AstraZeneca holds European patent No. EP 0907364 directed to a sustained release formulation of the drug quetiapine, which is useful in the treatment of schizophrenia. This patent has been litigated for years in a number of EPC contracting states. As far as I understand, in the majority of (but not all) cases, the patent was found invalid by national courts (see by way of example relevant blog posts here and there).
With a ruling issued on July 1, 2016, France has just joined the list of countries in which the quetiapine patent has gone quiet.
U.S.-based generics company Mylan filed a nullity complaint in front of the Paris Tribunal de grande instance (TGI) on April 28, 2015, requesting revocation of the EP’364 patent. This was part of Mylan’s preparation for the launch at risk of their generic version of AstraZeneca’s patented drug, Xeroquel LP. The first boxes of generic quetiapine were marketed during the week of September 14, 2015. By that time, AstraZeneca had already counterclaimed for infringement of the patent.
On October 6, 2015, AstraZeneca boldly requested a preliminary injunction (PI) in front of a different court, namely the Lyon Tribunal de commerce, on unfair competition grounds. They were initially successful. The injunction was in place for a little bit more than one month, before being lifted by the Cour d’appel. This interesting aspect of the litigation was already discussed in detail in a previous post.
Finally (at least for now), in a judgment handed down on July 1, 2016, the Paris TGI revoked the French part of EP’364 for lack of inventive step. This is 14 months after the filing of the complaint, which from a timing standpoint is a great outcome.
Another great outcome is that, whether you agree with it or not, the court’s inventive step reasoning is very thorough and well argued.
Quetiapine as a drug for treating schizophrenia was known from the prior art, and in particular from an earlier AstraZeneca patent EP 0240228. Mylan’s case was that it was obvious for the skilled person starting from this earlier EP’228 patent to come up with a sustained release formulation of the drug, in view of the well-known advantages of this type of formulation, such as a more controlled diffusion of the active and a reduction in the number of daily doses to be taken.
AstraZeneca developed a number of arguments as a defense. First off, they said the court should apply the problem-and-solution approach. Accordingly, the closest prior art was not the EP’228 patent but rather a scientific paper by Hirsch & Casey describing clinical trials conducted with an immediate release formulation of quetiapine. As a result, the objective technical problem was not the provision of a sustained release version of quetiapine, but more broadly the provision of an efficient anti-psychotic drug treatment.
This did not fly with the court:
However, the problem-and-solution approach is only one method of reasoning which can be used, but not the only one, to assess the validity of a patent with respect to the inventive step requirement. In the present case, the reformulation of the technical problem suggested by the defendants relates to an artificial approach, the purpose of which, by broadening the scope of the technical problem, is to make the patent’s choice to look at a sustained release quetiapine formulation appear inventive.
The court’s statement on the problem-and-solution approach is a reminder as a matter of principle that French courts are not bound by the EPO guidelines and case law. That being said, in practice, most judgments issued nowadays draw inspiration from the problem-and-solution approach: a starting point and a technical problem are defined, and the question of obviousness is analyzed through the lens of this technical problem – which is the very framework of the problem-and-solution approach. The present case is no exception.
It is well known that the formulation of the technical problem is critical in the assessment of inventive step. AstraZeneca proposed to get rid of the notion of sustained release in the formulation of the technical problem. To some extent, this makes sense as we are not supposed to include any pointer to the solution in the formulated problem.
But the issue was that the patent at stake itself formulated the technical problem as providing a sustained release formulation of quetiapine. The reformulation proposed by AstraZeneca was thus considered self-serving and ex post by the court. To put it otherwise, by arguing that the closest prior art should be a document concerned with an immediate release quetiapine formulation, the patent proprietor attempted to focus on a starting point suggesting a different direction from the one chosen in the patent, and therefore one that would almost necessarily lead to a finding of inventive step.
The court did not agree. First, an “efficient anti-psychotic drug treatment” (i.e. the problem offered by AstraZeneca) already existed at the priority date. Second, a press release by the patentee before the priority date implicitly suggested that sustained release formulations of quetiapine were being investigated.
Therefore, the realistic technical problem was the one originally mentioned in the patent, namely the provision of a sustained release formulation of quetiapine.
With that in mind, the prior art was replete with descriptions of sustained release formulations of other drugs similar to the sustained release formulation of the EP’364 patent.
Nevertheless, the proprietor argued that clinical studies at the priority date rather oriented the skilled person towards a regimen of one or two daily doses of an immediate release formulation, possibly with an increase in dosage. They added that the skilled person was not in a position to predict:
- Whether satisfactory bioavailability could be achieved with a sustained release formulation.
- Whether the size of a sustained release quetiapine tablet or pill would be acceptable or too large, leading to improper absorption and travel through the gastrointestinal tract.
Based on a report authored by two pharmacology experts, AstraZeneca more specifically argued that
the travel of a sustained release drug through the gastrointestinal tract is very different since the extended delivery time results in the delivery taking place in downstream areas of the digestive system, with different pH, metabolic and bacterial environment conditions, which has an impact on the release of the active substance, its metabolism, and the permeation of the active substance through the intestinal wall.
All of these arguments were rejected by the court, either because they were not substantiated by evidence, or because they were contradicted by some of the documents on the record:
- The necessity to increase the dose of quetiapine when switching from an immediate release formulation to a sustained release formulation was not proven. In fact the opposite was generally true based on pharmacology textbooks. Even if a larger size tablet had to be achieved, it was also possible to divide a single dose into two doses to be taken simultaneously.
- The half-life of quetiapine was already documented at the priority date and was compatible with a sustained release formulation.
- The undesired effect of pH on the release of the active substance was only shown in a post published document (which would not have been taken into account by the skilled person). The extent of the undesired effect was debatable in view of the declarations of the patentee’s own expert in the British litigation. And it was known by the skilled person how to thwart this pH effect by adjusting the drug formulation.
- The prior art taught that quetiapine bioavailability increased linearly with an immediate release formulation. It could be concluded from this finding that the disruptive effect of first pass metabolism emphasized in AstraZeneca’s submissions was at best limited and was not an obstacle to a sustained release formulation.
In other terms, there was no prejudice against a sustained release formulation of quetiapine, which the skilled person was able to achieve with routine testing. It can be derived from the judgment that the court at least partly based its findings on the British litigation, and in particular on the statements of an expert who took part in that lawsuit.
One last argument dealt with in the judgment is that clinical trials performed after the patent grant showed an improved bioavailability and broader therapeutic indications with the sustained release formulation than with the immediate release formulation. But the court held that the improved bioavailability resulted from routine optimization and was not surprising; and that the broader therapeutic indications could not be relied on as they were not addressed in the patent.
The take home message is probably that if inventive step rests on obstacles or prejudices, those have to be very fully and convincingly demonstrated. The burden of proof lies on the patentee and based on the decision at stake it is a relatively heavy one.
There are two interesting side issues in the judgment.
First, Mylan claimed that AstraZeneca was guilty of unfair competition because they had warned customers about risks of infringement related to the generic version of Xeroquel LP. The court rejected the claim because AstraZeneca’s communication was deliberate and objective.
Here are some interesting comments by the court which seem to be generally applicable to similar situations in the pharmaceutical field:
When it comes to competition between an original drug and a generic one, infringement can hardly be challenged. It disappears if the patent is held invalid, but until the invalidity judgment, it is legitimate for the patent proprietor to defend its patent monopoly. Besides, the circular letter sent to stakeholders mentioned the existence of a validity challenge in objective terms.
A generic drug manufacturer that decides to launch its product at risk before the patent on the original drug expires or is invalidated cannot blame the patent proprietor for defending its monopoly with its customers. Besides, the fact that the patent was finally revoked in other European countries does not result in a lesser legal scope for the French part of the patent as long as it is valid.
The second point of interest relates to the PI obtained and enforced by AstraZeneca during approximately one month. Mylan claimed and obtained damages in relation with the PI, pursuant to article L. 110-10 of the Code des procédures civiles d’exécution.
The damages award amounted to approximately 200,000 euros – which was however much less than Mylan had requested.
Part of the award was calculated based on an evaluation of lost sales, to which a margin of 30% was applied.
The other part corresponded to a loss of opportunity in relation with a public tender from which Mylan had been excluded due to the PI.
On the other hand, the court did not take into account the alleged harm suffered in terms of sales of other products or in terms of image injury, in the absence of convincing supporting evidence.
Finally, reimbursement of 300,000 euros of attorney’s fees were requested by Mylan. The court granted half of it.
It remains to be seen whether there will be an appeal decision, given that it may prove difficult for AstraZeneca to obtain it before the expiry of the patent on May 27, 2017 (no SPC was filed, as the judgment tells us).
CASE REFERENCE : Tribunal de grande instance de Paris, 3ème chambre 3ème section, July 1, 2016, Mylan v. AstraZeneca, RG No. 15/05880.