“relates to medicaments [sic] for increasing endogenous erythropoietin in the prevention, pretreatment or treatment of anemia, and to compounds that can be used in the methods”; ii) EP 531: “relates to compounds for use in the treatment or prevention of anemia”; iii) EP 301: “relates to compounds for use in the treatment or prevention of anemia associated with kidney disease”
“Unless defined otherwise, all technical and scientific terms used herein have the same meanings as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred methods, devices, and materials are now described. All publications cited herein are incorporated herein by reference in their entirety for the purpose of describing and disclosing the methodologies, reagents, and tools reported in the publications which might be used in connection with the invention. …”
“The invention also contemplates increasing iron transport, processing, and utilization using the methods of the invention. (See, e.g., commonly owned, copending U.S. Patent Application No. ____, entitled ‘Stabilization of Hypoxia Inducible Factor (HIF) Alpha,’ filed of even date, and incorporated herein by reference in its entirety.) Specifically, the methods of the invention may increase enzymes and proteins involved in iron uptake, transport, and processing. Such enzymes and proteins include, but are not limited to, transferrin and transferrin receptor, which together facilitate iron transport to and uptake by, e.g., erythroid tissue, and ceruloplasmin, a ferroxidase required to oxidize ferrous iron to ferric iron. As transferrin can only bind and transport ferric iron, ceruloplasmin is important for supply of iron to tissues. The ability of the methods of the invention to increase both endogenous erythropoietin and transport and utilization of iron in a single course of treatment provides benefits not addressed by current anemia therapeutics, such as administration of recombinant erythropoietin, in the treatment of anemic disorders including, but not limited to, rheumatoid arthritis, sideroblastic anemia, etc.”
“[0074] As HIF is modified by hydroxylation, a reaction requiring oxygen and Fe2+, the present invention contemplates in one aspect that the enzyme responsible for HIF hydroxylation is a member of the 2-oxoglutarate dioxygenase family. Such enzymes include, but are not limited to, procollagen lysyl hydroxylase, procollagen prolyl 3-hydroxylase, procollagen prolyl 4-hydroxylase (I) and (II), thymine 7-hydroxlase, aspartyl (asparaginyl) β-hydroxylase, ε-N-trimethyllysine hydroxylase, γ-butyrobetaine hydroxylase, etc. These enzymes require Fe2+, 2-oxoglutarate, and ascorbic acid for their hydroxylase activity. (See, e.g., Majamaa et al. (1985) Biochem J 229:127-133 [‘Majamaa 1985’]; Myllyharju and Kivirikko (1997) EMBO J 16:1173-1180 [‘Myllyharju and Kivirikko 1997’]; Thornburg et al. (1993) 32:14023-14033; and Jia et al. (1994) Proc Natl Acad Sci USA 91: 7227-7231.) [0075] Several small molecule inhibitors of prolyl 4-hydroxylase have been identified. (See, e.g., Majamaa et al., supra; Kivirikko and Myllyharju (1998) Matrix Biol 16:357-368 [‘Myllyharju and Kivirikko 1998’]; Bickel et al. (1998) Hepatology 28:404-411; Friedman et al. (2000) Proc Natl Acad Sci USA 97:4736-4741; and Franklin et al. (2001) Biochem J 353:333-338; all incorporated herein in their entirety.) The present invention contemplates the use of these compounds in the methods provided herein. [0076] Compounds that can be used in the methods of the invention include, e.g., structural mimetics of 2-oxoglutarate. Such compounds may inhibit the target 2-oxoglutarate dioxygenase family member competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron. (Majamaa et al. (1984) Eur J Biochem 138:239-45 [‘Majamaa 1984’]; and Majamaa et al., supra.).”
“The present invention contemplates the use of these compounds that are selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and betacarboline carboxamides.” ii) EP 531 [0064]: “The present invention contemplates the use of these compounds that are of Formula (I) as defined herein.” iii) EP 301 [0064]: “The present invention contemplates the use of these compounds that are of Formula (I) as defined herein.”
“Use of a heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and beta-carboline carboxamides that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase enzyme activity in the manufacture of a medicament for increasing endogenous erythropoietin in the prevention, pretreatment, or treatment of anemia associated with kidney disease, wherein the anemia is associated with chronic kidney disease.”
“A heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and betacarboline carboxamides that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase enzyme activity for use in increasing endogenous erythropoietin in the prevention, pretreatment, or treatment of anemia associated with kidney disease, wherein the anemia is associated with chronic kidney disease.”
“A heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and betacarboline carboxamides that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase enzyme activity for use in increasing endogenous erythropoietin in the prevention, pretreatment, or treatment of anemia associated with kidney disease, wherein the anemia is associated with chronic kidney disease, wherein the compound is a compound of Formula (I) wherein ….” wherein the compound is a compound of Formula (I) wherein ….”
“A heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and betacarboline carboxamides that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase enzyme activity for use in increasing endogenous erythropoietin in the prevention, pretreatment, or treatment of anemia associated with kidney disease, wherein the compound is a structural mimetic of 2oxoglutarate.” wherein the compound is a structural mimetic of 2oxoglutarate.”
“A heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and betacarboline carboxamides that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase enzyme activity for use in increasing endogenous erythropoietin in the prevention, pretreatment, or treatment of anemia associated with kidney disease, wherein the anemia is associated with chronic kidney disease, wherein the compound is a compound of Formula (I) wherein …, wherein the compound is a structural mimetic of 2oxoglutarate.” wherein the compound is a compound of Formula (I) wherein wherein the compound is a structural mimetic of 2oxoglutarate.”
“A compound for use in the treatment or prevention of anemia associated with kidney disease, wherein the compound is a compound of formula (I) … [Compound C].”
“A compound for use in preventing or treating anemia associated with kidney disease in a subject, wherein the compound is a compound of [Formula (I) wherein A is (C 1-C 4)-alkylene], wherein the compound inhibits HIF prolyl hydroxylase.”
“A compound for use in preventing or treating anemia associated with kidney disease in a subject, wherein the compound is a compound of [Formula (I) where A is (C 1-C 4)-alkylene but otherwise as defined previously], wherein the compound inhibits HIF prolyl hydroxylase, wherein the compound is a structural mimetic of 2oxoglutarate.”
“The principal finding of this study is that following renal injury a reduced number of interstitial cells expressed the Epo-TAg gene in response to anemia or hypoxia. This reduction in the number of positively staining cells was observed irrespective of the nature of the injury, and was apparent in both anemically and hypoxically stimulated animals. Several features of the response to injury were defined. First, the reduction in the number of cells expressing Epo-TAg was regionally correlated with severity of injury. In needlestick injured kidneys the reduction in positive cells was focal. In post-ischemic kidneys, where the most severe injury was observed in the outer medulla, the most striking reduction in interstitial cells expressing the Epo-TAg gene was also in this region. Second, even in severely injured regions occasional positive cells were observed, and there was no apparent difference in the intensity of staining in these cells when compared with those in normal kidneys. Third, in an individual injured area there was no apparent difference between the fibroblast-like cells that did or did not express the Epo-TAg gene. In particular, the intensity of desmin staining was similar. Fourth, although there were clear reductions in the number of positive cells in injured regions at all levels of stimulation, more intense anemic or hypoxic stimulation (as judged by the number of positive cells in the control kidney) resulted in a greater recruitment of cells in the injured kidney, so that the greatest disproportion between the injured and uninjured kidney was seen under conditions of mild stimulation.”
“These data suggest that the ability of the Epo production is well preserved in ESRD, indicating that acute hypoxic stimuli provoke a significant increase in serum Epo.”
“It is temporary, but the Epo response is temporary in the normal patient as well.”
“Although a few nephrologists may have been working on oxygen sensing or related projects in a research setting (as was the case for example in Peter Ratcliffe’s research group), the vast majority of practising nephrologists would likely have been unaware of the HIF system and it would not have formed part of the CGK of the Skilled Clinical Nephrologist [emphasis added].”
“I remain of the opinion set out in Winearls 1. For the reasons I set out there, details concerning the molecular pathways involved in renal anaemia were not issues that occupied the mind of the notional Skilled Clinical Nephrologist at the Priority Dates and the sort of research being carried out by the Semenza, Ratcliffe and Kaelin groups would have been seen as ‘fundamental science’ without immediate clinical application [emphasis added]”
“Clinical nephrologists concentrate on a very large number of subjects, and this was a mechanistic concept and research, which was very basic, and mostly published in scientific journals, though in that particular issue in 1997 Peter Ratcliffe described Epo as a model of oxygen-sensing. However, I think because it was in Kidney International in a single issue entitled ‘Hypoxia’ does not mean the general nephrologist would have read that. They tend to read things that are of immediate interest to them and their practice. If you were researching anaemia, you might well have read that, and, of course, because Peter Ratcliffe was a UK nephrologist originally, we had kept up with this particular story, but I do not think the ordinary nephrologists were as interested as you are implying, in the nuts and bolts of how the story had eventually been put together.”
“.. the skilled person is deemed to read with interest the papers and patents [to which reference is made in the specification] which are expressly advanced as being relevant to the sufficiency of the patent. In the alternative we contend that the skilled person would in the context of this case read those papers and patents.”
“Pyridine 2,6-dicarboxylate differed from all the other compounds in its inhibition pattern. This compound acts as a terdentate ligand [17] and thus cannot chelate the enzyme bound iron which provides two cispositioned sites for co-substrate binding only (Fig. 1). Nevertheless, pyridine 2,6-dicarboxylate can interact with free Fe2+, thus competing with the enzyme for the metal.”
“It has been pointed out ... that pyridine 2,5-dicarboxylate and 2oxoglutarate may bind to P4H in different ways, and thus the data concerning modifications of this compound must be interpreted with caution (Cunliffe et al, 1992).”
“… It seems very likely that oxaloglycine (3) and 2-oxoglutarate (1) bind to prolyl hydroxylase in a closely analogous way. Thus, the discovery that the structure-activity relationships in oxaloglycine series Approved Judgment differ so completely from those in the pyridine-2,5-dicarboxylic acid series calls into question the published assumptions 22 about the nature of the pyridine-2,5-dicarboxylic acid (2) binding site on prolyl hydroxylase and suggests caution in interpreting the physical reality underlying the observation of strictly competitive inhibition.”
“The novel P4H inhibitor, S 4682, directly inhibited purified P4H, being substantially more potent than the structurally related 2,4-PDCA [pyridine 2,4-dicarboxylate] and 2-PCA [pyridine 2-carboxylic acid] at the enzyme level. Based on the IC 50 values, S 4682 was 42 times more potent than 2,4-PDCA and 580 times more potent than 2-PCA (Table 1)”
“S 4682 differs from other structural analogs of 2-oxoglutarate, such as pyridine 2-carboxylic acid (2,4-PDCA) and pyridine 2-carboxylic acid (2-PCA) by inhibiting P4H in a noncompetitive fashion with respect to the cosubstrate, 2-oxoglutarate (Fig 3A).”
“Exemplary compounds according to Formula (Ia) are described in U.S. Patent Nos, 5,719,164 and 5,726,305. All compounds listed in the foregoing patents, in particular, those listed in the compound claims and the final products of the working examples, may be used. Exemplary compounds according to Formula (Ia) …”
“Such compounds may inhibit the target 2-oxoglutarate dioxygenase family member competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron.”
“165. Claim 24 states that the compound of claim 1, 2, 19 or 20 is a ‘structural mimetic of 2-oxoglutarate’. Based on the discussion in the description of EP 823 and the prior art cited in EP 823 …, the Skilled Medicinal Chemist would understand this to be an additional mechanism-based feature by which I mean that, for a compound to fall within the claim, it needs to be one that is replicating or mimicking the key interactions of 2-oxoglutarate in the enzyme binding pocket (particularly bidentate coordination to Fe2+ via dative bonding from the lone electron pairs possessed by the aromatic nitrogen and the carbonyl oxygen of the carboxamide moiety). If a compound replicates or mimics the other two interactions of 2-oxoglutarate in the enzyme binding pocket …, this would also be expected to contribute to that compound acting as a structural mimetic of 2-oxoglutarate. …. 166. To assess whether a given compound is a ‘structural mimetic of 2oxoglutarate’, the Skilled Medicinal Chemist would be able to make a visual assessment of its structure. In particular, the Skilled Medicinal Chemist would determine whether it is capable of replicating or mimicking the key interactions of 2-oxoglutarate with the active site of the enzyme, primarily whether it has at least two groups capable of forming dative bonds with Fe2+, for bidentate coordination in the active site. This could then be confirmed experimentally by assessing whether the compound in question competitively inhibits binding of 2oxoglutarate.”
“… the classical features of HIF induction by hypoxia, cobaltous ions, and iron chelators can be explained, at least qualitatively, by the properties of recombinant HIF-PH enzymes.”
“In mammals, the HIF system regulates not only cellular responses to oxygen, but also a range of systemic functions such as regulation of angiogenesis, erythropoiesis, and vasomotor control. …”
“Finally, the identification of the HIF-PHIs also raises therapeutic possibilities. Inhibitors of HIF-PHs might be used to activate HIF and enhance angiogenesis in ischemic/hypoxic disease. Application of the 2-oxoglutarate analog dimethyloxalylglycine to tissue culture cells strongly induces HIF target genes (D.R.M., unpublished observations). Though this compound is not specific for the HIF-PHs and inhibits other 2-oxoglutarate dioxygenases, structural and mechanistic studies of the defined enzymes may now permit design of more specific inhibitors for therapeutic development.”
“… we know that the damaged kidneys can produce extra Epo. What we would have been concerned about is, if the original stimulus to the HIF system was not working adequately in these patients, why would an alternative work?”
“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 extent of the disclosure necessary to make the patent sufficient depends on the nature of the invention, the scope of the claims and the art in which the invention is made …”
“98. … it is permissible to define an invention using general terms provided the patent discloses a principle of general application in the sense that it can reasonably be expected the invention will work with anything falling within the claim. As Lord Hoffmann said in Biogen Inc. v Medeva plc [1977] R.P.C. 1 at pp.48–49: ‘If the invention discloses a principle capable of general application, the claims may be in correspondingly general terms. The patentee need not show that he has proved its application in every individual instance. On the other hand, if the claims include a number of discrete methods or products, the patentee must enable the invention to be performed in respect of each of them. Thus if the patent has hit upon a new product which has a beneficial effect but cannot demonstrate that there is a common principle by which that effect will be shared by other products of the same class, he will be entitled to a patent for that product but not for the class, even though some may subsequently turn out to have the same beneficial effect: see May & Baker Ltd v Boots Pure Drug Co. Ltd. (1950) 67 R.P.C. 23, 50. On the other hand, if he has disclosed a beneficial property which is common to the class, he will be entitled to a patent for all products of that class (assuming them to be new) even though he has not himself made more than one or two of them.’ 99. In Kirin-Amgen Inc v Hoechst Marion Roussel Ltd[2004] UKHL 46 , [2005] R.P.C. 9 Lord Hoffmann further explained the concept of a principle of general application in this way: ‘112. In my opinion there is nothing difficult or mysterious about [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”
“The Court of Appeal's reference to ‘armchair inventors’ suggests that what they meant by speculative claiming was claiming by persons who had done nothing new or inventive at all but had simply sought to patent abstract possibilities. That may well be a particular risk in the case of patents for new uses of known compounds, especially when they are commercially successful in their existing use. In reality, however, speculative claiming of this kind is simply one of a number of ways in which a patentee may attempt to claim a monopoly more extensive than anything which is justified by his contribution to the art. Other ways in which this can happen include claiming a monopoly wider than the disclosure in the patent can support. An over-broad claim will not necessarily be speculative. The inventor may really have invented something corresponding to the full breadth of the claim. Research may subsequently demonstrate this. But the claim will still exceed his contribution to the art if that contribution is not sufficiently disclosed in the patent.”
“The principle is that the specification must disclose some reason for supposing that the implied assertion of efficacy in the claim is true. Plausibility is not a distinct condition of validity with a life of its own, but a standard against which that must be demonstrated. Its adoption is a mitigation of the principle in favour of patentability. It reflects the practical difficulty of demonstrating therapeutic efficacy to any higher standard at the stage when the patent application must in practice be made. The test is relatively undemanding. But it cannot be deprived of all meaning or reduced … to little more than a test of good faith.”
“Plausibility is not a term of art, and its content is inevitably influenced by the legal context. In the present context, the following points should be made. First, the proposition that a product is efficacious for the treatment of a given condition must be plausible. Second, it is not made plausible by a bare assertion to that effect, and the disclosure of a mere possibility that it will work is no better than a bare assertion. …. But, third, the claimed therapeutic effect may well be rendered plausible by a specification showing that something was worth trying for a reason, ie not just because there was an abstract possibility that it would work but because reasonable scientific grounds were disclosed for expecting that it might well work. The disclosure of those grounds marks the difference between a speculation and a contribution to the art. This is in substance what the Technical Board of Appeal has held in the context of article 56, when addressing the sufficiency of disclosure made in support of claims extending beyond the teaching of the patent. In my opinion, there is no reason to apply a lower standard of plausibility when the sufficiency of disclosure arises in the context of EPC articles 83 and 84 and their analogues in section 14 of the Patents Act. In both contexts, the test has the same purpose. Fourth, although the disclosure need not definitively prove the assertion that the product works for the designated purpose, there must be something that would cause the skilled person to think that there was a reasonable prospect that the assertion would prove to be true. Fifth, that reasonable prospect must be based on what the TBA in SALK (para 9) called ‘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.’ Sixth, in SALK, this point was made in the context of experimental data. But the effect on the disease process need not necessarily be demonstrated by experimental data. It can be demonstrated by a priori reasoning. For example, and it is no more than an example, the specification may point to some property of the product which would lead the skilled person to expect that it might well produce the claimed therapeutic effect; or to some unifying principle that relates the product or the proposed use to something else which would suggest as much to the skilled person. Seventh, sufficiency is a characteristic of the disclosure, and these matters must appear from the patent. The disclosure may be supplemented or explained by the common general knowledge of the skilled person. But it is not enough that the patentee can prove that the product can reasonably be expected to work in the designated use, if the skilled person would not derive this from the teaching of the patent.”
“The question is not whether [the medicament] works but whether the contribution to the art consisting in the discovery that it can be expected to work has been sufficiently disclosed in the patent. The inherent difficulty of demonstrating this before clinical trials is taken into account in the modest standard (ie plausibility) which is applied to test it. … This does not mean that subsequent data is never admissible in a dispute about sufficiency, but the purpose for which it is admitted is strictly limited. Where the asserted therapeutic effect is plausible in the light of the disclosure in the patent, subsequent data may sometimes be admissible either to confirm that or else to refute a challenger's contention that it does not actually work… But it cannot be a substitute for sufficient disclosure in the specification.”
“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] R.P.C. 7.”
“102. … patentees not infrequently seek to avoid the possibility that a claim covers products or methods which do not work by inserting a functional limitation. Such a claim may be allowed by the EPO if the invention can only be defined in such terms or cannot otherwise be defined more precisely without unduly restricting its scope. But, it must still be possible to perform the invention across the scope of the claim without undue effort. As I said in Novartis v Johnson & Johnson at [244]: ‘… 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.’ 103. … 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.’” ‘… 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.’ ‘… 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.’”
“In T 544/12 the board confirmed that a definition of a group of compounds in a claim by both structural and functional features is generally acceptable under Article 83 EPC as long as the skilled person is able to identify, without undue burden, those compounds out of the host of compounds defined by the structural feature(s) in the claim which also fulfil the claimed functional requirements (following T 435/91 and T 1063/06).”
“… it is necessary to distinguish between claims that are difficult to construe or that have a ‘fuzzy boundary’ (in the words of Lord Hoffmann in Kirin-Amgen Inc v Hoechst Marion Roussel Ltd[2004] UKHL 46 [2005] RPC 9 at [126]) on the one hand from claims that are truly ambiguous on the other. It is regrettably common for claims to be difficult to construe, but the court will nevertheless strive to give such claims a sensible meaning having regard to the inventor's purpose. It is also common for claims to have a fuzzy boundary, because an integer of the claim involves some question of degree or an imprecise functional limitation. It is well established that is not itself objectionable. If a claim is truly ambiguous, so that it is unclear what is the correct test to determine whether or not a product or process infringes, however, then the claim is insufficient…”
“I think that Lord Hoffmann's emphasis [in Kirin-Amgen] was simply intended to draw attention to the distance between the judge’s finding and a case which presented doubtful cases at the edge of a claim. For my part, I do not agree that the objection of uncertainty is answered simply because there is something within the claim which is clear, if there is a large territory (more than a fuzzy boundary) where the claim is uncertain.”
“(i) Notwithstanding that it is not within the literal meaning of the relevant claim(s) of the patent, does the variant achieve substantially the same result in substantially the same way as the invention, i.e. the inventive concept revealed by the patent? (ii) Would it be obvious to the person skilled in the art, reading the patent at the priority date, but knowing that the variant achieves substantially the same result as the invention, that it does so in substantially the same way as the invention? (iii) Would such a reader of the patent have concluded that the patentee nonetheless intended that strict compliance with the literal meaning of the relevant claim(s) of the patent was an essential requirement of the invention? In order to establish infringement in a case where there is no literal infringement, a patentee would have to establish that the answer to the first two questions was ‘yes’ and that the answer to the third question was ‘no’.”
“If the description discloses a plurality of possibilities for achieving a specific technical effect, but only one of those possibilities is catered for in the patent claim, the utilisation of any of the other possibilities properly does not constitute infringement of the patent with equivalent means.”
“The present invention relates to methods and compounds for regulating or enhancing erthropoiesis [sic] and iron metabolism, and for treating or preventing iron deficiency and anemia of chronic disease.”
“The present invention relates to methods and compounds for inducing enhanced or complete erythropoiesis in a subject. In particular, the methods comprise inducing enhanced or complete erythropoiesis by stabilizing HIFα in a subject. Methods of inducing enhanced erythropoiesis by inhibiting HIF prolyl hydroxylase are specifically contemplated. In specific embodiments, the methods comprise administering to a subject a compound of the invention. In various embodiments, the subject can be a cell, tissue, organ, organ system, or whole organism.”
“The invention provides various methods of regulating/enhancing iron processing and iron metabolism. In one aspect, the invention provides methods for increasing iron transport, uptake, utilization, and absorption in a subject, each of the methods comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). In particular embodiments, the invention provides methods for increasing transferrin expression, transferrin receptor expression, IRP-2 expression, ferritin expression, ceruloplasmin expression, NRAMP2 expression, sproutin expression, and ALAS-2 expression in a subject, each method comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). In other embodiments, the invention provides methods for decreasing hepcidin expression, the method comprising administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF). Methods for increasing heme synthesis in a subject by administering to the subject an effective amount of a compound that stabilizes the alpha subunit of hypoxia inducible factor (HIF) are also provided.”
“In particular embodiments, the present invention provides for use of structural mimetics of 2-oxoglutarate. Such compounds may inhibit the target 2-oxoglutarate dioxygenase family member competitively with respect to 2-oxoglutarate and noncompetitively with respect to iron. (Majamaa et al. (1984) Eur J Biochem 138:239-45 [‘Majamaa 1984’]; and Majamaa et al. (1985) Biochem J 229:127-133 [‘Majamaa 1985’].) …”
“… Reduced or ineffective erythropoiesis is a common pathology in patients with anemia of chronic disease. Reduced or ineffective erythropoiesis can result from various metabolic abnormalities in the erythropoietic pathway including, for example, …abnormal iron processing including for example abnormal or ineffective iron uptake, mobilization, storage, and absorption.”
“The present invention provides advantages over existing therapies for anemia of chronic disease, such as, for example, recombinant EPO administration. Reduced EPO production is only one aspect of decreased erythropoiesis and it is recognized that administration of recombinant EPO does not address other deficiencies associated with reduced erythropoiesis that exist in patients with anemia of chronic disease. These deficiencies include, for example, reduced EPO responsiveness of the bone marrow, as well as numerous aspects of iron metabolism that contribute to complete or total erythropoiesis including iron absorption from the gut, transenterocyte transport, oxidation of the iron to the ferric state by hephaestin or ceruloplasmin, binding and uptake of iron by transferrin and transferrin receptor and iron transport to the marrow where iron utilisation occurs, including heme synthesis. Many patients are refractory to administration of recombinant EPO for the reasons described above, in which responses to recombinant EPO administration are reduced or absent, even at high doses of recombinant EPO.”
“Anemia of chronic disease is associated with increased levels of ferritin. Despite high levels of ferritin, subjects with anemia of chronic disease are not able to utilize iron effectively. High levels of ferritin are indicative of reduced iron recycling to the marrow and enhanced iron storage, a functional iron deficiency often associated with anemia of chronic disease and a pseudo-inflammatory state often existing in uremic chronic kidney disease patients. By decreasing ferritin levels, methods and compounds of the present invention decrease stored iron and enhance iron recycling through transferrin and transferrin receptor. Reduced serum ferritin levels would be indicative of enhanced iron utilization and enhanced iron recycling to the marrow, thus increasing iron availability for heme production and erythropoiesis.”
“Iron is not available at a rate sufficient to allow normal hemoglobinization of erythrocytes, leading to reduced reticulocyte and erythrocyte cellular hemoglobin content. Functional iron deficiency is often seen in healthy individuals with apparently normal or even increased iron stores but with impaired iron availability, as measured, e.g., by low levels of percent transferrin saturation. This type of iron deficiency is frequently associated with acute or with chronic inflammation.”
“[0140] Numerous proteins mediate iron metabolism, including proteins such as … transferrin, transferrin receptor, iron transporters …, ceruloplasmin etc. Increases in transferrin and transferrin receptor expression stimulate iron uptake by erythroid progenitors and transport to marrow by macrophage ... Ceruloplasmin increases the oxidation of ferrous iron to ferric so that binding to transferrin occurs … In certain aspects, methods of the present invention increase iron metabolism by increasing expression or activity of proteins involved in iron metabolism including… transferrin, transferrin receptor… In other aspects, methods disclosed increase iron metabolism by decreasing expression or activity hepcidin and by modulating expression of ferritin. [0141] In one embodiment, the disclosure provides methods and compounds for increasing expression of genes whose products are involved in iron metabolism and processing including iron uptake, storage, transport, absorption etc. Such genes include but are not limited to transferrin receptor, ceruloplasmin … Therapeutic upregulation of genes involved in iron metabolism and processing will effectively increase iron availability and, thereby produce a beneficial effect in patients with anemia of chronic disease, anemia of iron deficiency, functional iron deficiency etc. In another embodiment, the disclosure provides methods and compounds for decreasing expression of hepcidin, a protein associated with iron regulation.” and compounds for decreasing expression of hepcidin, a protein associated with iron regulation.”
“Therefore, compounds of the present invention are useful for increasing transferrin receptor expression in various cell types. In addition, increased transferrin receptor expression would result in increased transferrin receptor-mediated endocytosis of ferric transferrin, thereby increasing iron transport, utilization, storage, and metabolism Therefore, compounds of the present invention are useful for enhancing erythropoiesis by increasing iron transport, utilization, storage, and metabolism.”
“A compound of formula (I) that stabilizes HIFα for use in treating anemia of chronic disease in a subject … wherein the subject has a percent transferrin saturation of less than 20%.”
“The compound of claim 1 for the use of that claim, wherein the subject has a percent transferrin saturation of less than 16% in adults.”
“A compound of formula (I) that stabilizes HIFα for use in treating anemia that is refractory to treatment with exogenously administered erythropoietin (EPO) in a subject wherein A, B, Q, R 1, R 2, R 4, Y and X are as defined in claim 1.”
“A compound of formula (I) that stabilizes HIFα for use in treating functional iron deficiency in a subject, and wherein the functional iron deficiency is associated with anemia wherein A, B, Q, R 1, R 2, R 4, Y and X are as defined in claim 1.”
“The compound for use according to any of the preceding claims 1, 2, 7, 8, 9, 15, 16, 17, 20, 21, 22, 27 and 28 wherein the compound is for decreasing hepcidin expression in a subject.”
“The compound for use according to any of claims 102, 7-9, 1517, 20-23, 27, 28, 31 and 32, wherein the compound is a structural mimetic of 2-oxoglutarate.”
“The compound for use according to any of the preceding claims wherein the compound is [Compound A].”
“A compound that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase activity for use in treating or preventing functional iron deficiency associated with anemia in a subject, wherein the compound is a structural mimetic of 2-oxoglutarate.”
“The compound according to claim 1, where the compound is of Formula (I) …”
“The compounds of claim 1, 2 or 3 for the use of that claim, wherein the compound is for decreasing hepcidin expression.”
“A structural mimetic of 2-oxoglutarate that inhibits hypoxia inducible factor (HIF) prolyl hydroxylase activity for use in treating anemia in a subject having a percent transferring saturation of less than 20%.”
“The mimetic of claim 1 for the use of that claim, wherein the subject has a percent transferrin saturation of less than 16% in adults.”
“The mimetic of claim 1 3A for the use of that claim, wherein the anemia is anemia of chronic disease is associated with a condition selected from the group consisting of an inflammation, an infection, an immunodeficiency disorder, and a neoplastic disorder.”
“The mimetic of claim 1 or 2 for the use of that claim, wherein the anemia is associated with iron deficiency, wherein the iron deficiency is functional iron deficiency”
“The mimetic of any one of claims 1, to 4, 5 or 6 for the use of that claim, wherein the mimetic is a compound of Formula I …” 518. (New) claim 15A: “The mimetic of any preceding claim for the use of that claim, wherein the mimetic is for decreasing hepcidin expression.”
“A speculative scheme in the regulation of iron balance by hepcidin is proposed in Figure 7. When anemia/hypoxia occurs, e.g., following severe bleeding or after PHZ [phenylhydrazine] treatment, erythropoietin expression increases, leading to a stimulation of the erythropoietic activity. In parallel, hepcidin gene expression is decreased, inducing a rapid mobilization of iron from reticuloendothelial cells to supply sufficient amounts of iron for the erythropoietic activity. Indeed, we demonstrated previously that a deficiency in hepcidin gene expression results in a dramatic decrease in iron stores in reticuloendothelial cells (6). At the moment, we cannot specify whether erythropoietin is involved in hepcidin downregulation or whether hepcidin and erythropoietin responses to hypoxia are independent.”
“These results [namely those reported in two prior papers] reinforce our hypothesis that hepcidin per se is a key component of the erythropoietic regulator of intestinal iron absorption.”
“Therapeutic implications of hepcidin … Elucidation of the receptor and its transduction pathways should lead to the development of hepcidin antagonists, some of which could be useful in treatment of anemia of inflammation, a condition often resistant to erythropoietin therapy 45. …. Conclusions Hepcidin may be the principal iron-regulatory hormone, the key mediator of anemia of inflammation, and a bridge between innate immunity and iron metabolism (Figure 2). Studies of the molecular mechanisms of hepcidin activity could transform our understanding of the regulation of iron transport and should lead to new therapies for hemochromatosis and anemia of inflammation.”
“Evidence from transgenic mice expressing mRNA for hepcidin suggests that it reduces iron absorption and iron release from macrophages. In inflammation, hepcidin production may increase substantially, so that it is possible that this substance plays an important role in EPO resistance.”
“To date, the relevance of hepcidin for the effectiveness of erythropoietin in chronic kidney disease patients is unclear.”
“Absolute iron deficiency rapidly develops during therapy with exogenous erythropoietin, and persistently high levels of hepatic hepcidin expression might explain why duodenum iron absorption remains inadequately low.”
“while the patent is in force and without the consent of the proprietor, he supplies or offers to supply in the United Kingdom a person other than a licensee or other person entitled to work the invention with any of the means, relating to an essential element of the invention, for putting the invention into effect when he knows, or it is obvious to a reasonable person in the circumstances, that those means are suitable for putting and are intended to put, the invention into effect in the United Kingdom.”
“i) The required intention is to put the invention into effect. The question is what the supplier knows or ought to know about the intention of the person who is in a position to put the invention into effect – the person at the end of the supply chain, [109]. ii) It is enough if the supplier knows (or it is obvious to a reasonable person in the circumstances) that some ultimate users will intend to use or adapt the ‘means’ so as to infringe, [107(i)] and [114]. iii) There is no requirement that the intention of the individual ultimate user must be known to the defendant at the moment of the alleged infringement, [124]. iv) Whilst it is the intention of the ultimate user which matters, a future intention of a future ultimate user is enough if that is what one would expect in all the circumstances, [125]. v) The knowledge and intention requirements are satisfied if, at the time of supply or offer to supply, the supplier knows, or it is obvious to a reasonable person in the circumstances, that ultimate users will intend to put the invention into effect. This has to be proved on the usual standard of the balance of probabilities. It is not enough merely that the means are suitable for putting the invention into effect (for that is a separate requirement), but it is likely to be the case where the supplier proposes or recommends or even indicates the possibility of such use in his promotional material, [131]”
“56. The principle I derive from these authorities is that the question the court is asking in every case is whether, viewed in all the relevant circumstances, there was a sufficiently strong probability that an injunction would be required to prevent the harm to the claimant to justify bringing the proceedings. In adding the word sufficiently to the word strong I do not mean to put a gloss on the words of Chadwick LJ, rather I am seeking to encapsulate the idea that the degree of probability required will vary from case to case depending on all the circumstances but that mere possibilities are never enough. To justify coming to court requires there to be a concrete, strong and tangible risk that an injunction is required in order to do justice in all the circumstances” 57. If a defendant really does, at the date of the proceedings, have no intention to do the act then in the majority of cases that will be conclusive of the question whether there was a sufficiently strong probability to justify proceedings. (e.g. London Borough of Islington). However it seems to me that the question is not confined to the defendant's subjective intentions. A defendant's overt acts must be capable of being relevant. To take an extreme case, if a man began taking actual preparatory steps to commit some unlawful act seriously damaging to the claimant and in infringement of the claimant's rights and did so in full view of the claimant and well aware that the claimant could see them, he could hardly complain if the claimant started proceedings and the court decided to grant a final injunction to prevent it. A statement at trial that he had never intended to go through with it would get short shrift. 58. I bear in mind that intentions are not necessarily simple. A state of mind need not merely be either one thing or another. Also in this case the defendants are corporate entities to whom an intention can only be imputed. 59. The way the matter is put in the Particulars of Claim contains the allegation that the defendant ‘threatens and intends’ to infringe. I think this is a useful expression in that it encompasses both the defendant's intentions and also the idea that the court should look from the outside at what the defendant is threatening to do. Both are relevant.”
“The primary endpoint of a clinical trial is the endpoint for which the subjects are randomised and for which the trial is powered. While iron metabolism parameters such as serum iron, TSAT and hepcidin may have been secondary endpoints, it is more difficult to draw any conclusions about the effect of the compounds on these parameters without an appropriately powered trial designed to investigate them. Interpretation of the results is further complicated by the fact that between different studies (and in some cases within the same study) some patients were provided with iron supplementation and some were not.”
“Regarding patients with low baseline iron, it is hard to draw any firm conclusions from the studies given that the patients in the relevant studies were permitted to take oral iron during the treatment period notwithstanding low baseline parameters. Furthermore, none of the studies provide support for HIF prolyl hydroxylase inhibitors being suitable for the treatment of iron deficiency or any other condition for which ESAs are not also suitable.”
“Another major advantage of HIF-PHI therapy would be the suppression of hepatic hepcidin production and its negative effects on iron mobilisation. Hepcidin plays a central role in the pathogenesis of functional iron deficiency as it inhibits gastrointestinal iron uptake and iron release from internal stores by down-regulating the surface expression of ferroportin, the only known cellular iron exporter. Clinical data from phase II studies have consistently shown ‘positive’ effects on iron metabolism as manifested by a reduction in plasma ferritin and hepcidin and simultaneous increase in plasma transferrin and TIBC … These results are consistent with experimental data from animal and cell culture studies, which demonstrated that the PHD/HIF axis coordinates iron metabolism with erythropoiesis via transcriptional regulation of genes involved in iron uptake, iron release and transport. … The observed effects on plasma hepcidin levels in CKD patients receiving HIF-PHIs are most likely indirect, as hepcidin is not a direct transcriptional target of HIF. Transcriptional suppression of hepcidin in the context of HIF activation requires erythropoietic activity and is mediated by bone-marrow derived factors such as erythroferrone. It is unclear, however, whether the effects of oral HIF-PHI therapy on iron metabolism are primarily mediated via the hepcidin-ferroportin axis (increase in erythropoietic activity with subsequent suppression of hepcidin and increased ferroportin-mediated iron release) or through direct transcriptional regulation of iron metabolism gene expression. Although several iron metabolism genes … are bona fide HIF-regulated genes and can be upregulated by oral prolyl hydroxylase inhibition, it has not been examined whether HIF-PHI doses currently used in clinical trials are sufficient to induce the expression of these genes in CKD patients. Nevertheless, the added HIF-PHI effect on iron mobilisation has the potential to reduce the need for IV iron supplementation in patients with renal anemia as suggested by Besarab and colleagues.”
“Guideline 2.1 – Treatment of Anaemia with Iron therapy – Iron repletion We recommend that patients should be iron replete to achieve and maintain target Hb whether receiving ESAs or not. (1B) Iron repletion is usually defined as: • %HRC <6% / CHr >29 pg / ferritin and TSAT (>100 microgram/L and >20%) • For children, aim for a target ferritin level greater than 100 microgram/L for CKD patients on dialysis as well as CKD patients not on ESA therapy. (ungraded)”
“[ESAs] would not be offered until the patient’s iron status is considered replete. In our unit we would consider this to be when serum ferritin is greater than 200 micrograms per litre and TSAT greater than 20% … For patients with anaemia related to CKD who are not iron replete according to these criteria, a clinical nephrologist would offer oral or intravenous iron until their iron status was replete.”
“For nearly a century the management of iron deficiency anaemia has included the use of iron supplementation; there is a level of comfort with the use of iron supplementation. Furthermore, iron is cheap and, as explained above, the results from the PIVOTAL study provide a basis for nephrologists to use iron supplementation more liberally in haemodialysis patients in order to achieve better patient outcomes. I therefore cannot see any motivation for nephrologists to move away from the use of iron therapy to treat iron deficiency anaemia.”
“All other causes of anaemia (e.g. iron deficiency, vitamin deficiency, metabolic or chronic inflammatory conditions, bleeding, etc.) should be evaluated and treated prior to initiating therapy with [vadadustat]. The management of anaemia due to chronic renal failure should be individualized.”