“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 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.”
“10. 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. 11. 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. 12. A number of growth factor receptors belong to the RTK family, including the receptors for the growth factors EGF, bFGF, PD-ECGF and VEGF …”
“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.”
“Finally, although a variety of substances have been demonstrated to block angiogenesis using in vivo assays, none has been demonstrated to function physiologically.”
“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.”
“In my judgment, at the filing date, there was nothing approaching a concluded view as to which if any of the many growth factors which had been identified would be the right or best one to target for therapeutic purposes. Each of the growth factors had its enthusiasts, but there was no way of predicting which of the growth factors would be necessary for pathological angiogenesis. There was plainly a justifiable concern that a process as important as angiogenesis would have built in redundancy, so that no single factor could be targeted alone to achieve an effect. Workers in the field were continuing research on factors other than VEGF. The obviousness and insufficiency cases will have to be approached with this state of the art in mind.”
“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.”
“[0016] 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. [0017] The term “hVEGF receptor” or hVEGFr” as used herein refers to a cellular [receptor] for hVEGF, ordinarily a cell-surface receptor found on vascular endothelial cells, as well as variants thereof which retain the ability to bind hVEGF...”
“Variants of hVEGFr also are included within the scope hereof. Representative examples include truncated forms of a receptor in which the transmembrane and cytoplasmic domains are deleted from the receptor, and fusions proteins in which non-hVEGFr polymers or polypeptides are conjugated to the hVEGFr or, preferably, truncated forms thereof…”
“[0071] The hVEGF antagonists are useful in the treatment of various non-neoplastic diseases and disorders. [0072] Non-neoplastic conditions that are amendable to treatment include rheumatoid arthritis, psoriasis, atherosclerosis, diabetic and other retinopathies, retrolental fibroplasias, neovascular glaucoma, thyroid hyperplasias (including Grave’s disease), corneal and other tissue transplantation, chronic inflammation, lung inflammation, nephrotic syndrome, pre-eclampsia, ascites, pericardial effusion (such as that associated with pericarditis), and pleural effusion.”
“In Example 4, three different tumour cell lines were examined in a mouse xenograft test. These cells were injected into nude mice and after tumour nodules formed, the anti-VEGF antibody or controls were administered. The anti-VEGF antibody caused a significant decrease in the rate of tumour growth in one of the cell lines and the size and weight of the tumours at the end of the 5 week experiment were substantially lower in mice treated with the antibody when compared to the negative controls. The results also show a dose-dependent response. Tumour weights from the other two cell lines were also significantly lower in the antibody treated mice compared to the negative controls, and also showed a dose-dependent response. The antibody is identified as A4.6.1. This antibody is described in the prior art relied on in this action, Kim 1992.”
“Example 6 shows the effect of the VEGF antagonist antibody on endothelial cell chemotaxis induced by synovial fluid from RA patients. Cell chemotaxis is the process by which cells direct their movements according to chemicals in their environment. Synovial fluid of the RA patients contained an activity which caused endothelial cells to migrate - which is required as part of the angiogenic process. This chemotactic activity was significantly and reproducibly inhibited by the A4.6.1 antibody. By contrast, it had little effect on the (lesser) chemotaxis induced by synovial fluid from patients with osteoarthritis (in which angiogenesis does not occur).”
“52. As to the more general question as to the identification of diseases, Genentech contends that the claim would be understood by the skilled reader to refer to a disease or disorder in which new blood vessel growth contributes directly or indirectly to the pathology of the condition. Accordingly they submit that the claim is directed to reducing the undesired angiogenesis in that disease state. The claimants contend that the phrase under consideration means any disease in which excessive neo-vascularisation is known to be associated with the disease state, whether that neo-vascularisation is causative of the pathology, or caused by it, and whether it is VEGF mediated or not.”
“53. In my judgment the skilled person would understand that the diseases in question were those characterised by excessive undesired angiogenesis. That is the question which has to be answered for the purposes of infringement. I see no reason to recast the definition either as sought by Genentech or by the claimants. There was no evidence that anyone skilled in the art would have any difficulty in identifying a disease which is characterised by undesirable, excessive angiogenesis and one which is not. Further, the skilled person would not understand that the patentee was saying that the treatment would necessarily successfully deal with anything other than undesired angiogenesis in that disease. Thus, for example, the skilled person would not understand that the treatment would necessarily deal with other aspects of the disease state which were independent of angiogenesis.”
“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.”
“110. … If one approaches the matter in the way suggested by Synthon and General Tire one asks first about what is disclosed. A disclosure that a compound might have a therapeutic effect is not a disclosure of the fact that it does have that effect. If one then asks whether there are clear and unmistakeable directions to do what the patentee has invented, namely use it in therapy, the answer is that there are not. The prior inventor is not giving clear and unmistakeable directions to use the compound in therapy. The directions in the prior document are equivocal, which is the opposite of clarity and lack of ambiguity. The reason that the directions are equivocal is that the prior inventor has not arrived at the same invention as the patentee. What he has said might be a signpost, but he has not planted a flag at the precise destination defined by the claim. 111. In my judgment, Kim 1992 falls short of being an anticipation of the claims of the patent. It is true that Kim 1992 discloses an antibody which in fact has the properties claimed. But it cannot sensibly be argued that the disclosure of the antibody alone - ignoring for a moment the passages of the text which suggest potential use in therapy - discloses the fact that the antibody in use achieves the claimed therapeutic effect. Equally it seems to me, the passages in the text which discuss the potential use in therapy do not disclose that the therapeutic effect is in fact achieved. The data in Kim 1992 does not amount to a disclosure from which it can be directly and unambiguously deduced that the antibody will have a therapeutic effect …”
“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.”
“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.”
“(1) (a) Identify the notional ‘person skilled in the art’. (b) Identify the relevant common general knowledge of that person. (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?”
“Professor Shima said there were compelling reasons to do so. He accepted, in terms of a research objective, it was the next logical step. I accept that the skilled person would want to discover whether anti-VEGF antibodies were effective in an animal model of disease to prevent angiogenesis. They would of course only be effective if VEGF was necessary for pathological angiogenesis, something which was not known at the time, and which the experiment might establish.”
“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.”
“90. One of the matters which it may be appropriate to take into account is whether it was obvious to try a particular route to an improved product or process. There may be no certainty of success but the skilled person might nevertheless assess the prospects of success as being sufficient to warrant a trial. In some circumstances this may be sufficient to render an invention obvious. On the other hand, there are areas of technology such as pharmaceuticals and biotechnology which are heavily dependent on research, and where workers are faced with many possible avenues to explore but have little idea if any one of them will prove fruitful. Nevertheless they do pursue them in the hope that they will find new and useful products. They plainly would not carry out this work if the prospects of success were so low as not to make them worthwhile. But denial of patent protection in all such cases would act as a significant deterrent to research. 91. For these reasons, the judgments of the courts in England and Wales and of the Boards of Appeal of the EPO often reveal an enquiry by the tribunal into whether it was obvious to pursue a particular approach with a reasonable or fair expectation of success as opposed to a hope to succeed. Whether a route has a reasonable or fair prospect of success will depend upon all the circumstances including an ability rationally to predict a successful outcome, how long the project may take, the extent to which the field is unexplored, the complexity or otherwise of any necessary experiments, whether such experiments can be performed by routine means and whether the skilled person will have to make a series of correct decisions along the way …”
“The claimants also advance an obviousness case along the lines permitted by the decision of the Technical Board of Appeal in the Agrevo case: T 939/92. In substance they say that the claim that VEGF antagonists would be useful for preventing angiogenesis in the treatment of all non-neoplastic diseases was not plausible. Accordingly, in respect of those diseases for which it is implausible, the patent does not solve any technical problem. Indeed, they say that in fact the claim extends to diseases such as atherosclerosis for which the treatment would not work.”
“236. 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 .”
“… 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 of28 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.”
“168. The claimants say that it was not possible to make a reasonable prediction from the data in the patent that anti-VEGF therapy would be effective in the whole range of diseases claimed. Accordingly they say that the patent is insufficient for undue breadth of claim. Genentech say that the patent discloses a principle of general application as regards the relevant claim integer, and accordingly justifies a claim of this breadth.”
“I think that viewed with her other evidence, Dr Paleolog’s position overall was that the patent would not enable one to deduce that VEGF therapy would definitely be effective in treatment of non-neoplastic diseases. One would need first to confirm whether VEGF was expressed in the disease. But I do not think that she qualified her more general evidence that the skilled team would still be encouraged by data in the patent to expect success in animal testing, and thereby success in therapy.”
“189. I consider that the patent discloses a principle of general application within the meaning of the authorities in so far as it claims anti-VEGF antagonism as a treatment for all non-neoplastic diseases. The tumour data in the patent establish that VEGF blockade is likely to be a successful strategy for treatment in cancer. The skilled reader would appreciate that the reason it is likely to be successful is because blocking VEGF is a sufficient intervention to prevent angiogenesis, at least in models of cancer. It is common ground that it is possible to extrapolate that reasoning to at least some non-neoplastic diseases. Thus Professor Harris explained why he thought that VEGF antagonists would be likely candidates for treating diabetic retinopathy in these terms: “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.” 190. It is implicit in this evidence that Professor Harris regarded it as possible to make a fair prediction that VEGF blockade would work for diabetic retinopathy. His reasoning is dependent on it being an angiogenic disease. As to whether it would be necessary, before making such a prediction, to have evidence that VEGF was upregulated in the disease, he said that this was something which one would have “ideally” wanted and which would have “heightened his confidence” that a VEGF antagonist could treat the disease in question. It was clearly not an obstacle to making a fair prediction. 191. It would of course not be possible to make a fair prediction if the evidence showed that angiogenesis was significantly different in character from disease to disease, so that entirely different molecules might be the target for VEGF antagonism in different diseases. In my judgment the evidence did not show this at all. Professor Harris’ more extreme evidence on this topic was not supported by any references from the literature or put to any Genentech witness, and I am unable to accept it. Once the inventors had shown that blockade of VEGF was sufficient to prevent pathological angiogenesis in tumours, it was reasonable to predict that it would be sufficient in other diseases. Of course the patent had not proved that this was the case – but it does not have to. If the patent is to be held insufficient, therefore, it cannot be simply on the basis that it claims a therapeutic effect in all non-neoplastic diseases.” “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.”
“… I do not consider that it is established that claim 1 is insufficient in so far as it extends to anti-flk-1 as a treatment for RA by blocking angiogenesis. The evidence does not show that the treatment is ineffective to treat angiogenesis.”
“Q. Take any condition in which the presence of VEGF had not yet been established in the tissue in question, okay? A. Okay. Q. A two-part question to you. I think the first one you have answered already. First of all, you just could not make a prediction about whether VEGF blockade worked or not at that Q. A two-part question to you. I think the first one you have answered already. First of all, you just could not make a prediction about whether VEGF blockade worked or not at that stage? 128. A. I can answer the question with confidence in the context of RA. VEGF had not been shown to be expressed in RA. However, VEGF was known to be a key angiogenic factor. Inhibition of VEGF in a disease model involving angiogenesis had not been shown at the time of filing, but angiogenesis was known to be a feature of RA. So with data showing the effectiveness of VEGF inhibition in an angiogenesis-dependent model, taking that together with the presence of angiogenesis in a disease such as RA, and indeed other diseases, I think that would have given you every confidence that blocking VEGF/VEGF receptor 129. Q. Doctor, you have taken my question which was not about RA back to RA. I get the impression ---- 130. A. I apologise, I was trying to answer the question more 131. generally, like giving RA as an example, so other diseases in which, for example, VEGF expression had not been shown, but in which angiogenesis had been demonstrated to be a feature - increased blood vessels. As I said, I cannot comment on any specific disease, but I am just using RA here as an example. But in other diseases as well, I think that would have given you confidence that inhibiting angiogenesis, and specifically VEGF, would be a viable therapeutic option.”
“I think it is a valid scientific hypothesis which underlies many scientific studies to try and extrapolate from disease condition to another.”
“I do not consider that the evidence establishes that anti-VEGF treatment generally is ineffective for treatment of atherosclerosis. It is true that regulatory approval of such a treatment would be, on the evidence, unlikely due to the risk of unacceptable side effects. But the evidence does not establish that the VEGF antagonism would not deal effectively with angiogenesis in the context of atherosclerosis. I will deal separately below with the allegation that a particular antagonist, anti-Flk1, is ineffective against atherosclerosis.”
“The second basis on which it is sought to undermine the evidence in the Luttun and De Bandt articles is that they do not measure angiogenesis, merely the swelling and redness in the joints. The suggestion is that the treatment may be tackling the angiogenic component of the disease but not the inflammatory one. Dr Paleolog pointed out in re-examination that it was the case that the articles measured swelling and redness not angiogenesis. Professor Harris accepted that this was so as well.”
“Given where the burden on this issue lies, I do not consider that it is established that claim 1 is insufficient insofar as it extends to anti-flk1 as a treatment for RA by blocking angiogenesis. The evidence does not show that the treatment is ineffective to treat angiogenesis.”
“217. The claimants also contend that the evidence shows that anti-VEGF antibodies are ineffective in RA. De Bandt (above) shows that treatment with anti-VEGF antibodies merely produced a transient effect in delaying the onset of clinical symptoms, reverting to mirror the control after a few days. Lu et al showed that while the antibodies were effective during the early stages, mice treated for established disease failed to show improvement. In Sone et al some efficacy was shown for anti-VEGF antibodies. 218. I was not persuaded that this material, considered as a whole, established insufficiency in respect of anti-VEGF antibodies for RA.”
“Luttun et al also reports results on anti-flt1 and flk1 in a mouse model of atherosclerosis. The authors report that, whilst the former appeared to work (although independently of angiogenesis), the latter was ineffective. In cross-examination Dr Paleolog was shown these conclusions, but not asked to express her agreement with them, far less to accept that they demonstrated that anti-Flk1 treatment was ineffective in atherosclerosis. I do not consider that this point takes the claimants’ case of insufficiency any further.”
“Hovering around the case was a suggestion that the process of getting the invention to work in the form of an approved treatment for diseases such as RA involved too much by way of research and experimentation. The claimants pointed to the absence of any such approved treatment. I do not think that this is an adequate evidential approach to an allegation of classical insufficiency in a case such as this, as it imposes too high a standard. What the claimants need to show is that the skilled person would not be able to establish without undue burden whether a given anti VEGF therapy has an effect on angiogenesis in a given disease. The evidence was not really directed to this issue at all. I reject this allegation as well.”
“The claimants said that there was difficulty in determining what was a disease or disorder characterised by undesirable excessive neo-vascularisation. In the end the evidence did not support this. Mr Waugh relied on a passage of cross-examination in which Professor Shima accepted that a clinical trial would be necessary to know whether one has a successful treatment. But that is an entirely separate question. There was no evidence that the skilled addressee would have any difficulty in determining whether a given disease would fall within the terms of the claim as I have construed them.”
“209. The fact that a claim may extend to further inventions which make use of the principle disclosed in a patent does not necessarily render the patent insufficient. I do not consider that the fact that the claim extends to VTE makes the present patent insufficient, even in the light of the evidence which I have accepted. Lord Hoffmann put it pithily in Kirin-Amgen at [117]: “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.” 210. All that applies here. The patent is not insufficient because it extends to 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.”