REGENERON PHARMACEUTICALS, INC v KYMAB LTD

[2018] R.P.C. 14 535 REGENERON PHARMACEUTICALS, INC v KYMAB LTD COURT OF APPEAL [2018] EWCA Civ 671; [2018] R.P.C. 14 Patents – European patents – Pharmaceuticals – Antibody production – Genetic engineering – Transgenic mice – Infringement – Construction – Insufficiency – Biogen insufficiency – Nature of the invention – Whether a principle of general application – Enablement – Whether scope of monopoly exceeding technical contribution to the art – Appeal to Court of Appeal H1 H2 H3 This report concerns the hearing of cross-appeals following the trial of a patent proceedings concerning European Patent (UK) No. 1 360 287 (“the 287 patent”) and its divisional European Patent (UK) No. 2 264 163 (“the 163 patent”). The patents concerned the production of human antibodies using transgenic mice. The disclosure of the 287 and 163 patents was essentially the same, the material differences lying in the claims. The claimant (“Regeneron”) alleged that three strains of transgenic mice of the first defendant (“Kymab”), referred to as HK, HL and HKL, infringed claims 5 and 6 of the 287 Patent. Those claims, which were product by process claims, are set out at [45] of the judgment reported here. The HK and HKL mice were also alleged to infringe claim 1 of the 163 patent. This was a product claim and is set out at [44] of the judgment. Kymab denied infringement and counterclaimed for revocation of Regeneron’s patents for lack of novelty, lack of inventive step and insufficiency. Regeneron had also advanced claims of infringement against a second defendant (“Novo Nordisk”) but these had been discontinued shortly before trial. Novo Nordisk’s own invalidity attack remained however and it adopted Kymab’s submission in respect thereof. At the trial of the action, Henry Carr J. had dismissed both the novelty and obviousness attacks on the validity of the patents but had found claims 1, 5 and 6 of the 287 patent and claim 1 of the 163 patent invalid on grounds of insufficiency. The judge had also held that Kymab’s transgenic mice would have infringed the patents had they been valid. Regeneron appealed against the finding of invalidity on grounds of insufficiency and Kymab appealed on infringement. On appeal, as below, there was a dispute as to the proper construction of claim 1 of both the 278 and 163 patents and, in particular, as to the meaning of the term “in situ replacement” as used in those claims. Kymab argued that an “in situ replacement” required deletion of the murine variable gene segments and the insertion of human variable segments in the same place. Regeneron’s case was that “in situ replacement” merely required a replacement “in the position of” the murine variable gene segment (which it described as “positional replacement”) and did not require deletion. The judge had held that Regeneron’s construction was the correct one, since the skilled person would have appreciated that the patentee was using this language to distinguish [2018] R.P.C., Issue 8 ß Crown copyright 2018. This article contains public sector information licensed under the Open Government Licence v3.0 (http://www. nationalarchives.gov.uk/doc/open-government-licence/version/3/) Kitchin, Floyd and Arden L.JJ.: 17-20 October and 28 March 2018 536 H4 H6 targeted replacement from random insertion into the genome, which was one of the distinguishing features over the prior art. The construction issue was central to infringement because, in the Kymab mice, the murine variable segments were inverted and appeared in a different location in the genome where they substantially ceased to function but had not been physically removed or deleted. It followed from the judge’s decision on construction that Kymab’s mice would have infringed. As to insufficiency, at first instance, Henry Carr J. had focussed on claim 1 and Example 3 of the 287 patent. Claim 1 was a method claim and is also set out at [45] of the judgment. The judge held, inter alia, that the minimum replacement using large targeting vectors (“LTVECs”) as described in Example 3 was a deletion of 100 kb of mouse sequence and an insertion of 200-300 kb of human sequence and that the minimum replacement required by claim 1 involved a larger deletion (150 kb) but a smaller insertion (75 kb). However, neither would have been feasible as at the priority date of the 287 patent. He concluded that the whole subject matter of the claim was not capable of being performed at the priority date without undue burden and without invention. In particular, none of the methods of the 287 patent for achieving the contemplated insertion and deletion, as disclosed in Example 3, would have worked. The task contemplated was unprecedented and could not have been achieved without a great deal of creative thinking. He also held that the embodiments within the claim were not unified by the single principle of a reverse chimeric locus as Regeneron had contended. This was not a principle that enabled the method to be performed but the result of successfully carrying it out. The judge held that claims 5 and 6 of the 287 patent and claim 1 of the 163 patent were considerably wider and so necessarily insufficient also. On appeal Regeneron argued that the judge had made a series of errors of principle which fatally undermined his decision: (i) he had failed properly to appreciate the true nature of the reverse chimeric locus, and should have held that it embodied a new principle of general application; (ii) he had wrongly sought to identify whether there were any products or processes which fell within the claims which were not enabled when he ought to have considered whether the claims were properly enabled across their breadth having regard to the technical contribution of the patent; (iii) he had wrongly held that claim 1 of the 287 patent required positional replacement by an insertion of at least 75 kb when the claim only required a fragment of greater than 20 kb; (iv) having found claim 1 of the 287 patent insufficient, the judge had applied this finding in a mechanistic way to the product claims when he ought to have considered the sufficiency of the product claims on their own merits; and (v) he had approached the evidence on the wrong basis in several respects. More specifically, Regeneron contended, inter alia, that the judge had focussed unduly on the details of Example 3 and had failed to consider whether the skilled team could have made mice falling within claim 1 of the 163 patent and cells and mice within claims 5 and 6 of the 287 patent by gene targeting and, in particular, by inserting a minigene (a term explained at [153] to [155] of the judgment) at the proximal end of the mouse immunoglobulin variable region using traditional techniques of homologous recombination. There was no dispute that such a construct of up to 20 kb in length could be made and inserted successfully. Further, the judge ought to have found that the skilled team could have implemented the rev (...truncated)