On March 22, 2012, Justice Floyd of the Chancery Division of the High Court of Justice held that Regneron’s VEGF-TRAP-EYE infringes European Patent (UK) No. 1 238 986 and that the ‘986 Patent was valid. The Claimants, Regeneron and Bayer, had separately sought revocation of the ‘986 Patent and a declaration of that VEGF-TRAP-EYE does not infringe the ‘986 Patent.
The ‘986 Patent is generally directed to use of certain human vascular epithelial growth factor (hVEGF) antagonists to prevent the undesirable growth of blood vessels in non-neoplastic diseases. The patent discloses the construction of certain hVEGF antagonists, including a fusion protein of the extracellular domain (ECD) of the fit hVEGF receptor (hVEGFR) and a human IgG1 constant region sequence. The patent also discloses the results of several in vitro and in vivo assays employing a specific anti-VEGF monoclonal antibody. Claim 1 of the ‘986 patent reads as follows:
Use of a hVEGF antagonist in the preparation of a medicament for the treatment of a non-neoplastic disease or disorder characterised by undesirable excessive neovascularisation, wherein the hVEGF antagonist is
(a) an anti-VEGF antibody or antibody fragment;
(b) an anti-VEGF receptor antibody or antibody fragment; or
(c) an isolated hVEGF receptor.
VEGF-TRAP-EYE (aflibercept) is an immunoadhesin containing Ig domain 2 of VEGFR-1 and Ig domain 3 of VEGFR-2 fused to the constant region of IgG1. Aflibercept is approved in the US and Australia under the trade name EYLEA for the treatment of wet age related macular degeneration.
Construction / Infringement
The major infringement issue was the proper construction of element (c) of claim 1. The Claimants submitted that unlike elements (a) and (b), which explicitly contemplate fragments, “ìsolated hVEGF receptor” should be construed to mean the complete VEGF receptor or, in the alternative, fragments that comprise the entirety of the extracellular domain (ECD) of VEGFR. Justice Floyd did not accept the Claimants’ proposed construction, finding:
Once it is accepted that the claim is not excluding fragments as a matter of language, I see no technical reason why the claim should be read as limited to any particular size of fragment provided that the fragment retains the essential ability to bind hVEGF and inhibit its biological activity. I do not think that the skilled person would have a perception that anything less than the complete ECD would lead to insufficiency. On the contrary, he or she would be surprised if the patentee had intended to leave the field open to anyone who could eliminate unnecessary domains, whilst still making use of the invention. Whether in fact the claim so construed is insufficient is a matter which I will have to return to under that head.
The Claimants also submitted that the development of VEGF-TRAP-EYE involved a major research project, and that the skilled person would not understand VEGF-TRAP EYE to be contemplated within the claims of the patent. Justice Floyd held that this was not the proper infringement analysis – VEGF-TRAP-EYE is an hVEGF antagonist and “is plainly within the language of the claim as it would be understood by the skilled reader”.
The Claimants alleged that the ‘986 patent was invalid on three grounds: anticipation, obviousness and insufficiency.
The Claimants relied on a reference disclosing the development of anti-hVEGF monoclonal antibodies that provided experimental results showing that these antibodies can bind to endothelial cells and prohibit their growth in vitro, as well as neutralizing the activity of VEGF in two in vivo animal models. This reference concluded that:
The potent neutralizing mAb A4.6.1, which binds three forms of VEGF, may be valuable in determining the importance of the production of VEGF in regulating the growth and metastasis of tumor cells and in inflammation. These well defined mAbs could be potential tools to determine the level of VEGF in many pathological conditions and to understand the structural and functional relationship of VEGF with its receptor(s). Further, VEGF neutralizing mAbs could be potential therapeutic agents in diseases involving excess endothelial cell proliferation.
Justice Floyd found that for anticipation the prior disclosure must contain material from which the skilled person could “directly and unambiguously deduce the claimed therapeutic effect”. A disclosure that a compound might have a therapeutic effect is not a disclosure of the fact that it does have that effect. Since the reference did not provide data from which it could be deduced that the antibody will have a therapeutic effect, Justice Floyd concluded the reference did not deprive the claim of novelty.
Justice Floyd held that in a use case like the one before him, the prior art must provide the skilled person with an expectation of success “sufficient to induce the skilled person to use the invention”. Where the invention lies in the claim that a compound has a particular use, a finding that a product might work for the claimed use is not the proper analysis. Because of the uncertainty at the relevant time on the mechanisms and factors involved in angiogenesis, including that other research groups were investigating many factors other than VEGF, Justice Floyd concluded:
I bear in mind that there was the strongest of motivations to discover a therapy that would target a molecule within the body responsible for angiogenesis. That motivation was, however, being channelled down far more avenues than anti-VEGF therapy. I also bear in mind that there is no suggestion that there would be any unusual difficulty in carrying out the mouse xenograft test. Against that I have to place the fact that VEGF was only one of many factors and other agents which could be investigated, the commonly accepted view that there was no single factor responsible, the confusing picture presented by the common general knowledge and the view that achieving anti-angiogenesis therapy would be difficult. I cannot accept that the publication of Kim 1992 altered the landscape to the extent that it was now obvious that VEGF could be used in therapy, or that it was now obvious to try that use.
In finding claim 1 non-obvious, Justice Floyd also relied on the accolades and scientific awards received by one of the inventors of the ‘986 Patent.
The Claimants attacked the breadth of the claims on two major grounds. First, that the claims were directed to all non-neoplastic diseases and second that the claims were directed to all hVEGF antagonists. On the first ground, Justice Floyd accepted that it is possible to extrapolate results showing that VEGF antagonists slow the progression of tumors to at least some non-neoplastic angiogenic diseases, including diabetic retinopathy. The ‘986 patent discloses a principle of general application and the patentee was not required to prove the hVEGF antagonist was effective in non-neoplastic diseases.
In respect of the second ground of insufficiency, the Claimants submitted that it would involve undue burden to develop different hVEGF antagonists containing truncated forms of the extracellular domain of VEGFR. Justice Floyd found that the biotech industry is ”one where careful experimentation with a degree of trial and error, sometimes extending over months and years, is entirely normal” and concluded that the refinement of the inventive concept to its most elegant embodiment, does not make earlier constructs insufficient.
A copy of the Judgement may be found here.