“A heterocyclic carboxamide compound selected from the group consisting of pyridine carboxamides, quinoline carboxamides, isoquinoline carboxamides, cinnoline carboxamides, and betacarboline carboxamides that inhibits 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 the compound is a structural mimetic of 2-oxoglutarate ”
“[366] As counsel for the Defendants accepted, this does not mean that the skilled person or team must be able to identify all compounds covered by the claim without undue burden. Rather, what is required is that the skilled person or team must be able to identify substantially all compounds covered by the claim without undue burden.”
“[399] Taking all of the evidence into account, the conclusion I reach is that the invention cannot be performed across the scope of the claims in issue without undue burden. It would require a substantial research project to identify any compounds other than those specifically identified in the specification which met the criteria for efficacy, and success would not be guaranteed. While it is probable that, if sufficient resources were thrown at the project, the skilled medicinal chemist would be able to identify some compounds falling within Formula (I) (and more which constituted Carboxamides) which were effective, they would not be able even in many lifetimes of sustained effort to make and test more than a tiny fraction of such compounds, and a substantial proportion either could not be made or would not work. This is not only setting the skilled team a research project and claiming the results, it is a never-ending one. Accordingly, on this ground also I conclude that the claims in issue are insufficient”
“. . . 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.”
“[275] […] The Board [ in Princeton/OLEDs ] appears to take the view that a functional definition will be necessarily insufficient simply because, as the BGH noted in the [ Dipeptidyl-Peptidase-Inhibitoren ] case, such language covers things which have not been invented yet. Stated in such a general way I respectfully disagree with the Board and I note that Lord Briggs [ in Kymab ] did not take that view either. This absolutist approach would strike down all functional language and represent a radical change for no discernible benefit to the public. A functional definition cannot help cover things which are not yet invented. That may not necessarily matter at all. What matters is that the skilled person must be able to put the invention into practice without undue burden. They need to be able to come up with components which will work and, if that involves testing things, that testing must not introduce an undue burden.”
“2.5 The Boards of Appeal have indeed recognized that in the context of the requirement of sufficiency functional features require particular attention, as such features are defined by means of an effect that has to be achievable (see G 1/03, reasons 2.5.2 ). Occasional failure to achieve a defined effect does not necessarily imply insufficiency and reasonable experimentation by trial and error may be permissible, if the skilled person has adequate information, from the specification or on the basis of the common general knowledge, to achieve success in spite of initial failure (see Case Law of the Boards of Appeal, supra, section II.C.6.6.1, see also T 14/83, OJ 1984, 105, Headnote, and T 2220/14, reasons 63). Similarly, the definition of a group of compounds by both structural and functional features may be acceptable under Article 83 EPC, if the skilled person is able to identify without undue burden the compounds which fulfil the claimed functional requirements within the structurally defined group of compounds (see Case Law of the Boards of Appeal, supra, section II.C.6.6.9 with reference to T 544/12). However, claims may not represent an invitation to perform a research programme without effective guidance towards success (see T 435/91, OJ 1995, 188, Headnote and Reasons 2.2.1). A crucial consideration in the assessment of the requirement of sufficiency in relation to functional definitions is the need for fair protection commensurate with the disclosed actual technical contribution (see T 1063/06, OJ 2009, 516, Headnote, T 694/92, OJ 1997, 408, Headnote and T 409/91, OJ 1994, 653, Headnote).”
“17. The examining division denied sufficiency of disclosure for the reason that it would be undue burden to obtain all antibodies falling within the scope of the claims. As explained above, it is the board's opinion that all necessary information for doing so is contained within the application. Thus, assuming for the sake of discussion that the skilled person would ever want to isolate all of the antibodies falling within the scope of the claims, the possibly undue amount of work involved would not stem from deficiencies in the way the invention was described but rather from the task which he/she chose to accomplish.”
“392. Dr Bhalay clarified the nature of this exercise in cross-examination: i) the medicinal chemist would start with an SAR analysis, involving tens, hundreds or even thousands of compounds to see what kind of changes are tolerated, testing for activity in an enzyme assay; ii) depending on the strategy, there might be “spot checks” to see whether the compounds were competitive with respect to 2-OG; iii) compounds which looked promising would be progressed to cell-based Epo induction assays; iv) after that, promising compounds would go on to in vivo Epo induction assays, but not before completion of some initial pharmacokinetic studies. 393. The number of compounds involved in this initial SAR analysis (even if ran to thousands) would obviously not scratch the surface in terms of the number of permutations envisaged by Formula (I). Dr Bhalay envisaged that the medicinal chemist would then undertake further SAR “streams”, each involving a different chemotype, by which he meant pyridine, isoquinoline, quinoline etc. In each case, the medicinal chemist would adopt the lead optimisation strategies described in paragraphs 83-85 above.”
“[397] The data show that success in the HIF-PH assay (applying Dr Bhalay’s criteria) is not predictive of success (again applying Dr Bhalay’s criteria) in cell-based/and or in vivo Epo-induction. Moreover, of the compounds for which there is assay data, only 182 (16%) are shown to meet Dr Bhalay’s criterion for Epo-induction in vivo (which is not to say that 84% fail - in fact, Dr Bhalay’s evidence was that the pass rate amongst those tested was 86%). The majority of these compounds are isoquinolines. In the class of pyridines, there are only two compounds which were tested for in vivo Epo- induction. Only one of them passed, namely vadadustat. The other failed.”
“Prof Ward’s evidence was to the same effect. Indeed, he was cross-examined on the basis that the search for active compounds constituted a “development programme”
“By its very nature, SAR analysis is an exercise of genuine research in which the medicinal chemist is trying to discover new information. Moreover, it involves matters of choice and judgement.”
“ there is no principle of law that the skilled team are deemed to read all documents cited in a patent. It is a context- and fact- dependent question, and thus it depends firstly upon the wording of the specification and secondly on the evidence. ”
“(a) The skilled person is a legal construct and is not put off by having to read large amounts of material (citing Rockwater v Technip[2004] RPC 46 at paragraphs 6-7). (b) If a patent advances a document as being relevant to putting the invention into effect the skilled person is deemed to read that document with interest - unless there are special reasons why he or she would not do so. (c) The notional skilled team is deemed to have sufficient resources to read the literature. The evidence was that to review all the papers and the patent applications in these passages would take one person 4 days, which is plainly proportionate.”
“386. Nor does the specification give the skilled medicinal chemist any assistance at all with regard to such matters as finding compounds within Formula (I) which have suitable ADME profiles. The medicinal chemist could, of course, apply their common general knowledge rules of thumb such as Lipinski’s rules, but predictions made using such rules would not always be correct. ”
“ […] 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.”
“[0069] […] 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; and Majamaa et al., supra.)”
“303. I therefore conclude that the skilled medicinal chemist would be uncertain as to the meaning of the expression “structural mimetic of 2-oxoglutarate”
“54. The main iron pathways are shown diagrammatically in a figure from Prof Winearls’ first report which I reproduce below. 55. On the left is shown absorption of dietary iron in the duodenum, and the use of iron in bone marrow for erythropoiesis. The central rectangles (in purple and red) show iron in the bloodstream, where it is either bound to transferrin or in the form of haemoglobin in red blood cells. On the right are the iron stores, from where iron is released into (or to which iron is removed from) the circulating, transferrin-bound pool. When red blood cells reach the end of their 120-day life, their iron is also recycled into these stores via macrophages. ”
“57. Absolute iron deficiency occurs when a patient does not have enough iron in stores to supply the body’s needs. Absolute iron deficiency may be caused by a low-iron diet, reduced iron absorption and/or bleeding. Absolute iron deficiency is characterised by a low TSAT and a low level of serum ferritin, namely, a TSAT < 20% (or < 16% in more extreme cases) and serum ferritin < 50-100 ng/ml. 58. Functional iron deficiency occurs where there is sufficient iron in stores, but where there is inadequate delivery of that iron from stores to the bone marrow. Inflammation can result in iron being sequestered into iron stores and the reticuloendothelial blockade, which prevents release of the stored iron, being activated. Functional iron deficiency is characterised by a low TSAT and normal or high serum ferritin. 59. Patients who are “iron replete” are usually defined as those with a TSAT of at least 20% and a serum ferritin level of at least 100 ng/ml; but TSAT measurements show considerable diurnal and day-to-day variation for a given patient. ”
“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.”
“[555] I have set out the disclosure of WO 997 above. Before turning to the issues on obviousness, it is convenient first to consider in general terms what the skilled team, and i n par ticular the nephrologist, would make of [0072] (quoted in paragraph 133 above). As is common ground, there are no data in WO 997 to support the suggestion that the methods of the invention increase iron transport, processing and utilisation. Prof Winearls described this as “a very bold claim” that was “totally unsubstantiated”, but he accepted that it would have been an interesting one. Prof Haase agreed that, as a scientist, he would want to see data before accepting that the effect was a real one. Prof Winearls agreed that the pre-clinical researcher in the skilled team, who would have known that HIF regulated transferrin, transferrin receptor and ceruloplasmin, would have thought that the statements about HIF-PHIs increasing the amount of transferrin, transferrin receptor and ceruloplasmin were plausible. On the other hand, Prof Haase agreed that none of transferrin, transferrin receptor and ceruloplasmin had been implicated in 2004 as a cause of iron deficiency or ACD or anaemia in general. ”
“562. The Defendants contend that, given that it was obvious from WO 997 to use the disclosed HIF-PHIs to treat ACD, then it follows that the skilled team would inevitably be treating at least some subjects with a TSAT at the claimed levels. I accept this. In any event, Prof Haase’s evidence was that patients with a TSAT of less than 20% or 16% were treated with ESAs, including some patients whose TSAT dipped below those levels due to diurnal or periodic variation. Given that HIF-PHIs are disclosed by WO 997 as an alternative to ESAs, they would be administered to patients with the relevant TSAT levels.”
“As the Defendants point out, the Family B Patents do not show, or even attempt to show, that HIF-PHIs confer any benefit over ESAs in terms of iron delivery.”
“that HIF prolyl-hydroxylase inhibitors of Formula (I) have a beneficial and unexpected effect on iron metabolism, such that they can be used to treat disorders of iron metabolism, and, in particular, the three particular disorders which you have seen in the claims.”
“[496] … The figures reported do not appear to show a clear trend, however, and there is no statistical information. As Prof Haase explained, and Prof Winearls accepted, there is nothing to demonstrate that this effect is independent of erythropoiesis, although both witnesses considered that this was a possibility.”
“563. As the Defendants point out, the Family B Patents do not show, or even attempt to show, that HIF-PHIs confer any benefit over ESAs in terms of iron delivery. If and in so far as there is such a benefit, however, the Defendants contend that this would have been discovered by the skilled team by taking obvious steps . As Prof Winearls accepted, the skilled team would have been motivated by WO 997 to do some relatively straightforward tests. These would have included the transferrin and transferrin receptor tests in animal cells in WO 121, which would (if WO 121 is correct in its assertions) have shown an “enhancement” of erythropoiesis through increasing iron transport etc. This would have led to the other tests done in WO 121 to measure iron uptake, including measuring haemoglobin levels, and then ultimately comparative tests on iron uptake over ESAs. The Defendants submit, and I agree, that, taken as a whole, Prof Haase’s evidence was also consistent with this.”
“[65] First, it is relevant to consider whether at the priority date something was ‘obvious to try’, in other words whether it was obvious to undertake a specific piece of research which had a reasonable or fair prospect of success: Conor v Angiotech (above) para [42] per Lord Hoffmann; MedImmune Ltd v Novartis Pharmaceuticals UK Ltd[2012] EWCA Civ 1234 , [2013] IP & T 536,[2013] RPC 659 (paras [90] and [91]) per Kitchin LJ. In many cases the consideration that there is a likelihood of success which is sufficient to warrant an actual trial is an important pointer to obviousness. But as Kitchin LJ said in Generics (UK) Ltd (t/a Mylan) v Novartis AG[2012] EWCA Civ 1623 ,[2012] All ER (D) 126 (Dec) (para [55]), there is no requirement that it is manifest that a test ought to work; that would impose a straightjacket which would preclude a finding of obviousness in a case where the results of an entirely routine test are unpredictable. As Birss J observed in this case (para [276]), some experiments which are undertaken without any particular expectation as to result are obvious. The relevance of the ‘obvious to try’ consideration and its weight when balanced against other relevant considerations depend on the particular facts of the case.”
“[0018] of WO 997 expressly teaches use of the compounds of the invention for the treatment of anaemia “associated with defects in iron transport, processing or utilisation” i.e. functional iron deficiency. The same message appears from [0072]. Yet further, as discussed above, ACD involves functional iron deficiency. The Claimants do not suggest that the mode, format or dosage involved in treating functional iron deficiency in accordance with the Family B Patents is any different to those involved in treating ACD. Nor, as discussed above, is it a requirement of the relevant claims that there should be any increase in iron parameters. It follows that WO 997 also makes it obvious to use the compounds for the treatment of functional iron deficiency associated with anaemia. ”
“The Claimants submitted that the relevant claims require the HIF-PHIs to act “by overcoming the reticuloendothelial block which prevents the release of iron from stores”
“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, R1, R2, R4, Y and X are as defined in claim 1.”
“263. Since this is a question of the interpretation of a chemical formula, the relevant skilled person through whose eyes it must be considered is the medicinal chemist. It was addressed by all three medicinal chemists in their evidence. As will appear, however, the issue of interpretation depends not on medicinal chemistry, but on the structure of the lists of substituents, and in particular the manner in which the relevant list is punctuated and laid out, and on the way in which certain substitutions are described, and in particular the fact that some groups are said to be “optionally substituted” without more. All three medicinal chemists agreed in cross-examination that there was no chemical reason why the substitution in question should or should not be permitted. It follows that their opinions as to the correct interpretation of Formula (I) are all inadmissible.”
“282. The Defendants contend that there must be some limit to the possible substitutions encompassed by Type 2, whereas the Claimants contend that there is no limit. In my view the skilled person would assume that some limit was intended, since otherwise the formula would embrace compounds that would be practically impossible to make and/or insoluble and a formula that covers a staggeringly large number of compounds anyway (as explained below) would cover a limitless number of compounds.”
“286. The conclusion I have reached is that the Claimants’ interpretation is the better one. Although the skilled reader would assume that some limit to “optionally substituted” was intended, there is nothing to indicate that the passage in question was intended to supply that limit. The skilled reader would consider that the most important factor was the structure of the definitions, and in particular the structure of the definition of R 1 , R 2 and R 3 . […] ”
“Turning to the present case, the patent is implicitly promising that substantially all compounds which satisfy the structural definitions in the claims in issue will have the claimed therapeutic efficacy. Otherwise, the skilled team would be faced with a situation where the structural definition covers around 10 183 compounds (or a little less or even more), but the specification only demonstrates that five compounds, namely Compounds C, E, F, J and K, satisfy the criteria for therapeutic efficacy. That would amount to no more than an invitation to the skilled team to find the other compounds covered by the claim which work. It would not involve an inventive step, because it would not solve the technical problem of identifying compounds which have the desired activity, and it would not sufficiently disclose the invention, because it would leave most of the work to the reader.”
“As counsel for the Defendants accepted, this does not mean that the skilled person or team must be able to identify all compounds covered by the claim without undue burden. Rather, what is required is that the skilled person or team must be able to identify substantially all compounds covered by the claim without undue burden.”