Regeneron Pharmacueticals Inc. (Claimant in Hc 11 C00127) Bayer Pharma Ag (Claimant in Hc 11 C00131) v Genentech Inc.

Hearing dates: 13 th, 16 th-19 th, 24 th and 25 th January 2012

Approved Judgment

I direct that pursuant to CPR PD 39A para 6.1 no official shorthand note shall be taken of this Judgment and that copies of this version as handed down may be treated as authentic.

Mr Justice Floyd

In two separate actions Regeneron Pharmaceuticals Inc and Bayer Pharma AG ("Regeneron" and "Bayer" respectively) have applied for revocation of European Patent (UK) No 1 238 986 ("the patent"), which belongs to Genentech Inc. Regeneron are planning to market a product called VEGF Trap Eye ("VTE") for the treatment of age-related macular degeneration of the eye. Bayer are licensees of Regeneron in respect of this product. Regeneron and Bayer also seek a declaration of non-infringement of the patent in respect of VTE. Genentech counterclaimed, positively alleging that VTE is an infringement. Regeneron and Bayer were represented by separate teams of leading and junior counsel and solicitors, Mr Waugh QC appeared for Bayer, with Mr Thomas Mitcheson; Mr Meade QC appeared for Regeneron with Mr Chacksfield. Bayer and Regeneron presented the same case, through Mr Waugh, although Mr Meade cross-examined one of the experts. Mr Tappin QC and Ms Jamal presented the case for Genentech. Genentech, although nominally defendant, opened the case and called its evidence first.

The patent is concerned with therapeutic agents for the treatment of a range of diseases by preventing the growth of blood vessels ("angiogenesis") which is associated with them. In particular it is concerned with agents which inhibit the action of VEGF (vascular endothelial growth factor). The claims are limited to non-neoplastic, that is to say non-cancerous, diseases.

The validity of the patent is attacked on the grounds of lack of novelty and lack of inventive step over a single prior art citation, and insufficiency of description.

Technical background

Blood vessels and angiogenesis

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.

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

A neoplasm, which is also known as a tumour, is an aberrant new growth of abnormal cells or tissues, in which cell growth is not under normal physiological control. Thus neoplastic diseases are those that involve tumour growth, whilst non-neoplastic diseases are all those which do not.

Antigens, antibodies, and receptors

Antibodies are molecules which are generated by the immune system to assist in neutralizing or destroying foreign material (such as bacteria and viruses). When foreign material enters the body, the proteins on its surface are recognized as foreign by the immune system, which then operates to destroy, remove or neutralize the foreign material, in part through the use of antibodies. Antibodies aid the immune response by blocking some adverse activity of the foreign molecule or by recruiting other components of the immune system to destroy or remove the material to which they are bound.

Each foreign molecule (known as an antigen) will usually have a number of sites on its surface that antibodies can bind to. Each binding site will have a unique structure and an antibody must have a complementary structure in order to bind to it. The immune system is capable of naturally engineering antibodies to have the necessary structure to bind foreign antigens.

Because of their ability to recognize specific antigen binding sites, antibodies are important in cell biology research, and in therapy. It is possible to block interactions using antibodies which recognize a binding site which is within, or adjacent to, the region of the antigen which is responsible for receptor binding. By binding in this region, the antibody obstructs normal or unwanted interactions between the antigen and its receptor.

A receptor is a site or structure which binds a signal molecule (a ligand). Cell-surface receptors are located in or on the plasma membrane with their ligand-binding site exposed on the outside of the cell. Intracellular receptors bind ligands that diffuse into the cell across the plasma membrane. Soluble receptors are receptors that are not cell-associated and that bind to a particular ligand without stimulating a cellular response. Soluble receptors can be used to antagonize a ligand's effect by reducing the amount of free ligand available to bind to efficacious receptors.

One common type of cell-surface receptor is the receptor tyrosine kinase family (RTK). RTKs generally comprise three basic elements: an extracellular domain (ECD) which is responsible for ligand binding, a transmembrane domain which anchors the receptor in the cell membrane, and an intracellular domain. The figure below shows a tyrosine kinase receptor spanning a cell wall.

A number of growth factor receptors belong to the RTK family, including the receptors for the growth factors EGF, bFGF, PD-ECGF and VEGF (see below).

Angiogenesis and cancer assays

The chick chorioallantoic membrane assay (CAM) is a model for studying the angiogenic or anti-angiogenic properties of a compound. The membrane is found underneath the external shell of chick eggs. In a typical CAM assay, fertilized chick eggs are incubated at 37°C for 3 to 4 days. The egg shell is then partially removed to produce a window in which the assay may be performed. To assess the angiogenic or anti-angiogenic activity of a particular substance, the compound is contacted locally with the CAM, usually by its incorporation into a slow release polymer pellet or absorption into a porous disc or sponge which is then implanted onto the CAM. The angiogenic or anti-angiogenic effects of the compound may be assessed by examination of the vasculature around the delivery vehicle following incubation for a further 3–4 days. The newly formed blood vessels appear in a radial pattern around the implant.

Miles' permeability assay is an assay for measuring the leakiness of blood vessels. Blue dye with a very high affinity for serum albumin, the most abundant protein in blood plasma, is injected into a test animal's veins. The dye leads to vivid and long-lasting staining of the blood serum. Following the injection, test substances are injected intradermally into shaved regions on the back or flank of the animal. Increased vascular permeability leads to an increase in extravasation of the dye, which can be visually observed as a blue patch around the injection site.

Neither the CAM assay nor Miles' permeability assay can be used to determine whether a factor is necessary for pathological angiogenesis. By contrast, the mouse xenograft test is a widely used in vivo model for determining the anti-cancer properties of test compounds. The assay involves implantation of tumour cells into mice with subsequent measurement of the resulting tumor. The anti-cancer effects of test compounds are determined by comparing the size of tumours, with or without treatment, at fixed time points following implantation. Use of "nude" mice allows human cancers to be examined in the mouse model. Nude mice have a genetic mutation which prevents the mouse from mounting an immune rejection response. Human tumour cells can therefore be grown in these mice without being recognized as foreign and thus without being attacked by the mouse's immune system.

Rheumatoid arthritis

Rheumatoid arthritis (RA) is a disease of the joints. RA involves the formation of pannus in the joint. Pannus is highly inflamed tissue which is infiltrated by cells from the bloodstream, and invading cartilage, bone and possibly tendon. It is also characterised by an abundance of blood vessels.

The patent

The patent is entitled "Use of vascular endothelial cell growth factor antagonists". It has a filing date of 28 ^th October 1992, and does not claim any earlier...