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 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.

Sufficiency at the EPO

Exxon/Fuel Oils (T 409/91) (1993) directly addressed sufficiency in a claim for a range of products: “the disclosure... is only sufficient if it enables the skilled person to obtain substantially all embodiments falling within the ambit of the claims…” The Board of Appeal (BoA) considered the relevance that the invention disclosed as general principle, and decided it made no difference, stating that the claim must fail “regardless of whether or not the alleged ‘principle’… would be novel and inventive”, leading Lord Walker in Generics v Lundbeck (Generics (UK) Ltd v H Lundbeck A/S [2009] RPC 13) to describe the requirement that the invention be enabled across the whole scope of the claim as the ‘Exxon principle’. In Unilever/Detergents(‘Detergents’) (T 435/91) (2008) the BoA confirmed that “the whole subject matter of the claims, not only a part of it, must be capable of being carried out by the skilled person without the burden of an undue amount of experimentation or the application of inventive ingenuity” (emphasis added) and that a patent which enables an invention across a broad claim must disclose “a technical concept fit for generalisation which makes available to the skilled person the host of variants encompassed by the respective ‘functional’ definition of the ... claim.” Lord Briggs contrasted these cases considering product claims with Genentech I/Polypeptide expression (T 292/85) 1988 (‘Polypeptides’), which the respondent relied on in their defence. In Polypeptides, the claims (e.g. claim 1, a recombinant plasmid suited for transformation of a bacterial host comprising a homologous regulon … and claim 9, a bacterium transformed with the cloning vehicle of claim 1 …) were framed by reference to function, and sought to protect products and processes that achieved that

Heavy chain

function when applied to a broad range of input variables, none of which were themselves embodiments of the claim. Specifically, the terms bacteria, regulon and plasmid covered (e.g. bacteria, or plasmids which may not even have been identified), but the process would work for bacteria not yet discovered, and would produce the same result: an expressed polypeptide. In contrast, in the (later) Detergents case, the patent failed to disclose any general technical principle by which the skilled person could achieve the desired result across the whole range of claimed embodiments.

Why Does the Current Case Follow ‘Detergents’ not ‘Polypeptides’? In the present case (claim 1), the whole of the human variable region gene locus had already been mapped, and could be inserted into mice, and had been, but only when attached to the human constant regions, giving rise to murine immunological sickness. The problem facing the skilled person at the priority date was that there was no known way, either using the teaching in the Regeneron patents or using the common general knowledge, to combine more than a very small part of the human variable region gene locus with the endogenous murine constant region gene locus, in the same hybrid gene structure. The ‘inventive shortfall’ lay not in the range of possible inputs to which the invention could be applied, but in the inability to actually put the invention into effect for anything other than a very small part of the scope of the claim.

Sufficiency in the UK Lord Briggs found that the UK cases follow a similar approach to the existence and nature of the exception to the ‘Exxon

Light chain

Mouse constant regions

Human antibody Reverse Chimeric antibody

principle’ illustrated by Polypeptides for ‘principles capable of general application’. In considering UK cases (Biogen Inc v Medeva plc [1995] RPC 25 and [1997] RPC 1, KirinAmgen Inc v Hoechst Marion Roussel Ltd [2005] RPC 9 Generics (UK) Ltd v H Lundbeck A/S [2008]); Lord Briggs found that the UK case law provides clear guidance for product claims, in contrast to the situation for a process such as described in ‘Polypeptides’, reciting Hoffmann on insufficient disclosure: “The patent may claim results which it does not enable, such as making a wide class of products when it enables only one of those products and discloses no principle which would enable others to be made.” “In the case of a product claim, performing the invention for the purposes of section 72(1) (c) means making or otherwise obtaining the product. In the case of a process claim, it means working the process. A product claim is therefore sufficiently enabled if the specification discloses how to make it” (emphasis added).

Lord Briggs Set Out Principles for Determining Sufficiency The following principles for determining sufficiency were outlined [56]: i) The requirement of sufficiency imposed by Article 83 of the EPC exists to ensure that the extent of the monopoly conferred by the patent corresponds with the extent of the contribution which it makes to the art. ii) In the case of a product claim, the contribution to the art is the ability of the skilled person to make the product itself, rather than (if different) the invention. iii) Patentees are free to choose how widely to frame the range of products for which they claim protection. But they need to ensure that they make no broader claim than is enabled by their disclosure. iv) The disclosure required of the patentee is such as will, coupled with the common general knowledge existing as at the priority date, be sufficient to enable the skilled person to make substantially all the types or embodiments of products within the scope of the claim. That is what, in the context of a product claim, enablement means. v) A claim which seeks to protect products which cannot be made by the skilled person using the disclosure in the patent will, subject to de minimis or wholly irrelevant exceptions, be bound

V segments n= 125 D segments J segments Constant region exons n= 27 n= 9

VH1 VH2 VH3 VHn DH1-DHn JH1-n CH1-3

Variable region Constant region

to exceed the contribution to the art made by the patent, measured as it must be at the priority date. vi) This does not mean that the patentee has to demonstrate in the disclosure that every embodiment within the scope of the claim has been tried, tested and proved to have been enabled to be made. Patentees may rely, if they can, upon a principle of general application if it would appear reasonably likely to enable the whole range of products within the scope of the claim to be made. But they take the risk, if challenged, that the supposed general principle will be proved at trial not in fact to enable a significant, relevant, part of the claimed range to be made, as at the priority date. vii) Nor will a claim, which in substance passes the sufficiency test, be defeated by dividing the product claim into a range denominated by some wholly irrelevant factor, such as the length of a mouse’s tail. The requirement to show enablement across the whole scope of the claim applies only across a relevant range.

Put broadly, the range will be relevant if it is denominated by reference to a variable which significantly affects the value or utility of the product in achieving the purpose for which it is to be made. viii) Enablement across the scope of a product claim is not established merely by showing that all products within the relevant range will, if and when they can be made, deliver the same general benefit intended to be generated by the invention, regardless of how valuable and ground-breaking that invention may prove to be. • Application of those principles to the current case shows that claim 1 fails for insufficiency, because only a small range of the products could be made, and mice at the more valuable end of the range could not be made. Interesting Observations (Unusual Nature of the Court of Appeal Order) Kymab obtained a stay of the injunction, the order for delivery up and the order for disclosure pending resolution of their appeal to the Supreme Court. Under the terms of the stay, Kymab’s collaborative work with humanitarian bodies, including the Bill & Melinda Gates Foundation and the International AIDS Vaccine Initiative to treat diseases with unmet clinical need, was allowed to continue. Specifically, Kymab was permitted to ‘dispose or export’ antibodies or mouse serum for the purposes of: • Kymab’s collaborations with the Bill & Melinda Gates Foundation and the

International AIDS Vaccine Initiative and Heptares Therapeutics Limited; and • Preparing and conducting pre-clinical or clinical trials, antibody producing CHO cells for use by Kymab’s manufacturing

CRO Lonza (and which will remain under Kymab’s control) solely for the purposes of manufacturing antibodies under GMP conditions for use in preclinical or clinical trials.

The Court of Appeal considered that in the absence of a stay, Kymab’s loss would include serious disruption, putting an end to Kymab’s work and outweighed Regeneron’s loss. A requirement for Kymab to ring-fence damages was also rejected – the Court of Appeal considered that there was a real prospect that it would drive Kymab out of business, frustrating any further appeal and leading to a termination of the humanitarian work that Kymab was undertaking.

Summary A patent reflects a bargain between the inventor and the public. The inventor gains a time-limited monopoly over the making and use of a product. In return, the public gains the ability to make the product after the expiry of the monopoly. As part of this bargain, the inventor must publish sufficient information to enable a skilled member of the public to make the product. This ensures that patent holders only gain legal protection which is proportional to their actual technical contribution to the art, and encourages inventors to conduct research for the benefit of society. The decision makes a clear distinction between the requirements for a product claim (that the product can be made across the breadth of the claimed range at the effective date of the patent), and a process claim capable of general application, where the process can be applied to a range of inputs, and will always provide the benefit. Whereas the Court of Appeal gave the patentee a tantalising glimpse of a world where the patentee might receive the benefit for having a good idea, even though they could not make it work across the board, this decision puts the balance back firmly with the public.

Martin MacLean

Martin has over 20 years of IP experience with particular expertise in patent portfolio management for corporates and government. With a strong biotech background, he specialises in technologies such as the protein therapeutics, antibodies, vaccines, expression systems, diagnostic assays, and ‘green’ agrochemicals. Martin’s expertise is recognised by his Band 1 ranking in Chambers UK, recommendation in The Legal 500, and his rankings as a leading individual in IAM’s Strategy 300 and Patent 1000 directories.

Andrea Hadfield

Andrea works in all areas of the life sciences and has experience working for a wide range of clients, including universities, spin-outs, SMEs and multinational corporate clients. She has experience in drafting and the prosecution of patent applications in the UK, Europe and worldwide, as well as post-grant opposition and appeal proceedings before the EPO.