It-which-must-not-be-named

Some pharma cases are somewhat delicate to discuss in a blog post.

Case in point, if I provide the commercial name of the drug at stake in today’s litigation, I am afraid that this post may be classified as a spam and may thus never reach my email subscribers.

You see, it is the sort of drug which is prescribed for the treatment of erectile dysfunction, and which keeps coming up in these pestering unsolicited email messages that you may receive on a daily basis.

Just to be clear, today’s drug-which-must-not-be-named is not the famous one that starts with a V (containing sildenafil as an active compound), but the other famous one that starts with a C (containing tadalafil as an active compound).

He-who-must-not-be-named.

Icos Corporation (of the Eli Lilly group) is the owner of a number of European patents in connection with the C. drug.

First, there is EP 0740668, which was the basic patent for a French Supplementary Protection Certificate (SPC No. FR 03C0017), which expired in November 2017. Second, there are EP 1173181 and EP 1200092, designated as “secondary patents” by the Paris Tribunal de grande instance (TGI).

In November 2014, generic drug company Mylan obtained a marketing authorization (MA) related to the C. drug. In January 2016, Mylan initiated nullity proceedings with respect to the EP’181 and EP’092 patents in front of the Paris TGI. The parties later reached a settlement agreement with respect to EP’092, so that only the fate of EP’181 remained to be decided upon. Icos Corporation and the French distributor Lilly France counterclaimed for infringement of EP’181. The first instance judgment was issued in May 2018.

EP’181 or equivalents thereof were or are also litigated in other countries. According to the summary provided by the court, the patents were revoked in Germany, the United Kingdom, Canada and Japan. It may thus come as little surprising that the same outcome was achieved in this country. On the other hand, the ground for nullity that the TGI took into consideration is relatively unexpected, as will be apparent below.

But before getting there, let’s first look at the statute of limitations defense raised by Icos.

Mylan argued that the statute of limitations is not applicable to patent nullity suits. This argument was rejected by the court, in keeping with earlier decisions.

Turning to the determination of the starting point for the limitation period, the court recalled its now established principle of an in concreto determination.

The court thus explained that the grant of the EP’181 patent was not the starting point for the limitation period. The general principle is the following:

The starting point for the limitation period must thus be set at the date, determined in concreto, at which Mylan was or should have been aware of EP’181, due to its intent to market a generic of the drug [C.], which led to the MA obtained on November 21, 2014, since this patent is an impediment to its exploitation.  

In this case, a determining factor to be taken into account was the date at which Icos obtained its own MA:

In this case, the first MA for [C.] was granted in November 2002. By way of application of article R. 5121-28 of the Code de la santé publique, the generic company can only apply for an MA as from the eighth year after the grant of the originator’s MA, and cannot be granted one before the tenth year. Therefore, Mylan could not file an MA application before November 2010.

This reasoning is fully consistent with that applied in another recent case which already involved Mylan.

However, this is not the end of the story here. The court further held:

In this case, an additional fact should be taken into account in the in concreto analysis of standing and the starting point for the limitation period. […] [Namely, Icos corporation] filed a request for limitation of the EP’181 patent on February 14, 2014 with the European patent office, and the limitation of the patent was published on March 25, 2015. 

Thus the patent enforceable against Mylan could only be known on this date, so that the starting point for the limitation period is March 25, 2015. 

In another recent case, the starting point of the limitation period was postponed by a court to the date of the decision of the Board of appeal of the EPO in the opposition appeal regarding the patent at stake. The relevant paragraph of this decision may be worth quoting again here:

[…] It is only on [July, 7, 2014, i.e. the date of the Board of appeal’s decision] that the drafting of the patent which is sought to be revoked was stabilized and that Ethypharm was able to precisely know the content of the claims of said patent as well as all the facts making it possible for them to act, so that the action is not time-barred and is admissible. 

We now have a confirmation that limitation proceedings, just like opposition proceedings, may result in a postponement of the limitation period for nullity actions.

It remains to be seen how general this principle is and in particular whether it extends e.g. to the impact of other lawsuits involving third parties.

Turning now to the merits of the case, claim 1 of EP’181 as limited reads as follows:

A pharmaceutical unit dosage composition comprising 1 to 5 mg of [tadalafil], said unit dosage form suitable for oral administration up to a maximum total dose of 5 mg per day.

Independent claim 10 is a Swiss-type claim containing similar features.

Mylan raised all classical grounds for nullity, but the court focused on insufficiency of disclosure.

After reviewing the description of the patent, the court noted the following facts:

  • There are several molecules belonging to the class of type 5 phosphodiesterase (PDE5) inhibitors.
  • Among them, particular reference may be made to sildenafil, the active compound of V., marketed at the priority date of the patent in doses of 25, 50 and 100 mg.
  • However, sildenafil generates a number of side effects, such as facial red patches, or a lowering of blood pressure.
  • The invention thus relates to a low dosage of the known alternative drug tadalafil, in order to provide an effective treatment of erectile dysfunction without the side effects associated with sildenafil.
  • The patent also contains a number of examples showing the efficacy and the absence of side effects of low dosage forms of tadalafil.

The court was apparently quite puzzled by the patent as a whole:

The problem expressed in the description of the patent is to provide a principle which avoids the issues of red patches and side effects of sildenafil by a particular dosage of tadalafil. 

Indeed, and as rightly noted by Mylan, no side effect associated with tadalafil is mentioned in the patent, so that the dosage suggested for tadalafil curiously addresses a problem associated with another active compound. 

The court then referred to a standard mentioned in the so-called “finasteride” judgment of December 6, 2017 by the Cour de cassation, commented on this blog:

[…] When a claim relates to a [second] therapeutic application of a substance or composition, obtaining this therapeutic effect is a functional technical feature of the claim. Therefore, in order to meet the requirement of sufficiency of disclosure, it is not necessary to clinically demonstrate this technical effect; but the patent application must directly and unambiguously reflect the claimed therapeutic application, so that the skilled person can understand, based on commonly accepted models, that the results reflect this therapeutic application.

The court then came back to the technical problem presented in the patent:

Icos Corporation and Eli Lilly do not dispute that no prior art document describes any side effect related to the use of tadalafil.
And they cannot validly argue that the absence of documentation in this respect does not amount to the absence of a problem, because the onus is on them to show that there was a problem to be solved and that it is solved by the teaching of the patent.
It thus appears that the problem described in the patent relates to sildenafil and not tadalafil, and it cannot be extrapolated that both active compounds have the same side effects, unless one were to admit the resolution of artificial or speculative problems.
In fact, the examples cited in the patent demonstrate that the dosage mentioned in the patent does not address the listed “problems”. 

In summary, the problem to be solved cannot be considered as the reduction in the side effects of tadalafil, because such side effects were not known in the prior art – only side effects of sildenafil were known.

Most of the examples of the patent also do not demonstrate the existence of side effects of tadalafil associated with higher dosages, so that these were held not to “reflect” the alleged therapeutic application (using the wording of the Cour de cassation).

The conclusion reached by the three-judge panel will not doubt cause a stir, as the invention recited in claim 1 was found not to be sufficiently disclosed in the patent.

The finasteride case related to a second therapeutic application invention, for a known molecule. It is well accepted both at the EPO and in French national courts that the new therapeutic application has to be demonstrated in a plausible manner in the patent, otherwise the patent is insufficient.

Yet, in the present case, claim 1 is a classical product claim, with no functional feature. According to EPO case law, there should be no problem of insufficiency of disclosure, because the skilled person is able to manufacture the composition containing the active substance at stake in the claimed dosage range. The question of whether said claimed dosage range provides any technical benefit or not only pertains to the appraisal of inventive step.

Now, as regular readers of this blog are well aware, the French approach to validity is much more fluid than the EPO’s.

If a court is convinced that an invention does not properly solve the alleged technical problem, or that the technical problem is artificial, this can give rise to a number of invalidity objections, including insufficiency of disclosure. My understanding is that the technical problem tends to be viewed by French courts as an integral part of the claimed invention itself.

But there is yet another cause for controversy in the judgment.

I mentioned above that most of the examples of the patent do not demonstrate the existence of side effects of tadalafil associated with higher dosages. That said, there is one example, namely example 7, which does analyze in detail the occurrence of various side effects depending on the dosage of tadalafil. The table of results is in fact even reproduced in the judgment. The court first remarked that some side effects are not present at all at any dosage. So far so good. But, regarding those side effects which are indeed shown to be less frequent in the claimed dosage range than at a higher dosage, the court noted:

Regarding headache, back pain and myalgia […], the reasoning is the same because these effects were never previously observed.

This part of the judgment seems to imply that, at least in the context of drug dosage patents, the existence of the technical problem to be solved must be acknowledged in the prior art, and cannot be demonstrated for the first time in the patent itself.

The invention can thus not be a so-called “problem invention“.

Things should be put into perspective, though, and the present case may not necessarily be generalized. Maybe the court did not believe that example 7 was convincing at all. At the very least, the fact that the dosage originally claimed in the patent, namely from 1 to 20 mg, had to be later restricted to 1 to 5 mg, due to some relevant prior art, certainly contributed to the court’s perception of the patent being invalid.

In fact, the court reviewed all the following claims and concluded that they suffered from the same deficiencies as claim 1, mentioning a lack of inventive step in passing for some of them. Fluidity of the grounds for nullity indeed.

As a final note, this is probably one of the last judgments penned by Ms. Courboulay, who, given her seniority and her involvement in many conferences and events, was often considered as the leading judge in the 3rd (IP) chamber of the Paris TGI.

Ms. Courboulay has now officially retired; but given the large number of important rulings which she authored, there is little doubt that her influence will continue to be felt in the coming years.


CASE REFERENCE: Tribunal de grande instance de Paris, 3ème chambre 1ère section, April 5, 2018, Mylan v. Lilly France & Icos Corporation, RG No.16/05073.

A clear judgment

For better or worse, lack of clarity is not a ground for opposition at the EPO. This is not to say that lack of clarity is not a frequent issue in granted patent claims. But there is not much you can do about it. Unless, that is, the lack of clarity also translates into a different type of defect which happens to be a ground for opposition. Such as insufficiency of disclosure, lack of novelty or extension of subject-matter.

So it is a very common game during opposition proceedings for patentees to claim that objections raised against their patents are disguised clarity attacks. And for opponents to reply that no, they are much more than that.

At which point do unclear things become so unclear that they can actually not be reproduced?

The same game can also be played in front of national courts, as lack of clarity is not a ground of nullity either. 

The game seems to be somewhat less popular there. But today’s judgment issued by the Paris Tribunal de grande instance (TGI) provides an illustration.

Guerbet is a French company specialized in medical imaging products. It owns a French patent No. FR 2927539 on a composition of contrast agent. Bayer Pharma (which I probably do not need to introduce) filed a nullity suit against this patent in July 2015. In May 2016, Guerbet’s patent was limited at the INPI.

Interestingly, this French patent is part of a much broader family including several European applications or patents, two of which were opposed by several competitors. But the litigation was restricted to this French priority patent.

The court nicely summarized the invention in the judgment. The patent at stake relates to an MRI (Magnetic Resonance Imaging) contrast agent formulation.

The formulation is based on a metal of the lanthanide series, such as gadolinium, which is complexed by a macrocyclic chelate, known as DOTA. Free lanthanide is toxic, therefore it needs to be bonded in the complex. In fact, a slight excess of chelate is desirable in order to prevent any risk of undesirable release of free metal within the patient’s body.

But the excess of chelate needs to remain small because the chelate itself is also toxic – although, I assume, less so than gadolinium. An amount of excess free chelate of 0.002 to 0.4% has been found to be optimal. One difficulty is how to accurately achieve this precise dosage on the industrial scale, and in a stable manner. The invention consists in a preparation process in which a certain concentration of free chelate or free lanthanide is achieved in an intermediate formulation, and then an adjustment is carried out in order to reach the proper concentration specifications.

There are two independent process claims 1 and 2 in the patent as limited at the INPI.

For once, let’s start with looking at claim 2:

A process for preparing a liquid pharmaceutical formulation containing a complex of macrocyclic chelate with a lanthanide and a mol/mol amount of free macrocyclic chelate of between 0.002% and 0.4% […], the macrocyclic chelate being DOTA and the lanthanide being gadolinium, said process comprising the following successive steps:
a) determination of a theoretical target concentration in free macrocyclic chelate Ctcl in the final liquid pharmaceutical formulation;
b) preparation of a liquid pharmaceutical composition containing the complex of macrocyclic chelate with a lanthanide, and free macrocyclic chelate and/or free lanthanide, by mixing free macrocyclic chelate and free lanthanide in a solution, so as to obtain complexation of the lanthanide by the macrocyclic chelate, the amounts of free macrocyclic chelate and of free lanthanide added being such that there is a deviation between the amounts of added free macrocyclic chelate and free lanthanide and stoichiometric proportions, and such that all the lanthanide is complexed and Ccl > Ctcl, […];
c) measurement in the pharmaceutical formulation obtained in step b) of the concentration of free macrocyclic chelate Ccl, the concentration of free lanthanide Cll being equal to 0;
d) adjustment of Ccl so as to obtain Ccl=Ctcl and Cll being equal to 0, by suppressing free macrocyclic chelate and/or by adding free lanthanide and/or by modifying the pH. 

Claim 1 is very similar except that at step b) all the lanthanide is not complexed. The amount of free lanthanide is measured at step c) and more free marocyclic chelate is added at step d) to achieve the target concentrations.

This now leads us to the objection of extension of subject-matter raised by Bayer Pharma.

Bayer Pharma noted that there is a contradiction in step b) of claim 2, which refers to the preparation of a composition which may contain free lanthanide, although it is specified at the end of the step that all the lanthanide is complexed. Such a combination of features was not disclosed in the original application as filed, they said. They also added that the claim was the result of an intermediate generalization, since the feature that all the lanthanide is complexed at step b) was originally disclosed only in connection with a particular embodiment, called case B (involving in particular the use of an excess of macrocyclic chelate at step b)).

But the court was not convinced that this feature could not be generalized to other embodiments, and considered that the contradiction mentioned by Bayer Pharma was a mere lack of clarity, not an issue of extension of subject-matter:

Although this functional feature is made explicit for one of the three variants of the manufacturing process (case “B”), without being contemplated for cases A and C, it remains that it is indeed contemplated as an option disclosed in the initial application. Its title, related to a process for manufacturing a formulation, can lead the skilled person, who is a chemist used to combining different formulas, not to consider that this feature is excluded of all the other embodiments. The fact that this requirement […] can be in contradiction with another feature of this claim (namely the presence of free lanthanide) may potentially be a matter of lack of clarity but not of undue extension of the subject-matter of the patent. 

This clarity discussion then continues in the next part of the judgment dedicated to Bayer’s insufficiency objection.

Here is what the court had to say in this context (as usual, I am taking the liberty of slicing our beloved never-ending sentences into shorter phrases):

[…] It can be derived from common general knowledge that it is impossible for both free lanthanide to be present and for the complexation of the lanthanide to be total. Therefore, [the skilled person] will read the patent in a manner which will give it effect. [The patent] recites various steps for making the dissolution process, measuring and adjusting. [The skilled person] will understand that the total complexation of lanthanide can be performed later and that this circumstance does not result in an impossibility to reproduce the [invention], which requires to implement claim 2 as a whole, without focusing on one of its steps only without taking the other ones into account. 

Here, the approach of reading the patent in a constructive manner, with a “mind willing to understand“, as they are wont to say at the EPO, goes as far as making it possible to ignore an apparent contradiction in the wording of a claim.

In other words, the skilled person is presumed to resolve the contradiction by correcting and adding information to the claim.

It is not really surprising that the French court adopted this approach, in view of the longstanding tradition in this country of extensively relying more on the description for interpreting the claimed invention, instead of focusing on the exact wording of the claims.

Apart from this, the rest of the insufficiency discussion is also quite enlightening.

Regarding claim 1 in particular (the variant wherein there is some free lanthanide left at the end of step b)), Guerbet relied on example 2 of the patent.

But Bayer Pharma said that the example was not according to claim 1. Actually, when reproducing this example, a significant amount of free chelate was obtained at the end of step b). This is a problem because, at the following measuring step c), the concentration of free chelate is supposed to be zero, according to claim 1.

The TGI addressed this objection by stating that claim 1 does not require that all the chelate should necessarily be complexed at the end of step b). Otherwise, measuring step c) would actually be useless.

The court added:

Consequently, this step c) comprises a functional feature – achieving a total complexation of DOTA – in order to perform the measurement of free gadolinium which will precisely be made on a sample taken during step c), and which would be useless if the complexation of DOTA were total at the end of step b), as alleged by Bayer Pharma. 

Therefore, even if step c) of claim 1 does not explicitly mention that it requires a modification of the collected sample, this modification implicitly derives from the functional feature that it requires to perform the desired measurement, namely a concentration in free macrocyclic chelate Ccl that has to be equal to zero.

Here again, the court did not restrict the interpretation to what the claim actually recites.

Although the claim is silent as to the collection of a sample and the modification of the sample before performing the measurement, the court considered that these features are implicitly present in the claim in view of the description and in particular example 2.

The court also accepted Guerbet’s explanations that the modification of the sample at step c) could be performed by raising the pH through the addition of meglumine, and that the skilled person could rely on common general knowledge to perform such a modification.

Bayer Pharma further argued that the range of pH making it possible to achieve full complexation was not known. The court again sided with Guerbet on this aspect and accepted that a specialized scientific article and a university textbook discussing chemical equilibriums in general provided the skilled person with the necessary information.

Thus, the process of claim 1 was found to be sufficiently disclosed.

Turning again to claim 2, the patent in suit does not contain any example of implementation. But the court was satisfied that the process of claim 2 was analogous to the process of claim 1, so that it could also be carried out without undue burden.

In keeping with the case law of the Boards of appeal of the EPO, the presence of an example of a chemical invention in the patent is thus not an absolute requirement for sufficiency of disclosure to be acknowledged:

Thus, the skilled person, who may implement claim 1 as indicated above, for the same reasons […], is also able to implement claim 2 notably by relying on common general knowledge, so that the absence of an example to illustrate this claim does not make it insufficiently disclosed. 

The judgment then goes on with addressing an inventive step attack, which was also rejected.

Bayer Pharma’s nullity action thus failed. Who said pharma-oriented patents are always invalidated in this country?


CASE REFERENCE: Tribunal de grande instance de Paris, 3ème chambre, 2ème section, March 23, 2018, Bayer Pharma Aktiengesellschaft v. Guerbet, RG No. 15/12348.

Will case law crystallize?

Today, it is back again to one of the topics regularly addressed on this blog, namely the statute of limitations for patent nullity actions in France (but not only!).

Matthieu Dhenne was kind enough to send me a brand new decision from the Paris Tribunal de grande instance (TGI) which, once more, sheds new light on this thorny issue.

The patent at stake is the French part of EP 1455756, to Merck Sharp & Dohme Corp. (MSD). The patent was granted on July 9, 2008. It was opposed by two generic drug manufacturers. At first instance, the patent was maintained in amended form, according to a decision dated December 3, 2010. The opponents appealed, and their appeals were dismissed by the Board of appeal in a decision dated July 17, 2014. The publication of the amended patent took place on September 23, 2015.

Soon thereafter, on December 2, 2015, Ethypharm filed a nullity action with the Paris TGI, requesting that the French part of the patent should be revoked.

Quite predictably, MSD argued that the nullity action was time-barred.

If one directly applied the recent case law of the Paris Cour d’appel (discussed here), this should be a winning argument. Indeed, the Cour d’appel has proposed that the five year-limitation period be computed from the date of grant of the patent. With this in mind, in this case, the limitation period would have ended on July 9, 2013.

But you and I know that things are not that straightforward, as the Paris TGI does not follow the case law of the upper court, and generally favors an in concreto determination of the starting point for the limitation period (see a recent example here).

Yet, in today’s ruling you will not find any protracted discussion of an in concreto starting point. Instead, the issue is disposed of in just one paragraph:

[…] It is only on [July, 7, 2014, i.e. the date of the Board of appeal’s decision] that the drafting of the patent which is sought to be revoked was stabilized and that Ethypharm was able to precisely know the content of the claims of said patent as well as all the facts making it possible for them to act, so that the action is not time-barred and is admissible. 

I must say I have mixed feelings about this.

My initial reaction was, oh no, you must be kidding me, there is now yet another way of determining the starting point for the limitation period? This is not legal uncertainty anymore, this is legal chaos.

A few seconds later, I thought, well yes, it does make sense after all, you can’t possibly be expected to shoot at a moving target. When a patent is modified during opposition proceedings, any appeal filed at the EPO has a suspensive effect, and thus it is only once the appeal proceedings are terminated that the content of the patent is final.

A party must act within five years from the date at which they knew or should have known that the patent at stake is a possible impediment for their current or future business activities, or else be time-barred (this is more or less what I understand to be the TGI’s usual position). And how can a party know this before the patent is even its final form?

However, this ruling raises more questions than it provides answers.

What if an opposition is rejected by the opposition division and the patent thus maintained as granted instead of as amended? Should the reasoning be the same? What if an opposition is filed by a straw man (which is allowable at the EPO) and there is thus an unverifiable suspicion that the nullity claimant itself may be the true opponent, in an attempt to artificially extend the limitation period by several years?

In his message to me, Matthieu Dhenne also noted that the court’s reasoning could be applicable to other situations: limitation proceedings, but also a prior nullity suit brought forward by a third party. Taking this one step further, he observed that a patent right can in fact be modified at any time and is therefore theoretically never “stabilized” until it expires (sometimes, it can even be retroactively “stabilized” only after its expiry). He thus suggested that the full consequence of the court’s reasoning should be that the limitation period can only start running at the expiry of the patent, so that the well-identified drawbacks of this limitation period should in practice never occur.

Matthieu added that there would thus be a complete parallelism between the limitation period for infringement actions and nullity actions. Accordingly, invalid patents would not be able to unduly hinder free competition.

Definitely an interesting suggestion, but is it really what the TGI had in mind? I am quite sure we can expect more surprises in future decisions.

Apart from this, the decision is worth the read beyond the admissibility part.

First, it turns out that the nullity claim was held ill-founded on the merits and thus dismissed. As the patent in suit is a pharma patent, this is already quite remarkable. A majority of pharma patents which are litigated in this country are revoked one way or another.

Second, the decision tackles the very interesting issue of plausibility.

There has been a significant trend in France for patents to be revoked when they are held to be of a speculative nature. See for instance previous posts here, here and there.

In the present case, Ethypharm argued that the patent was of the speculative kind, which resulted in insufficiency of disclosure and lack of inventive step.

Now may be a good time to have a look at claim 1:

A nanoparticulate composition comprising the compound 2-(R)-(1-(R)-(3,5-bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluoro)phenyl-4-(3-(5-oxo-1H,4H-1,2,4-triazolo)methylmorpholine, or a pharmaceutically acceptable salt thereof, the compound having adsorbed on the surface thereof at least one surface stabilizer in an amount sufficient to maintain an effective average particle size of less than about 1000 nm; where “effective average particle size of less than about 1000 nm” means that at least 95% of the particles, by weight, have a particle size of less than about 1000 nm.

This drug composition is useful in the treatment of nausea and vomiting, especially those induced by a chemotherapeutic treatment. The short name of the active compound is aprepitant. According to the patent, the technical problem at stake was to improve the bioavailability of aprepitant. This is stated in the patent but no experimental test results are present, which led Ethypharm to consider that there was no evidence in the patent that the technical problem was properly solved.

Ethypharm also tried to use some of MSD’s posterior testing against them, by claiming that they proved that there were features missing in the patent which were essential for successfully implementing the invention.

The court was not convinced that there were indeed such essential features missing. The court also noted that there was a reference in the patent in suit to a prior U.S. patent disclosing the so-called “Nanocrystal” method, for making nanoparticles with a surface modifier adsorbed thereon, having an average size of less than 400 nm. This Nanocrystal patent also taught that such nanoparticles improve the bioavailability of poorly water-soluble actives.

Thus, said the court, the improvement in bioavailability provided by the nanoparticle form of aprepitant was plausible.

In such a case, the court continued, evidence which is external to the patent can indeed be taken into consideration for demonstrating that the technical problem is solved. The court then reviewed a number of articles and reports and was satisfied that the technical effect of improving bioavailability was well achieved.

In summary, this is an important decision for the fine-tuning of the appraisal of a speculative patent-type objection.

To me, the take-away message is that a reference in a patent to a prior art document disclosing a technical effect provides some plausibility that the technical effect is indeed achieved.

From drug crystals to crystal balls: could they possibly help us decipher future case law?

The patent survived other attacks of insufficiency of disclosure, extension of subject-matter and lack of inventive step. Quite remarkably, the main claim was in particular found to be non-obvious over the “Nanocrystal ” European patent of the same family as the U.S. patent mentioned above, which was used for supporting the plausibility of the technical effect.

The court held that:

[The “Nanocrystal” prior art] does not disclose chemical structures or features of drugs intended to be used by this process. It only mentions that it can be implemented with a large variety of medicinal substances, the substance having to be poorly soluble, that is less than 10 mg/mL, so that the skilled person does not know which actives […] can be tested with a reasonable expectation of success. He was all the less incited to do so that in December 2001, i.e. almost ten years after the priority date of [the Nanocrystal patent], the nanonization process, which has a number of constraints (in particular the heat released during milling may change the structure of the active substance and reduction to a very small size may create a problem of chemical and physical stability), was used on only four active substances (danazol, steroid A, compound WIN 63,394 and naproxene) with a verified effect on bioavailability […]. 

I have the uneasy feeling that there may be a contradiction here between the sufficiency and inventive step prongs of the court’s reasoning.

If the teaching of the Nanocrystal patent cannot be applied in an obvious manner to aprepitant, and if there are many technical uncertainties, why is it then not necessary for the MSD patent to contain evidence in the form of experimental tests showing that the process can in fact be effectively applied to this particular drug?


CASE REFERENCE: Tribunal de grande instance de Paris, 3ème chambre 2ème section, January 26, 2018, Ethypharm SAS v. Merck Sharp & Dohme Corp., RG No. 16/01225.

A patent in the cross hairs

Frankly, I am not so fond of the finasteride litigation, previously discussed here, here and there. But this may simply have something to do with the fact that I am sensitive to the issue of hair loss.

That said, I am grateful to Denis Schertenleib for drawing my attention to the cassation ruling issued a few days ago on this topic.

As a reminder, European patent No. EP 0724444 to Merck Sharp & Dohme Corp. relates to the second medical use of finasteride for the treatment of androgenic alopecia, with a particular dosage regimen.

The French part of EP’744 was declared invalid twice by the Paris Cour d’appel: the first time for lack of novelty (what I would call the Actavis part of the lawsuit), and the second time for insufficiency of disclosure (the Teva part of the lawsuit).

Merck did not bow and tried its luck in front of the Cour de cassation – to no avail.

The cassation ruling (Teva part) is interesting in that it confirms the sufficiency standard to be applied in the field of therapeutic inventions.

Merck argued that the appeal decision (which, again, can be found on this page) was legally incorrect on 9 different grounds – or “branches“, as they are nicely called in the supreme court parlance. As I tend to find cassation decisions unreadable, I will try to reformulate these grounds in my own words.

On a general standpoint:

1. The question that the appeal judges should have addressed is only whether the drug with the right dosage could be manufactured by the skilled person.

2. The appeal judges mixed up sufficiency with novelty and inventive step, as they examined whether there was a “specific technical teaching” in the patent, and wrongly looked for a comparison of the invention with the state of the art in the patent. They should have focused on whether the information in the patent made it plausible that the claimed dosage was therapeutically effective.

Example 4 of EP’444 describes a protocol for measuring haircount in subjects. As I commented in my earlier post, its conclusion is rather vague and unspecific in terms of technical effect achieved, which led it to be disregarded by the Cour d’appel. The following grounds were raised in relation with this example 4:

3. The appeal judges failed to realize that the example 4 shows the technical effect linked to the claimed low dosage of finasteride.

4. The appeal judges said that clinical tests are not required for showing a therapeutic use, but then contradicted themselves when they disregarded the example as not corresponding to an actual clinical test.

5. The appeal judges failed to realize that the example provides a methodology making it possible for the skilled person to verify the claimed therapeutic use.

As for example 5 of the patent, it is supposed to show a reduction in the amount of dihydro testosterone (DHT) in the scalp of patients taking finasteride. But it is also quite imprecise and kind of looks like a paper example (just like example 4). The following grounds were raised in relation with this example 5:

6. The same contradiction already mentioned in item 4. happened again when the appeal judges discussed example 5.

7. The appeal judges failed to realize that example 5 shows that the claimed dosage has an effect on the metabolic mechanism involved in alopecia – so that example 5 indirectly also supports the technical effect linked to the claimed low dosage of finasteride.

8. The appeal judges held that the example was doubtful in view of the leaflet of the Propecia drug, without checking if this leaflet was available to the skilled person at the priority date.

9. The example mentions a reduction in the amount of DHT in the scalp of patients after 6 weeks, which is why the Cour d’appel found it doubtful, as the effect on hair growth is supposed to occur after 12 weeks at least. But the court should have realized that this is normal as hair growth can only occur after the reduction in the amount of DHT.

Is Santa going to mail some interesting decisions to me this Christmas?

As usual, the Cour de cassation did not address in a detailed manner each criticism and basically simply stated that the Cour d’appel was right and that the grounds of cassation are ill-founded.

In particular, there is (alas) no general discussion on the level of plausibility required from a patent, and on the conditions under which post-published evidence may be relied upon.

Items No.8 and 9 in the above list were treated slightly differently, though. Those were found to relate to a redundant ground (“un moyen surabondant“) in the appeal decision, which means that the Cour de cassation refrained from stating whether they are correct or not, as anyway there are enough correct grounds in the appeal decision for it to be confirmed.

The key part of the ruling is translated in its entirety below (I have taken the liberty of dividing up the never-ending single sentence of the ruling into hopefully more intelligible bits):

[…] Firstly, when a claim relates to a [second] therapeutic application of a substance or composition, obtaining this therapeutic effect is a functional technical feature of the claim. Therefore, in order to meet the requirement of sufficiency of disclosure, it is not necessary to clinically demonstrate this technical effect; but the patent application must directly and unambiguously reflect the claimed therapeutic application, so that the skilled person can understand, based on commonly accepted models, that the results reflect this therapeutic application. 

The decision mentions first that, regarding claim 1 […], the description does not indicate what the technical advantage or effect resulting from this type of oral administration is. It does not contain any element showing the potential efficacy of any finasteride dosage, and does not comprise any information on the new effect of the claimed dosage and the particular properties of this new therapeutic application. The dosage between 0.05 and 1.0 mg is unrelated to the administration rate and patient body weight. Then, according to the decision, the description of the patent only mentions the “surprising and unexpected” discovery of this new therapeutic application, without describing its particular pharmacological properties relative to the state of the art, which only derive from an arbitrary selection. In view of these findings, the Cour d’appel was in a position to deduce that the patent application did not directly and unambiguously reflect the claimed therapeutic applications; and that the skilled person unaware of any specific technical teaching was not able to reproduce the invention and had to implement a research program him/herself; so that [claims 1 to 3 were] insufficiently disclosed.  

Secondly, regarding the the examples cited in the description of the patent, the appeal decision […] disregarded examples 1 and 2, which relate to the preparation of finasteride, the manufacturing process of which was known for years; and example 3, which does not relate to androgenic alopecia.

[The decision] notes on the one hand that example 4 discloses a photographic protocol for detecting hair growth by counting on a period of twelve months and holds that, since [the example] does not give any information on the conditions of a potential test and does neither describe the experiments nor the technical effect resulting from the lowering of the claimed dosage relative to prior art dosages, this example appears to be a measurement method and cannot be considered as a report on a trial. 

[The decision] notes on the other hand that example 5 does not provide any detail on the experimentation or protocol applied when finasteride is administered for six weeks. The results have shown a significant reduction in the amount of DHT but have not established hair growth or the stop of hair loss. [The decision] holds that, in the absence of any comparison criterion, whereas the reduction in DHT levels in scalp due to the administration of finasteride was already known, this example does not make it possible to compare the effects of the claimed dosage relative to a higher dosage, of the order of 5 mg, disclosed in the state of the art. 

Based on these findings, the Cour d’appel did not misrepresent the patent and did not require a clinical demonstration of the therapeutic effect of the new dosage. [Thus, the Cour d’appel rightly] considered that these examples did not directly and unambiguously reflect the claimed therapeutic application and could not remedy its insufficiency of disclosure as already noted above.

This approval of the approach taken by the appeal judges is of course important for all practitioners in the pharma field.

The trend is now once and for all confirmed, per which patents considered as “paper patentsi.e. seen as overly speculative at the date of filing, will not fare well in France.

Before concluding this post and wishing all readers happy holidays, a final word on two procedural aspects.

First, Merck also criticized the appeal decision for holding Teva’s nullity claim admissible, although, when the first instance judgment was issued in the Teva part of the lawsuit, the patent had already been revoked by the Tribunal de grande instance in the Actavis part of the lawsuit.

The Cour de cassation held that:

[…] The Cour d’appel rightly stated that the decision revoking a patent has an absolute effect [with respect to third parties] only once it is res judicata, that the [Actavis first instance] judgment was under appeal, and deduced that the Teva companies were admissible in seeking the revocation of the same patent. 

This is a welcome clarification.

The last point is that Merck of course also filed a cassation appeal against the other appeal decision in which the same patent was revoked for lack of novelty, as requested by Actavis. Here, the Cour de cassation trod the easiest path and simply dismissed the cassation appeal in a distinct ruling by noting that the patent claims have now been definitely held invalid in view of the Teva ruling.

Too bad for us commentators, as the Actavis part of the lawsuit also involved some interesting legal points.

With that, as promised, I wish all readers happy holidays.


CASE REFERENCE: Cour de cassation, chambre commerciale, December 6, 2017, Merck Sharp & Dohme Corp. v. Teva Pharmaceutical Industries Ltd. & Teva santé, pourvoi No. 15-19726. 

An eccentricity issue

Judgments in which a mechanical engineering patent is revoked for insufficiency of disclosure are few and far between. Typically, insufficiency problems tend to arise in the context of chemical or medicinal inventions – although they are not unheard of with mechanical inventions.

So, today’s decision may be viewed as somewhat eccentric in this respect. But the best part is that the feature which was found to be problematic revolves around… an eccentric (mechanism). End of pun.

In the case at hand, the patent (EP 1023111) was commonly owned by its three inventors, and licensed to a company called LPG Systems. LPG are the initials of one of the inventors, who, not unexpectedly, was a partner of the licensee.

At some point of time, things must have gone wrong, as LPG put an end to the license agreement. As a result, the two other owners of the patent filed suit for wrongful termination. And as a counter-strike, LPG filed a patent nullity action.

The patent was revoked for insufficiency of disclosure in first instance. This was confirmed in a judgment by the Cour d’appel de Paris dated September 9, 2014. The two disgruntled patent proprietors filed an appeal on points to law with the Cour de cassation (judicial supreme court). This final appeal was dismissed in a judgment dated October 4, 2016.

In order to properly understand what was wrong with this patent, it is easier to go back to the 2014 appeal ruling, as judgments from the Cour de cassation have this tendency to be somewhat cryptic and in particular to only partially recall the relevant facts.

The patent at stake relates to an apparatus for restoring the balance of the human body.

Due to various medical conditions, patients sometimes need to have their balance corrected or restored. This can be achieved owing to a training apparatus, such as the one claimed in the patent:

Apparatus for restoring the balance of the human body, consisting essentially of a mobile circular platform intended to support the subject to be treated and which can have an oscillatory movement imparted to it, and in which the said platform has its oscillatory movement imparted to it about a central support point, this movement being combined with a reciprocating rotational movement, by means of a single motor connected to transmission means and without the intervention of the patientthis being in the plane of the platform supporting the subject, about the geometric axis perpendicular to the said platform and passing through its centre, the amplitude and speed both of the oscillation and of the rotation being adjustable and capable of being varied during use, means being associated with the said apparatus so that the subject can be held on the platform either in a standing position or in a crouched or seated position.

The expressions highlighted above are probably the most significant ones for the decision.

LPG claimed that the patent at stake does not disclose appropriate means for adjusting the amplitude of the oscillation and rotation during use and that the skilled person would not be able to implement this feature of the claim.

The Cour d’appel agreed. The court reviewed the description of the patent. Said description does disclose a mechanism for providing the claimed oscillatory and rotary movement of the platform: the platform is mounted at the extremity of a shaft of a cylinder, which imparts the desired oscillations. And rotation can be generated owing to another shaft connected to an eccentric.

The court stated that both the rotation amplitude and the oscillation amplitude could be adjusted by acting on respective relevant parts (cylinder shaft and eccentric). However, it was only possible to do so when the apparatus was not working. But the claim required the possibility to adjust this amplitude in use. Such possibility was not taught in the patent.

The appellants submitted two expert opinions aiming at showing possible ways to implement the claimed feature. The description of the opinions is very brief in the judgment. It seems that the first one suggested to use an electric or hydraulic cylinder for the eccentric itself, so that the patient could actuate it during use; and that the second one offered to mount an electric or hydraulic cylinder on the eccentric so as to actuate it and rotate with it.

The court dismissed these expert opinions. They noted that the first opinion called for the intervention of the patient; and that both relied on the presence of an additional motor. And this was not consistent with the teaching of the patent. They also added that the technical solutions contemplated in the expert opinions required more than mere implementation steps.

Eccentricity can sometimes be brilliant.
Eccentricity can sometimes be brilliant.

In order to challenge an appeal judgment in front of the Cour de cassation, it must be shown that the law was not correctly applied. This is seldom an easy task. It is often said that appeal courts are skilled in drafting judgments relying almost entirely on facts (and not on any particular interpretation of the law) in order to reduce the risk of being overturned. Conversely, cassation appellants tend to artificially disguise arguments that the Cour d’appel erroneously assessed facts as arguments that the Cour d’appel violated the law. An interesting game indeed.

In the present case, first the appellants stated that the Cour d’appel had come up with an argument of its own (which they are not supposed to do) without hearing the parties on it (which they are not supposed to do either). The argument in question was that the adjustment at stake could not possibly be made by the patient him/herself. The Cour de cassation disagreed because this argument made by the appellate judges was actually derivable from the main claim itself.

Second, the appellants submitted that the patent does not require the claimed adjustment to be made without the intervention of the patient, and with a single motor – as asserted by the appellate judges. The main claim requires on the one hand that the oscillatory movement is “combined with a reciprocating rotational movement, by means of a single motor“; and on the other hand that “the amplitude and speed both of the oscillation and of the rotation [are] adjustable and capable of being varied during use“.

In other words, there is no explicit limitation in the claim to an adjustment by means of a single motor, without any intervention of the patient. Paragraph [0026] of the description mentions an “oscillatory movement around a central support point, which is combined with an alternate rotation movement, owing to a single motor connected to transmission means and without any intervention of the patient”. Here again, it is not explicitly stated that the requirements of a single motor and of the absence of intervention of a patient apply to the adjustment of the movement.

Here is how the cassation judges dealt with the argument:

This description is not clear and accurate. It does not mention that the single motor does not provide the adjustment of the speed and amplitude of oscillation or of the alternate rotation. Nor does it mention that another means should be used for that purpose. The Cour d’appel held that the addition of a supplementary motor was contrary to the teaching of the patent based on an interpretation which had to be made due to the ambiguity of the description – and therefore the decision was correctly reasoned. 

In other words, the appellate judges were at a liberty to interpret the claim in a restrictive manner because the description of the patent did not clearly and unambiguously lead to a different interpretation. Again, it is not the Cour de cassation’s job to redo the work done by the Cour d’appel. They only focus on possible errors of law. I figure that a blatant interpretation mistake could be considered as misapplying the law, but this was not the case here.

The appellants also blamed the Cour d’appel with not sufficiently taking into account the experts’ opinions in its reasoning. But the Cour de cassation considered that the reasoning was sufficient: based on the above claim interpretation, the movement adjustment was supposed to be performed owing to the single motor – according to the patent. Since the experts’ opinions relied on an additional motor, the Cour d’appel did not err in rejecting those.

I guess this is one of those cases where it is in fact a lack of clarity of the claims which made the patent fall down the abyss of insufficiency of disclosure.

Probably not that eccentric an outcome, if you ask a chemical engineering patent attorney.


CASE REFERENCE: Cour de cassation, ch. com., October 4, 2016, Bardon & Tudico v. Guitay & LPG Systems, appeal No. Y 15-12.294.