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Petitioner: Kymab Ltd VS Respondent: Regeneron Pharmaceuticals Inc
Court Name: Supreme Court of United Kingdom Judge(s): Lord Reed, Lord Hodge, Lady Black, Lord Briggs, Lord Sales Title: Kymab Ltd vs Regeneron Pharmaceuticals Inc Case No.: On appeal from: [2018] EWCA Civ 671 Date of Judgment:2020-06-24 Reported As: 2020 SCMR 1437 Result: Appeal allowed
JUDGMENT
JUDGMENT LORD BRIGGS: (with whom Lord Reed, Lord Hodge and Lord Sales agree) The Issue 1. This appeal challenges the validity of two patents, which seek to confer a monopoly over the creation of a range of types of transgenic mouse. The subject matter, genetic engineering for medical purposes, is, of great technical complexity, but the legal question which falls for determination in this court may be quite shortly stated. 2. It is a general requirement of patent law both in this country and under the European Patent Convention ("EPC") that, in order to patent an inventive product, the patentee must be able to demonstrate (if challenged) that a skilled person can make the product by the use of the teaching disclosed in the patent coupled with the common general knowledge which is already available at the time of the priority date, without having to undertake an undue experimental burden or apply any inventiveness of their own. This requirement is labelled sufficiency. It is said that the invention must be enabled by the teaching in the patent. 3. Patent protection is sometimes claimed for a single product, but sometimes for a range of products. Whether the patent claims one or the other is a question of construction of the claim (or claims) in the patent. In the latter case the sufficiency requirement has usually been expressed as meaning that the invention must be enabled over the whole of the range of products for which the claim is made. In the present case both the trial judge (the late Henry Carr J) and the Court of Appeal construed the relevant claim as extending to a range of products (transgenic mice) answering a certain description. The judge held that the teaching in the patent did not enable any type of mouse within the range to be made, let alone mice across the whole of the relevant range. 4. The Court of Appeal held, to the contrary, that the teaching in the patent, coupled with the available common general knowledge as at the priority date, did enable some types of mouse within the range to be made, but not all types across the whole range. There is no appeal against that essentially factual finding. But they held that
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the sufficiency requirement was nonetheless satisfied, because the invention for which protection was claimed amounted to an inventive, indeed ground-breaking, general principle, such that every type of mouse with the specified characteristics would display the particular benefits which the invention was designed to achieve, benefits which would not be displayed by any types of mouse outside the specified range. The invention constituted by the specified characteristics was therefore sufficiently enabled across the whole scope of the claim, and matched the contribution which the disclosure of the invention made to the art. 5. The question for this court is therefore whether a product patent, the teaching of which enables the skilled person only to make some, but not all, of the types of product within the scope of the claim, passes the sufficiency test where the invention would contribute to the utility of all the products in the range, if and when they could be made. This is a pure question of law, but an understanding of its implications requires at least a bare summary of the technical context in which it arises. A full description of the technical context may be found in the judgments of the courts below. The Technical Background in Outline 6. By the priority date, which was 16 February 2001, it was well recognised that antibodies (also known as immunoglobulins) could be used for treatment of disease in humans, by way of augmentation of, or in substitution for, antibodies produced by the patients' own immune systems. Since the development of antibodies is a natural process shared by mammals generally, and since ethical constraints prevented the use of fellow humans as platforms for antibody development, mice had been identified as suitable platforms for the development of antibodies suitable for use in treatment of humans, and were already in use for that purpose by the priority date. 7. Two main problems inhibited the use of mice for that purpose. The first was that humans tend to reject murine antibodies. The second was that if human antibody genes are genetically implanted in mice, so that the mice then produce human antibodies coded from those genes, then the mice suffer from a reduced immune response, and therefore reduced development of suitable antibodies in response to antigens, which seriously impairs their efficiency as platforms for antibody development. In the jargon of this litigation, this rendered the mice immunologically sick. The solution, which is the innovative idea at the heart of this case, was to develop a hybrid (chimeric) antibody gene structure, consisting in part of human and in part of murine elements, created by insertion into the genome of the mouse. 8. Mammalian antibodies are proteins which all share a characteristic structure consisting of four polypeptide chains, two identical "heavy chains" and two identical "light chains" bonded in a Y formation. Each chain has a constant region, so named because it does not vary in its segments, called C segments, and a variable region, in which the segments vary between different antibodies. In both mice and humans the variable regions consist, in the light chains, of V (variable) and J (joining) segments and, in the heavy chains, of V, D (diversity) and J segments. Production of antibodies is one of the major functions of B cells. 9. The natural development of specific antibodies in humans and mice involves a complex process of rearrangement among the segments in the variable regions, within the B cells which are created in the bone marrow. During this stage of development, each B cell acquires a B cell receptor on its surface. As a result of different combinations of the V, D and J segments, B cells are created with a variety of B cell receptors. As all the antibodies made by one B cell are identical, it is necessary to produce a diversity of B cells in order to have a diversity of antibodies. The degree of variety is important, because the body faces invasion by a wide variety of antigens associated with disease. The effectiveness of the body's immunological response against a specific antigen depends upon the body producing a B cell whose receptor happens to be capable of binding to that antigen. The chances of that happening are increased the greater the number of different B cells (with different receptors) which the body produces. Repeated rearrangements of the V, D and J segments (known as somatic gene rearrangement or "V(D)J recombination") through combinatorial use of a number of different gene segments coding for the polypeptide chains means that a huge variety of antibodies can be generated eventually. Where a B cell does encounter an antigen to which it binds, it is activated and induced to divide and differentiate. Repeated cell divisions give rise to sizeable clones that depend on antigen recognition for their
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survival. B cells that are unable to bind the antigen simply die. Those that do bind the antigen can be taken and subjected to other processes to produce antibodies in quantities which can be introduced into humans to combat or vaccinate against that particular antigen. It was generally understood, at least as at the priority date, that these processes of rearrangement were likely to be optimised, and the range of potential and effective antibodies increased, if the antibody, genes implanted in the mice had as many as possible of the human V, D and J segments included within them. 10. A typical human heavy chain gene locus has around 125 V segments (each different from the others), 27 D segments and nine J segments in the variable region. If the V and J segments in the light chains gene loci are factored in as well, the number of possible combinations which may be made from the human antibody gene loci is about 1.5m. 11. The hybrid gene structure at the heart of the present dispute was designed to combine within one antibody gene structure the murine constant region and the whole of the human variable region. That was indeed what the patents in issue taught. But the judge found that the formidable difficulties in producing such a hybrid gene structure could not be surmounted at all by the combination of the existing common general knowledge and the disclosure in the patents. By contrast, the Court of Appeal found that it could be done, by a combination of the prior knowledge and the disclosure in the patents, but only so as to produce a hybrid gene structure with a small sub-set of the 125 human V segments in the variable region (on the appellant's estimate between two and six V segments), and an unspecified number of human D and J segments. Transplantation of the whole of the human variable region into a hybrid gene structure has since been achieved but only with the benefit of further inventive processes not forming part of the disclosure of the patents or the prior art. 12. The name given to this type of hybrid gene structure, containing the murine constant region and all or part of the human variable region is the "Reverse Chimeric Locus". Once created in the mouse genome, it operated as the code for the production of a variety of hybrid antibodies which, when the B cells which contain the relevant coding are isolated and removed, could then have the murine constant regions removed and replaced with human equivalents before mass production and use in humans for therapy. The Patents in Issue 13. The foregoing bare outline of the technical background makes it possible to understand the relevant claims of the patents in issue, to the limited extent necessary for the resolution of the single issue of law before this court. The dispute relates to two patents obtained by the respondent, Regeneron Pharmaceuticals Inc, each with a priority date of 16 February 2001, and each with substantially the same disclosure for the purpose of justifying different claims. They are European Patent (UK) No 1 360 287 ("the 287 Patent") and European Patent (UK) No 2 A 264 163 ("the 163 Patent"). The 163 Patent is a divisional of the 287 Patent. The challenge to validity arose because Regeneron alleged infringement by Kymab Ltd of claim 1 in the 163 Patent and claims 5 and 6 of the 287 Patent by the offer to the pharmaceutical industry of its own "Kymouse", a transgenic mouse with a Reverse Chimeric Locus some of which included the whole of the human variable segments in both the heavy and the light chain loci. The judge found infringement proved, but that all three claims were invalid for insufficiency. 14. It was common ground before this court that the outcome for the validity of all three claims turns on the validity of claim 1 of the 163 Patent ("Claim 1"), which reads as follows: "A transgenic mouse that produces hybrid antibodies containing human variable regions and mouse constant regions, wherein said mouse comprises an in situ replacement of mouse VDJ regions with human VDJ regions at a murine chromosomal immunoglobulin heavy chain locus and an in situ replacement of mouse VJ regions with human VJ regions at a murine chromosomal immunoglobulin light chain locus." 15. This is of course a product claim, seeking a monopoly for the "making" (at first sight a strange but serviceable word to use of an animal) of a genetically engineered mouse having the characteristics described in the claim. The characteristics related both to what such a mouse does (namely produce the hybrid antibodies described) and to what is contained in its genome, namely the Reverse Chimeric Locus, achieved by a process of "in situ replacement" of the murine variable regions in both the light and heavy chain gene loci with the
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corresponding but of course different human variable regions. The claim seeks protection for the making and exploitation of any type of mouse having those characteristics. Since the description of what the mouse does is more loosely worded than the description of what lies within its genome, it is the latter description which mainly controls the breadth of the claim. 16. All issues as to the construction of Claim 1, ie as to what it means, were resolved in the courts below, and none are subject to appeal in this court. There were, for example, issues as to the meaning of "in situ replacement", which no longer matter. But there was a more important issue about whether Claim 1 described a single type of mouse or a range of types which the courts below also resolved, in favour of the range, arising from the meaning of the phrase "with human VDJ regions" in the heavy chain locus, and the phrase "with human VJ regions" in the light chain locus. Did this mean (only) all the segments in the VDJ and VJ regions, or did it include any of them? Looking at the V segments, did this capture only a mouse with all 125 human V segments, or also a mouse with only one such segment, and therefore mice with any number of V segments between one and 125? 17. Both the judge and the Court of Appeal concluded that the quoted phrase meant both all and any. It was this interpretation which led them both to conclude that Claim 1 extended to a range of qualifying types of mice, rather than to a single type. Taking the V segments in the heavy chain locus as the best example, the range was denominated by reference to the number, between one and 125, of the human V segments introduced into the mouse's genome as part of the human variable region. The conclusion that Claim 1 sought to protect the making of a range of transgenic mice was not in dispute on this appeal, even though every type (or embodiment) within the range would necessarily have a form of Reverse Chimeric Locus as part of its genome. The fact that there is such a range is the foundation for the agreed identification of the legal issue before this court, since the question, as framed above, makes no sense if there is not a relevant range with different types or embodiments within it. 18. There was nonetheless a sharp difference in this court between the parties' submissions on the relevance or otherwise of the existence of this range to the question of sufficiency. For the appellant it was 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. A mouse fitted with only (say) four V segments from the human variable region gene locus would produce only a small fraction of the variety of B cells that would be produced by a mouse fitted with the entire 125 V segments in the human variable region gene locus. That at least (as the judge found) was the assumption made by the skilled person as at the priority date, even though research and development since 2001 have called into question to some extent the assumpo in that the full range of 125 V segments is necessary to optimise the desirable combinatorial possibilities needed for there to be a reasonable prospect of delivery of useful antibodies. 19. For the respondent it was 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 was the product of the retention in the hybrid gene structure of the murine constant region genes. 20. In a functional sense, both these submissions are to an extent literally true, on the facts found by the courts below. The amount of human variable region DNA inserted into the murine genome does substantially affect the usefulness of the mouse fitted with the Reverse Chimeric Locus as (to use the judge's summary) a platform for therapeutic antibody discovery. More to the point that was the general understanding at the time of the priority date, and the patents in issue did not teach the contrary. But the ground-breaking invention encapsulated and disclosed in the Reverse Chimeric Locus would (and eventually did) deliver a solution to murine immunological sickness across the whole of the range captured by Claim 1, making all of them better platforms than mice which had (as previously) been fitted with fully human antibody gene structures. 21. That analysis does not of itself lead to a conclusion that the range which is denominated by reference to the amount of human variable segments in the hybrid gene structure is irrelevant, for sufficiency purposes. One can
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imagine an obviously irrelevant range, such as mice which are large and small, of differing colours, or having tails of varying length. No-one would say that Claim 1 fails for insufficiency because it includes mice with very short tails (which it does) merely because it does not teach how to make such mice. The quality and diversity of the stream of antibodies which the mouse exists to produce is, so far as is known, wholly unaffected by the length of its tail. 22. The question whether the range denominated by the amount of human segments in the variable region within the Reverse Chimeric Locus is relevant for sufficiency purposes is best answered from the terms of Claim 1 itself. The claim is to mice which produce a stream of antibodies with human variable regions, and the disclosure more generally shows that this stream is for eventual use (after further engineering and mass production) in treating disease in humans. True it is that the particular ground-breaking contribution achieved by the invention of the Reverse Chimeric Locus is the delivery of a means of preventing (or greatly reducing) murine immunological sickness, to which the range of embedded human variable segments is irrelevant, but murine immunological health is not an end in itself. It is a means to a different end. Sufficiency - the Basic Principle 23. Sufficiency is one of the established tools by which is measured the correspondence, or lack of it, between the protection afforded by the claim and the technical contribution to the art made by the disclosure of the invention in the patent. The other main tools are novelty, inventive step and industrial application: see Actavis Group PTC EHF v ICOS Corpn [2019] UKSC 15; [2019] Bus LR 1318, para 57 per Lord Hodge. The essence of the bargain between the patentee and the public is that the patentee dedicates the invention to the public by making full disclosure of it, in return for a time-limited monopoly over its use. The benefit afforded to the public is not merely the disclosure, but the ability to "work the invention" after the expiry of the monopoly by the use of the disclosure. Where the invention enables patentees to make a particular product, and they seek a monopoly over the making and exploitation of the product (which is what a product claim does), they must disclose enough in the teaching of the patent to enable the public also to make the product. In that context "work the invention" means make the product: see Generics (UK) Ltd v H Lundbeck A/S [2008] EWCA Civ 311; [2008] RPC 19, para 30 per Lord Hoffmann. If the patentee were able to obtain a product monopoly without disclosing how to make the product, the public would get nothing of substance in return for the grant of the monopoly. Furthermore, other inventors would be deterred from conducting the research and development in fact necessary to take advantage of the inventive idea for the benefit of society as a whole, since during the period of the monopoly they could derive no benefit frbm their own inventiveness. Similar basic principles apply to the patenting of processes, but such distinctions as there may be do not call for examination here. 24. Disclosure does not, of course, have to enable the product to be made by any member of the public, or solely by using the teaching in the patent. The law creates, distinctly for each patent under scrutiny, a notional skilled person or (as here) skilled team who must be enabled to make the product by the combination of the teaching in the patent, the general technical knowledge available at the priority date, and a reasonable (ie not burdensome) element of experimentation. But the skilled person is not expected to be inventive or even, as is sometimes said, imaginative: see Rockwater Ltd v Technip France SA [2004] RPC 46, paras 7 and 10 per Jacob LJ. Sufficiency - Enablement across the Range 25. Starting to apply those basic principles to the question before the court, is disclosure "sufficient" if the teaching in the patent enables only some but not all of the products within the claimed range to be made? Subject to de minimis exceptions, the instinctive answer would be: surely not. If in principle the patentee should be entitled to a monopoly only over the making of a product which the teaching in the patent enables the skilled person to make, why should not the same principle apply to every product type within the relevant range for which a monopoly is sought? The essential patent bargain is not satisfied in relation to products in that part of the range which cannot be made, using the teaching in the patent. 26. This analysis may be tested by a simple example. Suppose that five types of product (types A to E) were all claimed to be more efficient or useful than their predecessors by the application to their manufacture of the
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same new invention. The patentee made separate claims in relation to each type, all supported by the same disclosure. Each claim would be subjected to the sufficiency test: could a product of that type be made by use of the teaching in the patent, coupled with the existing common general knowledge? Suppose that types A and B could but C, D and E could not. Then claims A and B would be valid, and the remainder invalid. But now suppose that all five types were covered by the more compendious wording of a single claim. Would this enable the patentee also to obtain a monopoly for the making of types C, D and E? Surely not. 27. The Court of Appeal did not doubt this analysis as a general rule, but concluded that it would defeat the implementation of the essential patent bargain if applied to a case in which the invention amounted to a principle of general application, which would yield the relevant increase in efficiency or usefulness across a range of potential product types if they incorporated the invention, as and when they could be made, even if only a few could be made as at the priority date by using the teaching in the patent. In bare outline their reasoning was as follows. The patent bargain requires that the reward given to the patentee should be commensurate with the contribution which the invention makes to the art. An invention which consists of a new generally applicable principle may contribute to the art by its use, not only in products which can currently be made, but equally in products which will only be capable of being made in the future, after further inventive research and development. To limit the patentee strictly to a monopoly over the products which can immediately be made would be to deprive the patentee of any reward for the public benefit which will be derived from the use of that same invention in future types of product. In a fast-moving field, where new products quickly outperform their predecessors so as to render them obsolete, the reward of a monopoly limited to those immediately capable of being made would be short-lived and illusory. Accordingly the invention should be regarded as sufficiently enabled across the range if it can be seen that it will in due course benefit all products in the range, provided that, as at the priority date, the teaching in the patent enables at least one type to be made immediately. Since the Reverse Chimeric Locus would be likely to deal with murine immunological sickness in mice whose genomes were fitted with "all or any" amount of the human variable segments, up to and including the whole of the human variable region, its invention was one of those principles of general application which should be regarded as enabled across the whole range contemplated by Claim 1. A monopoly over the making and exploitation of the whole range would correspond with the contribution made by the Reverse Chimeric Locus to the art. 28. This is a sophisticated and internally logical process of reasoning, which certainly would tend to…
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