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You are here: BAILII >> Databases >> England and Wales High Court (Patents Court) Decisions >> Regeneron Pharmacueticals Inc v Genentech Inc [2012] EWHC 657 (Pat) (22 March 2012) URL: https://www.bailii.org/ew/cases/EWHC/Patents/2012/657.html Cite as: [2012] EWHC 657 (Pat) |
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Case No: HC 11 C00127 HC11 C00131 |
CHANCERY DIVISION
PATENTS COURT
Royal Courts of Justice Strand, London, WC2A 2LL |
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B e f o r e :
____________________
REGENERON PHARMACUETICALS INC |
Claimant in HC 11 C00127 |
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BAYER PHARMA AG and - |
Claimant in HC 11 C00131 |
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GENENTECH INC |
Defendant |
____________________
Richard Meade QC and Mark Chacksfield (instructed by Bird & Bird LLP) for the Claimant in HC 11 C00127
Michael Tappin QC and Isabel Jamal (instructed by Marks & Clerk Solicitors) for the Defendant
Hearing dates: 13th, 16th-19th, 24th and 25th January 2012
____________________
Crown Copyright ©
Mr Justice Floyd :
Technical background
Blood vessels and angiogenesis
Neoplastic and non-neoplastic diseases
Antigens, antibodies, and receptors
Angiogenesis and cancer assays
Rheumatoid arthritis
The patent
"In view of the role of vascular endothelial cell growth and angiogenesis, and the role of those processes in many diseases and disorders, it is desirable to have a means of reducing or inhibiting one or more of the biological effects of VEGF. It is also desirable to have a means of assaying for the presence of VEGF in normal and pathological conditions, and especially cancer."
"The present invention as defined in the claims provides the use of antagonists of VEGF, including (a) antibodies and variants thereof which are capable of specifically binding to hVEGF or hVEGF receptor and (b) hVEGF receptor and variants thereof in the manufacture of a medicament for the treatment of non-neoplastic diseases or disorders characterized by undesirable excessive neovascularization, including by way of example rheumatoid arthritis, psoriasis, atherosclerosis, diabetic and other retinopathies, retrolental fibroplasia, neovascular glaucoma, hemangiomas, thyroid hyperplasias (including Grave's disease), corneal and other tissue transplantation, and chronic inflammation."
"The present invention provides antagonists of hVEGF which are capable of inhibiting one or more of the biological activities of hVEGF, for example, its mitogenic or angiogenic activity. Antagonists of hVEGF act by interfering with the binding of hVEGF to a cellular receptor. Included within the scope of the invention are antibodies, and preferably monoclonal antibodies, or fragments thereof, that bind to hVEGF or hVEGF receptor. Also included within the scope of the invention are hVEGF receptor and fragments and amino acid sequence variants thereof which are capable of binding hVEGF."
"The antibodies included within the scope of the invention include variant antibodies, such as chimeric (including "humanized") antibodies and hybrid antibodies comprising immunoglobulin chains capable of binding hVEGF or hVEGFr, and a non-hVEGF epitope.
The antibodies herein include all species of origin, and immunoglobulin classes (e.g., IgA, IgD, IgE, IgG, and IgM) and subclasses, as well as antibody fragments (e.g., Fab, F(ab')2 and Fv), so long as they are capable of binding hVEGF or hVEGFr. and are capable of antagonizing a biological activity of hVEGF."
The claims
"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."
The skilled addressee
The witnesses
Professor Shima
Dr Paleolog
Professor Harris
"Anti-VEGF antibodies are effective systemically in mice because they were able to block VEGF [when] administered subcutaneously in high amounts. So anti-VEGF administered systemically are effective in mice"
Q. You would not be able to deduce from the known properties of VEGF that it would have a significant role in pathological angiogenesis.
A. Yes, you would be able to deduce from all these properties listed here that it would be the best candidate to look at. That is why I personally, and many others, switched to have a look at it.
Q. I am not sure you are answering quite the same question. I am not asking whether you would have thought it was the best candidate to look at. I am asking you whether you would be able to deduce from the properties that it would have a significant role in pathological ----
A. I am saying it would.
Professor Plate
Issues of construction
"Use … for the treatment of a non-neoplastic disease or disorder characterised by undesirable excessive neovascularisation"
"an isolated hVEGF receptor"
The common general knowledge
The work of Dr Judah Folkman
Angiogenesis research
"In summary there appear to be many stimulators of angiogenesis. Their properties, in particular the ability to stimulate endothelial cell migration and proliferation, their specificity, and their ability to be secreted are summarized in Table 1. The effects of angiogenesis factors on endothelial cells in culture vary dramatically. FGF, VEGF/VPF, PD-ECGF and TGF-a, are examples of angiogenesis factors that directly stimulate endothelial cell migration and proliferation. Angiotropin stimulates migration, but not proliferation. Angiogenin seems to have no effect on endothelial cell migration and proliferation. TGF-ß and TNF-α are inhibitors of endothelial cell proliferation, but they can induce 3-dimensional tube formation and angiogenesis. Angiogenesis factors differ in target cell specificity. VEGF, PD-ECGF, and angiotropin are the only angiogenesis factors that appear to be specific for endothelial cells. Finally, with the exception of FGF and PD-ECGF, most of the angiogenesis factors are secreted, which suggests paracrine[1] functions. FGF and PD-ECGF may be released by cell lysis. Thus it is clear from the different properties of these various factors that angiogenesis can be induced by different mechanisms, most or which have yet to be elucidated. Some factors influence angiogenesis by stimulating migration and proliferation, while others appear to be more active in the differentiation pathway. Some angiogenesis factors probably work directly on endothelium, while others most likely work indirectly by activating a secondary cell to produce angiogenesis factors. The large number of angiogenesis factors suggests redundancy in the vascularization process. The process of angiogenesis is sufficiently important so that tissues do not rely on one angiogenesis factor alone. The redundancy of angiogenesis factors, however, might make anti-angiogenesis therapy difficult. It will be of interest to see if the various angiogenesis factors act synergistically and are differentially regulated."
Q. What they say in here, is it not, is that anti-angiogenic therapy is likely to be difficult?
A. Correct.
Q. The reason for that is that unless one can find a factor which is necessary for the pathological angiogenesis, inhibiting that factor is not going to produce a therapeutic effect.
A. Correct.
"The field of angiogenesis has seen dramatic progress over the last two decades since Folkman first pointed out the importance of this process to tumor vascularization. Initially it seemed that there might be an angiogenic factor unique to tumors. This concept was displaced by the finding that at least one angiogenic factor (bFGF) had wide tissue distribution in both tumors and normal tissue. Furthermore, it is now obvious that there are a number of angiogenic factors. Since the distribution and action of these factors is not yet known, it is difficult to speculate on their relative contributions to angiogenesis. It is clear that our knowledge is fragmentary and that a number of important questions remain to be answered before a complete picture will be elucidated concerning the control of angiogenesis. For instance, two of the angiogenic factors described (the FGFs and PD-ECGF) lack signal sequence and the mechanism of their release is therefore unclear. Localization of FGF to cell surfaces and matrix associated heparin-like molecules has led to the speculation that these may act as easily accessible reservoirs of FGF. How does the FGF gain access to these sites? Since no significant functional differences have been demonstrated between acidic and basic FGF, what is the purpose of the two forms of FGF? Are there qualitative differences among the various kinds of angiogenesis (e.g. embryogenesis, wound healing, tumor vascularization, and so on)? How is the process of angiogenesis regulated? Is quiescence maintained by a balance between stimulators and inhibitors? If so, might one be able to induce or block neovascularization simply by interfering with this balance? Some insight into these questions will require the use of specific reagents that can specifically block or stimulate vessel growth. A good example is provided by studies in which neutralizing antibodies against bFGF were shown to block neovascularization induced by a sponge implant, which strongly implicates a role for bFGF in wound repair. Finally, although a variety of substances have been demonstrated to block angiogenesis using in vivo assays, none has been demonstrated to function physiologically."
"VEGF is of particular interest in that it appears to be a specific growth factor for endothelium in contrast to the FGF and EGF families which are mitogenic for a wide range of cells."
"The number of factors known to affect endothelial growth has increased markedly. However, many of these are much less potent than FGF and it will be important to establish which are relevant in vivo. Analysis of human tumour biopsies to determine which particular angiogenic factors are produced by given tumour type and studies with human capillary endothelium may be particularly helpful in this regard. Capillary endothelium from different organs appears to respond to a different repertoire of growth factors, for example, lung capillary endothelium is stimulated by EGF but not that from adrenals. Nevertheless, it is likely that mechanisms of angiogenesis are common to many tumour types and the hope is that anti-angiogenic therapies may be widely applicable."
"Angiogenic factors and inhibitors have been discovered only in the past decade, and while their properties can be listed (Table 1) the elucidation of their interactions with each other is only beginning to be uncovered.
Now, completely sequenced angiogenic molecules can be tabulated, but we only have a dim conception about how they operate, how they mediate angiogenesis and how they are regulated. Also, most of these molecules have other effects, and the interrelations between the different factors and their effects are still largely unknown."
Reliance on Dvorak
Conclusion on common general knowledge on VEGF
Q. All those hypotheses made it a more interesting factor than the others in terms of prospects of success. Correct?
A. I do not believe that those would have actually given you any confidence of success.
Q. That was not an answer to my question. So far as prospects are concerned, VEGF had better prospects on the basis of those hypotheses, accepting that they are, than FGF or any of the others?
A. I do not agree.
Q. On what basis?
A. As I have already explained to you, FGF has been shown to be an extremely potent angiogenesis factor, as was TGF beta, working in completely different ways but they were shown to be relevant angiogenesis candidates. What I am saying is I think that those properties of VEGF are interesting but we do not really know their relevance until we understand how it works in vivo, either during embryonic angiogenesis or in a relevant animal model of disease.
Q. But you understand the relevance of secretion. You understand the relevance of selectivity.
A. I do not understand the relevance of selectivity. As I already said to you, that is an interesting property. We did not know how relevant it was going to be. I do understand, that I have already explained, that the properties were interesting, but they were not absolutely required at the time. We did not know. The field was not sure how to place that in context.
Q. Selectivity; you understood the proposition that if it was more selective it was a more desirable therapeutic target?
A. No, in fact, the opposite has also been proposed. It was too selective and maybe it would not be involved in pathological situations but maybe more likely in embryonic situations.
"Thus, blocking of a single angiogenic factor may indeed, in some cases, prevent tumour vascularisation. However, with the existence of multiple angiogenic factors it is unlikely to be a panacea. There exists an urgent need for more information concerning the release of angiogenic factors by different tumour types. How prevalent are the different factors? Which should we target?
We have found that some breast carcinoma cell lines produce mRNA for multiple angiogenic factors. For example, line MDA-23 I produces bFGF, VEGF (vascular endothelial growth factor), pleiotrophin and PDECGF (platelet-derived endothelial cell growth factor), and possibly many others. Thus, blocking the activity of a single angiogenic factor by whatever means is unlikely to give rise to a widely applicable therapy. Such a strategy has a chance of success only if it is found that certain types of tumours secrete a single common angiogenic factor that may be targeted. A notable candidate is VEGF which appears to be virtually universal to breast and brain tumours, in marked contrast to the FGF family of peptides which are quite rare in breast tumours."
Infringement
VEGF Trap-Eye
- the immunoglobulin-like domain 2 of the VEGF-R1 receptor; and
- the immunoglobulin-like domain 3 of the VEGF-R2 receptor; fused to
- the constant region (Fc) of human immunoglobulin G1.
Is VTE an isolated VEGF receptor?
Lack of novelty
Lack of novelty –Law
"2.-(1) An invention shall be taken to be new if it does not form part of the state of the art.
(2) The state of the art in the case of an invention shall be taken to comprise all matter (whether a product, a process, information about either, or anything else) which has at any time before the priority date of that invention been made available to the public (whether in the United Kingdom or elsewhere) by written or oral description, by use or in any other way."
"If the prior inventor's publication contains a clear description of, or clear instructions to do or make, something that would infringe the patentee's claim if carried out after the grant of the patentee's patent, the patentee's claim will be shown to lack the necessary novelty. The prior inventor, however, and the patentee may have approached the same device from different starting points and may for this reason, or it may be for other reasons, have so described their devices that it cannot be immediately discerned from a reading of the language which they have respectively used that they have discovered in truth the same device; but if carrying out the directions contained in the prior inventor's publication will inevitably result in something being made or done which, if the patentee's claim were valid, would constitute an infringement of the patentee's claim, this circumstance demonstrates that the patentee's claim has in fact been anticipated.
If, on the other hand, the prior publication contains a direction which is capable of being carried out in a manner which would infringe the patentee's claim, but would be at least as likely to be carried out in a way which would not do so, the patentee's claim will not have been anticipated, although it may fail on the ground of obviousness. To anticipate the patentee's claim the prior publication must contain clear and unmistakeable directions to do what the patentee claims to have invented…A signpost, however clear, upon the road to the patentee's invention will not suffice. The prior inventor must be clearly shown to have planted his flag at the precise destination before the patentee."
"If I may summarise the effect of these two well-known statements, the matter relied upon as prior art must disclose subject-matter which, if performed, would necessarily result in an infringement of the patent. That may be because the prior art discloses the same invention. In that case there will be no question that performance of the earlier invention would infringe and usually it will be apparent to someone who is aware of both the prior art and the patent that it will do so. But patent infringement does not require that one should be aware that one is infringing: "whether or not a person is working [an] ... invention is an objective fact independent of what he knows or thinks about what he is doing": Merrell Dow Pharmaceuticals Inc v H N Norton & Co Ltd [1996] RPC 76, 90. It follows that, whether or not it would be apparent to anyone at the time, whenever subject-matter described in the prior disclosure is capable of being performed and is such that, if performed, it must result in the patent being infringed, the disclosure condition is satisfied. The flag has been planted, even though the author or maker of the prior art was not aware that he was doing so."
Kim 1992 – disclosure
"These mAbs are expected to serve as powerful tools for elucidating the physiological role of VEGF, exploring the significance of the multiple forms of VEGF and the structural and functional relationship of VEGF with its receptor(s). Furthermore, in light of the importance of angiogenesis in chronic inflammation, atherosclerosis, diabetic retinopathy, rheumatoid arthritis and cancer … mAbs capable of neutralizing the biological activities of VEGF could be of therapeutic potential"
"These well-defined mAbs should be very powerful tools to understand the structure-function relationship of various domains of VEGF and may have therapeutic potential."
"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."
Novelty over Kim 1992?
Obviousness
Obviousness - law
"An invention shall be taken to involve an inventive step if it is not obvious to a person skilled in the art, having regard to any matter which formed part of the state of the art…"
"The question of obviousness must be considered on the facts of each case. The court must consider the weight to be attached to any particular factor in the light of all the relevant circumstances. These may include such matters as the motive to find a solution to the problem the patent addresses, the number and extent of the possible avenues of research, the effort involved in pursuing them and the expectation of success."
"Mere possible inclusion of something within a research programme on the basis you will find out more and something might turn up is not enough. If it were otherwise there would be few inventions which were patentable. The only research which would be worthwhile (because of the prospect of protection) would be in areas totally devoid of prospect. The "obvious to try" test really only works where it is more-or-less self evident that what is being tested ought to work."
"In the end the question is simply "was the invention obvious?" This involves taking into account a number of factors, for instance the attributes and cgk of the skilled man, the difference between what is claimed and the prior art, whether there is a motive provided or hinted by the prior art and so on. Some factors are more important than others. Sometimes commercial success can demonstrate that an idea was a good one. In others "obvious to try" may come into the assessment. But such a formula cannot itself necessarily provide the answer. Of particular importance is of course the nature of the invention itself."
"In the Court of Appeal, Jacob LJ dealt comprehensively with the question of when an invention could be considered obvious on the ground that it was obvious to try. He correctly summarised the authorities, starting with the judgment of Diplock LJ in Johns-Manville Corporation's Patent [1967] RPC 479, by saying that the notion of something being obvious to try was useful only in a case in which there was a fair expectation of success. How much of an expectation would be needed depended upon the particular facts of the case."
"16. In the board's judgement, the skilled person, although knowing that IL-5, as an endogenous humoral factor, was involved in a number of complex biological processes of activation and regulation, and although aware that any interference which (semble with) such phenomena could result in adverse responses by the organism, would not have been deterred from testing in an in vivo animal model the activity of an antagonist which had been shown by document (7) to have a dose-dependent effect in an in vitro model. In bio-medical sciences, studies in vitro wherein a given product is shown to have a biological effect, are normally, and logically, followed by experiments in vivo in an animal model where the effect can be tested in the more complex context of a living organism. One of the purposes of such animal models, from the simplest to the more complex, is indeed to serve as an intermediary step before clinical testing in patients, thus as a sort of barrier between potentially harmful products and human exposure. Thus, as already stated, far from being deterred, the skilled person would have considered the in vivo testing in mice as being the next logical step. The question here is rather whether this test would have been approached by the skilled person with scepticism, with a neutral attitude or with some expectation of success.
17. Although - as stated eg in document (35) - the control of eosinophilia was not completely understood at the date of the invention and an univocal link between eosinophilia and IL-5 was not yet demonstrated, the skilled person had good indications from the prior art (cf points 10 and 12 above) that IL-5, being involved in the final stages of eosinophilopoiesis, was the factor likely to be responsible for the increase in eosinophil numbers in response to infection. Although knowing that in vitro experiments cannot mimic the in vivo settings and that in vitro results are not always confirmed upon in vivo testing, the skilled person would have perceived the experiment reported in document (7) which showed in vitro dose-dependent neutralisation of the eosinophilopoietic effect of IL-5 by anti-IL-5 antibody as being encouraging, also in view of the raised IL-5 levels observed in vivo in mice infected with a parasite (cf document (35)). Thus, in spite of the understandable uncertainties which always characterise biological experiments, the skilled person had no reasons to adopt a sceptical attitude. He or she would have had either some expectations of success or, at worst, no particular expectations of any sort, but only a "try and see" attitude, which - as pointed out eg in decisions T 333/97 of 5 October 2000 and T 377/95 of 24 April 2001 - does not equate with an absence of a reasonable expectation of success."
"8.2 In the board's view, the cited state of the art pointed the notional skilled person in the direction of the claimed invention, and it only remained to confirm experimentally by a small number of routine tests that the thoroughly obvious result, namely the efficacy of DCL in the treatment of allergic rhinitis using the claimed dosage regimen, was in fact obtained. However, the necessity of experimentally confirming a reasonably expected result cannot contribute to an inventive step. Thus, in the absence of any evidence showing that the selection of allergic rhinitis was unexpectedly associated with a beneficial effect, or a significant advantage or a worthwhile improvement in the broadest sense, the conclusion must be drawn that the claimed use of the DCL shows only predictable effects and is therefore obvious. "
"(1) (a) Identify the notional 'person skilled in the art'.
(b) Identify the relevant common general knowledge of that person.
(2) Identify the inventive concept of the claim in question or, if that cannot readily be done, construe it.
(3) Identify what, if any, differences exist between the matter cited as forming part of the "state of the art" and the inventive concept of the claim or the claim as construed.
(4) Ask whether, when viewed without any knowledge of the alleged invention as claimed: do those differences constitute steps which would have been obvious to the person skilled in the art or do they require any degree of invention?"
Obviousness - facts
Difference over Kim 1992
Claimants' first obviousness case – obvious course of research
Q. Indeed, it would be plausible that VEGF antagonist would work in the nude mouse xenograft model having got the positive results that Ferrara describes in this paper.
A. I do not think that the results in this paper contribute in any way to the excitement you might have had or the plausibility about VEGF as a target. They are just characterising an antibody in this particular paper.
Q. That was not my question, professor?
A. Could you restate your question, please?
Q. If you got a positive result with a potent antibody showing potent blocking activities in vivo in the Miles permeability assay and in the CAM assay, it would be plausible at the very least that it would be effective in the nude mouse xenograft model.
A. It would be plausible, yes.
Q. Indeed we put the case, Professor Harris puts it, going back to his report, that you would be optimistic that it would work. That is his evidence. Correct?
A. I believe that is his evidence, yes.
Q. And it is one of those things you beg to differ.
A. I would not have been optimistic. I do not think that the skilled addressee would have been optimistic at that stage. Essentially what the Kim '92 paper does is describe the creation of an interesting tool.
Q. It goes further than that, does it not, professor? Go back to the Kim paper. It does not just describe an interesting tool. It specifically flags up "could therefore be of therapeutic potential".
A. It could be. It could potentially be if you knew that VEGF was a valid target, yes.
Q. All you have to do to assess that is to put it in the mice, correct?
A. That would be one way you could do it, yes.
Q. And that is a standard test?
A. It is a convincing test, yes.
"… lots of any molecules had been put into CAM assays over the years to see if they could elicit a response. Many did, but that did not mean they were each necessary for the neovascular pathology. Similarly, inhibitors to certain growth factors (e.g. bFGF) had also been tested in CAM assays (or similar assays) and had been shown to block the angiogenic activity of the target growth factor. But again, that did not mean that the targeted growth factor alone was responsible for the neovascular pathology, for the reasons explained above."
Reaction to the invention
Claimants' second obviousness case – Agrevo
Insufficiency
"(1) The Claimant contends that the recombinant chimeric homodimer (VEGF Trap) identified in the Claimant's confidential product description served on 16 February 2011 is not a VEGF antagonist falling within any of sub-paragraphs (a), (b) and/or (c) of claims 1 and/or 14 of the Patent
(i) If and insofar as it may contended otherwise then the specification is ambiguous and/or uncertain and is not sufficiently enabling to allow the skilled person to identify which polypeptides and/or proteins are hVEGF antagonists and/or within the scope of sub-paragraphs (a), (b) and/or (c) of claims 1 and/or 14 of the 986 Patent. Further or alternatively the 986 Patent does not allow them to do so without undue burden. Accordingly the claimed invention is not defined sufficiently for the skilled person to determine whether or not the claims are infringed.
(ii) If and insofar as it may be contended that any of the claims of the 986 Patent covers, or covers the use of an hVEGF antagonist which is an "isolated VEGF receptor" other than the full length hVEGF Receptor or the hVEGF Receptor - IgG Fusion Protein of Example 3 (column 21 lines 20 - 56) the 986 Patent contains no or no sufficient teaching as to how to identify and/or-manufacture such hVEGF antagonists. Further or alternatively the 986 Patent contains no, or no sufficient, teaching as to how to identify and/or manufacture such hVEGF antagonists across the scope the claims or any of them: a fortiori if and insofar as the claims of the 986 Patent (or any of them) are alleged to cover VEGF Trap.
(2) Not all hVEGF antagonists falling within the descriptions in sub-paragraphs (a) (b) and/or (c) of claims 1 and/or 14 are therapeutically active against all non-neoplastic diseases or disorders characterised by undesirable excessive neovascularisation (including those identified as such in the specification of the 986 Patent) or are therapeutically active against only some such diseases or disorders. The 986 Patent does not enable the skilled person to identify those that are therapeutically active against all non-neoplastic diseases or disorders characterised by undesirable excessive neovascularisation, further or alternatively those that are therapeutically active against specific diseases or disorders without undue burden.
(3) Further or alternatively there is no, or no sufficient, evidence in the 986 Patent to make it plausible that a solution was found to the problem purportedly solved still less so that such solution applies across the full width of the claims either as regards the scope of all hVEGF antagonists falling within the descriptions in sub-paragraphs (a) (b) and/or (c) of claims 1 and/or 14 and/or for all non-neoplastic diseases or disorders characterised by undesirable excessive neovascularisation.
Further or alternatively, claims 1 and 14 of the 986 Patent are ambiguous and/or their meaning is uncertain in that the specification does not teach the skilled person the meaning of the words "non-neoplastic disease or disorder characterised by undesirable excessive neovascularisation". Accordingly the claimed invention is not defined sufficiently for the skilled person to determine whether or not the claims are infringed. Further or alternatively, if and in so far as claim 1 of the 986 Patent covers non-neoplastic diseases or disorders characterised by undesirable excessive neovascularisation other than those listed in claim 2, and/or if and in so far as claim 14 of the 986 Patent covers diseases or disorders characterised by undesirable excessive neovascularisation other than those listed in claim 15, then the 986 Patent contains no, or no sufficient, teaching as to how to identify such diseases or disorders without undue burden.
Insufficiency – law
"i) A claim will be invalid for insufficiency if the breadth of the claim exceeds the technical contribution to the art made by the invention. As Lord Hoffmann confirmed elsewhere in his opinion, it follows that it is not necessarily enough to disclose one way of performing the invention in the specification.
ii) The breadth of the claim will exceed the technical contribution if the claim covers ways of achieving the desired result which owe nothing to the patent or any principle it discloses. Two classes of this are where the patent claims results which it does not enable, such as making a wider class of products when it enables only one and discloses no principle to enable the others to be made, and where the patent claims 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. "
iii) The patent in Biogen v Medeva was invalid because it was an example of the second class of objectionable claim."
"112. In my opinion there is nothing difficult or mysterious about [the notion of a principle of general application]. It simply means an element of the claim which is stated in general terms. Such a claim is sufficiently enabled if one can reasonably expect the invention to work with anything which falls within the general term. For example, in Genentech I/Polypeptide expression (T 292/85) [1989] O.J. EPO 275, the patentee claimed in general terms a plasmid suitable for transforming a bacterial host which included an expression control sequence to enable the expression of exogenous DNA as a recoverable polypeptide. The patentee had obviously not tried the invention on every plasmid, every bacterial host or every sequence of exogenous DNA. But the Technical Board of Appeal found that the invention was fully enabled because it could reasonably be expected to work with any of them.
113. This is an example of an invention of striking breadth and originality. But the notion of a 'principle of general application' applies to any element of the claim, however humble, which is stated in general terms. A reference to a requirement of 'connecting means' is enabled if the invention can reasonably be expected to work with any means of connection. The patentee does not have to have experimented with all of them."
"It follows, in my judgment, that a claim to a class of products said to possess a useful activity must be based upon the identification of a common principle which permits a reasonable prediction to be made that substantially all the claimed products do indeed share that activity. Further, it is not permissible to by-pass that requirement simply by adding a functional limitation which restricts the scope of the claim to all the products which do have the relevant activity, that is to say all those which "work". In the case of a claim limited by function, it must still be possible to perform the invention across the scope of the scope of the claim without undue effort. That will involve a question of degree and depend upon all the circumstances including the nature of the invention and the art in which it is made. Such circumstances may include a consideration of whether the claims embrace products other than those specifically described for achieving the claimed purpose and, if they do, what those other products may be and how easily they may be found or made; whether it is possible to make a reasonable prediction as to whether any particular product satisfies the requirements of the claims; and the nature and extent of any testing which must be carried out to confirm any such prediction. "
"Whether the specification is sufficient or not is highly sensitive to the nature of the invention. The first step is to identify the invention and decide what it claims to enable the skilled man to do. Then one can ask whether the specification enables him to do it. For example, in American Home Products Corporation v Novartis Pharmaceuticals UK Ltd [2001] RPC 159 the patentee claimed that the known drug rapamycin and any of its derivatives could be put to a new use. But the claim for such use of all derivatives was not enabled because only some derivatives could be so used and the specification did not enable the skilled man to identify which they were. The answer may well have been different if the claim was to a new process for making rapamycin and its derivatives or if rapamycin and its derivatives had been new products."
"Whether the specification discloses an invention clearly and completely enough for it to be performed by a person skilled in the art involves a question of degree. It is impossible to lay down any precise rule because the degree of clarity and completeness required will vary depending on the nature of the invention and of the art in which it is made. On the one hand, the specification need not set out every detail necessary for performance. The skilled person must be prepared to display a reasonable degree of skill and use the common general knowledge of the art in making routine trials and to correct obvious errors in the specification, if a means of correcting them can readily be found. Further, he may need to carry out ordinary methods of trial and error, which involve no inventive step and generally are necessary in applying the particular discovery to produce a practical result. On the other hand, he should not be required to carry out any prolonged research, enquiry or experiment: Mentor Corporation v Hollister Inc. [1993] RPC 7."
"Where a therapeutic application is claimed in the form allowed by the Enlarged Board of Appeal in its decision G 5/83 (OJ EPO 1985, 64), ie in the form of the use of a substance or composition for the manufacture of a medicament for a defined therapeutic application, attaining the claimed therapeutic effect is a functional technical feature of the claim (see G 2/88 and G 6/88, OJ EPO 1993, 93 and 114, Headnote III. and point 9 of the reasons, for non-medical applications, see also T 158/96 of 28 October 1998, point 3.1 of the reasons). As a consequence, under Article 83 EPC, unless this is already known to the skilled person at the priority date, the application must disclose the suitability of the product to be manufactured for the claimed therapeutic application. It is a well-known fact that proving the suitability of a given compound as an active ingredient in a pharmaceutical composition might require years and very high developmental costs which will only be borne by the industry if it has some form of protective rights. Nonetheless, variously formulated claims to pharmaceutical products have been granted under the EPC, all through the years. The patent system takes account of the intrinsic difficulties for a compound to be officially certified as a drug by not requiring an absolute proof that the compound is approved as a drug before it may be claimed as such. The boards of appeal have accepted that for a sufficient disclosure of a therapeutic application, it is not always necessary that results of applying the claimed composition in clinical trials, or at least to animals are reported. Yet, this does not mean that a simple verbal statement in a patent specification that compound X may be used to treat disease Y is enough to ensure sufficiency of disclosure in relation to a claim to a pharmaceutical. It is required that the patent provides some information in the form of, for example, experimental tests, to the avail that the claimed compound has a direct effect on a metabolic mechanism specifically involved in the disease, this mechanism being either known from the prior art or demonstrated in the patent per se. Showing a pharmaceutical effect in vitro may be sufficient if for the skilled person this observed effect directly and unambiguously reflects such a therapeutic application (T 241/95, OJ EPO 2001, 103, point 4.1.2 of the reasons, see also T 158/96 of 28 October 1998, point 3.5.2 of the reasons) or, as decision T 158/96 also put it, if there is a "clear and accepted established relationship" between the shown physiological activities and the disease (loc. cit.). Once this evidence is available from the patent application, then post-published (so-called) expert evidence (if any) may be taken into account, but only to back-up the findings in the patent application in relation to the use of the ingredient as a pharmaceutical, and not to establish sufficiency of disclosure on their own."
"The discovery on which the invention is based, even if representing an important piece of scientific knowledge, still needs to find a practical application in the form of a defined real treatment of any pathological condition in order to make a technical contribution to the art and be considered an invention eligible for patent protection." (original emphasis)
"However, when taking a closer look at the actual disclosure in the various references discussed in document (65), the Board is convinced that not only does this document not contain a disclosure that "the morphogens recited in the claims do demonstrate the technical effects asserted", but, on the contrary, that it is not possible to draw any conclusion from one specific morphogen and the biological effects obtained by it to any other morphogen. According to document (65) the generalization of the specific results obtained by the patent with regard to recombinant, mature human OP1 to other morphogens, as intended by the claims, is not scientifically tenable."
Insufficiency -facts
All non-neoplastic diseases – breadth of claim
Professor Shima's evidence
"VEGF was known to be widely expressed by many different cell types and the papers I refer to at paragraph 57 of my First Report suggested that it was found in the right time and place to be driving angiogenic growth and disease. Moreover, VEGF binding sites had been shown (in animal models) to be located on vasculature all throughout the body. Coupled with the proof-of-concept data in the Patent which demonstrated that VEGF was necessary for angiogenesis in tumors, the skílled team would therefore have thought it likely that VEGF was a wide-acting factor that would present a viable target for anti-angiogenesis therapy in any context. Further evidence from specífic animal models would be required before a therapeutic product could progress into clinical trials for any particular disease state, but the data in the Patent would have provided the skilled team with a great deal of confidence that the strategy would work for any neovascular disease."
Dr Paleolog's evidence
"Moving on from the date of the patent, it is known TNF-alpha is extremely important in rheumatoid arthritis.
A. That is correct.
Q. And agents against TNF, which work well in rheumatoid arthritis, have been found to be ineffective in cancer.
A. That is my understanding, yes.
Q. That is an observation that one can make now quite a few years on from the date of the patent. But it illustrates something that would have been realised at the date of the patent without knowledge of specific factors. Factors which would be effective to treat rheumatoid arthritis by antagonising them would not necessarily work for tumours and vice versa.
A. That is true, yes."
"Q. Can I suggest to you, doctor, that it is unsafe and unscientific to extrapolate from something you know about a tumour to rheumatoid arthritis, because of the differences between the tumour state and rheumatoid arthritis that I discussed with you right at the beginning of this discussion, i.e. the different constituents of the pannus in the tumour and the differences in the vasculature and the difference in the originating cause. You may hypothesise that what holds for a tumour holds for rheumatoid arthritis, but it is not really scientific to use it in sort of inductive reasoning.
A. I do not think I would agree with that, that it is not scientific. I think it is a valid scientific hypothesis which underlies many scientific studies to try and extrapolate from one diseased condition to another."
"Q. For conditions [such as atherosclerosis and psoriasis] where VEGF had not been demonstrated to be present as at the date of the patent, if we look at your three criteria in paragraph 32, none of them would be satisfied, evidently.
A. The criteria that I outline in paragraph 32 are used as a basis for a clinical trial of a particular approach. Whilst I cannot comment on whether VEGF expression was or was not known to be a feature of any of these diseases, I am, I guess, extrapolating that if angiogenesis was part of the process of these diseases, VEGF expression may have been demonstrated. As I said, I do not know specifically for the questions that you are asking.
Q. So you would be building in the additional assumption that all angiogenesis in pathology involves VEGF?
A. I do not think that is an assumption I should be building in, no.
Q. For a condition where VEGF had simply not been demonstrated to be present in the tissue inflicted by the disease, it would be completely unscientific to conjecture that VEGF blockade would be [in]effective for treatment?
A. If VEGF expression has not been demonstrated, then I do not think VEGF inhibition would be proposed as a therapeutic approach.
Q. No, it would be completely unscientific to make any sort of prediction that it would be effective.
A. That is true."
Professor Harris' evidence
"A number of diseases were thought to be angiogenesis dependent and it was thought that the same angiogenic and antiangiogenic molecules would have a central role in both 'normal' angiogenesis and in disease (hence the relevance of work on pathological angiogenesis (e.g. cancer, angiogenic eye diseases and rheumatoid arthritis) to embryonic angiogenesis and vice versa). It was therefore logical to assume that a blocker of angiogenesis would have potential therapeutic application in the treatment of more than one disease."
"I do not believe that one can extrapolate from the cancer data of the Patent to conclude that VEGF antagonism would be effective in the treatment of all other angiogenic diseases. The tumour data of the Patent (repeated in Kim 1993, ref. 38) are important in demonstrating that blocking VEGF-driven angiogenesis inhibits growth of these tumours. These data show that in these cancers, blocking a single factor, VEGF, has a beneficial effect and so give additional encouragement to investigate whether the same is true in other angiogenic diseases e.g. to investigate the role of VEGF in RA. However, for the reasons I set out in my first report, I believe that by 1992 the skilled person would already have considered VEGF as a leading candidate for playing a central role in pathological angiogenesis. I do not believe that Examples 4 and 5 add materially to the expectation that VEGF antagonism would be therapeutically effective in other angiogenic diseases. This would need to be investigated individually for each disease irrespective of the data in Examples 4 and 5."
"It is completely not logical that you would show that VEGF is important in cancer. You have another disease, and it says -- there are questions about the molecules involved in arthritis. The ones that were known to be involved in angiogenesis were not VEGF in fact. They were much smaller in molecular weight. So the very evidence she cites shows conclusively that the molecule that was first isolated in 1980 was not VEGF. So why would you then think a VEGF antibody would work when you saw it worked in cancer? I just did not follow the logic of that part of the evidence….You have looked at it in cancer. It is high in cancer. You can see clearly some of these factors are not VEGF in the joints. Why is that? That does not follow in logical arguing at all, that comment there, to me. She actually says that VEGF had not been shown to be expressed in RA. I keep coming to the point that in cancer we knew a lot about it. Every other disease we knew nothing about - atherosclerosis, 1997; psoriasis, 1994. Dr. Paleolog says we did not know about it. What we did know was that it was not VEGF. What I do not understand why you could say because it worked in cancer, it would then work in this disease for which there was no evidence."
"Although the concept of using Kim's monoclonal antibodies to investigate and treat a non-neoplastic disorder characterised by undesirable neovascularisation was obvious and this would have been an interesting avenue to pursue, there was less data that such diseases were dependent on angiogenesis and VEGF in the same way as cancer. Accordingly, before investigating the effect of blocking VEGF antibodies in a disease model for a disease other than cancer, one would ideally have wanted to demonstrate first the association between the disease in question and upregulation of VEGF activity (i.e. by demonstrating VEGF overexpression). This would have been relatively straightforward to investigate and, assuming that one had patient samples available for analysis, could have been accomplished within a few months. A positive finding would have heightened one's confidence that a VEGF antagonist could be used to treat the disease in question."
Principle of general application?
"Other than cancer, I believe that diabetic retinopathy (and other eye diseases associated with neovascularisation) would have been the most promising indication for development of a VEGF antagonist. By 1992 the association between diabetic retinopathy and angiogenesis was well established. It was known that the proliferation and permeability of blood vessels was a hallmark of diabetic retinopathy and a number of other eye diseases causing blindness. Further, it was known that laser surgery to reduce the vascular proliferation in the eye could be used to treat these diseases."
Specific diseases and disorders
Rheumatoid arthritis
Other tissue transplantation
Pre-eclampsia
Atherosclerosis
Undue research and experimentation
All antagonists
Truncated forms of the hVEGF receptor
"To go beyond looking at the whole ECD would have required the production of fragments of the ECD, and the testing of such fragments to ascertain their ability to bind VEGF. The skilled addressee would have needed to perform a series of experiments, refining that series as each set of results was obtained, so as to focus on the part(s) of the ECD that are necessary for the protein to retain its affinity for VEGF. This would have required the cloning of deletion mutants of the ECD of the receptor, the expression of these proteins in a suitable host, and the subsequent purification and testing of the protein obtained.
The skilled person would have appreciated that arriving at such a smaller fragment presented a number of challenges and there was no guarantee that a smaller fragment could be identified that would fold correctly and show good VEGF binding. In 1992 I would have expected that a project aimed at investigating the structure-function relationship of the receptor and identifying a fragment which could work as a VEGF antagonist would require several years work"
"While this manuscript was in preparation, Davis-Smyth et al. reported that soluble secreted domains 1+2 of Flt-1 were unable to bind VEGF or PlGF. However, binding was achieved with the addition of domain 3 to their fusion protein. The reasons for the discrepancy between our results and theirs probably lies with the delineation of domain 2. Our domain 1+2 construct possesses 10 additional amino acids on the C-terminus which may add to the structural integrity of domains 1+2 or alternatively directly participate in ligand interactions. Davis-Smyth et al., predict that these amino acids would constitute the extreme N-terminus of domain 3."
"Q. And the point you are making is that Cunningham found that a construct consisting of what they called domains 1 and 2 bound VEGF.
A. Yes.
Q. And the difference between them and Davis-Smyth lay in where they had cut between domains 2 and 3.
A. Yes.
Q. I think you go on and you make similar points relating to the work done on the Flk receptor as well.
A. Yes.
Q. All of these groups were able to prepare fragments of the receptor extracellular domain which bound VEGF using standard techniques.
A. Yes.
Q. They could have continued using the same standard techniques to further refine their fragment had they wished to do so.
A. Yes.
Q. I think your point is that you say there would not have been any motivation to do that because the Flt domain 1 to 3 construct produced by Davis-Smyth and also by Cunningham would have been regarded as suitable for taking into development.
A. Yes.
The work done on VTE
"The choice of a particular form of an integer falling within the terms of the claims may improve the way the invention works and be in itself an inventive step. The specification is not insufficient merely because it does not enable the person skilled in the art to make such an invention. The use of the improvement is still a way of working the original invention."
Anti-Flk1 treatment in RA
Anti-VEGF antibodies in RA
Anti-Flk1 in atherosclerosis.
Ambiguity as to disease
Conclusion on insufficiency
Overall conclusion