799/16, the Board of Appeal did not consider the identity of the MS patient (i.e. as a "responder" or "non-responders") to be unrelated to the core inventive concept of the claim. Instead, the Board of Appeal confirmed that a second medical use claim may include within its scope the treatment of non-responders, provided that efficacy has been plausibly shown for at least a subset of patients. 

When is a dosage regime not "obvious-to-try"?

The dose claim was found sufficiently disclosed, but was it inventive? The EPO usually takes a dim view of second medical use claims directed to a new dosage regime of a known drug. New dosage regimes are often dismissed as lacking inventive step. The EPO often finds that it would have been obvious for a skilled person to run clinical trials to determine the optimal dose of a known drug. In running these clinical trials it is further found that the skilled person would have had a "reasonable expectation of success" in finding a safe and efficacious dose (I-D-7.1). The UK Supreme Court followed this approach, as in for example Actavis v ICOS [2019] USKC 15 (IPKat).

The decision in T 0799/16 is remarkable for being a rare instance in which a dose claim was not found obvious in view of a reasonable expectation of success in running a dose-finding trial. The document considered the closest prior art (C27) was a financial statement from Acorda that reported the results of a phase II clinical trial to determine the optimal dose of Fampridine in MS patients. The clinical trial is reported as finding doses in the range of 10 to 25 mg Bid as improving walking speed in MS patients (MS-F201 trial). The report also disclosed that a larger clinical trial had been initiated to compare Fampridine doses of 10, 15 and 25 mg Bid (the MS-F202 trial). 

The difference between the patent claim and the closest prior art was therefore identified as the therapeutic efficacy of the 10 mg Bid dosage regime for increasing the walking speed of MS patients. The Opponents argued that, in view of this disclosure, a skilled person would have a reasonable expectation of success that a 10 mg Bid dose of Fampridine would be safe and effective in MS patients. Particularly it was argued that 1) a skilled person would be motivated to find the lowest effective dose of Fampridine; 2) given that a C27 disclosed that a phase III clinical trial was underway to test a 10 mg Bid dose, a skilled person would have a reasonable expectation of success that this dose would be effective; and 3) setting up a clinical trial to test the dose would be routine for the skilled person. 

Crib Goch

The Board of Appeal agreed that "it would have appeared realistic to the skilled person to investigate the dosages of 10, 15 and 20 mg bid, with the primary endpoint being an improvement in average walking speed" (r. 6.8.1). However, the patentee submitted that performing clinical trials in MS patients is far from routine. Particularly, the variability of systems between patients and even in the same patient over time, together with the high proportion of non-responders to treatment, meant that demonstrating efficacy of a treatment is difficult. Indeed, the pre-planned statistical techniques used to assess efficacy did not find the 10 mg Bid dose to be effective. As such "using conventional methods, the person skilled in the art would have thus failed to appreciate the utility of the 10 mg bid dosage regime" (r. 6.8.2(e)). It was only by applying, post hoc, a new statistical analysis that the inventors of the patent were able to identify the 10 mg Bid dose as effective. 

The Opponents did not submit arguments that the new statistical technique was in itself obvious. The Board of Appeal thus over-turned the Opposition division decision and found the claims to the 10 mg Bid dosage regime inventive. 

Final thoughts

The decision in T 0799/16 is a rare example of a second medical use patent that has successfully traversed a path through both the insufficiency and obviousness pitfalls. Interestingly, a Canadian dosage regime patent to a different MS drug was also recently found not obvious-to-try by the Canadian Federal Court (FCC) (Teva v Pharmascience, 2020 FC 1158, IPKat). Similar to the Board of Appeal's reasoning in T 0799/16, the critical factor swaying the case in the patentee's favour was the perceived complexity and likelihood of success of clinical trials in MS. Both of these decisions highlight that navigating a medicine through the various stages of clinical development is not the deterministic path to success the EPO sometimes suggests it is.