13 Jul 2020

The UK's Supreme Court ("UKSC") has handed down its eagerly awaited judgment in the dispute between Regeneron Pharmaceuticals Inc ("Regeneron") and Kymab Limited ("Kymab")[1]

The invention by Regeneron related to the creation of a type of transgenic mouse (the "VelocImmune") that is more effective in its receipt of human antibody genes, for the production of human antibodies. As such, this genetically modified mouse has been regarded as a major breakthrough in the field of bio pharmaceuticals. Nevertheless, despite such an advancement, the UKSC has held that the patents upon which Regeneron based its innovative platform are invalid for lack of sufficiency because the claims, as construed, would include a range of modified mice, some of which it would not have been possible to produce as at the priority date of February 2001.

Background

Antibodies (sometimes referred to as immunoglobulins) are proteins produced by mammalian immune systems in response to antigens – molecules from viruses, bacteria and other foreign organisms. The presence of antigens will prompt the lymphocyte B-cells (found in bone marrow) to secrete antibodies to sweep through the body to seek out the antigens. Each antibody is a Y-shaped structure consisting of four polypeptide chains – two identical 'heavy chains' and two identical 'light chains'. There are two sites (one on each arm of the Y) which work to bind to the antigen and counter its adverse effect.

Within each chain there is (i) a constant region (the "C segments") where the segments are the same across different antibodies and (ii) a variable region, in which the segments do vary depending on the particular antibody. In both mice and humans, the variable regions consist, in the light chains of variable ("V") and joining ("J") segments and, in the heavy chains, of V, J and diversity ("D") segments. 

Specificity is key to the immune response process. Antibodies are created to target a particular antigen – thus they are referred to as 'monoclonal'. Accordingly, in order to be effective against a specific antigen, the body needs to produce an antibody whose paratope can bind to the epitope of a particular antigen. When the antibody from the B-cell binds with an antigen, the cell will divide and differentiate and then through a process of agglutination/mass formation, neutralise the antigen. Some B-cells are memory cells in that after a primary infection, they will survive so that they can accelerate the immune response process if they encounter secondary infections.

Antibodies that do recognise and bind with antigens can be extracted and, through other processes, produce greater quantities of the specific antibodies for use in human treatment.

Since the antibodies made by one B-cell are identical, in order to be an effective remedy, the requirement of specificity makes it necessary for the production of a myriad of different B-cells to tackle the many different antigens that might invade the body. This diversity of B-cells and thus the variety of antibodies, is enhanced through the great number of different combinations that can be achieved by the rearrangement of the V, D and J segments of the protein. The evidence before the Supreme Court was that the number of possible combinations of the V, D and J segments which may be made from the four chains on the human antibody, is in the order of 1.5 million.

From before the priority date, it had been commonly known that the immune system could be supported and augmented by the production of antibodies outside the body. By the early 1980s, the first successful attempts to insert human DNA into mice which then were able to pass the transgene onto their offspring, had taken place. However, there were two key problems relating to the use of mice as a platform for the production of human antibodies. 

  1. The immune system of the human patient would tend to reject the murine antibodies.
  2. The implantation of human DNA into the mice tended to compromise the overall immune system of the host mouse making it far less effective in the production of human antibodies in response to the antigens – a condition described as 'immunological sickness'.

The two patents in dispute addressed these problems through the invention of a hybrid known as the Reverse Chimeric Locus ("RCL"), whereby all or part of the variable regions of the mouse's gene was replaced by human variable segments. 

Claim 1 of the main patent, European Patent No. 2,264,163 reads:

"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…"

This modification enables the VelocImmune to produce antibodies with a mixture of human and murine gene sequences so as to reduce the risk of 'immunological sickness'. The murine constant segment would be replaced later by human DNA so as to lessen the risk of rejection by the patient's immune system.

The issue

Founded in 2010 as the first spin out from the Wellcome Trust Sanger Institute, Kymab announced in March 2014 that it had devised as its platform a transgenic mouse known as the "Kymouse", with a RCL hydrid gene that retained the endogenous murine constant region but which contained the entire set (125 in total) of human antibody genes in the V region of the protein. As mentioned above, the greater the number of variable antibodies that can be achieved, then greater would be the utility, diversity and effectiveness of such a platform for drug development. 

Regeneron sued for infringement of its patents. Both the High Court and Court of Appeal construed the claims as covering a range of mice with any number of the V segments between 1 and 125. Equally both courts held that, whereas in the Velcolmmmune the murine gene segment is deleted and in the Kymouse it is repositioned to a different locus in the genome where it is then inactivated, this repositioning still constituted 'in situ replacement' as per Claim 1.

The High Court held that the patents were infringed but were invalid on grounds of insufficiency because, as at the priority date, what was disclosed in the two patents when combined with the common general knowledge at the time, would not have enabled the skilled person to make mice with a hybrid of more than a very small part of the human variable region gene locus. Accordingly, the High Court judge ruled that the disclosure in the patents did not enable the skilled person to carry out all of the embodiments falling with the claims as construed – i.e. the full range of the hybrid genes.

The requirement for sufficiency is laid down in Article 83 of the European Patent Convention which reads:

“The European patent application shall disclose the invention in a manner sufficiently clear and complete for it to be carried out by a person skilled in the art”.

This is transposed into national law by section 14(3) of the Patents Act 1977 which reads:

“The specification of an application shall disclose the invention in a manner which is clear enough and complete enough for the invention to be performed by a person skilled in the art”.

The Court of Appeal reversed the High Court's decision on validity on the basis that the patents described a general technical principle that could be applied to embodiments that might be developed or invented in the future[2]. The Court of Appeal adopted a classic technical problem/technical solution approach. It focused on how the RCL procedure led to a hybrid gene that addressed the problem of immunological sickness. Provided it could be proved that a least one of the embodiments described in the patents would work at the priority date, the Court of Appeal held that the patents would be regarded as sufficiently enabled across the range since all types of transgenic mice (including those unknown and/or from the future) within the range would eventually benefit the same from the RCL procedure.

The Supreme Court decision

Lord Briggs, who gave the majority judgment, emphasised how there is a bargain that lies at the heart of the European patent system. The nature of the bargain is that, in return for being granted a monopolistic right for a finite period, the inventor/patent applicant must disclose completely and clearly their invention such that a skilled person only applying common general knowledge as existed at the priority date – but with such person assumed to lack any imagination or ingenuity – can make the product or carry out the process that the patent describes. As a corollary to the tenets upon which this state/inventor bargain is based, the claims of the patent (and thus the monopoly being granted to the patentee) cannot go beyond the contribution which the product makes to the prior art as at the priority date.

The Supreme Court held (by 4:1) that Kymab's appeal should be granted because there was a fundamental shortcoming in the patents in that the RCL, as at the priority date, did not allow for the in situ insertion of anything more than a small part of the 125 human V segments. Whereas patentees do not have to demonstrate how every embodiment within the range can be made and they may choose to rely upon a general principle if it would appear reasonably likely to enable the whole range of products within the scope of the claim to be made, "…they take the risk, if challenged, that the supposed general principle will be proved at trial not in fact to enable a significant, relevant, part of the claimed range to be made, as at the priority date…", [Lord Briggs, paragraph 56] – i.e. because of such required subsequent further invention and developments.

The dissenting voice of Lady Black agreed with the focus of the Court of Appeal being upon the RCL being the invention rather than the range of murine products. She shared the lower appellate court's view that the benefit which was relevant for existing and future transgenic mice was a reduction in the incidence of immunological sickness. Her view was that this was an improvement over what went before which would carry forward into future products which would all benefit from the utility of the invention.

Comments

Although the UKSC stated that the rulings in its judgment about disclosure, enablement and general technical applications are in alignment with previous UK and European decisions, it looks as if the Court's strict interpretation may have significant implications for the drafting of patents. The UKSC did not go so far as to say that there is a need to disclose in the specification how the skilled person can make all the embodiments covered by the range. However, going forward from this judgment, it might prove hard to determine how the adoption of any new technique to enable future variants to incorporate the invention, might avoid invalidity challenges based upon the ground of a lack of sufficiency. Certainly, the judgment should cause patent applicants to be cautious about the breadth of ranges that they specify when describing their invention – perhaps adopting a more narrow range and hoping that the recent decisions broadening the definition for infringing acts (e.g. the Court's judgment in Eli Lily v Actavis [2017] UKSC 48) would give them the protection that they deserve. 

Nevertheless, patent strategists might also take a more pragmatic position and, in this regard, it is notable that antibody based drugs form a very valuable global market worth today the sum of around US$100 billion. Such drugs account for a significant majority of all drug sales. The VelocImmune was a ground-breaking advancement and, against this lucrative background, Regeneron did enjoy the benefit of a substantial portion of the patent term until it faced the competition of the Kymouse.

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[1] [2020] UKSC 27 (24 June 2020)

[2] See for instance Genetech 1/Polypeptide expression (Case T-292/85)