NL – LEO Pharma v. Sandoz

Posted: February 21st, 2018

LEO Pharma A/S v. Sandoz, Court of Appeal of The Hague, the Netherlands, 7 November 2017, published 12 February 2018, Case no. ECLI:NL:GHDHA:2017:4029

LEO Pharma is the holder of the European patent EP 2 455 083 B1 titled “Pharmaceutical composition for dermal use comprising calcipotriol and betamethasone for treating psoriasis”. The patent was granted on 18 September 2013 relying on the priority date of 23 April 1999. The patent is amongst others in force in the Netherlands and protects LEO Pharma’s product (Dovobet) for the dermal treatment of psoriasis. Claims 1 and 2 of EP ‘083 cover a pharmaceutical composition for the treatment of psoriasis, comprising calcipotriol and betamethasone.

In April 2016 Sandoz recorded a “Calcipotriol/Bethamethason Sandoz 50 microgram/g + 0,5 mg/g, ointment” product for the treatment of psoriasis in the G-standard and subsequently launched its product. LEO Pharma filed PI proceedings arguing that Sandoz infringed the Dutch part of EP 083. The PI judge dismissed LEO Pharma’s claims (see here). LEO Pharma lodged an appeal.

The Court of Appeal found that LEO Pharma was correct in appealing the decision of the PI judge regarding lack of novelty over mother application WO 00/644450 in light of the decision of the Enlarged Board of the EPO with regard to partial priority (Enlarged Board of Appeal 29 November 2016, G0001/15, ECLI:EP:BA:2016:G000115.20161129). This however according to the Court does not lead to a reversal of the decision in first instance, because the asserted claims of EP ‘083 lack inventive step.

It was not in dispute between the parties that Ortonne is the closest prior art. Ortonne describes an alternating monotherapy of calcipotriol in the morning followed by betamethasone in the evening. Claims 1 and 2 of EP 083 differ from Ortonne in two aspects. The first aspect concerns the combination of calcipotriol and betamethasone in one product instead of the alternating use of the two active substances. The second concerns the fact that the combination product is not watery.

It was not in dispute between the parties that therapeutic compliance was a technical effect arising from the distinguishing features. Long term stability was not accepted by the Court of Appeal as a technical effect arising from the distinguishing features. The fact that the claimed product is not watery only solves the negative effect arising from a PH difference in the short term. The solvent that solves the long term stability problem is not claimed in claims 1 and 2 of EP 083 (but only in claim 5). Long term stability is therefore not a technical effect which may be taken into account when formulating the objective technical problem. Thus the objective problem to be solved is therefore formulated by the Court of Appeal as: promotion of therapeutic compliance, while maintaining short term stability.

The average skilled person (existing of a dermatologist and an expert in formulation) would according to the Court of Appeal solve the objective technical problem as it was common general knowledge: 1. that a combination product promotes compliance and 2. to use a non-watery product as a first step to solve stability problems relating to a difference in PH.

LEO Pharma had argued that the combination product also had a synergistic effect over the alternating monotherapy. According to the Court of Appeal the patent however does not make this effect plausible which means that also this effect cannot be taken into account when assessing inventive step. LEO Pharma was right in arguing that the burden of proof lies with Sandoz.

With regard to the assessment of plausibility the Court finds that on the one hand, the patentee on the application date does not have to provide full proof of a certain effect (low threshold). On the other hand however, the threshold should be sufficiently high to prevent that inventive step is assessed on the basis of subject matter which has only been invented after the application date. This would be the case if inventive step is based on arguments or effects which the skilled person on the application date would have found mere speculation.

On the following grounds the Court finds that a synergistic effect has not been made plausible:
1. in the opposition proceedings it was not in dispute that there was no synergistic effect.
2. the claimed synergetic effect appeared unexpected.
3. the patent does not mention the synergistic effect.
4. it is uncertain from the patent whether the alternating use of the active ingredients would not have the same synergistic effect as the combination product.

LEO Pharma further argued that the results of the combination treatment as such (independent from improving therapeutic compliance) improved the therapy compared to the alternating treatment. According to the Court of Appeal this effect is only to be taken into account if the patent makes it plausible that the effect occurs over the whole scope of the claims and thus that the use of all products covered by claims 1 and 2 of EP 083 result in a better treatment of psoriasis than the alternating regime disclosed in Ortonne.

Since claims 1 and 2 also cover combination products which are not stable in the long term the skilled person would not regard it plausible at first glance that the combination product would improve treatment of psoriasis over the whole scope of the claim. While the patent description mentions that the claimed combination product has therapeutic advantages it does not provide any support for this in the form of research results or any other proof. The Court of Appeal therefore concludes that the PI judge was correct to disregard technical effects other than therapeutic compliance when assessing inventive step. The fact that there is post-published evidence does not help LEO  Pharma as this cannot be used to support effects that have not been made plausible.

The Court of Appeal finds that its decision does not collide with the decision of the UK Court of Appeal (accessible here) as in those proceedings EP 083 was defended in a more limited form also claiming a specific solvent (from claim 5) which did solve the long term stability problem.

A copy of the judgment (in Dutch) can be read here.

Headnote: Mattie de Koning and Daisy Termeulen, Simmons & Simmons LLP

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