Drug Discovery, Development & Delivery
Regeneron v Kymab: Transgenic Mice Claims Found Insufficient The Supreme Court judgment (24 June 2020) sends a clear “no” Brexit message to any big pharma contemplating corporate muscleflexing of excessively broad patent claims. This ruling overturned the position held by the Court of Appeal that, for patents relating to “a principle of general application”, there was no requirement to teach how to make the full range of claimed products. In this regard, the Court of Appeal held that Regeneron’s contribution to the field extended beyond the products (transgenic mice) that could be made back in 2001, and instead related to the general principle of providing ‘better’ mice (thereby overcoming a prior art immuno-sickness problem inherent to mice transfected with human DNA). With hindsight, the Court of Appeal allowed too much weight to be given to the relative contribution the ‘better’ mice aspect provided in producing a(ny) mouse having commercial utility. In sum, the Supreme Court considered the Court of Appeal had incorrectly watered down the “sufficiency of disclosure” requirement of patent law and, in doing so, this judgement maintains a sensible balance between patent law enforceability and invalidity and provides guidance on what might constitute a ‘principle of general application’ for which broad claim scope might be held valid. Background to the Case Regeneron obtained two patents with a priority date of 16 February 2001, EP(UK) 1 360 287 (“the ’287 Patent”) and EP (UK) 2 264 163 (“the ’163 Patent”, a division of the ’287 Patent). At the priority date, there were two main problems associated with the use of mice as a platform for antibody development. First, use of murine antibodies in humans typically resulted in a host rejection response. Secondly, the transfection of mice with human antibody genes was associated with the mice developing a reduced immune response function (and thus reduced antibody titres). Regeneron’s solution to this reduced 52 INTERNATIONAL PHARMACEUTICAL INDUSTRY
antibody production capability was to develop a hybrid (chimeric) antibody gene structure, consisting in part of human and in part of murine elements, created by insertion of ‘human variable regions’ into the genome of the mouse, whilst retaining the ‘mouse constant regions’. The ‘variable’ regions are primarily responsible for antibody recognition of its target antigen. In both mice and humans, the variable regions consist of V (variable) and J (joining) segments, with additional D (diversity) segments in the heavy chain but not the light chains. Evidence in the proceedings confirmed that a typical human heavy chain locus has around 125 different V segments, 27 D segments and nine J segments, and that one of each (V, D, and J) is found mature antibody. Including the light chain V and J segments, about 1.5 million different combinations are possible. Selection from a pool of V, (D) and J segments provides the rich diversity which is essential for generating antibodies against new targets. Kymab’s challenge to validity arose in defence to an infringement action brought by Regeneron against Kymab’s commercialisation of its own transgenic mice, “Kymouse”. In the first instance (Patents Court), Mr Justice Henry Carr [[2016] EWHC 87 (Pat)] found that the difficulties in producing a hybrid gene structure where the whole of the human variable region was combined with the murine constant region were not taught (enabled) by the technical disclosures offered by the Regeneron patents (even when combined with the common general knowledge at the time of the priority filing), concluding that “at the priority date, the skilled person would not have been able to perform the invention over the whole area claimed without undue burden and without needing inventive skill”. This decision was overturned by the Court of Appeal [[2018] EWCA Civ 671], holding that Regeneron’s patents contained enough information to insert some of the human material into a mouse’s genes. Whilst this would have created a hybrid mouse (as claimed), the prevailing genetic manipulation techniques available imposed a significant limitation on the amount of human DNA that could be transferred. Indeed, said limitations would, at best, have
permitted the transfer of up to six out of 125 of the human variable region V segments into a mouse genome and an unspecified number of D and J segments. Moreover, the necessary transfection techniques required for transfer of the full human repertoire, and, therefore, necessary to put into effect the full breadth of the claim, were not invented until 2011. Thus, the Regeneron patents taught how to make a transgenic mouse having up to 5% of the necessary human repertoire, which as such simply had no meaningful commercial utility. Despite this, however, the Court of Appeal upheld the Regeneron patents on the basis they related to a “principle of general application”, and did not, therefore, require any teaching of how to make products commensurate with the scope of the claims. Kymab appealed to the Supreme Court. The Claim in Question Covers a Range of Mice The validity of claim 1 of the ’163 Patent was central to the case. Both previous courts concluded that that claim covered all and any replacement of mouse VDJ regions with human VDJ regions in the heavy chain and replacement of mouse VJ regions with human VJ regions in the light chain, where replacing all equates to entirely replacing the mouse variable domains with human variable domains. Thus, the case turned on the relevance or otherwise of the existence of a very narrow range of mice having amounts (up to 5%) of the human variable domain repertoire, to the question of sufficiency. The appellant submitted that the range was of the highest importance because of its effect upon the ability of a particular type of mouse to produce a wide variety of B cells, and hence its potential to deliver a broad stream of useful antibodies (and thus have a meaningful commercial utility). The respondent/patentee submitted that the existence of this range was irrelevant, because the unique advantage conferred by the use of a reverse chimeric locus, namely a cure for the immunological sickness of the recipient mouse, worked across the whole range, regardless of the amount of the human variable region DNA inserted into the murine genome, because it retained the murine constant region genes. Autumn 2020 Volume 12 Issue 3
