The patent in suit is CH/EP 1 173 181 H1, after partial surrender of EP 1 173 181 B3 which itself came out of central limitation proceedings concerning EP 1 173 181 B1 before the EPO; see EPO Register and Swissreg for further information.
EP’181 is meant to protect Lilly‘s low dosage forms of tadalafil, i.e. Cialis® 2.5 mg and Cialis® 5 mg, for the treatment of erectile dysfunction. Cialis at these low dosages is sometimes referred to as the ‘weekend pill’ because it can not only be taken on demand but also once daily, without regard to timing of sexual activity. See drugs.com and Lilly’s prescribing information.
The feature analysis of claim 1 of CH/EP’181 H1 reads as follows:
|1.1||Pharmaceutical unit dosage composition|
|1.2||comprising a compound having the structural formula [tadalafil]|
|1.3||comprising 1 to 5 mg of this compound|
|1.4||said unit dosage form suitable for oral administration|
|1.5||up to a maximum total dose of 5 mg per day|
|1.6||for use in treating a condition where inhibition of PDE5 is desirable|
|1.7||wherein the condition is sexual dysfunction.|
No dosage regime
Note that the claim does not address the frequency of taking of tadalafil. In accordance with feature 1.5, tadalafil could be taken once or several times per day (prophylactic or on demand, as long as the dose of 5 mg per day is not exceeded), and it is not defined that tadalafil is taken each day. Similar to the German FPC (¶ II.1), the decision holds that the claim lacks an essential element of a dosage regime, i.e. the frequency of taking tadalafil.
Claim to priority presumably valid
The decision holds that the claim to priority is presumably valid, both formally (¶ 19) and on the merits (¶¶ 20-22).
Presumably no undue extension of subject-matter
The decision holds that the plea in defense with respect to an undue extension of subject-matter is presumably unfounded (¶¶ 23-24), because the skilled person would still have seriously contemplated the range of 1 to 5 mg in view of dependent claim 4 (2.5 mg) and example 7 (2 mg).
Novelty acknowleged …
Since the priority claim was held presumably valid, the only remaining document to be considered with respect to novelty was WO 97/03675 A1 (Daugan). The relevant disclosure therein reads as follows (p 5, l 1-11):
For administration to man in the curative or prophylactic treatment of the disorders identified above, oral dosages of [tadalafil] will generally be in the range of from 0.5-800 mg daily for an average adult patient (70kg). Thus for a typical adult patient, individual tablets or capsules contain from 0.2 – 400 mg of active compound, in a suitable pharmaceutically acceptable vehicle or carrier, for administration in single or multiple doses, once or several times per day. […] In practice the physician will determine the actual dosing regimen which will be most suitable for an individual patient and it will wary with the age, weight and response of the particular patient.
Specific examples in Daugan make use of 50 mg of active compound in a tablet (p 12 ff).
Now, is the range of 1-5 mg novel over the broad range disclosed in Daugan?
According to the EPO Guidelines (G-VI, 8, ed. 2018), a sub-range selected from a broader numerical range of the prior art is considered novel, if each of the following three criteria is satisfied (emphasis added):
- the selected sub-range is narrow compared to the known range;
- the selected sub-range is sufficiently far removed from any specific examples disclosed in the prior art and from the end-points of the known range;
- the selected range is not an arbitrary specimen of the prior art, i.e. not a mere embodiment of the prior art, but another invention (purposive selection, new technical teaching).
The decision only applies criteria a. and b. for novelty, while the requirement of a purposive selection / new technical teaching (c.) is said to be related to obviousness only. Note that this criterion is also abolished with in the 2019 edition of the EPO Guidelines, entering into force on 1 November 2019.
Clearly, 1-5 mg is a narrow range compared to 0.2 – 800 mg; criterion a. is thus fulfilled.
But is the range sufficiently removed from the working example of 50 mg in Daugan? The decision holds that even though the absolute difference is only 45 mg, the absolute amounts still differ by a factor of 10. Thus, criterion b. is also considered fulfilled.
… but the low dosage form is obvious
Actually, obviousness is at the heart of this multi-national dispute. Lilly argued that courts in strict application of the problem-solution approach had found that EP’181 B3 was valid (e.g. in DK and FI), whereas only courts that applied a somewhat different approach concluded that EP’181 B3 was invalid (e.g. in the U.K., DE and NL):
- UK Supreme Court with decision (2019) UKSC 15 of 27 March 2019;
- Federal Patent Court, Germany, with decision 3 Ni 22/15 (EP) and 3 Ni 27/15 (EP) of 24 October 2017;
- District Court of The Hague, The Netherlands, with decision C/09/532013 / HA ZA 17-488 of 14 March 2018;
- Søog Handelsretten, Denmark, with decision A-49-17 of 15 June 2018;
- Markkinaoikeus, Finland, with decision 131/19 of 25 March 2019.
Accordingly, Lilly pushed for a strict application of the problem-solution approach in the present proceedings. The FPC indeed applied the problem-solution approach, but still concluded that EP’181 H1 was invalid.
The parties agreed on WO 97/03675 A1 (Daugan) as the closest prior art.
The decision holds in ¶ 33 that the skilled person would understand the broad ranges in Daugan as ‘boiler plates’ which are aimed at claiming the broadest possible protection. This implies quite some knowledge of a patent practitioner. The discussion of the broad ranges is in the specification, not in the claims. What is more, the skilled person is defined earlier in the decision as follows (¶ 14):
[A] team consisting of a clinical pharmacologist (with knowledge of the pharmacokinetics of conventional medicines and biological preparations) and a clinician (with knowledge of urology, and in particular of sexual dysfunctions or erectile dysfunctions and available medicinal treatments such as sildenafil).
I wonder where any knowledge of a patent practitioner stems from in this team. When discussing patent literature in litigation, it is constantly assumed that the ‘skilled person’ just knows how to read patents, and that he is even able to understand what the drafting attorney might have had in mind and intended in legal terms when drafting the specification. This is anything but realistic, in my perception. On the contrary, the typical pharmacologist and clinician will be used to read scientific publications, and without any additional training in patent matters he will approach a patent document just like any other piece of scientific literature.
In view of WO 97/03675 A1 (Daugan) as closest prior art, the FPC defined the objective technical problem as to provide a clinically effective and safe dosage of tadalafil for the treatment of sexual dysfunction.
The decision holds that it is credible that the skilled person would always aim to find the lowest possible effective dosage of an active substance, for various reasons. First, because the skilled person knows that a lower dosage will have fewer side effects, and the avoidance of side effects is always a goal in drug research. Second, the skilled person will strive to find the lowest possible effective dosage, because it may well be that the regulatory authority asks for it. Although it is not certain that the approval authority will require this information, it is still reasonably possible. Even this possibility is a sufficient incentive to identify the lowest possible dosage: If the necessary studies would only be done at the request of the authority later on, the market authorisation would be considerably delayed.
Decision of 1 October 2019 in case of ICOS, Eli Lilly v. Sandoz Pharma re alleged infringement of Swiss part of EP 1 173 181 B3 by #Tadalafil Sandoz 5 mg (request for preliminary measures): request denied bc. invention likely not based on inventive step, https://t.co/lgItJl6ghl pic.twitter.com/6bJUReixex
— Swiss Patent Court (@PatentCourt) October 22, 2019
Interestingly, the decision also expands on the ‘reasonable expectation of success’ (see this Blog here) — and its irrelevance for the case at hand. A ‘reasonable expectation of success’ is not necessary if the skilled person has an incentive for any other reason (e.g. a potential inquiry from the approval authority to specify the lowest effective dosage in the present case). The skilled person will then just take the necessary steps towards the invention unless he has to assume that this is hopeless right from the outset (¶36):
[E]ine Erfindung [ist] naheliegend, wenn der Stand der Technik […] dem Fachmann einen Anlass (“Motivation”) bietet, den nächstliegenden Stand der Technik so abzuwandeln, dass er zum beanspruchten Gegenstand gelangt. Oft wird den Fachmann eine begründete Erfolgserwartung zu der Weiterentwicklung veranlassen, d.h. wenn er aufgrund wissenschaftlicher Erwägungen annimmt, dass die Abwandung des Standes der Technik mit hoher Wahrscheinlichkeit zur Lösung der Aufgabe führt, wird er diese Abwandlung naheliegenderweise vornehmen. Eine begründete Erfolgserwartung in diesem Sinne ist aber nicht notwendig, wenn der Fachmann bereits aus anderen Gründen einen Anlass hat, den nächstliegenden Stand der Technik zum Gegenstand des geltend gemachten Anspruchs weiterzuentwickeln. Er wird diese Entwicklung dann vornehmen, wenn er nicht geradezu annehmen muss, dass sie aussichtslos ist.
The decision holds that the skilled person would have routinely included a dose of 5 mg of tadalafil in the phase IIb clinical study to determine the dose-response curve, in particular in view of Goldstein et al. (1997) where quite some efficacy of the sildenafil, the first-in-class drug, had been reported for a dosage of as low as 5 mg.
The skilled person would then inevitably have realised that tadalafil at a dose of 5 mg was still clinically effective. Thus, the decision holds that the subject-matter of EP’181 H1 was prima facie obvious.
- The decision can still be appealed to the Supreme Court.
Reported by Martin WILMING
|(2)||Eli Lilly (Suisse) SA|
|Sandoz Pharmaceuticals AG|
Panel of Judges:
- Dr. Mark SCHWEIZER
- Dr. Martin SPERRLE
- Marco ZARDI
- Susanne ANDERHALDEN
Representative(s) of ICOS / Eli Lilly:
Representative(s) of Sandoz:
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