Low dosage form of tadalafil held obvious, preliminary injunction denied

Reading time: 13 minutes

Case No. S2019_007 | Decision of 1 October 2019

DISCLOSURE NOTICE

Hepp Wenger Ryffel is involved in this case on behalf of the defendant.

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.

Lilly sought for a preliminary injunction against Sandoz‘s generics Tadalafil Sandoz® 2.5 mg and Tadalafil Sandoz® 5 mg.

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

EP’181 is based on a national phase application of WO 00/66099 and claims priority of US 60/312,036.

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):

    1. the selected sub-range is narrow compared to the known range;
    2. 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;
    3. 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):

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.

Excerpt from Goldstein et al. (1997)

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

The ‘two bathtubs’ header image is a screenshot taken from one of Lilly’s Cialis® commercials at about 0:40 min.

BIBLIOGRAPHY

Case No. S2019_007 | Decision of 1 October 2019

(1) ICOS Corporation
(2) Eli Lilly (Suisse) SA
./.
Sandoz Pharmaceuticals AG

Panel of Judges:

    • Dr. Mark SCHWEIZER
    • Dr. Martin SPERRLE
    • Marco ZARDI

Court Clerk:

    • Susanne ANDERHALDEN

Representative(s) of ICOS / Eli Lilly:

    • Dr. Christian HILTI (Rentsch)
    • Dr. Demian STAUBER (Rentsch)
    • Dr. Andrea CARREIRA (Rentsch), assisting in patent matters

Representative(s) of Sandoz:

DECISION IN FULL

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Expectation of success: Please, be reasonable! (Part 1/2)

Reading time: 16 minutes
Famous dreamer

I have a dream today …

No, not about the civil rights movement. I am far less ambitious. I am just wondering: Wouldn’t it be great if one day we would all do the same when assessing obviousness?

I have a dream that one day we all agree on

Aiming high now: Maybe not only in prosecution, but even in litigation therafter!

We are surely not yet there.

For instance, the German Federal Court of Justice (FCJ) has some reservations, as discussed by judge Klaus GRABINSKI here:

The [EPO] Guidelines stipulate that deviation from this strictly schematic approach should be exceptional. The approach serves the interests of objective and predictable assessment in the examination procedure, in which, under Article 18(2) EPC, only the applicant and one member of the examining division are normally involved. Its appropriateness in this context is not to be questioned here; however, for a court procedure conducted on an adversarial basis between two or more plaintiffs and defendants, its suitability is limited.

But what are these reservations?

Firstly, the choice of a (single) closest prior art as the starting point in the assessment of obviousness, in GRABINSKI’s view:

Experience shows that, in nullity proceedings, the plaintiff generally presents several starting points (documents, public prior uses, etc.) in respect of inventive step. The court then has to assess whether the skilled person would actually have selected these starting points. According to the case law of the German FCJ, the choice of a specific starting point for the consideration of inventive step requires particular justification. This can be derived from the skilled person’s endeavour to find, for a specific purpose, a solution better than or different from the solution provided in the prior art. The test can be applied with one or more starting points (documents, public prior uses, etc.). There is no reason to limit the assessment of inventive step from the outset to the “closest prior art”. Otherwise, there is the risk of an inadmissible ex post evaluation of the prior art with regard to what is “closest”.

However, GRABINSKI holds that the EPO’s approach essentially does not differ much (what I believe is true, and I will come back to this in the below):

Ultimately, the same view would appear to prevail in the [then] current Guidelines for Examination. The authors concede, with reference to several decisions of the boards of appeal, that in some cases there are several equally valid starting points for the assessment of inventive step and that, in the event of refusal, it is sufficient to show, on the basis of relevant prior art in respect of at least one solution, that the claimed subject-matter lacks an inventive step. In such a situation, there is no need to discuss which document is “closest” to the invention; the only relevant question is whether the document used is a feasible starting point for assessing inventive step.

The formulation of the objective technical problem is key in the EPO’s problem-solution approach. Admittedly, this involves a somewhat artificial, retrospective approach. But it does so by design and in the interest of legal certainty, for that it be a reliable tool with predictable results. In my perception, the German FCJ takes a somewhat different approach; the problem(s) it typically refers to is/are not the objective technical problem of the problem-solution approach  at least not necessarily; see e.g. the discussion of the FCJ’s decision X ZR 29/15 - Pemetrexed by Rainer ENGELS here.

But be that as it may, I have no reason to blame the German FCJ for its approach. It may or may not be better suitable to avoid hindsight, or to provide legal certainty for users. There is more than one way to skin a cat, and the German FCJ never said to have adopted the EPO’s problem-solution approach.

However, the Swiss FPC did — repeatedly and in no uncertain terms (see e.g. O2015_018, ¶30):

Le Tribunal fédéral des brevets applique l’approche problème-solution développée par l’Office européen des brevets dans le cadre de l’évaluation de l’activité inventive.

Loosely translated:

The Federal Patent Court applies the problem-solution approach developed by the European Patent Office in the context of the evaluation of inventive step.

Hooray! They play the game as I know it!!

Thus, European patent attorneys in civil proceedings at the FPC can just do what they do all day long in proceedings at the EPO, at least in the assessment of obviousness? Actually, this would not come as a complete surprise since the second permanent judge (Tobias Bremi) and 27 of the non-permanent judges have a technological background and are European patent attorneys by training.

But hold on, it’s maybe not that easy.

Clearly, the FPC has the same reservations with respect to the choice of a (single) closest prior art; see O2013_011 in the hn and ¶5.6, with further reference to T 967/97, as well as S2017_001, ¶4.6.

But I feel that GRABINSKI is right in that this is nothing out of the ordinary in EPO practice (as it should be, taking into account the case-law of the Boards of Appeal); it is just that the term closest prior art used in the problem-solution approach might be misleading in that it suggests that this is always just a single document.

But what concerns me in recent times is the concept of a reasonable expectation of success; see this Blog here. The argument that there had been no reasonable expectation of success is easily made and thus frequently seen. And it is always easy to cast doubts in the assessment of obviousness:

Just imagine what could have gone wrong!

What is worse, such arguments cannot be proven wrong: Indeed, life is risky.

Not fully according to expectation …

Now, what the heck is actually a reasonable expectation in the skilled person‘s eyes?

The EPO Guidelines

The Guidelines are firm instructions to the first instance bodies of the EPO; see the foreword:

As a general rule, parties may expect the EPO to act in accordance with the Guidelines until such time as they – or the relevant legal provisions – are amended. […] In case of diverging decisions of the Legal or Technical Boards of Appeal, EPO examiners and formalities officers will, as a rule, follow the common practice as described in the Guidelines.

Patent applications filed with the EPO (Source: EPO)

More than 160’000 patent applications are filed with the EPO per year. And obviousness is to be assessed for all these applications; Art. 56 EPC.

If the concept of a reasonable expectation of success was of general importance for the daily practice of the first instance bodies at the EPO, one would readily expect it to be addressed in the Guidelines.

But, interestingly, it is not discussed at all — at least not in the chapter on assessment of obviousness.

The term reasonable expectation of success is only mentioned once in the Guidelines, but only a contrario, in the context of novelty of selection inventions in G-VI, 8:

The concept of seriously contemplating, or ‘ernsthaft in Betracht ziehen’ in German, is fundamentally different from the concept used for assessing inventive step, namely whether the skilled person would have tried, with reasonable expectation of success, to bridge the gap between a particular piece of prior art and a claim whose inventiveness is in question (see G-VII, 5.3), because in order to establish anticipation, there cannot be such a gap (T 666/89).

If you follow the link to G-VII, 5.3 in the hope to learn more about the concept of a reasonable expectation of success, you will be disappointed: There is nothing about reasonable expectation of success. G-VII, 5.3 is all about the could-would approach as we all know it. It reads as follows:

[T]he question to be answered is whether there is any teaching in the prior art as a whole that would (not simply could, but would) have prompted the skilled person, faced with the objective technical problem, to modify or adapt the closest prior art while taking account of that teaching, thereby arriving at something falling within the terms of the claims, and thus achieving what the invention achieves (see G‑VII, 4).

In other words, the point is not whether the skilled person could have arrived at the invention by adapting or modifying the closest prior art, but whether he would have done so because the prior art incited him to do so in the hope of solving the objective technical problem or in expectation of some improvement or advantage (see T 2/83).

What?!

Hold on a second.

It is worth reading the second paragraph again. The expectation of some improvement or advantage language is taken literally from T 2/83. But did you notice the other alternative?

I don’t know where the wording in the hope of solving the objective technical problem comes from; this inconsistency has already been discussed by discussed by Wooden, Blaseby and Visser recently. It somehow found its way into the Guidelines already back in 2003. But T 2/83 is silent about hope. The could-would approach clearly is not about hope; it is about an expectation.

Anyway, there is nothing about a reasonable expectation of success. It is only about an expectation of some improvement or advantage.

Now, do these terms maybe both mean essentially the same? I.e., is

  • success only the short for some improvement or advantage; and
  • the expectation (implicitly) meant to be reasonable in any event?
Too many people
making too many problems?

If so, fine. But wouldn’t it be good to use the same terms when referring to the same things? It’s a land of confusion anyway.

Or are they not the same? If that was the case, then the concept of a reasonable expectation of success just cannot be of any broader relevance for the first instance bodies at the EPO at all. Else, it would surely be referred to in the Guidelines.

Getting confused? Hold on tight, it’s not getting easier …

Learnings from the FPC

Decision S2017_001 in r 4.7 embraces the EPO’s could-would approach recited above. With reference to Kroher (Singer/Stauder, EPÜ, 7th ed., Art. 56, ¶73-74) the decision further holds that the ‘would’ is satisfied if there is a motivation to arrive at the claimed solution and an expectation of success that this solution actually works:

Dass der Fachmann die erfindungsgemässe Lösung effektiv finden würde gilt als gezeigt, wenn aus den Unterlagen ersichtlich ist, dass der Fachmann einen Anlass hatte (‘motivation’), zur erfindungsgemässen Lösung zu kommen, und er eine Erfolgserwartung hatte, dass die erfindungsgemässe Lösung auch funktioniert (‘expectation of success’).

Noteworthy, this does not even require the ‘expectation of success’ to be reasonable, and that the ‘success’ is realistically achievable — at least not explicitly. Kroher did not put it like this. This is what Kroher exactly says (emphasis added):

Zum Could-would Ansatz gehört auch die Wertung, ob für den Fachmann eine angemessene Erfolgserwartung bestand, ob er auf der Grundlage seines Wissens und Könnens realistisch mit einem Erfolg rechnen konnte oder nicht (vgl Rdn 136).161

161 T 60/89, Abl 1992, 268, Nr 3.2.5 ff; T 149/93 vom 23.03.1995, Nr 5; DE-BGH vom 15.05.2012 – Calcipotriol-Monohydrat, GRUR 2012, 803.

I have several issues with that.

First, none of the references cited in the fn actually says that the assessment of a reasonable expectation of success is part of the could-would approach. So, where does this come from?

Second, assuming that it really was part of the could-would approach, then how can it be that examiners and opposition divisions of the EPO deal with more than 160’000 cases per year in the absence of any instructions in the Guidelines? An integral part of the could-would approach did not make it into the Guidelines for decades? I can hardly believe that.

Third, the cross-reference to ¶136 in the Kroher chapter exclusively relates to biotech cases. And this is where it belongs — pretty exclusively, in my perception. Actually, the Boards of Appeal of the EPO have come up with the concept of a reasonable expectation of success in biotech cases. Frankly, I am not aware of any non-pharma or non-biotech case where the reasonable expectation of success argument had ever been successfully invoked to establish non-obviousness.

In sum, Kroher’s conclusion is not readily convincing to me, and it is not supported by the references given. I could only agree, again, if the reasonable expectation of success does not mean anything different than the expectation of some improvement or advantage according to the problem-solution approach.

What troubles me is that the FPC’s concise summary in S2017_001 is not just a summary of Kroher, or any other reference cited by Kroher. Rather, it adds further terms and interpretation, and appears to be more harsh in that the terms ‘reasonable’ and ‘realistic’ are just omitted.

Why adding to the confusion when mere application of the could-would approach — which is an integral part of the problem-solution approach — could just be it? The could-would approach (only) asks whether

[…] the skilled person would have arrived at the invention by adapting or modifying the closest prior art because the prior art incited him to do so […] in expectation of some improvement or advantage (see T 2/83).

In my understanding, the test is fairly easy. The skilled person could have done a lot. What the could-would approach is all about is to sort out what he actually would have done. Nothing more, nothing less. It does so by requiring prompters (sometimes referred to as pointers) or incentives in the prior art for the skilled person to arrive at the invention.

Ask Google for a definition of ‘motivation’, and you will get this.

Now, where does the ‘motivation’ referred to in S2017_001 come into play? There is no need for the additional term ‘motivation’ in the could-would approach. It might even cause confusion with the former teaching-suggestion-motivation (TSM) test in the U.S., or the Veranlassung approach of the German FCJ (which GRABINSKI says is very similar but not the same as the EPO’s could-would approach).

But be that as it may, a motivation in its broadest sense (according to Google) is

a reason or reasons for acting or behaving in a particular way.

Thus, I feel it is fair to say that the motivation referred to in S2017_001 is nothing more than the prompter or incentive. No need to fiddle around with yet another term in discussing the could-would approach. Talking about incentives, prompters (and pointers) is already complicated enough.

But that’s not the end of the story. The could-would approach cannot and does not just demand for an incentive in the prior art. An incentive to do … what? Adapting or modifying the closest prior art is no value in itself. It’s all about an incentive to achieve something; it must have a goal. The could-would approach consequently asks for an incentive to adapt or modify the closest prior art in expectation of some improvement or advantage — well, actually to solve the objective technical problem.

In a nutshell

The problem-solution approach which the FPC has comitted to apply includes the could-would approach which is a pretty decent tool that has been applied by the first instance bodies of the EPO for decades.

However, there is no mentioning of a reasonable expectation of success in the could-would approach. I am currently not sure whether the FPC tends to apply a somewhat modified could-would approach, or whether it understands and applies the expectation of some improvement or advantage in the sense of a reasonable expectation of success — a concept that the Boards of Appeal have developed and applied by now only in biotech cases, to the best of my knowledge.

On a sidenote, I do not readily agree with the threshold the FPC seemingly sets as reasonable; see S2017_001 (¶4.7; emphasis added):

Ob eine angemessene Erfolgserwartung gegeben ist, hängt immer stark von den konkreten Umständen und dem betrachteten technischen Gebiet ab und dabei unter anderem erheblich davon, ob es rational möglich ist, eine Vorhersage über den Erfolg zu machen. (Fn: Vgl. z.B. Medimmune Ltd v Novartis Pharmaceuticals UK Ltd & Ors [2012] EWCA Civ 1234 (10 October 2012), Reasons 91-95)

Note, that Medimmune v Novartis in no way puts such emphasis on the predictability of success, which is rather referred to as just one of many circumstances to consider. It reads as follows (¶91):

Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way.

The FPC apparently focusses on the predictablity of a success. I do not feel that this is supported by Medimmune v Novartis, nor by the case-law of the Boards of Appeal of the EPO and/or the problem-solution approach. Rather, it reminds me of the focus on predictability in the aftermath of KSR Int’l Co. v. Teleflex Inc.; see MPEP, ¶2141.

I will dig a bit further into this with a review of the case-law of the Boards of Appeal of the EPO in a second post on this issue soon.

/MW