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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The EPO assesses all aspects of entitlement to priority. Rightly so.

Reading time: 9 minutes

Proper assignment of the right to claim priority is intensely discussed in recent times, in particular the way how the EPO addresses such issues.

Why is that?

Broad’s logo

Most attention is where the biggest money is. Or where the most spectacular mishap occurs. Or both. The Broad Institute is upon to lose its CRISPR-Cas gene editing patents in Europe, for a lack of entitlement to priority. It’s not a question of ‘same invention’ this time, but rather of identity of inventor(s) / applicant(s) in both the priority application and the subsequent application.

Some priority basics at the EPO

Art. 87 to 89 EPC provide a complete, self-contained code of rules on claiming priority for the purpose of filing a European patent application (see J 15/80, confirmed in e.g. J 9/07). However, since the EPC — according to its preamble — constitutes a special agreement within the meaning of Art. 19 PC, it is clearly intended not to contravene the basic principles concerning priority laid down in the latter (see T 301/87, G 3/93 and G 2/98).

EPO logo

The EPO does not normally check the validity of a priority right during examination. A check, however, is made if relevant prior art has been made available to the public within the meaning of Art. 54(2) EPC on or after the priority date claimed and before the date of filing or if the content of the European patent application is totally or partially identical with the content of another European application within the meaning of Art. 54(3) EPC, such other application claiming a priority date within the above-mentioned period. In opposition proceedings this applies where prior art is invoked in connection with a ground for opposition under Art. 100(a) EPC in relation to which the priority date is of decisive importance. If the claim to priority turns out to be not valid, intervening prior art may lead to revocation of the patent.

All this is not very exciting; it’s just the law because the patentee cannot enjoy the benefit of an earlier effective date.

It is established practice at the EPO that the claim to priority is invalid if, at the filing date of the subsequent application, the applicant did not have the right to claim priority. Further, it is settled case-law at the EPO that the validity of the transfer of the right to claim priority is a matter of national law (cf. e.g. T 1008/96). All this is even reflected in the Guidelines, A-III, 6.1:

[T]he transfer of the application (or of the priority right as such) must have taken place before the filing date of the later European application and must be a transfer valid under the relevant national provisions. Proof of this transfer can be filed later.

A revolutionary new approach?

Tobias Bremi (second ordinary judge at the FPC) recently made an interesting contribution to the discussion on priority issues at the Fordham Conference (summarized on IPKat here). Tobias argued:

[The] EPO is not competent to assess entitlement to priority issues. […] As long as the formalities encoded in the law have been complied with, entitlement is to be presumed by the EPO.

And, finally, with respect to the CRISPR-Cas case referred to above, Tobias mentioned that he is

still hopeful that they will reconsider in the next instance.

The FPC has distributed a link to IPKat’s report, and the tweet is strict to the point: In Tobias’ view, third parties have no standing to challenge the assignment of the right to priority.

That’s a pretty bold statement, and Judge Grabinski apparently referred to it as ‘revolutionary’. Tobias’ key arguments are as follows:

  1. Analogy to entitlement proceedings

Tobias is cited on IPKat as follows:

Once the formal requirements for claiming priority have been complied with, there is actually no legal basis for questioning entitlement, there is no legal basis for the EPO to ask for proof, and there is also no legal basis for finding a loss of the priority right. [T]he general idea of the EPC was to keep the EPO completely out of entitlement issues as a matter of principle for a number of reasons and to leave that exclusively to the jurisdiction of national courts. It is for national courts to decide on entitlement issues when challenged by an allegedly entitled person. As long as the formalities encoded in the law have been complied with, entitlement is to be presumed by the EPO.

  1. General principles of property law

In Tobias’ view,

[i]t goes against the general principles of property law that priority entitlement issues can be brought up by any third party before the EPO and not just by the one who is allegedly entitled. This opens up rather opportunistic and destructive battles on the validity of priority claims.

  1. Clash with the Paris Convention

With respect to the same/all applicant(s) approach of the EPO (see e.g. T 788/05), Tobias held that

if the EPO uses that approach, actually they apply the ‘lex protectionis’, i.e. the law of the country where protection is sought, to the priority applicants. However, the gist of the Paris Convention is to reduce impediments for international protection.

In Tobias’ view, these principles are in jeopardy by forcing applicants to comply with the law of the country of subsequent filing.

In sum, arguments i) – iii) are also presented by Broad on appeal in opposition proceedings of EP 2 771 468 B1; see Broad's appeal brief (p. 19 ff).

I don’t agree.

Wholeheartedly. Here is my line of thinking:

  1. The analogy with entitlement proceedings is flawed

Entitlement proceedings concern only two sides; i.e. the applicant / patentee on the one hand, and yet another party who believes to be the legitimate owner on the other hand. The EPC explicitly applies the legal fiction that the applicant is entitled (Art. 60(3) EPC), until someone else comes along at a national court and challenges this. The EPO then steps back until the national court has decided on this issue, and thereafter continues its proceedings with the legitimate owner. In my view, this makes perfectly sense since the public is not concerned in any way.

On the other hand, entitlement to priority affects the effective filing date and is therefore decisive for the EPO to correctly assess patentability. There is no legal fiction of entitlement to priority. The EPO fulfills its duties according to Art. 114 in conjunction with Art. 87 to 89 EPC and aims to grant / maintain only those patents that comply with the EPC, to full extent. Rightly so.

  1. General principles of property law are not contravened

It is not just a ‘third party’ who challenges the right to claim priority. It is either the EPO when fulfilling its duties to check for compliance with the EPC, or it is a party to the proceedings in opposition / appeal proceedings who raises the issue. It is in no way ‘destructive’ or ‘opportunistic’ by the EPO or parties to proceedings to challenge a patent for non-compliance with the law. I fail to see how this might go against general principles of property law.

  1. There is no clash with the Paris Convention

The Paris Convention clearly aimed to facilitate international filings. The current practice at the EPO in no way contradicts this purpose. It definitely makes foreign filings much more simple than before the Paris Convention. Admittedly, the European approach is not absolutely fool-proof by design. But it doesn’t have to be. It’s the law: Practitioners are navigating a jungle of pitfalls every day — not only in their home jurisdictions, but in particular abroad. Messing up a priority claim before an IP5 office is just one of many potential nightmares. 

The mere fact that the USPTO more easily acknowledges entitlement to priority even in cases where not all initial applicants are named in the subsequent application doesn’t impress me much. In my view, they just overachieve the minimum standards defined in the PC. But that’s no good reason to abolish with decades of consistently developed case-law at the EPO.

Final thoughts

Consider a world where the EPO does not care anymore about who claims priority.

Bad guys could systematically just grab all early published European patent applications, or utility models, that are still within the priority year and then file subsequent applications with the EPO, claiming priority. The applications could proceed to grant without the entitlement to claim priority ever being challenged. Bad guy could only be stopped by the legitimate owner of the utility model.  If that just doesn’t happen because he/she doesn’t care anymore, or is afraid of costly litigation, bad guy has got the patent. This cannot be it.

Stay firm, EPO.

Reported by Martin WILMING

DISCLOSURE STATEMENT

Nil. I have nothing to disclose. In particular, I am not in any way engaged in the CRISPR-Cas proceedings referred to above. /MW

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