(1)Regeneron Pharmaceuticals Inc. (a company incorporated under the laws of New York, USA) (Appellant in Action 0931) (2) Bayer Pharma AG (a company incorporated under the laws of Germany) (Appellant in Action 0933) v Genentech Inc. (a company incorporated under the laws of Delaware, USA)

Hearing dates: 17/18/19/20 December 2012

Introduction

These are appeals from the judgment of Floyd J given on 22 March 2012 and his consequential order dated 4 April 2012 in two actions concerning the infringement and validity of EP (UK) 1,238,986 (the patent) owned by the respondent (Genentech).

The patent discloses and claims the use of particular agents called human vascular endothelial growth factor (hVEGF) antagonists for the treatment of non-cancerous (non-neoplastic) diseases which are characterised by excessive blood vessel growth (neovascularisation or angiogenesis). It has a filing date of 28 October 1992.

The appellants (Regeneron in one action and Bayer in the other) sought revocation of the patent on the grounds of lack of novelty, obviousness and insufficiency. They also sought a declaration of non-infringement in respect of a product called VEGF-Trap which has been developed by Regeneron and which Bayer wishes to sell in the UK for the treatment of neovascular age-related macular degeneration (ARMD), a leading cause of premature blindness. The proceedings were designed to clear the way in advance of launch. Genentech counterclaimed for infringement.

The judge rejected all the attacks on the patent, holding the claims novel, inventive and sufficient. He also held that they encompass VEGF-Trap. On this appeal, the appellants submit that, in so concluding, the judge made a number of errors of principle which may be summarised as follows:

i) Construction: The appellants say the judge misconstrued the claims of the patent as not requiring any therapeutic effect on the disease or disorder in question, and that he was inconsistent in his application of his claim construction in considering the various attacks on the patent. They also say the judge wrongly held that the claims encompass any variant of a naturally occurring receptor which retains the ability to bind VEGF and inhibit its activity.

ii) Infringement: The appellants contend that, had the judge properly construed the claims, he would have found that VEGF-Trap does not fall within their scope.

iii) Novelty: The appellants argue that the judge ought to have found that Kim 1992 discloses VEGF antagonists in the form of antibodies and their use for treating relevant diseases and disorders. The patent merely provides more information about that known use, and this cannot found novelty.

iv) Inventive step: The appellants say the judge applied the wrong test in assessing whether it was obvious to take the step from the prior art to the invention. Further, he should have held the patent obvious because it was not plausible that all VEGF antagonists would be useful in the treatment of non-neoplastic neovascular diseases.

v) Sufficiency: The appellants argue that the judge's conclusions are based upon an inconsistent approach to the interpretation of the claims and that, on his own factual findings, he ought to have held the claims insufficient. Despite being framed as a medical use patent, the claims are entirely speculative and cover a huge range of non-neoplastic diseases and disorders without the experimental work needed to support them. More specifically, some non-neoplastic neovascular diseases cannot be treated with VEGF antagonists; some VEGF antagonists are not therapeutically active; and the patent imposes on the skilled person an undue burden to establish which antagonists are effective for which disease states. Moreover, VEGF-Trap does not fall within the claims on their proper interpretation; alternatively, if it does, the claims cover products which they do not enable and are insufficient for this reason too.

The skilled team and the witnesses

The judge identified the skilled team to whom the patent is addressed as being a team concerned with the development of a therapeutic agent for use in the treatment of non-neoplastic neovascular conditions. The team would include a vascular biologist and a molecular biologist.

The parties each called two witnesses to assist the judge as to the knowledge and understanding of such a team. Genentech called Professor David Shima and Dr Ewa Paleolog, both as expert witnesses. The appellants called Professor Adrian Harris and Professor Karlheinz Plate, the former as an expert witness and the latter as a witness of fact.

Professor Shima is the Professor of Translational Vision Research at University College London Institute of Opthalmology. In 1992 he was engaged in research for his PhD at Harvard University in the laboratories of Dr Judah Folkman and Dr Patricia D'Amore. Dr Folkman's laboratory was at that time, and had been for many years, a focal point for pioneering vascular biology and a leader in identifying novel angiogenic growth factors. The judge found Professor Shima to be a helpful and knowledgeable witness.

Dr Paleolog is Reader and Director of Post Graduate Studies at the Kennedy Institute of Rheumatology and in 1992 was a post-doctoral researcher at that Institute. The appellants criticised the evidence she gave about two of the relevant scientific papers but although the judge characterised this aspect of her evidence as unfortunate, he was satisfied it did not affect her evidence as a whole.

Professor Harris is Professor of Medical Oncology at the University of Oxford. He is also leader of the Growth Factor Group at the Weatherall Institute for Molecular Medicine, which he set up in the late 1980s. The judge recognised Professor Harris as a man of outstanding intellect, with enormous breadth and depth of knowledge of his subject. However, he formed the view when listening to Professor Harris that he was allowing his obvious enthusiasm for the subject to transfer to enthusiasm, in some cases misplaced, for the case which he was presenting. The judge was sure that this was not deliberate, but that it was happening was apparent to him from a number of incidents which, collectively, gave him serious concern about accepting Professor Harris' evidence as a whole. Indeed, the judge came to the conclusion that he must regard with considerable caution some of the more extreme statements made by Professor Harris in the witness box. These were serious findings and they affected the judge's approach to the key issues in the case, as I shall explain.

Finally, the judge heard evidence from Professor Plate who is a Professor and Director at the Edinger Institute at Goethe University, Frankfurt. In 1992 he was conducting post-doctoral research on the molecular mechanisms of tumour angiogenesis mediated by VEGF in the laboratory of Professor Werner Risau at the Max-Planck Institute in Munich. No criticism was made of Professor Plate as a witness of fact beyond the fact that he was plainly highly skilled and so not representative of the notional addressee of the patent.

Technical background and common general knowledge

The judge summarised the technical background at [4]–[16]. I gratefully adopt the following aspects of that description which have a particular bearing on the issues arising on this appeal. I begin with the structure of blood vessels, angiogenesis and neoplastic and non-neoplastic diseases:

"Blood vessels and angiogenesis

4. Blood vessels comprise two main cellular components: the endothelium and the mural cells. The endothelium is a continuous, cylindrical layer of cells, called endothelial cells, which interface with blood in the vessel.

5. Vasculogenesis is the formation of blood vessels from scratch. Vasculogenesis primarily occurs during embryonic development of the circulatory system. Angiogenesis, or neo-vascularisation, on the other hand, is the process of new blood vessel growth by endothelial cell proliferation and outgrowth from pre-existing vessels. In a number of normal physiological processes, such as wound healing and during the female reproductive cycle, new blood vessels are required to supply oxygen and nutrients to developing tissues. In these processes new blood vessels are produced by angiogenesis from the existing vasculature. Excessive angiogenesis, on the other hand, is a contributing factor to the pathology of a number of diseases, including cancer. In cancer, tumour cells cause new blood vessels to be produced by angiogenesis in order to supply nutrients and oxygen to the tumour, enabling it to survive and grow. These new blood vessels also enable tumour cells to escape into the bloodstream and spread to other areas of the body in a process known as metastasis. In diseases such as diabetic retinopathy and neovascular age-related macular degeneration, new blood vessels directly disrupt or interfere with the structure or normal function of other tissues.

Neoplastic and non-neoplastic diseases

6. A neoplasm, which is also known as a...