EP ‘761, owned by Shire-NPS Pharmaceuticals Inc. (‘NPS’), relates to the API cinacalcet, which is used for the treatment of conditions of impaired regulation of calcium levels in human blood and tissue fluid. The product is marketed under the name Mimpara®.In September 2017, Accord Healthcare Ltd. and Accord Healthcare B.V. (‘Accord’) initiated invalidity proceedings before the District Court of The Hague. By decision of 6 February 2019, the District Court invalidated EP ‘761 for lack of inventive step. NPS appealed this decision. The CoA rendered its judgment on 18 August 2020 (published on 24 August 2020).
For the assessment of inventive step, the CoA considered with which compound(s) cinacalcet must be compared to determine whether the requirement of an unexpected improvement over the prior art had been met. Or alternatively, if the ‘problem solution approach’ is applied, which compound(s) can be regarded as the closest prior art. From the prior art, the CoA inferred that the compound(s) must have an EC50 value of 5 µM or less, as this EC50 value indicates a certain calcimimetic activity suitable for the treatment of disorders characterized by abnormal bone and mineral homeostasis. The CoA considered a compound named ‘R-568’ to be the closest prior art, because it was identified in the prior art as the “lead calcimimetic compound” at the relevant date. According to its EC50 value, R-568 had the highest calcimimetic activity. With the designation of R-568 as the closest prior art, the CoA departs from the decision of the District Court, which considered every calcimimetic compound with an EC50 value of 5 µM or less suitable to be compared with cinacalcet.
The CoA considered that the goal of the patent was to select, from a Markush formula disclosed in the prior art, a compound with a significantly better calcimimetic activity beyond that disclosed in the prior art for known compounds derived from that Markush formula. Also, the compound selected must be suitable for administration as a medicinal product (i.e. must be therapeutically effective). It was not contested by Accord that the skilled person in the art would assume that cinacalcet was therapeutically effective.
Contrary to the District Court’s decision, the CoA found the increased calcimimetic activity of cinacalcet to be unexpected. The CoA considered that results from in vivo research, which were submitted by NPS during prosecution, made clear that the EC50 value for cinacalcet was almost three times lower than the known EC50 value of R-568. Also, the CoA held that the person skilled in the art would not assume a ‘try and see’ attitude. The CoA considered that there can only be a ‘try and see’ situation if the person skilled in the art clearly has certain compound(s) in mind without this requiring undue burden on his part. According to the CoA, it was unclear for the person skilled in the art that routine testing of compounds from the Markush formula would result in him finding compound(s) with a low EC50 value. Also, the number of compounds within range of the Markush formula is very extensive (exceeding at least a hundred thousand compounds). Therefore, the person skilled in the art would have insufficient incentive to test all possible compounds. The general encouragement in the prior art “to determine other useful lead molecules or novel molecules of this invention” was found too broad by the CoA to function as a pointer for the person skilled in the art. Taking into account the immense number of possibilities within the Markush formula, the CoA held that Accord’s assertion that cinacalcet’s structure is (chemically) not complex, does not detract from the fact that the person skilled in the art would not have arrived at cinacalcet without any inventive labour.
From the foregoing it follows that the selection of cinacalcet from the known range on the application date was not obvious for the average skilled person starting from R-568 and that cinacalcet shows unexpectedly improved calcimimetic activity relative to the activity known for the range in the art. Thus, EP ‘761 was held valid by the CoA.
The CoA ordered Accord to pay NPS the full costs of the proceedings in both instances.
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