“… characterized by two types of lesions in the brain, senile plaques and neurofibrillary tangles. Senile plaques are areas of disorganized neuropil up to 150 1-m across with extracellular amyloid deposits at the center visible by microscopic analysis of sections of brain tissue. Neurofibrillary tangles are intracellular deposits of tau protein consisting of two filaments twisted about each other in pairs.”
“The principal constituent of the plaques is a peptide termed Aβ or β-amyloid peptide. Aβ peptide is an internal fragment of 3943 amino acids of a precursor protein termed amyloid precursor protein (APP). Several mutations within the APP protein have been correlated with the presence of Alzheimer’s disease. … Such mutations are thought to cause Alzheimer’s disease by increased or altered processing of APP to Aβ, particularly processing of APP to increased amounts of the long form of Aβ (i.e. Aβ1-42 and Aβ1-43). Mutations in other genes … are thought indirectly to affect processing of APP to generate invreased amounts of long form Aβ … These observations indicate that Aβ, and particularly its long form, is a causative element in Alzheimer’s disease.”
“[0007] In one aspect, the invention provides a pharmaceutical composition comprising an antibody to Aβ and a pharmaceutically acceptable non-toxic carrier or diluent, for use in methods of preventing or treating a disease characterized by amyloid deposition in a patient, wherein the isotype of the antibody is human IgG2 [sic – it is common ground that this is a typographical error and should read ‘IgG1’]. Such methods entail inducing an immune response against a peptide component of an amyloid deposit in the patient by administration of an antibody that has the human IgG1 isotype. In some patients, the amyloid deposit is aggregated Aβ peptide and the disease Alzheimer’s disease. In some methods, the patient is asymptomatic. In some methods, the patient is under 50 years of age. In some methods, the patient has inherited risk factors indicating susceptibility to Alzheimer’s disease. Such risk factors include variant alleles in presenilin gene PS1 or PS2 and variant forms of APP. In other methods, the patient has no known risk factors for Alzheimer’s disease. [0008] In some methods, the immune response is directed to aggregated Aβ peptide without being directed to dissociated Aβ peptide. For example, the antibodies bind to aggregated Aβ peptide without binding to dissociated Aβ peptide. The immune response is induced by administering an antibody to Aβ to the patient. [0009] The antibody is typically administered orally, intranasally, intradermally, subcutaneously, intramuscularly, topically or intravenously. In some methods, the patient is monitored followed administration to assess the immune response. In some methods, the patient is monitored following administration to assess the immune response. If the monitoring indicates a reduction of the immune response over time, the patient can be given one or more further doses of the antibody.”
“[0019] The term ‘antibody’ is used to include intact antibodies. Optionally antibodies can be chemically conjugated to, or expressed as, fusion proteins with other proteins. 129. [0022] The term ‘immunological’ or ‘immune’ response is the development of a beneficial humoral (antibody mediated) and/or a cellular (mediated by antigen-specific T cells or their secretion products) response directed against an amyloid peptide in a recipient patient. Such a response can be an active response induced by administration of immunogen or a passive response induced by administration of antibody or primed T- 130. cells. A cellular immune response is elicited by the presentation of polypeptide epitopes in association with Class I or Class II MHC molecules to activate antigen-specific CD4+ T helper cells and/or CD8+ cytotoxic T cells. The response may also involve activation of monocytes, macrophages, NK cells, basophils, dendritic cells, astrocytes, microglia cells, eosinophils or other components of innate immunity. The presence of a cell-mediated immunological response can be determined by proliferation assays (CD4+ T cells) or CTL (cytotoxic T lymphocyte) assays …. The relative contributions of humoral and cellular responses to the protective or therapeutic effect of an immunogen can be distinguished by separately isolating IgG and T-cells from an immunized syngeneic animal and measuring protective or thereapeutic effect in a second subject. 131. [0026] The term ‘patient’ includes human and other mammalian subjects that receive either prophylactic or therapeutic treatment. 132. [0027] Disaggregated or monomeric Aβ means soluble, monomeric peptide units of Aβ. One method to prepare monomeric Aβ is to dissolve lyophilized peptide in neat DMSO with sonication. The resulting solution is centrifuged to remove any nonsoluble particulates. Aggregated Aβ is a mixture of oligomers in which the monomeric units are held together by noncovalent bonds.”
“The invention provides pharmaceutical compositions for use in methods for prophylactic or therapeutic treatment of diseases characterized by accumulation of amyloid deposits. Amyloid deposits comprise a peptide aggregated to an insoluble mass.”
“Therapeutic agents for use in the present invention induce an immune response against Aβ peptide. These agents are human IgG1 antibodies reactive with Aβ peptide. Induction of an immune response is passive, as an antibody is administered that itself binds to Aβ in patient.”
“[0032] Aβ has the unusual property that it can fix and activate both classical and alternate complement cascades. In particular, it binds to Clq and ultimately to C3bi. This association facilitates binding to macrophages leading to activation of B cells. In addition, C3bi breaks down further and then binds to CR2 on B cells in a T cell dependent manner leading to a 10,000 increase in activation of these cells. This mechanism causes Aβ to generate an immune response in excess of that of other antigens. [0033] The antibody of the invention can bind to any of the naturally occurring forms of Aβ peptide, and particularly the human forms (i.e. Aβ39, Aβ40, Aβ42 or Aβ43)….”
“Therapeutic agents of the invention include human IgG1 antibodies that specifically bind to Aβ. Such antibodies can be monoclonal or polyclonal. Some such antibodies bind specifically to the aggregated form of Aβ without binding to the dissociated form. Some bind specifically to the dissociated form without binding to the aggregated form. Some bind to both aggregated and dissociated forms. The production of nonhuman monoclonal antibodies, e.g., murine or rat, can be accomplished by, for example, immunizing the animal with Aβ. ... Such an immunogen can be obtained from a natural source, by peptides synthesis or by recombinant expression.”
“[0045] Agents for inducing an immune response can be administered by parenteral, topical, intravenous, oral, sub-cutaneous, intraperitoneal, intranasal or intramuscular means for prophylactic and/or therapeutic treatment. The most typical route of administration is subcutaneous although others can be equally effective. The next most common is intramuscular injection. This type of injection is most typically performed in the arm or leg muscles. Intravenous injections as well as intraperitoneal injections, intraarterial, intracranial, or intradermal injections are also effective in generating an immune response. In some methods, agents are injected directly into a particular tissue where deposits have accumulated. [0046] Agents of the invention can optionally be administered in combination with other agents that are at least partly effective in treatment of amyloidogenic disease. In the case of Alzheimer’s and Down’s syndrome, in which amlyoid deposits occur in the brain, agents of the invention can also be administered in conjunction with other agents that increase passage of the agents of the invention across the blood-brain barrier.”
“The lack of Aβ plaques and reactive neuronal and gliotic brains of the Aβ1-42 injected mice indicate that no or extremely little amyloid was deposited in their brains, and pathological consequences, such as gliosis and neuritic pathology, were absent. PDAPP mice treated with Aβ1-42 show essentially the same lack of pathology as control nontransgenic mice. Therefore, Aβ1-42 injections are highly effective in the prevention of deposition or clearance of human Aβ from brain tissue, and elimination of subsequent neuronal and inflammatory degenerative changes. Thus, administration of Aβ peptide has therapeutic benefit in prevention of AD.”
“To determine if the Aβ-specific antibodies elicited by immunization that were detected in the sera of AN1792- treated mice were also associated with deposited brain amyloid, a subset of sections from the AN1792- and PBS-treated mice were reacted with an antibody specific for mouse IgG. In contrast to the PBS group, Aβ plaques in AN1792-treated brains were coated with endogenous IgG. This difference between the two groups was seen in both 15-and 18-month groups. Particularly striking was the lack of labeling in the PBS group, despite the presence of a heavy amyloid burden in these mice. These results show that immunization with a synthetic Aβ protein generates antibodies that recognize and bind in vivo to the Aβ in amyloid plaques.”
“The results of this study show that AN1792 immunization of PDAPP mice possessing existing amyloid deposits slows and prevents progressive amyloid deposition and retard consequential neuropathological changes in the aged PDAPP mouse brain. Immunizations with AN1792 essentially halted amyloid developing in structures that would normally succumb to amyloidosis. Thus, administration of Aβ peptide has therapeutic benefit in the treatment of AD.”
“[0122] The results obtained by quantitation of total Aβ or Aβ1-42 by ELISA and amyloid burden by image analysis differ to some extent. Treatment with AN1528 had a significant impact on the level of cortical amyloid burden when measured by quantitative image analysis but not on the concentration of total Aβ in the same region when measured by ELISA. The difference between the two results is likely to be due to the specificities of the assays. Image analysis measures only insoluble Aβ aggregated into plaques. In contrast, the ELISA measured all forms of Aβ, both soluble and insoluble, monomeric and aggregated. Since the disease pathology is thought to be associated with the insoluble plaque-associated forms of Aβ, the image analysis technique may have more sensitivity to reveal treatment effects. However since the ELISA is a more rapid and easier assay, it is very useful for screening purposes. Moreover it may reveal that the treatmentassociated reduction of Aβ is greater for plaque-associated than total Aβ. [0123] To determine if the Aβ-specific antibodies elicited by immunization in the treated animals reacted with deposited brain amyloid, a subset of the sections from the treated animals and the control mice were reacted with an antibody specific for mouse IgG. In contrast to the PBS group, Aβ-containing plaques were coated with endogenous IgG for animals immunized with the Aβ peptide conjugates Aβ1-5, Aβ1-12, and Aβ13-28; and the full length Aβ aggregates AN1792 and AN1528. Brains from animals immunized with the other Aβ peptides or the APP peptide pBx6 were not analyzed by this assay.”
“These results show that AN1792 and AN1528 stimulate strong T cell responses … The absence of an Aβ specific T cell response in animals immunized with Aβ 1-5 is not surprising … Siince the Aβ1-5 conjugate was effective at significantly reducing the level of Aβ in the brain, in the apparent absence of Aβ-specific T cells, the key effector immune response induced by immunization with this peptide appears to be antibody.”
“The levels of Aβ protein in the hippocampus, the cortex and the cerebellum were very similar for all four groups despite the wide range of antibody responses to Aβ elicited by these vaccines. … Thus, the presence of a high circulating antibody titer to Aβ for almost three months in some of these animals did not alter the total Aβ levels in their brains. The levels of Aβ in the CSF were also quite similar between the groups. The lack of large effect of AN1792 immunization on endogenous Aβ indicates that the immune response is focused on pathological formations of Aβ.”
“1. A pharmaceutical composition comprising an antibody to Aβ and a pharmaceutically acceptable non-toxic carrier or diluent, for use in preventing or treating a disease characterised byamyloid deposit in a patient, wherein the isotype of the antibody is human IgG1. 4. The pharmaceutical composition for use in preventing or treating a disease characterised by amyloid deposit in a patient of any preceding claim wherein the antibody binds specifically to the aggregated form of Aβ peptide without binding to the dissociated form. 5. The pharmaceutical composition for use in preventing or treating a disease characterised by amyloid deposit in a patient of any of claims 1-3 where the antibody binds specifically to the dissociated form of Aβ peptide without binding to the aggregated form. 6. The pharmaceutical composition for use in preventing or treating a disease characterised by amyloid deposit in a patient of any of claims 1-3 where the antibody binds specifically to both aggregated and dissociated forms of Aβ peptide.”
“To our knowledge, this is the first report of a clinically relevant treatment that reduces the progression of AD-like neuropathology in a transgenic animal model of the disease. Although it remains unproven, it is not unreasonable to expect that a similar reduction of neuropathology in AD patents would be of clinical benefit. Although our understanding of the precise aspects of the immune response that result in reduced pathology is incomplete, we have shown that Aβ 42 immunization results in the generation of anti-Aβ antibodies and that Aβ-immunoreactive monocytic/microglial cells appear in the regions of remaining plaques. Thus, one possible mechanism of action is that anti-Aβ antibodies facilitate clearance of amyloid-β either before deposition, or after plaque formation, by triggering monocytic/microglial cells to clear amyloid-β using signals mediated by Fc receptors. It has been suggested that a chronic inflammatory state exists in the brain of patents with Alzheimers’s disease: specifically the levels of complement, cytokines and acute-phase proteins are raised. These observations have led to the hypothesis that antiinflammatory regimens might be of therapeutic value. The findings presented here argue that an alternative approach, one that augments a highly specific immune response, can markedly reduce pathology in an animal model of the disease. Collectively, the results suggest that amyloid-β immunization may prove beneficial for both the treatment and prevention of Alzheimer’s disease.”
“… In exploring factors that alter Aβ metabolism and clearance, we found that that a monoclonal antibody (m266) directed against the central domain of Aβ was able to bind and completely sequester plasma Aβ. Peripheral administration of m266 to PDAPP transgenic mice, in which Aβ is generated specifically within the central nervous system (CNS), results in a 1,000-fold increase in plasma Aβ due, in part, to a change in Aβ equilibrium between the CNS and plasma. Although peripheral administration of m266 to PDAPP mice markedly reduces Aβ, m266 did not bind to Aβ deposits in the brain. Thus, m266 appears to reduce brain Aβ by altering CNS and plasma clearance.”
“A second medical use claim only survives because the compound is effective to achieve a new treatment. If it is not effective, or not discernibly so, it is not suitable for that treatment. If administration of the compound results in some patients getting better, but the same improvement would be achieved by the administration of any placebo, that is not enough. …”
“17. The second answer is one of construction. Mr Waugh's argument involves reading in the further limitation that the antibody should be ‘useful’ (assuming that this has a sufficiently precise meaning). Such a construction would divide antibodies to neutrokine-α into two classes, those which are ‘useful’ and those which are not. And it would involve undue effort to find out whether a particular antibody was useful or not; to separate the wheat from the chaff. 18. The trouble with that submission is that [claim 13] does not contain any limitation to ‘useful’. One does not read words into patent claims (or other documents for that matter) unless the context compellingly so requires. The context here does not. The skilled reader would know perfectly well that the patentees had discovered neutrokine-α, that it had some biological function similar to other members of the TNF ligand superfamily and that it or its antibodies might be useful. The antibody claim, just like the neutrokine-α claims, are all to things which could be valuable. He would not see from the patent any intention to limit the monopolies claimed to that which was ‘useful’ for he would well know that the patentee had not limited himself to any particular utility – he was saying no more ‘I know of no particular utility yet, but all these products have potential utility.’ So there is no reason why the skilled reader would read the claim as having a limitation to ‘useful’ antibodies. … which was ‘useful’ for he would well know that the patentee had not limited himself to any particular utility – he was saying no more ‘I know of no particular utility yet, but all these products have potential utility.’ So there is no reason why the skilled reader would read the claim as having a limitation to ‘useful’ antibodies. 51. The Judge was not invited to construe [claims 18 and 19] and did not expressly do so. He simply proceeded on the basis that they were limited to the pharmaceutical or diagnostic equivalent of a ‘workable prototype’ (a phrase taken from Mentor v Hollister,[1993] RPC 7 ). If that were right, then the claims would indeed be insufficient on his findings of fact. But before us Mr Thorley contended that the Judge had proceeded on an erroneous construction. He submitted that read in the context of the specification as a whole the skilled reader would not expect the patentee to have intended these claims to be directed to compositions with immediate practical use as a pharmaceutical or diagnostic. On the contrary he would know that no such compositions had been disclosed and that what the patentee had discovered and disclosed is neutrokine-αand its antibodies with a practical use for these purposes yet to discovered. So there is no reason to suppose that in these claims the patentee intended any specific application for the claimed compositions. They are not tied to any particular application. It follows that all he must have meant is compositions which could be formulated as suitable for administration as a pharmaceutical or suitable for use as a diagnostic. That could be done and so the claims are sufficient. 52. I accept that submission. It is in accordance with the principles of claim construction laid down in Kirin-Amgen[2005] RPC 9 . The contrary view is not, involving as it does the skilled reader in ignoring the very general high level nature of this invention.” 196.Lewison LJ added: “62. … The judge found as a fact that all members of the class could be made. But I cannot see that there is an additional requirement that, once made, all or substantially all members of the class can be ‘put into practice’. That would only be the case if the claim specified some use to which the claimed product had to be put. In this case the judge held that, as a matter of construction, claim 13 did not contain a use limitation. … 72. HGS argues that the judge's findings are based on the assumption that the claims did claim a medical use. In fact they do not. They claim products. Since claim 1 (to a compound) has been upheld by the Supreme Court both on industrial applicability and sufficiency, and claim 13 (to an antibody) must also be upheld, it must follow that the patentee is entitled to claim a product (manufactured without undue effort and without invention) containing the compounds covered by claims 1 and 13. They, too, point to the decision of the TBA which held that claims 18 and 19 were sufficient. As long as the product is suitable for pharmaceutical or diagnostic use, in the sense that it can be put into a suitable carrier, the claim is sufficient. It does not matter that the claim does not specify a particular condition or disease that such a product could treat or diagnose. It is open to pharmaceutical companies downstream to find specific medical uses for such compositions (in which case a ‘Swiss-type’ patent for a second medical use could be granted); or to identify specific antibodies which have particular properties.”
“39. … The following points are, I think, material. First, the claim is concerned with non-neoplastic diseases which have, as one of their characteristics, undesirable excessive neovascularisation, that is to say angiogenesis. The angiogenesis must therefore contribute to the pathology of the disease though it need not necessarily be the cause of it. Hence the specification explains in the section to which I have referred at [24] above, angiogenesis is an important component of a variety of diseases of which a number are then identified. 40. Second, the medicament must treat the disease. That is not to say that the medicament must cure the disease; plainly many diseases characterised by angiogenesis cannot be cured. But it must improve the patient's condition, and it must do so by treating the angiogenic component of the disease from which the patient is suffering. 41. Third, the medicament does not have to treat all, or indeed any other, aspects of the disease, of which, in the case of some diseases, such as RA, there may be many. It is only directed at the angiogenic aspect of the disease and its efficacy is derived from its activity as a VEGF antagonist. 42. Against this background, I do not believe the judge's analysis can be faulted. It was not suggested by any party at trial that the claim does not require any therapeutic effect. It clearly does, and the judge so held. But it does not require a medicament which will cure or even treat all aspects of a disease and, in particular, it does not require treatment of those aspects of a disease which are independent of angiogenesis.” does, and the judge so held. But it does not require a medicament which will cure or even treat all aspects of a disease and, in particular, it does not require treatment of those aspects of a disease which are independent of angiogenesis.”
“… For the Board in relation to claim 1 which is drafted in the form of a first medical use claim with the only disclosed medical use specifically mentioned in the claim, a technical feature that requires to be sufficiently described in the patent is how to achieve prophylaxis or effective treatment of AIDS for the whole target group, here, humans, the only known organism developing AIDS after infection with HIV. …”
“Where a therapeutic application is claimed either in the form of a composition for a specific therapeutic use or in the form allowed by the Enlarged Board of Appeal in its decision G 5/83 (OJ EPO 1985, 64), i.e. 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 decisions 2/88 and 6/88, OJ EPO 1993,93 and 114; point 9 of the reasons, for non-medical applications, see also decision T 158/96 of 28 October 19888; 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 substance or composition for the claimed therapeutic application. Once evidence for this suitability is available from the patent application, then post-published expert evidence may be taken into account, but only to back-up the findings in the patent application in relation to the use of substance or composition, and not to establish sufficiency of disclosure on its own (cf decision T 609/02 of27 October 2004 ; point 9 of the reasons).”
“A pharmaceutical composition comprising an agent effective to induce an immune response against Aβ in a patient, and a pharmaceutically acceptable adjuvant.”
“In one aspect, the invention provides a pharmaceuticalcomposition comprising an antibody to Aß and apharmaceutically acceptable non-toxic carrier or diluent, foruse in methods of preventing or treating a disease characterized by amyloid deposition in a patient, wherein the isotype of theantibody is human IgG2. Such methods entail inducing an immune response against a peptide component of an amyloid deposit in the patient. Such induction can be active byadministration of an immunogen or passive by administration of an antibody that has the human IgG1 isotypeor an activefragment or derivative of the antibody.”
“Human or humanized antibodies can be designed to have IgG, IgD, IgA and IgE constant region, and any isotype, including IgG1, IgG2, IgG3 and IgG4.”
“The instant invention provides for monoclonal antibody which is specific for βA4 peptide [i.e. Aβ], and in particular the free C-terminus of βA4 ‘1-42’ but not ‘1-43’, and stains diffuse and fibrillar amyloid, vascular amyloid, and neurofibrillary tangles. The instant invention further provides for antibody fragments and constructs thereof which have the same binding specificity. The instant invention also provides for methods of diagnosis, screening and therapeutics for treating unique forms of βA4”
“The instant invention also provides for methods of generating ßA4 specific antibodies which recognize the free C-terminal residue 42. The instant invention also provides for methods for detecting the presence of ßA4 peptides ending at position 42, in tissue comprising contacting a tissue sample with monoclonal antibody of the instant invention, be detecting the presence of monoclonal antibody in a selective fashion. The instant invention also provides for methods for selective purification of ßA4 peptides ending at position 42, comprising contacting a sample to be purified with monoclonal antibody of the instant invention, separating the ßA4 peptide from the sample to be purified, and isolating the ßA4 peptide. In a further embodiment, the instant invention provides for methods of detection of ßA4 peptide associated with Alzheimer’s Disease, comprising a sample to be tested with monoclonal antibody of the instant invention, and detecting the presence of ßA4 peptides. Thus the instant invention also provides for methods for the prevention of aggregation of ßA4 peptide any administering monoclonal antibody of the instant invention.”
“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. Lord Hoffmann summarised the position in this way in Conor at [42]: ‘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 where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case.’ 92. Moreover, whether a route is obvious to try is only one of many considerations which it may be appropriate for the court to take into account. In Generics (UK) Ltd v H Lundbeck,[2008] EWCA Civ 311 ,[2008] RPC 19 , at [24] and in Conor[2008] UKHL 49 ,[2008] RPC 28 at [42], Lord Hoffmann approved this statement of principle which I made at first instance in Lundbeck: ‘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.’ 93. Ultimately the court has to evaluate all the relevant circumstances in order to answer a single and relatively simple question of fact: was it obvious to the skilled but unimaginative addressee to make a product or carry out a process falling within the claim….”
‘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 where there was a fair expectation of success. How much of an expectation would be needed depended on the particular facts of the case.’ ‘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.’
“The specification must disclose the invention clearly and completely enough for it to be performed by a person skilled in the art. The key elements of this requirement which bear on the present case are these: (i) the first step is to identify the invention and that is to be done by reading and construing the claims; (ii) in the case of a product claim that means making or otherwise obtaining the product; (iii) in the case of a process claim, it means working the process; (iv) sufficiency of the disclosure must be assessed on the basis of the specification as a whole including the description and the claims; (v) the disclosure is aimed at the skilled person who may use his common general knowledge to supplement the information contained in the specification; (vi) the specification must be sufficient to allow the invention to be performed over the whole scope of the claim; (vii) the specification must be sufficient to allow the invention to be so performed without undue burden.”
“… the Boards of Appeal of the EPO have recognised that in the case of a claim to the use of a product to make a medicine for a particular therapeutic purpose it would impose too great a burden on the patentee to require him to provide absolute proof that the compound has approval as a medicine. Further, it is not always necessary to report the results of clinical trials or even animal testing. Nevertheless, he must show, for example by appropriate experiments, that the product has an effect on a disease process so as to make the claimed therapeutic effect plausible. It was put this way in T609/02 Salk at [9]: “… 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.” “… 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.”
“100. It must therefore be possible to make a reasonable prediction the invention will work with substantially everything falling within the scope of the claim or, put another way, the assertion that the invention will work across the scope of the claim must be plausible or credible. The products and methods within the claim are then tied together by a unifying characteristic or a common principle. If it is possible to make such a prediction then it cannot be said the claim is insufficient simply because the patentee has not demonstrated the invention works in every case. 101. On the other hand, if it is not possible to make such a prediction or if it is shown the prediction is wrong and the invention does not work with substantially all the products or methods falling within the scope of the claim then the scope of the monopoly will exceed the technical contribution the patentee has made to the art and the claim will be insufficient. It may also be invalid for obviousness, there being no invention in simply providing a class of products or methods which have no technically useful properties or purpose.”
“5. AIDSVAX is a compound falling under the definition of unclipped HIV env of claims 1 and 5, and has been produced with the co-operation of the inventors at a date subsequent to the filing of the patent. The compound was the subject of a clinical trial the results of which were published in February 2003 (document D35). The Board can thus only assume that the results for AIDSVAX are representative of the best of what is achievable according to the teaching of the patent. … 5.2 Hence, in summary, a large scale clinical trial involving more than five thousand persons whose lifestyle put them at risk of HIV infection, of whom two thirds were given AIDSVAX and the remaining third were a control given a placebo, showed that for the group as a whole there was no statistically significant effect attributable to AIDSVAX. Most of those partaking were white males, and for that subgroup, too, no beneficial effect attributable to AIDSVAX was shown. Prima facie the Board can only conclude that the information in the patent is not sufficient to enable a skilled person to achieve what is claimed in claims 1 and 5. 6. Appellant I has questioned whether results of a statistical analysis of a vaccine trial are appropriate means to challenge sufficiency of disclosure of a patent. 6.1 The statistically evaluated results of a vaccine trial allow predictions on the probability of the efficacy of a compound for prevention of an infection. In effect, the statistical evaluation of large groups is the only way to achieve conclusive results on efficacy in human beings, because of the unavailability for humans of any direct efficacy test such as is done in animals by vaccination with subsequent active infection with, for example, a virus. In this particular case, given that only humans infected with HIV develop AIDS, but chimpanzees infected with HIV do not develop AIDS, the Board considers that the results of the AIDSVAX vaccine trial are much more relevant evidence, than the results in chimpanzees so heavily relied on by the appellant I before the opposition division as evidence of the effectiveness of what is claimed. 6.2 The Board is not stating that all vaccine trials or clinical trials are necessarily relevant, as some may relate to issues not relevant to the sufficiency of disclosure of a patent. However, it is common practice in proceedings before the EPO that a decision about the presence or absence of a certain medical effect of a compound is made on the basis of all sorts of evidence, be it in vitro or in vivo experiments provided that they render the intended effect credible. This includes data filed after the filing date of the application, in particular where the issue is sufficiency of the patent disclosure in relation to medicines or vaccines, since highly relevant evidence concerning actual attempts to put the invention into practice may not be available until many years after the date of the patent, in contrast to in vitro or in vivo preliminary tests carried out to allow an initial assessment of the likelihood of success. Amongst the available data in a certain case the highest evidential weight is adjudged to those experiments reflecting in the best way the envisaged use. 7. Even if the AIDSVAX clinical trial data were taken into consideration, appellant I argued that an analysis of the results of subsets of participants demonstrated that AIDSVAX was efficient in the prophylaxis of AIDS, in particular in human subgroups, namely women, Asians and Blacks, and this partial success was by itself enough to support the presence of sufficiency of disclosure. 7.1 Leaving aside initially the question whether the subset results in fact demonstrated any success, which was in dispute between the parties, this argument for sufficiency fails for the Board because success for part of the area claimed in claims 1 and 5, does not compensate for lack of disclosure how to succeed for humans as a whole. The patent in suit contains no suggestion that the intended vaccine might succeed only for selected human groups, and certainly no identification of such groups. If what is claimed works only for some groups, this suggests that some other (unknown) factors are in play, and raises questions whether for these groups there is any significance in the difference between ‘unclipped’ as claimed and the (partly) clipped env form present in the prior art suggestions. … 7.4 In summary, the Board concludes that the evidence at best shows that it might be worth investigating further whether the results for a larger sample of certain subgroups would still come up with a protective effect, and then to carry out research to try and explain the cause for any real difference so established. But the evidence does not show that the teaching of the patent will ensure success.”
“Q. … Would you go this far, doctor, that the data in the patent suggests that the antibodies have crossed the blood-brain barrier? A. Yes, I would. Q. One explanation is that the blood-brain barrier has been compromised in some way. A. Yes, that would be one. Q. And that could have happened as a consequence of inflammatory events associated with active immunisation. A. Yes, it could. Q. It could have been triggered either by the aggregated immunogen themselves. A. Yes. Q. Or it could have been, we do not know, because the control was not done, the immunogen plus the adjuvant used in the examples? A. Yes, it could. Q. If that is right, then higher amounts of antibody would be expected to cross the blood-brain barrier if you are using an active immunisation approach? A. If that were right. Q. Now, you agree that there is no basis in the patent to assume that antibodies are able to cross the blood-brain barrier in the absence of impairment in some way? A. There is no basis in the patent for that, that is correct.”
“Q. Do you see the last sentence: ‘I asked whether the vaccination improved cognitive performance in the mice, but as far as I recall he did not answer this point.’ Why did you ask the question? A. Because I believed that was an important factor. My research effort was around cognition and behaviour in dementia. I would be interested in any new medication or approach, whether it would improve or potentially improve cognition. Q. The fact that it might have affected the amyloid burden, okay, but you would have wanted to know whether in fact it was accompanied by some improved cognition in mice. A. Yes, I would. Q. What was your reaction to the fact that he did not tell you? A. I said, ‘When are you going to tell me?’ Well, I could not tell whether he just was not telling me because it was confidential or that he had not done it or there was a problem with the mice. I had no way of knowing, and he gave an enigmatic smile.”