The Cialis Litigation - Actavis Group PTC EHF and Others v Icos Corp and Another

A wife complains to the Qadi about her husband's impotence

Artist: Hamse-i Atai (18th century Ottoman miniature)
Source Wikipedia

Mr Justice Birss: Actavis and Others v Eli Lilly and Another [2016] EWHC 1955 (Pat) (10 Aug 2016) 

Although it is not spelt out anywhere in the 492 paragraphs and annexes to Mr Justice Birss's judgment, this complicated litigation appears to have been an action by a group of generics suppliers led by the Icelandic company Actavis Group PTC EHF for the revocation of European patent (UK)  1,173,181 entitled Composition comprising phosphodiesterase inhibitors for the treatment of sexual dysfunction and European patent (UK) 1,200,092 Beta-carboline drug products and a counterclaim against two of those companies for patent infringement. No less than 4 separate actions were consolidated in a trial that took place between the 15 June and 1 July 2016. Judgment was delivered on 10 Aug 2016.

Commercial Importance of the Litigation

The patents in suit (that is to say, the patents the subject of the litigation) concern tadalafil which is better known as Cialis. As everybody known Cialis is one of two drugs used to treat erectile dysfunction. The other is sildenafil which is sold under the trade mark Viagra. At para [1] of his judgment, Mr Justice Birss observed:

"The commercial value of these proceedings is very high. Based on public IMS data, branded sales of CIALIS for 2014 in the United Kingdom come to about $99 million while sales of ADCIRCA were $1 million. The European sales amount to about $¾ billion annually and Lilly's accounts for 2014 showed a figure of $2.29 billion for global turnover of CIALIS."

The first of those patents ("181") related to dosing of tadalafil while the second ("092") related to the optimum formulation of that pharmaceutical.

Validity

The validity of both patents was challenged on grounds of anticipation, obviousness, added matter and insufficiency.

In order to understand the challenge, it should be remembered that a patent can be granted only for an invention that is new and involves an inventive step (see s.1 (1) (a) and (b) of the Patents Act 1977). Anticipation means that the invention for which a patent is sought or has been granted has already been invented and is therefore not new. Obviousness means that it lacked an inventive step having regard to everything that would have been known to skilled addressees ("men of women skilled in the art" or experts in the relevant technology) at the time of the invention. In other words, the step between the invention and what was known was obvious to such persons.

Added matter arises where a patent or application for a patent has been amended.  S.76 (1) of the Act  provides:

"An application for a patent which -
(a) is made in respect of matter disclosed in an earlier application, or in the specification of a patent which has been granted, and
(b) discloses additional matter, that is, matter extending beyond that disclosed in the earlier application, as filed, or the application for the patent, as filed,
may be filed under section 8(3), 12 or 37(4) above, or as mentioned in section 15(9) above, but shall not be allowed to proceed unless it is amended so as to exclude the additional matter."

Essentially added matter means attributes of an invention for which a monopoly is claimed that had not been disclosed in a previous patent or patent application.

S.14 (3) of the Act requires applicants for patents to disclose the invention in their specification

"in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the art."

S.72 (1) (c) provides that a patent may be revoked if

"the specification of the patent does not disclose the invention clearly enough and completely enough for it to be performed by a person skilled in the art."

Insufficiency basically means that the patentee has failed to disclose the invention in sufficient detail or clarity for it to be performed by the skilled addressees that I mentioned above.

Priority

Both patents claimed priority from earlier American patents. The significance of priority is that the novelty of an invention is to be determined not from the time that of the application for the patent in suit but at the time of the application for the patent from which the patent in suit claims priority. That is because art 4 A (1) of the Paris Convention for the Protection of Industrial Property provides:

"Any person who has duly filed an application for a patent, or for the registration of a utility model, or of an industrial design, or of a trademark, in one of the countries of the Union, or his successor in title, shall enjoy, for the purpose of filing in the other countries, a right of priority during the periods hereinafter fixed."

Art 4 C (1) of the Convention further provides that the period of priority referred to above shall be 12 months for patents and utility models,

The argument, in this case, was that the previous American patents did not disclose tadalafil either at all or in sufficient detail for the inventions for which the European patents were granted to be performed by skilled addressees. If priority was lost then the novelty might have been challenged on the ground that patent applications published after the US patent applications but before the European patents anticipated the subject matter of the European patents.

Patent 181

Claim 1 of that patent was for

"A pharmaceutical unit dosage composition comprising 1 to 5 mg of a compound having the structural formula:


said unit dosage form suitable for oral administration up to a maximum total dose of 5 mg per day."

The compound disclosed in the formula was tadalafil and the invention was the optimum dosage to treat erectile dysfunction without significant side effects. As the judge put it at para [131] of his judgment:

"The invention presented in the patent specification is the discovery that tadalafil can be administered at low doses in a manner which is still clinically effective but also has low adverse side effects."

Priority Date for 181

S.5 (2) of the Patents Act provides that an invention is entitled to priority from a previous application filed before the patent application if it is supported by matter disclosed in that document. Patent 181 claimed priority from a US provisional patent application Ser. No. 60/132,036, which was filed on 30 Apr 1999. That application is referred to in Compositions comprising phosphodiesterase inhabitors for the treatment of sexual disfunction which was granted a US patent under publication number US 6943166 B1. The judge's task was to consider whether the US provisional patent application disclosed the optimum dosage of tadalafil as claimed in claim 1 of patent 181.

In approaching that task he referred to the Court of Appeal's decision in Medimmune Ltd v Novartis Pharmaceuticals UK Ltd and Others [2012] EWCA Civ 1234, [2013] RPC 27 (10 Oct 2012) and Mr Justice Floyd's in Samsung Electronics Co. Ltd v Apple Retail UK Ltd and Another [2013] EWHC 467 (Pat) (7 March 2013). In Medimmune the Court made clear at paras [151] to [154] of their judgment that "the approach to considering whether the 'same invention' has been taught is not formulaic but is a matter of technical disclosure, explicit or implicit, and that the important thing is whether the disclosure as a whole is enabling and effectively gives the skilled person what is in the claim." In Samsung the learned judge summarized the task of the court in the following way:

"(a) to read and understand, through the eyes of the skilled person, the disclosure of the priority document as a whole;

(b) to determine the subject matter of the relevant claim;

(c) to decide whether, as a matter of substance not of form, the subject matter of the relevant claim can be derived directly and unambiguously from the disclosure of the priority document."

Mr Justice Birss endorsed that approach at para [141] of his judgment and in particular with the emphasis on the decision being a matter of substance not form.

His Lordship's analysis is to be found between paras [143] and [234]. He concluded at [234] that although one of the examples in the previous application was not clearly tadalafil the use claims were supported by what was disclosed in the earlier document and thus all but two of the claims maintained priority.

Added Matter in Respect of 181

The judge directed himself at para [235] that the correct comparison was between the granted patent and the application as filed. He considered the question shortly at [236]:

"There is no issue about identifying tadalafil in the application both as a chemical entity and as the drug used in the relevant examples. That is clearly and unambiguously disclosed. The argument is about the references to dosage forms of 1-5 mg and administration up to a maximum total dose of 5mg per day. The application contains more examples than the priority document, including examples of dosing up to 100 mg, but nevertheless on page 8 of the application the same text about dosing is present as appears in the priority document at pages 6-7. Nothing in the extra material in the application undermines a conclusion that if, as I have held, the claims are supported by that passage in the priority document then they are also supported by the application. Accordingly there is no added matter in the claims."

Novelty in Respect of 181

The law on novelty was agreed by the parties and the judge considered the issue of novelty from para [238] to [256]. Except for the two claims mentioned above that were conceded by Icos the judge rejected the challenge on anticipation.

Inventive Step in 181

Mr Justice Birss took as his starting point the Court of Appeal's guidance in Pozzoli Spa v BDMO SA and Another [2007] EWCA Civ 588, [2007] FSR 37, [2007] BusLR D117.  The prior art relied upon was Daugan's patent (Controlled-release pharmaceutical formulations containing a cgmp pde-5 inhibitor (WO 2000024383 A1)) and the judge analysed the issue of obviousness as follows:

"i) In terms of motives to find a solution to the problem the patent addresses, the skilled team would be highly motived by Daugan and the success of sildenafil to investigate tadalafil as a treatment for erectile dysfunction.

ii) As for possible avenues of research, overall tadalafil would be obvious to investigate. In terms of doses however, 5 mg/day is a significantly lower dose than the 50 mg dose exemplified in the Daugan prior art and the marketed doses of sildenafil. It is also significantly lower than the 50 mg dose which would be chosen for the first test of efficacy at Phase IIa. It would not be chosen in the routine first dose ranging study. The team would not have anticipated daily dosing as something to be studied from the outset but once the half-life was discovered it is likely that daily dosing would be included.

iii) In terms of effort, overall the programme would involve very substantial resources of time, money and people but it would be pursued. However, by the time the idea of investigating lower doses presents itself, the team would have established safe, tolerable and effective doses of tadalafil at 25mg on demand and 10 mg for daily dosing. At that stage the impetus to investigate lower doses would be reduced but not eliminated.

iv) Expectations of success can be considered overall and in relation to particular studies. Overall the team would embark on the project with a reasonable expectation of success in establishing tadalafil as a safe, tolerable and effective treatment for tadalafil. However, the claimants failed to prove that efficacy at 5mg tadalafil was predictable or worth considering by the skilled team based on the properties of tadalafil as compared to sildenafil. The team would know that in principle there would be a minimum effective dose for tadalafil but would also know that its definition depends on a value judgment made by the team. In relation to the dose ranging studies, the team would conduct them hoping for a dose response. Following discovery of a plateau starting at 25 mg or 10mg, there would very likely be a subsequent dose ranging study which included 5 mg. The team would include a 5 mg dose in this study hoping to see a dose response but that does not mean they would have a reasonable expectation that 5mg would produce a clinically relevant effect at all nor one with minimal side effects. Assuming a 5 mg /day dose of tadalafil was tested, it would not be tested with a reasonable expectation of success.

v) Considering unexpected or surprising results, the position is as follows. The path to a 5 mg dose requires the discovery of new information such as the half life and the IC50 vs PDE6. That information would inevitably be found in any clinical programme. The path includes an important result which is unexpected even if it is not actually surprising, i.e. the plateau in the dose response from 10 to 100 mg. There is also a surprising result: the existence of a useful effect with reduced side effects. The claimed 5mg /day dose has that property.

vi) A number of value judgments would be required of a skilled team in a programme which reaches the claimed invention. One is to define the level of clinical effect to be regarded as relevant. Another is to embark on investigating daily dosing. An important value judgment is what to do when an unexpected plateau in the dose response has been identified at the same time as a marketable dose."

He concluded at [344] that at least one of the claims of 181 involved an inventive step.

Insufficiency of 181

The insufficiency point was abandoned in the course of the trial.

Infringement of 181

As all attacks on the patent's validity failed, the judge concluded at para [491] that at least one of the claims would be infringed. He set out his reasoning at para [137] and decided at [355] that the appropriate remedy was an injunction.

Patent 092

Mr Justice Birss made a different decision in respect of the 092 patent. He found all the claims to be invalid and dismissed the counterclaim.

The invention for which the patent was granted was essentially for a faster acting tadalafil tablet which consisted of a number of product and use claims (see paras [385] - [391]).

Claim 1 was for:

"A free drug particulate form of a compound having a formula



and pharmaceutically acceptable salts and solvates thereof in which the compound is present as solid particles not intimately embedded in a polymeric co-precipitate, wherein at least 90% of the particles have a particle size of less than about 40 microns."

The patent's validity was challenged on very much the same grounds as in 181

The priority and added matter challenges failed (see paras [392] - [394] for priority and [385[ to [399] for added matter) but those for want of novelty (paras [400] to [409]), obviousness ([410] to [458]) and insufficiency (paras [459] to [489]) succeeded.

The judge's approach to obviousness is interesting. The issue before him was whether the prior art having regard to the skilled team's common general knowledge was sufficient to make the invention obvious. His Lordship had to decide between two seemingly conflicting lines of authority:

"If the relevant standard is as high as Jacob LJ put it in St Gobain [2005] EWCA Civ 177 at paragraph 35 ("more or less self-evident that what is being tested ought to work") then I should reject the obviousness case. However as Floyd J said in Omnipharm [2011] EWHC 3393 (Pat) that formulation of the test was explained by Lord Hoffmann in Conor v Angiotech [2007] EWCA Civ 5 as a "fair expectation of success" with the degree of expectation depending on the facts of the case. Moreover in Teva v Leo when Jacob LJ referred again to paragraph 35 of St Gobain, the passage quoted did not include the sentence about "more or less self-evident". On the facts of this case I do not believe the St Gobain way of putting the question is the appropriate one."

Mr Justice Birss resolved the issue through the following analysis:

"i) In terms of motives to find a solution to the problem the patent addresses, the skilled team would be highly motived by Daugan and the success of sildenafil to investigate tadalafil as a treatment for erectile dysfunction.

ii) As for possible avenues of research, overall tadalafil would be obvious to investigate. With low solubility and given the high dose required relative to it (i.e. a high dose number) there are some but not many options to consider. Top of the list is micronisation. It is simple and well known. The micronised formulation would include a surfactant.

iii) In terms of effort, overall the programme would involve very substantial resources of time, money and people but it would be pursued. The impetus to look at possible formulations would be substantial. At the point the formulations were being tested, the team would not have an alternative successful avenue available to them.

iv) Overall the team would embark on the project with a reasonable expectation of success in establishing tadalafil as a safe, tolerable and effective treatment for erectile dysfunction. The team would not know for sure that tadalafil could be formulated successfully but they would not give up without testing a fairly short list of expedients, of which micronisation would be one. In relation to the test of the formulation itself the team would have a high expectation that micronisation would improve the formulation. I have rejected Prof Frijlink's views on the skilled team's expectations of success both based on timings in the gastrointestinal tract and based on inferences from Daugan.

v) In terms of unexpected or surprising results, the low solubility of tadalafil is not unexpected although it does present a problem for the team. Nevertheless it is a problem the team is familiar with in general terms. The team would not be surprised that micronisation worked.

vi) The only significant value judgment which would be required of a skilled team in a programme which reached the claimed invention would be to test a micronised formulation of tadalafil (including a surfactant). That would not be a difficult decision."

The case turned to a large extent on its own facts but the judge did state some principles in relation to priority, novelty and obviousness of general application. Should anyone wish to discuss this case or the issues raised in it, he or she should call me on 020 7404 5252 during office hours or use my contact form.