Regeneron v Kymab and the effect of claim scope on the requirement of sufficiency of disclosure

Regeneron v Kymab and the effect of claim scope on the requirement of sufficiency of disclosure

By Tom Leonard
Contributions by Oliver Chammas
 
Earlier this year, the UK Supreme Court (UKSC) heard pleadings on behalf of Kymab Ltd (“Kymab”) and Regeneron Pharmaceuticals, Inc (“Regeneron”) in their ongoing dispute over patents relating to transgenic mice capable of producing antibodies suitable for use in humans. In a judgment handed down today (24 June 2020), the UKSC overturned an earlier Court of Appeal ruling and allowed Kymab’s appeal on the basis the patents asserted by Regeneron were invalid for reasons of insufficiency.
 
In this article, we summarise the background of the case and discuss what this could mean for the requirement of sufficiency of disclosure in the UK. The take home message for your patent filing strategy is this: when drafting applications, consider in detail the scope of each feature of your claims. If a feature is both (1) broad and (2) responsible for the advantages of the invention, consider including (optional) language in your specification that limits the breadth of that feature if the skilled person cannot put the invention into practice across its whole scope based on their common general knowledge.
 
For a detailed analysis, read on.


 

How did we get here?

The case relates to two of Regeneron’s Patents, European Patent (UK) No 1360287 and its divisional European Patent (UK) No 2264163 ("the ‘287 patent" and "the ‘163 patent", respectively). 
 
Regeneron initially brought an infringement claim against Kymab, who counterclaimed for invalidity. In the first instance, Henry Carr J ruled the patents were invalid due to insufficiency. However, if the patents were found to be valid, Kymab’s various strains of transgenic mice would have infringed claims 5 and 6 of the `287 patent and claim 1 of the `163 patent.
 
Regeneron appealed the finding of invalidity and Kymab cross-appealed the finding of infringement. The Court of Appeal overturned the original decision and found the patents valid as well as dismissing Kymab’s cross appeal, therefore finding that the patents were also infringed. Kymab was granted leave to appeal to the Supreme Court. The injunctive relief granted by the Court has been the subject of many a blog post, given it was stayed pending the outcome of the second appeal, but that is outside the scope of this article.
 
Today’s judgment reverses the Court of Appeal’s finding, revoking both of the patents for not meeting the requirement of sufficiency of disclosure.
 

The technological background

The technological background is highly complex. In summary, the patents in general relate to transgenic mice for the production of human antibodies. Antibodies (aka immunoglobulins) are a key part of the immune system that target foreign proteins known as antigens. The structure of an antibody is traditionally depicted as having a Y-formation, and all antibodies share a characteristic unit structure made up of two identical “heavy” chains and two identical “light” chains. These heavy and light chains are themselves made up of segments known as the variable (V), diversity (D), joining (J) and constant (C) gene segments. The heavy chain of an antibody has V, D, J and C segments. The light chains have only V, J and C segments.
 
V, D, and J segments (in the case of the heavy chain) and the V and J segments (in the case of the light chain) are joined together at the DNA level in a process known as VDJ recombination, or somatic gene rearrangement. The way in which the segments are combined determines the specificity of the antibody (i.e. to what antigen or antigens the antibodies bind). Following VDJ recombination, the VDJ sequences undergo further rounds of mutation to improve the affinity of the antibodies for their antigen, in a process known as somatic hypermutation.
 
The eventual result is the production of a huge array of different antibodies from a relatively small pool of starting materials. This process is crucial to enable the production of antibodies that specifically bind a wide variety of antigens with high affinity.
 
A complication is that the V, D, J and C gene segments are different in different animals. So, although it is relatively easy to produce mouse antibodies to an antigen by inoculating the mouse with the antigen and allowing the murine immune system to generate antibodies that target the antigen, those antibodies are not suitable for use in humans, because a human host would react to the mouse antibodies themselves as foreign proteins. This is known as the human anti-mouse antibody (HAMA) response. The inventors of the ‘287 and ‘163 patents aimed to solve this HAMA problem when using mice to produce antibodies for later use in humans.
 
Transgenics is the term used to describe the introduction of DNA fragments encoding functional gene products from one species into the germ line of a different species. In transgenics, one can take (for example) human antibody genes and insert them into a mouse genome. This method can be used to create antibodies in a mouse that can later be administered to a human without inducing a HAMA response, because human genes were used to make the antibodies.
 
The insertion of the entire human immunoglobulin genes (i.e. all of the V, D, J and C segments) had already been achieved prior to the filing of the patents at issue here. However, the immune response in these mice was poor, and the mice were deemed “immunologically sick”. To avoid this problem, the patents proposed what is known as the “reverse chimeric locus”, in which only the mouse V, D and J segments are replaced with the human counterparts, and the mouse constant (C) regions are retained. The provision of mice with this reverse chimeric locus was the foundation of the Regeneron patents. When mice having the reverse chimeric locus are inoculated, the immune response is much improved compared to mice in which the C segments have been replaced as well, and the mice are not “immunologically sick”. The antibodies produced by such mice can easily be made suitable for use in humans by later replacement of the mouse constant region with human sequences, which is a technologically simple thing to do.
 
However, this is where one runs into a problem. The specific replacement of only the mouse V, D and J sequences with the human equivalents is extremely challenging due to the amount of DNA that must be targeted to a specific location in the mouse genome. It was not until over a decade after the original patent was filed that the replacement of all the mouse V, D and J segments with corresponding human segments, whilst retaining the mouse C segments, was actually achieved.
 

The patents at issue

Claim 1 of the ‘163 patent is as follows:

1. 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.

 
Claims 1, 5 and 6 of the ‘287 patent are as follows:

1. “ A method of modifying an endogenous immunoglobulin heavy chain variable region gene locus in an isolated mouse embryonic stem (ES) cell by an in situ replacement of V, D, and J gene segments of the endogenous locus with orthologous human V, D and J gene segments, to create a modified immunoglobulin locus that produces hybrid antibodies containing human variable regions and mouse constant regions, said method comprising:

a) obtaining a large cloned genomic fragment greater than 20kb containing orthologous human V, D, and J gene segments;
b) using bacterial homologous recombination to genetically modify the cloned genomic fragment of (a) to create a large targeting vector for use in a mouse ES cell (LTVEC);
c) introducing the LTVEC of (b) into a mouse ES cell to replace said V, D, and J segments in situ with the orthologous human V, D and J gene segments; and
d) using a quantitative assay to detect modification of allele (MOA) in the mouse ES cell of (c) to identify a mouse ES cell in which said V, D and J segments have been replaced in situ with the orthologous human V, D and J gene segments.

5. A genetically modified eukaryotic cell or a mouse comprising a genetically modified immunoglobulin heavy chain variable region locus obtainable by the method of any one of the preceding claims in situ in place of the endogenous immunoglobulin heavy chain variable region gene locus.

6. A mouse embryonic stem (ES) cell containing a genetically modified immunoglobulin heavy chain variable region gene locus obtainable by the method of any one of claims 1 to 4 in situ in place of the endogenous immunoglobulin heavy chain variable region gene locus.”

 
Much was made of the construction of these claims during the High Court and Court of Appeal trials. Notably, the claims are silent on the extent of the in situ replacement of the V, D and J segments. In the end, it was determined the claims encompassed mice in which at least a portion of each of the mouse V, D and J segments had been positionally replaced with at least a portion of each of the human V, D and J segments. It was also determined the claim scope extended to mice in which all of the mice V, D and J segments had been replaced with human segments. The lower end of this range was technologically feasible at the priority date and, moreover, the resulting mice did not suffer from immunological sickness. However, the range of antibodies than can be produced in such mice is limited (and it required the skilled person to use a method different to the one described in the patent, a matter that was considered extensively in the earlier judgments but is not of relevance here).
 
However, most of the range of the claim, up to and including the significantly more ambitious aim of providing mice with entirely replaced V, J and D segments was not possible without a person coming up with several inventive developments of their own. Yet the scope of the claims clearly extended to these technologically advantageous mice. Moreover, the Kymab mice did have replacement of all the V, J and D segments whilst retaining the mice C segments, and hence the scope of the claim needed to extend to this extreme if there was to be infringement.
 
This is the big question: is the scope of the claims justified on the basis of the disclosure of the general principle of a “reverse chimeric locus”? Or does the claim lack sufficiency because the disclosure enables only the provision of mice with a small portion of their genome replaced?
 

The relevant legal principles

The main point of contention between the parties was whether the idea to provide a mouse in which at least some of the V, J and D segments are replaced, but the C segments are retained (i.e. the idea of the reverse chimeric locus itself) represented a “principle of general application” that was applicable to all products falling with the scope of the claims. Kymab conceded the reverse chimeric locus was an inventive advance. Moreover, all mice falling within the scope of the claims would have the advantage of not being immunologically sick.
 
However, to Regeneron’s detriment, the UKSC found the legal concept of a “principle of general application” to be limited in scope.
 
It is well established that for a patent monopoly to be considered sufficiently disclosed, it must be possible for the skilled person to make substantially all the types or embodiments of products falling within the scope of the claim (T226/85, Unilever/Stable Bleaches). Regeneron attempted to rely on T292/85, a seminal decision of the Board of Appeal of the EPO, which stated “an invention is sufficiently disclosed if at least one way is clearly indicated enabling the skilled person to carry out the invention”. However, in the UKSC’s view, and referring to T435/91 on this point, taken in context one had to bear in mind “at least one way” was enough “as long as there are suitable variants known to the skilled person through the disclosure or common general knowledge which provide the same effect for the invention” (emphasis added). It is those variants that enable the rest of the scope of the claim.
 
In Regeneron’s case, it was not possible to rely on either the content of the disclosure or the common general knowledge to enable the remaining scope, because of the technical difficulties associated with the specific and targeted replacement of larger parts of the mouse genome.
 
Rather, the “general principle”, if it is to be relied upon, must itself allow the scope of the claim to be practised by the skilled person. The Regeneron patents failed to meet this test, because the contribution of the general principle of a “reverse chimeric locus” did not itself enable the scope of claims. Quoting Chiron Corpn v Organon Teknika Ltd (No 3) [1994] FSR 202, the UKSC judgment notes at paragraph 51;
 

This shows that there is more than one way in which the breadth of a claim may exceed the technical contribution to the art embodied in the invention. 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. Or it may claim every way of achieving a result when it enables only one way and it is possible to envisage other ways of achieving that result which make no use of the invention.” (emphasis present in UKSC judgment)

Furthermore, it is also well established the patent monopoly conferred by the patent must correspond to the extent of the contribution to the art (the “patent bargain”). In the case of a product claim, the contribution is the ability of the skilled person to make the product itself. Whilst patent applicants are free to choose how widely they frame their claims when filing an application, they risk an attack of a lack of sufficiency (and also lack of inventive step) if that framing is too broad.
 
In this case, it is clear the UKSC considered the breadth of the claims to be wider than justified by the contribution to the art, because only a small area of the invention could actually be put into practice at the priority date. It is important to note here the UKSC made specific reference to the context of the invention, namely the provision of mice that can produce a diverse range of potentially useful antibodies for human therapy. Mice having only a small amount of the V, J and D segments replaced with their human counterparts are limited in the diversity of antibodies they can produce. Mice having all of the V, D and J segments replaced, on the other hand, are significantly more useful. This range of segment replacement is what the UKSC referred to as a “relevant range”. Where one falls on that range “significantly affects the value or utility of the product in achieving the purpose for which it is to be made” (paragraph 56 of the UKSC judgment). The ability (or not) of the skilled person to provide products falling within that “relevant range” is therefore pertinent to sufficiency.
 
In this regard, the UKSC referred to T409/91 (Exxon/Fuel Oils), cited in the UK by Generics v Lundbeck among others. In that case, the claim referred to fuel oils containing wax crystals having an average particle size of less than 4,000 nm. Smaller wax crystals were advantageous, because they did not clog filters. However, it was not technically possible to produce wax crystals having a size of less than 1,000 nm, and therefore the range of “less than 4,000 nm” without a lower limit was insufficient.
 
The same considerations were applied by the UKSC in this case:
 

The extent to which that variable region of the human antibody gene structure could be included in the hybrid antibody gene structure was, at that date, understood to be a very important factor affecting the diversity of useful antibodies capable of being “discovered” by the use of transgenic mice, so that the range thus denominated was a relevant range for sufficiency purposes, even though it did not affect the immunological health of the transgenic mouse. Thus the claim to a monopoly over the whole of that range went far beyond the contribution which the product made to the art at the priority date, precisely because mice at the more valuable end of the range could not be made, using the disclosure in the patents”. (paragraph 57 of the UKSC judgment)

On that basis, the UKSC overturned the finding of the Court of Appeal and allowed Kymab’s appeal, revoking both patents.
 

The wider impact of this judgment

For Kymab, this is clearly a significant win, avoiding damages potentially in excess of £60 million, as well as the delivery up of infringing mice. But there are also wider implications of this judgment from the UKSC.
 
The UKSC made a clear distinction in this case between the inception of an idea (the concept of the reverse chimeric locus) and the reduction of that idea to practice. The completion of both of these are required to arrive at a patentable invention. Regeneron met the first stage of this test, but only met the second part of this test for a small area of the eventual claim scope. Without the further contribution to the art of how to reduce the idea to practice across the remainder of the claim scope, sufficiency for the claim as a whole was denied.
 
This serves as an important reminder: one must include optional language in patent drafts that puts limits on the scope of each feature, where the range of that feature directly influences the “value or utility” of the invention by virtue of it being responsible for the advantages of the invention. It may also be sensible to include these limitations in dependent claims, to allow them to more easily be relied upon during post-grant proceedings, in particular national proceedings where the ability to amend claims may be more limited than in post-grant proceedings before the EPO. One can easily see why Regeneron would not have wanted such a limitation be introduced into their own claim since, although it would have been less vulnerable to a sufficiency attack, it would not have encompassed Kymab’s mice and there would have been no infringement. That being said, Regeneron still has several pending divisional applications in the same family, so it is possible further proceedings could eventually be forthcoming.
 
 
To this author it seems possible Regeneron could have fared better had the contribution to the art been considered by the Court as the provision of mice that do not suffer from immunological sickness, rather than the downstream and more ambitious goal of providing a diverse library of antibodies for human therapy.
The fact the actual utility of the mice was framed in this latter way meant the invention was only achieved in part. The reduction of immunological sickness, however, was achieved for the entire scope of the claim. Indeed, this appears to be the basis for the sole dissent in this judgment (by Lady Black). Perhaps this judgment may therefore also serve as a word of caution against promising too much in patent specifications. If a defence to a sufficiency attack relies (at least in part) upon the framing of the contribution of the invention in a particular way, it would probably be more convincing if said contribution corresponds with what the patent itself says.
 
An additional consideration, one that is already on the mind of patent applicants, is the decision of when to file an application. If claim breadth is important, should you wait to file the application when you have more examples or have further refined the technique? That will not always be an option, such as in this case when it was many more years before the entire scope of the claim was enabled. At the very least, have detailed conversations with your inventors about each feature of the claims, and determine where the scope is justified (does the common general knowledge enable the remaining scope), or where more evidence or explanation might be needed on filing to support that scope. At the very least, optional limiting language should be included, should you need to narrow that feature in future.
 
Finally, it is curious the UKSC judgment is in direct contradiction to the Board of Appeal’s finding in proceedings relating to one of the two Regeneron patents (EP1360287 in T2220/14) and, curiouser still, the UKSC judgment makes no reference to this contradiction, other than to state at paragraph 30 “the interpretative objective is to strive for consistency between European and UK patent law”. Yet the jurisprudence of the Boards of Appeal at the EPO clearly influenced the final conclusion of the Court. Clearly one cannot rely on the outcome of proceedings before the EPO to predict the outcome of national proceedings, and this judgment is another example of that. Perhaps this UKSC judgment will, nevertheless, influence the awaited Board of Appeal decision in connection with the other Regeneron patent (EP2264163), which was upheld at first instance by the Opposition Division but for which there is a pending appeal (T1043/18).
 
If you have any questions on this judgment, please feel free to contact Tom Leonard, or your usual Kilburn & Strode advisor.

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