In a technically complex dispute, Kymab Limited and Novo Nordisk A/S have succeeded in the UK with their claim for revocation of two important Patents owned by Regeneron Pharmaceuticals Inc (see here). These Patents (EP(UK)1360287 and its divisional EP(UK)2264163) relate to Regeneron’s Velocimmune® transgenic mice suitable for therapeutic antibody discovery. Regeneron initially brought a claim for infringement of their Patents, and it was decided by the High Court that Kymab’s transgenic mice were within the scope of the claims of both Patents. The defendants were however, successful in challenging the validity of the Patents for lack of sufficiency. This case is of significant interest for its consideration of fundamental platform technology in the therapeutic antibody field, in addition to the legal issues discussed concerning construction of product-by-process claims and insufficiency.
Normal murine antibodies are unsuitable for therapeutic use in humans because they elicit an immune response. Technologies have been developed to resolve this issue including chimeric antibodies (having mouse variable regions and human constant regions) and humanised antibodies (where the CDR regions of a murine antibody have been grafted onto a human antibody). Prior to the priority date of Regeneron’s Patents, transgenic mice had also been engineered so as to carry the human immunoglobulin loci allowing the mice to generate fully human antibodies; however, it was subsequently found that these mice were unable to mount a strong immune response such that high quality antibodies cannot readily be produced using this platform.
The Patents at issue in this case describe methods for generating transgenic mice capable of producing “reverse chimeric” antibodies having human variable regions and mouse constant regions. The methods involve replacing gene segments of the variable regions (the V,D,J segments) in the murine immunoglobulin loci with the human counterparts, instead of the full-length loci. The transgenic mice having the reverse chimeric loci exhibit improved antibody production as compared with the fully-human transgenic mice, and the hybrid antibodies may be subsequently humanised by the addition of a human constant region for testing as therapeutic candidates.
The claims of the ‘287 Patent included process claims reciting methods of modifying an endogenous immunoglobulin heavy chain variable region gene locus in an isolated mouse embryonic stem cell. There were also two product-by-process claims covering genetically modified eukaryotic cells, ES cells or mice containing a genetically modified immunoglobulin heavy chain variable region locus obtainable by the process of the preceding claims. In construing the product-by-process claims, it was noted that their scope was considerably wider than the process claims. On the one hand, the modified murine locus was required to have every characteristic which is the inevitable consequence of the process; however, on the other hand, the claims did not impose any limitation as to the amount of endogenous sequence which may have been deleted or the amount of orthologous sequence which may have been inserted. Claim 1 of the ‘163 Patent was a product claim reciting a transgenic mouse having replacements in both the murine heavy and light chain loci such that hybrid antibodies are produced containing human variable regions and mouse constant regions.
In considering sufficiency, the focus was primarily on process claim 1 of the ‘287 Patent given that the product-by-process claims were held broader in scope. Taking into account the wealth of technical information and expert evidence presented, it was concluded by the judge that the process defined in the claim was not capable of being performed at the priority date without undue burden and without invention. This conclusion was based primarily on the fact that that there was no means available (either described in the Patent or presented as an alternative by the Patentee) by which the skilled person could have made the insertions and deletions at the murine immunoglobulin loci of the size required by the claimed process. The ‘163 Patent was invalidated on the same grounds on the basis that the product claims were broader in scope than the process claim of the parent Patent.
Interestingly, the claims of ‘287 Patent considered by the English High Court in these proceedings were the amended claims approved by the EPO Board of Appeal at the Oral Proceedings held on 27, 28, 29 October and 9 November 2015. The Board of Appeal’s conclusions on sufficiency clearly differ from the decision reached in this judgment. However, until the Board’s written decision is publicly available, the reasons for this divergence are not yet entirely clear.