The patent in suit is Lilly‘s EP 1 313 508 B1; see the EPO Register and Swissreg for further details. In a nutshell, EP’508 relates to combination of pemetrexed disodium and vitamin B12. See this Blog here for a discussion about earlier infringement proceedings concerning the same patent.
Now, nullity is at stake.
An Opposition Division of the EPO had maintained the patent as granted with decision of 27 December 2010; an appeal had initially been lodged but withdrawn later. Related decisions in civil proceedings elsewhere had also addressed the validity of EP’508, e.g. in
USA (Court of Appeals for the Federal Circuit, 2015-2067, decision of 12 January 2017 relating to the corresponding US patent 7,772,209 and maintaining the patent);
Japan (IP High Court, 2015 (Gyo-Ke) 10249 et al., decision of 2 February 2017 relating to the corresponding JP patent 5102928 and maintaining the patent).
Thus, it was an uphill fight for the plaintiff. And even though the FPC took the parallel decision of the German FPC into account, it explicitly disagreed. It is held on p 19 (penultimate and lastparagraph), that the German FPC erred with the finding that
[…] bei einer Pemetrexedgabe durch die Blockierung der drei Schlüsselenzyme Thymidylatsynthase (= TS), Dihydrofolatreduktase (= DHFR) und Glycinamidribonukleotidformyltransferase (= GARFT) im «DNA- Zyklus» nicht nur dieser Zyklus, sondern auch der «Methylierungszyklus» blockiert wird.
Consequently, the FPC did not put much weight (if any) on the parallel decision in Germany.
On the contrary, the decision holds that the claimed subject-matter was novel over Worzalla et al. since mere reference to a diet ‘Purina Chow #5001’ did not implicitly, yet clearly and unambiguously, disclose the presence of vitamin B12 (or folic acid).
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:
Pharmaceutical unit dosage composition
comprising a compound having the structural formula [tadalafil]
comprising 1 to 5 mg of this compound
said unit dosage form suitable for oral administration
up to a maximum total dose of 5 mg per day
for use in treating a condition where inhibition of PDE5 is desirable
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.
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 range of ‘1 to 20 mg’ in EP’181 B1 — with ‘5 to 20 mg’ being preferred — had been limited to ‘1 to 5 mg’ in EP’181 B3.
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.
On a personal note, I doubt that time was already ripe for changing the Guidelines. The recent 2019 edition of the book ‘Case Law of the Boards of Appeal’ in chapter I.C.6.3.1 correctly holds that there are several decsions that disregard criterion c., but still there are even recent decisions that do apply criterion c. There have been constant rumors for quite a while that this might be sth for the EBoA to finally decide. I would have preferred to await final clarification on BoA level over the uncertainty of an early change in first instance proceedings that might perhaps need to be reversed again in a worst-case scenario. In my view, criterion c. when correctly applied is a test whether there is a ‘new technical teaching’ (not just a formally new numerical value); see emphasis above. I cannot see any fundamental misconception in doing so under the title of novelty. A new technical teaching must not be confused with a non-obvious technical teaching. But be this as it may, I am still hopeful that the EBoA might finally have its say.
… 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):
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.
It’s no more than a sideshow for the outcome of the decision, but an interesting one:
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.
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 facieobvious.
The decision can still be appealed to the Supreme Court.
1. Use of pemetrexed disodium in the manufacture of a medicament for use in combination therapy for inhibiting tumor growth in mammals wherein said medicament is to be administered in combination with vitamin B12 or a pharmaceutical derivative thereof, said pharmaceutical derivative of vitamin B12 being hydroxocobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-chlorocobalamin perchlorate, azidocobalamin, chlorocobalamin or cobalamin.
12. A product containing pemetrexed disodium, vitamin B12 or a pharmaceutical derivative thereof said pharmaceutical derivative of vitamin B12 being hydroxocobalamin, cyano-10-chlorocobalamin, aquocobalamin perchlorate, aquo-10-chlorocobalamin perchlorate, azidocobalamin, chlorocobalamin or cobalamin, and, optionally, a folic binding protein binding agent selected from the group consisting of folic acid, (6R)-5-methyl-5,6,7,8-tetrahydrofolic acid and (6R)-5-formyl-5,6,7,8-tetrahydrofolic acid, or a physiologically available salt or ester thereof, as a combined preparation for the simultaneous, separate or sequential use in inhibiting tumor growth.
It’s all about a combination of the antifolate pemetrexed disodium, vitamin B12 and, optionally, folic acid. Briefly, pemetrexed is an antifolate that inter alia inhibits synthesis of thymidine and thus de novo DNA synthesis. Evidently, antifolates are quite toxic. But according to EP’508, toxicity can be successfully controlled by co-administration of pemetrexed with vitamin B12 and, optionally, folic acid.
EP’508 had already been litigated in infringement proceedings in Switzerland, resulting in a landmark decision of the Supreme Court on the Doctrine of Equivalents and how amendments of the patent during prosecution are to be dealt with in this respect; see this Blog here.
This time, validity of EP’508 is being challenged, based on a lack of novelty or, at least, lack of an inventive step; and added matter. Only inventive step has been pleaded in the hearing. With respect to the other grounds of nullity, the Sandoz merely referred to the written submissions.
It was evident from the pleadings that the opinion of the judge-rapporteur had been in favour of the defendant. This interim opinion is in line with the decision of an EPO opposition division, the Rechtbank Den Haag (Case No. C/09/533354 / HA ZA 17-581; judgment available as Dutch original and inofficial English translation), the IP High Court of Japan and the U.S. CAFC. On the other hand, the German Federal Patent Court had revoked the German part of EP’508; an appeal before the Supreme Court is still pending.
Sandoz started from Jackman as closest prior art in the assessment of inventive step. With reference to Worzalla et al., Jackman describes experiments in which pemetrexed was administered alongside with folic acid. Further, phase I clinical trials had been reported in which pemetrexed was administered together with folic acid (Hammond et al.). In consideration of the biochemical pathways, Sandoz argued that it had been obvious to add vitamin B12 to said known combination.
Eli Lilly of course disagreed. In Lilly’s view, the skilled person would not have pursued a combination of pemetrexed and folic acid, let alone to add vitamin B12. In real life, phase II clinical trials began with pemetrexed alone, irrespective of the experiments of Hammond et al. Toxicity of pemetrexed had intially been deemed controllable. It was only in the course of phase II clinical trials that the therapy scheme was switched because toxicity was found to be too severe.
A significant point of discussion was whether a skilled person would have been motivated to add vitamin B12 in light of some marker experiments. Niyikiza, the main inventor of the patent in suit, had published a report that described a correlation of pemetrexed toxicity with an unspecific marker (homocysteine), but not with the vitamin B12-specific marker MMA (methlymalonic acid). Accordingly, in Lilly’s view, a skilled person would not have been prompted towards the invention.
The basic EP’668 had lapsed already back in 2015; and the SPC has also lapsed meanwhile, on 4 May 2019. But the present decisions relate to an apparent mishap shortly before the SPC finally lapsed.
Sandoz had Swissmedic’s market authorization for its generic ‘Tadalafil Sandoz’ since 7 November 2017, but did not yet put it on the market. Still, the plaintiffs came across database entries for ‘Tadalafil Sandoz’ in HCI Solutions‘ medINDEX (for physicists) and pharmINDEX (for pharmacists). These databases are used by practitioners to order pharmaceuticals. Even though ‘Tadalafil Sandoz’ could not be ordered at that time, the President held that the effect of the database entries was essentially comparable to an inquiry of future needs (see S2014_001). Potential customers are made aware that the launch of a generic is imminent. This may tempt them to postpone orders for the original product and to order the cheaper generic once it becomes available. The generic manufacturer benefits from this advertising effect to the detriment of the supplier of the original product. During the term of the SPC, such advertising constitutes a violation of the exclusive rights of the owner of the SPC.
At the face of it, the situation was apparently so clear that the President granted interim injunctive relief without hearing Sandoz beforehand, and obliged Sandoz to immediately request the database provider to delete the entries.
Decision of 21 March 2019 in case of ICOS Corp, Eli Lilly SA v. Sandoz Pharma AG re SPC for tadalafil: inclusion of product in database of available products infringes patentee’s exclusive rights even if the product cannot be ordered (ex parte injunction), https://t.co/5SLv4kFPKQ
After hearing the defendant, it turned out that Sandoz’ had not made the entries in the databases. The entries had been made the database provider, an independent third party, without Sandoz’s knowledge and intervention. The database entries had meanwhile been deleted on Sandoz’s request, and thus there was no basis anymore for interim injunctive relief. The request was thus denied.
Now, what about the costs?
As a rule, the costs are clapped on the unsuccessful party; Art. 106(1) CPC. But the court may diverge from the general principles and allocate the costs at its own discretion when a party was caused to litigate in good faith; Art. 107(1) lit. b.
The President held that even though the plaintiff’s course of action may be understandable under the given circumstances, this still does not justify that the defendant bears the costs incurred in view of the unlawful conduct of an unrelated third party:
The plaintiffs have refrained from issuing a warning to the defendant before submitting the request for action. The applicants’ action may be understandable in the circumstances, but it does not justify the defendant having to bear the costs of the proceedings. As the defendant credibly demonstrates, it had nothing to do with the unlawful conduct of a third party; it is to be regarded neither as an instigator nor as an accomplice nor as a collaborator. Nor does it exercise any control over the third party. Since the defendant is not responsible for the unlawful conduct and has not created the appearance of being responsible for it, it cannot be ordered to pay the costs.
The court fee and a compensation for legal representation of the defendant are thus to be borne by the plaintiffs.