The UK Supreme Court, by majority, has held invalid two patents owned by Regeneron on their transgenic mice technology.
The decision and what it means
The case, Regeneron Pharmaceuticals Inc v Kymab Ltd [2020] UKSC 27, was handed down on 24 June and the patents in question will now be revoked for insufficiency.
The case will worry patentees, especially given that the Supreme Court stated in its press release on the case an apparent need to rebalance patent law: "[the Court of Appeal's] analysis watered down the sufficiency requirement which is a bedrock of patent law, tilting the balance of patent law in favour of patentees and against the public."
This comment, however, appears largely to be a response to a misapplication of a key principle of law concerning sufficiency by the Court of Appeal, rather than a re-set of the law or a change in direction. Instead, the decision is concerned with clarifying a long-standing principle, albeit in the context of a class claim to transgenic mice – you cannot claim products that you cannot make at the priority date of the patent.
What the case was about
The case concerns the following Regeneron patents, each with substantially the same disclosure:
- EP1360287 (specifically process claim 1, and product claims 5 and 6): claims methods of modifying the antibody variable regions of a mouse cell by replacement of the mouse antibody variable genes with the equivalent human genes (a human antibody light chain – variable (V) and joining (J) – or heavy chain – V, Diversity (D) and J – variable region), while retaining the mouse constant regions; creating a "reverse chimeric locus".
The method described in the patent employs, in particular, large targeting vectors (LTVECs) for use in eukaryotic cells in combination with a particular assay, the modification of allele (MOA). The use of LTVECs is made possible by the MOA assay which detects unmodified alleles, so that a cell in which one allele has been modified can be distinguished from a cell in which neither has been modified.
- a divisional of the above, EP2264163 (specifically, claim 1): claims the range of transgenic mice that result from the above methods, containing the reverse chimeric locus.
The genes for these regions undergo rearrangement during the B-cell maturation process in the mouse as well as a process of somatic hypermutation that introduces potentially dozens of mutations in the variable region, and thus the potential for specificity.
The hybrid antibodies produced by these techniques are not, however, the final therapeutic product, because they contain mouse constant regions which would be liable to induce the human anti-mouse antibody (HAMA) response. That said, they can be engineered to produce fully human antibodies in a subsequent step, by replacing the mouse constant regions with human constant regions.
Importantly, in this case, by virtue of the reverse chimeric locus, the mice produced using the above techniques are not immunologically sick – they are able to produce antibodies normally. This was a significant inventive advance compared to the techniques of the prior art and an important element in the decisions of the Court of Appeal and the Supreme Court.
A number of issues had been in dispute in both the Patents Court and the Court of Appeal, including infringement of the patents by Kymab's Kymouse technology (which, as a result of the Supreme Court holding the patents invalid, does not infringe them). However, the only issue before the Supreme Court was whether the patents were invalid for lack of sufficiency. The focus of the Supreme Court decision is on claim 1 of the '163 patent, but if this is invalid for sufficiency so too are the other relevant claims.
The decisions on sufficiency at first and second instance
At first instance, the late Mr Justice Henry Carr had held (Regeneron Pharmaceuticals Inc v Kymab Ltd & Anor [2016] EWHC 87 (Pat) (01 February 2016)) that the method of the '287 patent was not capable of being performed at the priority date without undue burden and without invention, and was therefore insufficient. As a result the judge also held that the product claims in issue, which relied on the method and were considerably wider in scope, must necessarily also be insufficient.
A specific aspect of Carr J's findings, focusing on claim 1 of '287 and the relevant Example 3, was that they required techniques in which mouse DNA sequences would be replaced with equivalent human sequences of a size too large (replacement of 100 kb of mouse sequence by 200-300 kb of human sequence, or replacement of 150 kb of mouse sequence by 75 kb of human sequence). This was not possible at the priority date using the LTVEC method described. The alternative technique of Example 3, using recombinase-mediated cassette exchange (RMCE), would not have worked either. Indeed, Example 3, had been shown by Regeneron's own scientists not to be reproducible at the priority date.
The Court of Appeal agreed (Regeneron Pharmaceuticals, Inc v Kymab Ltd & Anor [2018] EWCA Civ 1186 (23 May 2018)) with the trial judge that Example 3 would not have worked at the priority date, but it overturned the judge on insufficiency, on the principle that the common general knowledge of the skilled person or team can be used to make the invention work if it does not require undue effort and invention, even if this means the teaching of the patent is not followed precisely.
In this case, expert evidence from the trial, which the judge had not considered in this context (an issue which Regeneron had also failed to raise with the judge when it received the draft judgment) suggested that a skilled person would have considered it obvious to use other techniques, which were common general knowledge at the priority date of the patents, to shorten the inserts to a manageable size. These included the use of a genetically engineered construct which includes the V, D and J segments, but in which non-essential DNA sequences (such as introns) have been removed – the ‘minigene’ approach.
These techniques, according to the Court of Appeal, provided the necessary support for the claim, even though they could produce only a hybrid gene structure with a small sub-set of the 125 human V segments in the variable region, and an unspecified number of human D and J segments. Transplantation of the whole of the human variable region into a hybrid gene structure, as taught by the patent, would not be possible (indeed, this has only since been achieved with the benefit of further inventive processes not forming part of the disclosure of the patents or the prior art).
There was, however, another issue concerning sufficiency. Only a very small range of the mice claimed could be made, even allowing for the common general knowledge techniques, and none at all containing the entire human variable region. The product claims nonetheless claimed all mice containing a reverse chimeric locus. The claims therefore covered many mice that could not be made at all at the priority date.
The Court of Appeal held that this fact did not render these claims invalid, because there was a "principle of general application" disclosed by the patent that did cover all the claims: the inventive concept that using a reverse chimeric locus prevents the mice being immunologically sick. This principle, would apply to all mice that could be made under the claim or made in the future, and as such the claim was sufficient across its breadth.
As a consequence, the Court of Appeal held the patents to be sufficient and valid, a decision that they noted to be consistent with the Board of Appeal decision upholding the validity of the '287 patent in T 2220/14 (9 November 2015).
The reasoning of the Supreme Court
It is the second part of the Court of Appeal's reasoning – the lack of immunological sickness of all the mice claimed was a principle of general application supporting the claim across its breadth – with which the Supreme Court disagreed, and as a result held the patents invalid for insufficiency.
In particular, the Supreme Court, led by Lord Briggs, re-iterated that the requirement of sufficiency imposed by Article 83 of the European Patent Convention 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. The contribution to the art of the claims in this case is transgenic mice containing the reverse chimeric locus. It is not the inventive concept that the mice produced are not immunologically sick. The latter is just an idea, which if it cannot be made is not a technical contribution to the art at all.
Patents are for products and processes and here the technical contribution – the 'product' – was transgenic mice with the reverse chimeric locus. This was far from being enabled across the claim.
As if to emphasise the public policy of limiting patent protection to the contribution it makes, Lord Briggs addresses what the Court of Appeal decision would have meant if it had been upheld:
"It is now known that the type of mouse fitted with a Reverse Chimeric Locus which actually does serve as the gold standard in the art has the whole of the human variable region gene locus as part of its hybrid antibody gene structure. Yet the Court of Appeal would have upheld a monopoly for its manufacture and exploitation when the disclosure in the patent, coupled with the common general knowledge, would not have enabled a skilled person to make such a mouse at all. The ability of both the appellant and the respondent to make such a mouse now depends upon further (and different) inventions separately made by each of them some years after the priority date."
In short, the Supreme Court reiterates in Regeneron v Kymab, in the context of a class claim to transgenic mice, the rule that a patent cannot claim products that it has not enabled to be made.
This is a long-standing principle of patent law. Consequently, the decision appears not to place and new limits on patent protection, but has instead clarified the application of those principles in a new technological context.
