This article first appeared in the Intellectual Property Forum journal, published by Intellectual Property Society of Australia and New Zealand. Andrew Bowler and Alex Calver, ‘Current Developments – Europe: United Kingdom: Trapped: insufficiency deals the final blow to Regeneron’s ground-breaking transgenic mouse patents’ (2020) 121 Intellectual Property Forum 95.
On 24 June 2020, the UK Supreme Court brought an end to the long running dispute regarding the validity of Regeneron’s patents relating to transgenic mice, used ultimately to produce fully human antibodies. The hugely complex and fascinating dispute boiled down to a (relatively) simple question of law asked of the Supreme Court: in a product claim that encompasses a range, is it sufficient that the patent discloses how to make only some, but not all, of the products within that range? The conclusion was no. Their Lordships ruled 4-1 in favour of Kymab (with Lady Black dissenting), therefore overturning the decision of the Court of Appeal which had included 2 specialist patent lawyers in the tribunal, including Lord Kitchin (as he now is) . The UK’s highest court had a firm eye on the balance of the so-called ‘patent bargain’, and decided that sufficiency requires substantially the whole of the range of products within the scope of the claim to be made by means of the disclosure in the patent at the priority date.
It is worth noting that by the time of the Supreme Court’s judgment, all debate as to the technical disclosure and construction of the patents had fallen away. However, for context and for the general interest of readers not familiar with the technology, a summary is set out in the following paragraphs.
By 2001, the priority date of the patents in issue, transgenic mice were an established tool for discovering therapeutic antibodies. However, transgenic mice with fully human antibody sequences frequently exhibited a poor immune response (something characterised in the litigation as being ‘immunologically sick’). Regeneron discovered this was because the human constant region of the antibody interacted poorly with the downstream mouse immune response effector proteins. Regeneron’s invention, acknowledged as “ground-breaking” by the Supreme Court, was to create an antibody sequence that retained the mouse constant region, and replaced only the mouse variable regions with human counterparts. This was named the “Reverse Chimeric Locus”. The Reverse Chimeric Locus would give rise to hybrid antibodies that comprised human variable regions and mouse constant regions, which could then be transformed into fully humanised antibodies by a subsequent, known process.
The diversity of antibodies that a body (in this case a mouse) may produce arises in part from recombination of different antibody variable region gene segments (known as V, D, J gene segments). At the priority date, it was considered that the more human antibody variable gene segments inserted into the mouse genome, the greater the number and variability of antibodies that would be generated from these gene segments and thus the more efficient and valuable the transgenic mouse.
In 2001, Regeneron filed process and product patents based on its Reverse Chimeric Locus. Claim 1 of the relevant product patent (EP (UK) 2 264 163), upon which the validity of all other claims in issue rested, claims:
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.
Proceedings were brought by Regeneron in 2013 alleging infringement by Kymab’s product, a transgenic mouse known as Kymouse. Kymab counterclaimed that the patents were invalid due to lack of novelty, inventive step and insufficiency of disclosure. An important feature of construction was that at both first instance and on appeal, Claim 1 above was found to extend to a range of mice, which varied in the number of human variable V, D or J gene segments inserted into the mouse genome.
At first instance Henry Carr J found the patents novel, inventive and infringed, but invalid for lack of sufficiency. He held that the methods disclosed in the patents would not have been workable by the skilled person at the priority date without undue burden or invention, as insertion or deletion of large pieces of DNA was not possible at that time.
On appeal, Regeneron presented a new argument that the skilled person would have used his/her common general knowledge (CGK) to make adjustments to the methods in the patent so as to introduce smaller inserts of DNA (known as minigenes) into the mouse genome in a stepwise manner. Regeneron accepted that these minigenes would only allow the skilled person to make a small range of the mice claimed by the patent (i.e. it would only allow the skilled person to make transgenic mice with a small subset of the human variable region V, D and J gene segments inserted). The Court of Appeal was persuaded by this argument. Crucially, it also considered that the invention amounted to a “principle of general application”, which might contribute to the art not only in its use in current products, but also in products which might become capable of being made in the future. It was held that every transgenic mouse with a reverse chimeric locus (not just those with the whole human variable region) would benefit from the invention, because the invention essentially cured murine immunological sickness by its retention of the mouse constant region, no matter whether the human variable region inserted was a whole or just part. The Court of Appeal found that this teaching of the Reverse Chimeric Locus was properly taught in the patent, and that it amounted to a new generally applicable principle. The sufficiency requirement was therefore met.
The question the Supreme Court had to answer was framed as follows by Lord Briggs, who gave the leading judgment: 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 pure question of law was set against the context of the so-called ‘patent bargain’: in return for a time-limited monopoly to work his/her patent, the patentee must disclose the invention to the public in enough detail to enable the skilled person to work that invention. Sufficiency is one of the tools (alongside inventive step, for example) that serves to keep in check the patentee’s contribution to the art by reference to what is actually disclosed and can be made by the skilled person. Following a detailed analysis of both EPO and UK case law on the interpretation of sufficiency requirements, at paragraph 56 of the judgment Lord Briggs set out 8 inter-related principles which will surely be rolled out in (in)sufficiency pleadings going forwards. Among these, he confirmed that, for a product claim, what must be disclosed is the product and the ability to make the product, rather than the alleged invention / inventive concept (if different). In the context of a patent claiming a range of products, the patentee is required to disclose enough information that, coupled with the CGK, would be sufficient to enable the skilled person to make substantially all of the embodiments of products within the scope of the claim’s relevant range (where ‘substantially all’ provides scope for de minimis arguments, something that was not in issue here). It was also confirmed that a patentee may rely on a principle of general application (i.e. an integer expressed in general terms) if it would appear reasonably likely to enable the whole range of products within the scope of the claim to be made.
Applying these concepts, Lord Briggs ruled that the Court of Appeal had erred in two respects. First, the Court of Appeal wrongly held that the contribution to the art in this case was the invention, rather than the ability of the skilled person to make the product claimed. Lord Briggs captured this sentiment in the soundbite, “Patents are about products and processes, not pure ideas”. Second, the Court of Appeal had been wrong to say that a patent is sufficient if products within the claim cannot be made, as long as the benefit of the invention would be enjoyed over the whole range of the claim if and when those embodiments could be made in the future .
Regeneron’s patents only enabled the skilled person to make transgenic mice containing a small section of human antibody variable region genetic material. It was accepted at the priority date that transgenic mice containing more human variable region gene segments would be desirable by resulting in the production of more diverse antibodies. This therefore was the relevant range even though it did not affect the alleged invention (the immunological health of the transgenic mice). Thus, it was not possible for the skilled person to make the whole of the claimed relevant range and, specifically, it was not possible for the skilled person to make mice within the more valuable regions of Regeneron’s claim. Returning to the balance of the patent monopoly and the requisite ‘bargain’, Lord Briggs commented that the Court of Appeal’s decision effectively upheld a monopoly over a more valuable transgenic mouse when the disclosure of the patent (plus the CGK) did not enable that mouse to be made until years after the priority date, following further inventions.
In respect of the Court of Appeal’s reliance on a “principle of general application”, Lord Briggs characterised this as giving a monopoly for unlocking benefits that would be realised in the future. Overturning its decision, he made clear that any such principle must still actually make the embodiments within the claim available to the skilled person. The Reverse Chimeric Locus does not in itself enable the products to be made. Rather, the Reverse Chimeric Locus is the result of successfully making the products, the full range of which could not be done.
Kymab’s appeal was therefore allowed, with Lords Reed, Hodge and Sales agreeing with Lord Briggs’ judgment. Regeneron’s patents were invalid for insufficiency.
In short, Lady Black agreed with the Court of Appeal that Regeneron’s invention of the Reverse Chimeric Locus was a principle of general application. In her view, the claim was enabled across its scope by the deployment of the general principle that it would cure immunologically sick mice across the range, irrespective of the amount of human material incorporated into its genome. When characterised in a way that focusses on the Reverse Chimeric Locus as a general principle in itself, rather than the quantum of material replaced, every mouse across the range enjoys the benefit of that aspect of the invention and the claim would be sufficient.
The decision will surely be poured over in future debates about sufficiency. However, the authors of this article see that being due to the clear restating of existing law, not because it suggests anything radical. A key aspect of the disagreement between the Court of Appeal and the Supreme Court (and indeed the first instance judge, and Lady Black within the Supreme Court) seems to come down to a desire to reward a genuinely ground-breaking technology. How could Regeneron have properly claimed its invention in a way that would reward its contribution to such a fast-moving field as genetic engineering, but not be deemed insufficient? Could the claim have been a method claim along the lines of achieving the benefit advocated by Lady Black and the Court of Appeal (“A method of curing immunological sickness in transgenic mice…”)? Would this obviate the reliance on the underlying understanding of the art that the greater number of inserts possible, the more useful the mouse at producing a variety of antibodies? Or would insufficiencies remain, perhaps based on another ground such as breadth of claim? Lord Briggs himself acknowledged that the patentee might have had to confine itself to “scant and short lived reward for their efforts and ingenuity”, but that what matters is the settled, strict reading of law that a product claim must properly enable the products to be made. This “both reflects and applies the principle that the contribution to the art is to be measured by the products which can thereby be made as at the priority date, not by the contribution which the invention may make to the value and utility of products, the ability to make which, if at all, lies in the future.”