Construction and Sufficiency in the Court of Appeal

In Regeneron v Kymab ([2018] EWCA Civ 671), the Court of Appeal recently provided a detailed analysis of the assessment of sufficiency of disclosure in a complex biotech case. The Court considered whether the skilled person could work the claimed invention without undue burden (so-called “classical insufficiency”) and whether the breadth of the claim was commensurate with the contribution to the art (often called “Biogen insufficiency” in the UK). Claim construction was also considered. 

 

In its decision of 28 March 2018, the Court of Appeal (“CoA”) reversed the High Court decision of Mr Justice Carr that Regeneron’s patents EP(UK) 1360287 and EP(UK) 2264163 were insufficiently disclosed.  The CoA agreed with Carr J that certain claims were infringed. 

 

The patents relate to the technology used in Regeneron’s Velocimmune^® mice. At first instance, Regeneron brought infringement proceedings against Kymab (in view of its Kymouse^TM) and Novo Nordisk. The defendants denied infringement and counterclaimed alleging invalidity of the patents based on a lack of novelty, inventive step and sufficient disclosure. Carr J held that the mice at issue fell within the scope of the product claims, that the claims were novel and inventive, but that the patents insufficiently described the claimed invention and so were invalid. 

 

Kymab appealed the finding of infringement and Regeneron appealed on insufficiency.

 

The patents

 

The patents are concerned with the production of human antibodies using transgenic mice. The mice are produced by “in situ replacement” of mouse variable regions with human variable regions.  The mouse constant regions are retained in the mouse, resulting in a “reverse chimeric locus”. The antibodies produced by these transgenic mice have the desired human variable regions, while the presence of mouse constant regions prevents the mice from becoming immunologically sick.

 

Claim 1 of EP ‘287 relates to a method of producing transgenic mice that have human variable regions, by “in situ replacement” of the mouse variable region gene segments with orthologous human segments.  The method involves obtaining a large cloned genomic fragment (>20kb) that contains human V, D and J regions into a large targeting vector (LTVEC) and introducing this vector into a mouse embryonic stem cell.  A modification of allele (MOA) assay is then used to screen for successful replacement of the mouse variable regions with human variable regions. Claims 5 and 6 are product'by'process claims directed to a genetically modified eukaryotic cell, mouse, or mouse embryonic stem cell, obtainable by the method of claim 1.

 

Claim 1 of the divisional patent EP ‘163 is a product claim to the transgenic mouse comprising an in situ replacement of the mouse V(D)J segments with the human orthologues.

 

Construction

 

The case turned on the meaning of the term “in situ replacement”. Kymab argued that this term required the deletion of the mouse variable segments, whereas Regeneron’s construction was that the term required only the insertion of human variable sequence into the position previously occupied by the murine variable sequence.

 

The CoA preferred Regeneron’s construction as a matter of language, and sawno technical reason in the specification why the skilled person would understand that the patentee meant anything more than this.  In coming to this conclusion, the Court cautioned against the temptation to “mix up” what a claim means, in the sense of what it requires as a minimum, versus what it includes or covers, in the sense of what is included within the monopoly.

 

Infringement

 

The Kymab mice had a displaced and inactivated (but not deleted) mouse variable region. In light of the Court’s construction that deletion was not required, these mice were found to infringe the product claims. Given this finding of literal infringement, it was not necessary to consider infringement based on equivalents (as established by the Supreme Court in Actavis v Eli Lilly [2017] UKSC 48). The Court noted that it “would have been troubled by the suggestion that it could approach the issue for the first time on appeal” and would have remitted the matter back to the High Court.  

 

Sufficiency

 

Example 3 of both patents describes a two-step process for the in situ replacement of mouse variable regions with human variable regions, resulting in a reverse chimeric locus. The first step is to construct a LTVEC that contains a human insert of 200-300kb spanning from several V segments through the entire DJ region, to replace the mouse sequence of 100kb. The second step involves a second LTVEC that contains 200-300kb of human V segments that are upstream (towards the 5’ end) from the human variable region contained in the first LTVEC.

 

However, the technical evidence at first instance led Mr Justice Carr to hold that at the priority date the skilled team could not have deleted 100kb of mouse sequence and inserted 200-300 kb of human sequence in a single step based on Example 3, without undue burden. He concluded that:

“The difficulty does not relate to some hypothetical puzzle at the edge of the claim, but rather to the central disclosure of the specification…The task contemplated was unprecedented and could not have been achieved, if at all, without a great deal of creative thinking at the priority date”.

 

On appeal, Regeneron did not question the finding that the skilled team could not have deleted 100kb of mouse sequence and inserted 200-300 kb of human sequence in a single step at the priority date. Instead, Regeneron’s appeal was based on the skilled team implementing the reverse chimeric locus without undue effort by making simple and obvious adjustments to Example 3. These adjustments involved reducing the size of the inserts in the LTVEC by cutting down the number of V, D and J regions and by cutting out the intergenic regions to make a minigene. 

 

The minigene issue was not explicitly addressed by the High Court Judgment. However, it was originally raised by Kymab as part of its obviousness case and was addressed in cross-examination, so the CoA was satisfied that this issue did form part of the case at first instance and could be discussed on appeal. It did so with caution that it was of “considerable concern” that the minigene sufficiency issue was not raised with the first instance Judge upon receipt of the draft judgment. 

 

The CoA held that minigenes were part of the common general knowledge. It then concluded that given the idea of the reverse chimeric locus, it would have been obvious and technically feasible to the skilled team that the transgenic mouse could have been created without undue burden by using a minigene construct containing a subset of the human V, (D) and J segments. Each patent therefore enabled an embodiment within the claim scope.

 

The final question was then whether the invention was enabled across the entire scope claimed. The Court first reviewed EPO Board of Appeal case law discussing the need for enablement across the scope of the claim, including the following quote from the well-known T409/91:

 

“…the extent of the patent monopoly, as defined by the claims, should correspond to the technical contribution to the art in order for it to be supported, or justified.”

 

The equivalent English jurisprudence was then considered.  The concept of the reverse chimeric locus was deemed to be a major contribution to the art and so represent a principle of general application as set out by the House of Lords in Biogen v Medeva ([1997] RPC 1) and Lundbeck v Generics ([2009] UKHL 12). Noting that “if the invention discloses a principle capable of general application, the claims may be in correspondingly general terms”, the broad claims were thus held not to exceed the contribution to the art.  With reference to Regeneron v Genentech ([2013] EWCA 93), the Court observed that:

 

“A claim is not insufficient simply because it encompasses inventive improvements provided they embody the technical contribution the disclosure of the invention has made to the art.”

 

The Court concluded that the specifications of the patents disclose the claimed inventions clearly enough and completely enough for them to be performed by a person skilled in the art.

 

Kymab has indicated that it will seek leave to appeal to the Supreme Court.